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Volume 28 Number 3 July 2015 The peer-reviewed journal of Baylor Scott & White Health Scott & White Hospital -Brenham McLane Children’s Scott & White Hospital - Temple Baylor Medical Center at McKinney Metroplex Health System - Killeen Baylor All Saints Medical Center at Fort Worth Baylor Scott & White Hospital - Hillcrest Baylor Regional Medical Center at Grapevine Baylor University Medical Center Proceedings Baylor University Medical Center at Dallas Volume 28, Number 3 • July 2015 Pages 289–432 www.BaylorScottandWhite.com The largest not-for-profit health care system in Texas, and one of the largest in the United States, Baylor Scott & White Health was born from the 2013 combination of Baylor Health Care System and Scott & White Healthcare. For more information on our 43 hospitals and more than 500 patient care sites, please visit www.BaylorHealth.com and www.sw.org. Original Research 291 West Nile virus and the 2012 outbreak: the Baylor University Medical Center experience by A. Mora Jr. et al 296 Comparison of long-term follow up of laparoscopic versus open colectomy for transverse colon cancer by S. Agarwal et al 300 Mortality by treatment in patients ≥80 years of age with gastroesophageal cancer seen in a 20-year period at a single medical center by T. Barnett et al 304 Trends in the neonatal mortality rate in the last decade with respect to demographic factors and health care resources by V. Govande et al 307 Effect of adding tetracaine to bupivacaine on duration of analgesia in supraclavicular brachial plexus nerve blocks for ambulatory shoulder surgery by L. T. Pearson et al 312 Comparison of documentation and evidence-based medicine use for non–ST-segment elevation myocardial infarction among cardiology, teaching, and nonteaching teams by A. Metting et al 317 Assessment of leadership training needs of internal medicine residents at the Massachusetts General Hospital by T. N. Fraser et al 321 Abstracts from the First Annual Scholarly Day Review Article 325 Uses, limitations, and complications of endobronchial ultrasound by B. A Jalil et al Case Studies 331 Recurrent hospitalization for self-injuries and suicide attempts: case study of a super-utilizer by J. W. Roden-Foreman et al 334 Radiographic findings in the nail-patella syndrome by J. A. West and T. H. Louis 337 Solitary supratentorial Listeria monocytogenes brain abscess in an immunocompromised patient by J. A. West et al 340 Asplenia and fever by M. L. Huebner and K. A. Milota 342 Myroides odoratimimus bacteremia in a diabetic patient by T. R. Endicott-Yazdani et al 344 Right-sided hydropneumothorax as a presenting symptom of Boerhaave’s syndrome (spontaneous esophageal rupture) by S. Rassameehiran et al 347 Pneumomediastinum in inflammatory bowel disease by N. Mihatov and A. Z. Fenves 350 Pulmonary veno-occlusive disease as a cause of pulmonary arterial hypertension by M. Porres-Aguilar et al 353 Pulmonary artery catheter–induced perforation treated with coil embolization by D. S. Kumar et al 355 A hybrid repair of a superior mesenteric artery pseudoaneurysm using open mesenteric bypass and endovascular exclusion by T. A. Cumbie et al 358 Allergic acute coronary syndrome (Kounis syndrome) by S. Memon et al 363 Blood cyst of the anterior mitral leaflet causing severe mitral regurgitation by S. Madhavan et al 365 Right-sided superior vena cava draining into the left atrium in a patient with persistent left-sided superior vena cava emptying into the right atrium diagnosed by echocardiography by C. Clark and L. MacDonald 367 Spontaneous coronary artery dissection in a 22-year-old man on lisdexamfetamine by A. M. Afzal et al 369 Worsening dyspnea in a 38-year-old woman by D. L. Glancy et al 371 Chronic pulmonary embolism in a young athletic woman by T. R. Larsen and T. C. Ball 375 Nonhepatic hyperammonemic encephalopathy due to undiagnosed urea cycle disorder by T. Mahmood and K. Nugent 378 Anaplastic large-cell lymphoma in AIDS by M. Krol et al 381 Primary follicular lymphoma of the duodenum by R. Graham et al 384 Tubulocystic carcinoma of the kidney by V. Podduturi et al 386 Unusual presentation of metastatic ovarian carcinoma as an enlarged intramammary lymph node by C. Mason et al 389 Leukoencephalopathic changes on magnetic resonance imaging associated with a thermogenic dietary supplement (Thermatrim) by C. I. Olivas-Chacon et al Editorials and Interview 397 Precision medicine: hype or hope? by R. G. Mennel 401 Update on the Baylor Scott & White Quality Alliance by C. E. Couch 404 Nobel laureates and their medical schools: who selected whom? by A. B. Weisse 406 On camel rides and Moses Maimonides by J. D. Cantwell 409 David Bruce Hellmann, MD: a conversation with the editor by D. B. Hellmann and W. C. Roberts From the Editor 421 Facts and ideas from anywhere by W. C. Roberts Miscellany 290 295 303 320 370 380 383 392 420 Clinical research studies enrolling patients Acknowledgment of contributors Proceedings’ annual editorial board meeting Avocations: Photograph by Dr. Solis Avocations: Photograph by Dr. Rosenthal Avocations: Poem by Dr. Khan In memoriam Baylor news Reader comments: Low-voltage electrocardiogram in a patient with takotsubo syndrome associated with hyperthyroidism (J. E. Madias, with response by S. Omar) www.BaylorHealth.edu/Proceedings Indexed in PubMed, with full text available through PubMed Central Baylor University Medical Center Proceedings The peer-reviewed journal of Baylor Scott & White Health Volume 28, Number 3 • July 2015 Editor in Chief William C. Roberts, MD Associate Editor Michael A. E. Ramsay, MD Founding Editor George J. Race, MD, PhD Dennis R. Gable, MD D. Luke Glancy, MD Paul A. Grayburn, MD Bradley R. Grimsley, MD Joseph M. Guileyardo, MD Carson Harrod, PhD H. A. Tillmann Hein, MD Daragh Heitzman, MD Priscilla A. Hollander, MD, PhD Roger S. Khetan, MD Göran B. Klintmalm, MD, PhD Sally M. Knox, MD John R. Krause, MD Bradley T. Lembcke, MD Jay D. Mabrey, MD Michael J. Mack, MD David P. Mason, MD Peter A. McCullough, MD, MPH Gavin M. Melmed, JD, MBA, MD Robert G. Mennel, MD Michael Opatowsky, MD Joyce A. O’Shaughnessy, MD Dighton C. Packard, MD Harry T. Papaconstantinou, MD Gregory J. Pearl, MD Robert P. Perrillo, MD Daniel E. Polter, MD Irving D. Prengler, MD Chet R. Rees, MD Randall L. Rosenblatt, MD Lawrence R. Schiller, MD W. Greg Schucany, MD Jeffrey M. Schussler, MD S. Michelle Shiller, DO wc.roberts@BaylorHealth.edu Editorial Board Jenny Adams, PhD W. Mark Armstrong, MD Raul Benavides Jr., MD Mezgebe G. Berhe, MD Joanne L. Blum, MD, PhD C. Richard Boland Jr., MD Jennifer Clay Cather, MD James W. Choi, MD Cristie Columbus, MD Barry Cooper, MD Gregory J. Dehmer, MD R. D. Dignan, MD Gregory G. Dimijian, MD Michael Emmett, MD Andrew Z. Fenves, MD Giovanni Filardo, PhD James W. Fleshman, MD Editorial Staff Managing Editor Cynthia D. Orticio, MA, ELS Administrative Liaison Dana M. Choate, MBA, RHIA, CHP Michael J. Smerud, MD Marvin J. Stone, MD C. Allen Stringer Jr., MD William L. Sutker, MD Marc A. Tribble, MD James F. Trotter, MD Gary L. Tunell, MD Lawrence S. Weprin, MD F. David Winter Jr., MD Larry M. Wolford, DMD Scott W. Yates, MD, MBA, MS Residents/Fellows Aasim Afzal, MD Timothy Ball, MD Philip M. Edmundson, MD Design and Production Aptara, Inc. Cynthia.Orticio@BaylorHealth.edu Baylor University Medical Center Proceedings (ISSN 0899-8280), a peer-reviewed journal, is published quarterly (January, April, July, and October). Proceedings is indexed in PubMed and CINAHL; the full text of articles is available both at www. BaylorHealth.edu/Proceedings and www.pubmedcentral.nih.gov. The journal’s mission is to communicate information about the research and clinical activities, continuing education, philosophy, and history of the Baylor Health Care System. Subscriptions are offered free to libraries, physicians affiliated with Baylor, and other interested physicians and health care professionals; donations are requested for print subscriptions. To add or remove your name from the mailing list, call 214-820-9996 or e-mail Cynthia.Orticio@BaylorHealth.edu. POSTMASTER: Send address changes to Baylor Scientific Publications Office, 3500 Gaston Avenue, Dallas, Texas 75246. Funding for the journal is provided by the following: Advertising is accepted. Acceptance of advertising does not imply endorsement by Baylor Scott & White Health. For information, contact Cindy Orticio at Cynthia.Orticio@BaylorHealth.edu. • Baylor Health Care System Foundation • Helen Buchanan and Stanley Joseph Seeger Endowment for Surgery Funding is also provided by donations made by the medical staff and subscribers. These donations are acknowledged each year in a journal issue. For more information on supporting Proceedings and Baylor Health Care System with charitable gifts and bequests, please call the Foundation at 214-820-3136. Donations can also be made online at http://give.baylorhealth.com/. Statements and opinions expressed in Proceedings are those of the authors and not necessarily those of Baylor Health Care System or its board of trustees. Guidelines for authors are available at http://www.baylorhealth.edu/Research/ Proceedings/SubmitaManuscript/Pages/default.aspx. July 2015 Permission is granted to students and teachers to copy material herein for educational purposes. Authors also have permission to reproduce their own articles. Written permission is required for other uses and can be obtained through Copyright.com. Copyright © 2015, Baylor University Medical Center. All rights reserved. Printed in the United States of America on acid-free paper. Press date: June 8, 2015. To access Baylor’s physicians, clinical services, or educational programs, contact the Baylor Physician ConsultLine: 1-800-9BAYLOR (1-800-922-9567). 289 Clinical research studies enrolling patients through Baylor Research Institute Currently, Baylor Research Institute is conducting more than 800 research projects. Studies open to enrollment are listed in the Table. To learn more about a study or to enroll patients, please call or e-mail the contact person listed. Research area Specific disease/condition Contact information (name, phone number, and e-mail address) Asthma and pulmonary disease Chronic obstructive pulmonary disease, asthma (adult) Rose Boehm, CCRC, RRT, RCP Jana Holloway, RRT, CRC Cara Kraft, RRT/RCP, AE-C 214-818-9495 214-820-9888 214-865-1169 RoseB@BaylorHealth.edu janahol@baylorhealth.edu Cara.Kraft@baylorhealth.edu Breast, ovarian, endometrial, prostate, brain, lung, bladder, colorectal, pancreatic, and head and neck cancer; hematological malignancies, leukemia, multiple myeloma, non-Hodgkin’s lymphoma; melanoma vaccine; bone marrow transplant Grace Townsend 214-818-8472 cancer.trials@BaylorHealth.edu Treatment-naive colorectal cancer Allison Cox 214-820-6779 marya.cox@baylorhealth.edu Type 1 and type 2 diabetes, cardiovascular events Kris Chionh 214-820-3416 kristen.chionh@BaylorHealth.edu Pancreatic islet cell transplantation for type I diabetics, who either have or have not had a kidney transplant Kerri Purcell, RN 817-922-4640 kerri.purcell@baylorhealth.edu Type 2; cardiac events Trista Bachand, RN 817-922-2587 trista.bachand@baylorhealth.edu Pancreatic islet cell transplantation for type I diabetics, who either have or have not had a kidney transplant; high cholesterol Kerri Purcell, RN 817-922-4640 kerri.purcell@baylorhealth.edu Gastroenterology Inflammatory bowel disease Dr. Themistocles Dassopoulos 469-800-7180 T.Dassopoulos@baylorhealth.edu Heart and vascular disease (Dallas) Aortic aneurysms, coronary artery disease, hypertension, poor leg circulation, heart attack, heart disease, congestive heart failure, angina, carotid artery disease, familial hypercholesterolemia, renal denervation for hypertension, diabetes in heart disease, Merielle Boatman cholesterol disorders, heart valves, thoracotomy pain, stem cells, critical limb ischemia, cardiac surgery associated with kidney injury, pulmonary hypertension 214-820-2273 MeriellH@BaylorHealth.edu Heart and vascular disease (Fort Worth) Atrial fibrillation, atrial fibrillation post PCI Meagan King 817-922-2583 Meagan.king@baylorhealth.edu Heart and vascular disease (Legacy Heart) At risk for heart attack/stroke; previous heart attack/stroke/PAD; cholesterol disorders; atrial fibrillation; overweight/obese; other heart-related conditions Angela Germany 469-800-6409 lhcresearch@baylorhealth.edu Heart and vascular disease (Plano) Aortic aneurysm; coronary artery disease; renal stent for uncontrolled hypertension; poor leg circulation; heart attack; heart disease; heart valve repair and replacement; critical limb ischemia; repair of aortic dissections with endografts; surgical leak repair; atrial fibrillation; heart rhythm disorders; carotid artery disease; congestive heart failure; gene profiling Tina Worley 469-814-4712 c19459@BaylorHealth.edu Cancer Diabetes (Dallas) Diabetes (Fort Worth) Hepatology Infectious disease Nephrology Neurology Liver disease Jonnie Edwards 214-820-6243 jonnie.edwards@baylorhealth.edu HIV/AIDS Bryan King, LVN 214-823-2533 bryan.king@ntidc.org Hepatitis C, hepatitis B Jonnie Edwards 214-820-6243 Jonnie.edwards@baylorhealth.edu Homocysteine and kidney disease, dialysis fistulas, urine/protein disorders in cancer patients Lisa Mamo, RN Dr. Harold Szerlip 214-818-2526 214-358-2300 Lisa.Mamo@BaylorHealth.edu Harold.Szerlip@baylorhealth.edu Stroke Quynh Lan Doan 214-818-2522 quynh.doan@BaylorHealth.edu Migraine Quynh Lan Doan 214-818-2522 quynh.doan@baylorhealth.edu portland.pleasant@baylorhealth.edu Multiple sclerosis Portland Pleasant, RN 214-820-7903 Neurosurgery Cerebral aneurysms Kennith Layton, MD 214-827-1600 KennithL@BaylorHealth.edu Rheumatology (9900 N. Central Expressway) Rheumatoid arthritis, psoriatic arthritis, lupus, gout, ankylosing spondylitis Giselle Huet Michael Thomas 214-987-1253 214-987-1249 ruth.huet@baylorhealth.edu e90834@baylorhealth.edu Surgery Chronic limb ischemia, pain management with chest tubes, colon polyps, diaphragm stimulators, and surgery as it pertains to GERD, breast cancer, esophagus, colon, colon cancer, pancreas, lung, hernias, dialysis access, per-oral endoscopic myology (POEM), thoracic outlet syndrome Tammy Fisher Martha Mueller 214-820-7221 214-820-7755 tammyfi@BaylorHealth.edu martha.mueller@BaylorHealth.edu Bone marrow, blood stem cells Grace Townsend Gabrielle Ethington 214-818-8472 214-818-8326 Grace.Townsend@BaylorHealth.edu gabriele@baylorhealth.edu Solid organs Jonnie Edwards 214-820-6243 jonnie.edwards@baylorhealth.edu Obesity Kris Chionh 214-820-3416 kristen.chionh@BaylorHealth.edu Transplantation Weight management Baylor Research Institute is dedicated to providing the support and tools needed for successful clinical research. To learn more about Baylor Research Institute, please contact Kristine Hughes at 214-820-7556 or Kristine.Hughes@BaylorHealth.edu. 290 Proc (Bayl Univ Med Cent) 2015;28(3):290 West Nile virus and the 2012 outbreak: The Baylor University Medical Center experience Adan Mora Jr., MD, Mariangeli Arroyo, MD, Kyle L. Gummelt, DO, MPH, Gates Colbert, MD, Anna L. Ursales, MD, Michael J. Van Vrancken, MD, MPH, George J. Snipes, MD, Joseph M. Guileyardo, MD, and Cristie Columbus, MD West Nile virus (WNV) has been responsible for multiple outbreaks and has shown evolution in its clinical manifestation. The Centers for Disease Control and Prevention has provided diagnostic criteria in classifying the variety of WNV infection; however, application of these criteria can prove challenging during outbreaks, and understanding the array of presentations and patient population is clinically important. In this article, we present the challenges encountered during the 2012 outbreak at one institution. I n 1937, West Nile virus (WNV) was isolated in Uganda’s West Nile region (1). Initial outbreaks described self-limited febrile illnesses with polyarthralgias and rash (2, 3). After 1990, outbreaks reported neurological symptoms (4). In 1999, the first US epidemic was in New York City, resulting in 59 encephalitis cases and 7 deaths (5). The most common presentation is West Nile fever (WNF), a self-limited illness with fever, fatigue, myalgia, rash, and headache lasting 3 to 10 days. Patients may experience persistent fatigue, difficulty concentrating, and a delayed return to baseline functioning (6). The virus may penetrate the central nervous system (CNS), causing several forms of West Nile neuroinvasive disease (WNND). West Nile meningitis, characterized by fever, headache, nuchal rigidity, and cerebrospinal fluid (CSF) pleocytosis, is associated with favorable outcomes (7–9). Most feared, West Nile encephalitis varies from mild confusion to severe encephalopathy, leading to coma or death in 10% to 20% of cases (7). Symptoms include myoclonus, parkinsonism, extrapyramidal symptoms, ataxia, cranial nerve involvement, altered consciousness, and seizures (9–11) resulting in prolonged hospital courses requiring mechanical ventilation and intensive care. WNND is associated with long-term morbidity, delayed physical and cognitive recovery, and prolonged disability (12). Baylor University Medical Center (BUMC) at Dallas cared for many WNV-infected patients during the 2012 epidemic. This study was conducted to explore challenges faced and lessons learned. METHODS A retrospective medical record review identified cases of WNV cases in the emergency department and inpatient service at BUMC from January to December 2012. Cases were Proc (Bayl Univ Med Cent) 2015;28(3):291–295 identified using two databases. The hospital’s reference laboratory (med fusion) was queried for positive results that included serum or CSF WNV IgM and IgG antibodies and WNV polymerase chain reaction (PCR) tests. Our laboratory used the IgM Capture DxSelectTM enzyme-linked immunosorbent assay and Focus Diagnostics IgG DxSelectTM enzyme-linked immunosorbent assay for qualitative detection of WNV IgM and IgG antibodies. Positive results were submitted to the Texas Department of State Health Services for confirmatory testing. Tests for WNV PCR were submitted to ARUP Laboratories, which uses qualitative real-time PCR to test serum and CSF in accordance with Roche Molecular Systems methods (13). The institutional administrative coding database was crossreferenced for diagnoses of WNV infection. Patients with prior WNV disease or only WNV IgG antibodies whose clinical picture wasn’t compatible with acute disease were excluded. Extracted data included demographics, comorbidities, symptoms, relevant physical examination findings, admission location, complications, diagnostic test results, and disposition. Immunosuppression was considered if records documented another disease known to affect the immune system or immunosuppressive therapy with systemic steroids (prednisone >20 mg or equivalent steroid longer than 2 weeks), biologic agents, or other immunomodulatory drugs. Cases were classified as confirmed WNF, probable WNF, confirmed WNND, or probable WNND per case definition criteria of the Centers for Disease Control and Prevention (CDC) (14). To address variable clinician evaluation and capture patients not fulfilling CDC definitions whose composite clinical and laboratory data suggested WNF or WNND, categories of “possible” WNF and WNND were created. For example, some patients not meeting the definition of fever had laboratory evidence in serum or CSF supporting active WNV infection. The study was approved by the institutional review board of BUMC. From the Division of Pulmonary Disease (Mora), Department of Internal Medicine (Arroyo, Gummelt, Colbert, Ursales), Department of Pathology (Van Vrancken, Snipes, Guileyardo), and Division of Infectious Diseases (Columbus), Baylor University Medical Center at Dallas. Corresponding author: Adan Mora Jr., MD, Division of Pulmonary Disease, Department of Internal Medicine, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: adam.mora@baylorhealth.edu). 291 RESULTS Sixty-eight cases were identified and 13 eliminated by our exclusion criteria. Fifty-five cases were evaluated: 12 comprised the WNF group (7 probable, 5 possible, and none confirmed), and 43 comprised the WNND group (7 confirmed, 29 probable, and 7 possible). Patient characteristics and comorbidities are summarized in Table 1. The age range was 19 to 84 years, with a mean of 53.4 years. Most patients were white, non-Hispanic men. Body mass index ranged from 15.7 to 62.4 kg/m2, with a mean of 28.8 kg/m2. The most common comorbid condition was hypertension. Presenting complaints and findings are outlined in Table 2. Subjective fevers were reported by 52 patients (42 had a documented fever of >100.4°F), classifying 10 patients as “possible” WNV infection (5 WNF, 5 WNND). Other findings were headache, altered mental status, hyponatremia, and gastroenteritis. Less common were seizures, acute kidney injury, acute respiratory failure, elevated transaminases, elevated total bilirubin, acute flaccid paralysis, rhabdomyolysis, tremors, myoclonus, and atrial fibrillation. In the WNND group, 26 had headache, 27 had altered mental status, 12 had seizures, and 3 had acute flaccid paralysis. The most commonly reported symptoms in the WNF group were headache and gastrointestinal symptoms. In this group, fever >100.4°F was documented in 7 patients and altered mental status was an uncommon presentation. Table 2 also outlines diagnostic laboratory findings. Serum WNV IgM antibodies were positive in most patients. Two patients (both WNND) had detectable total WNV antibodies that weren’t fractionated into IgM or IgG components, deeming them “possible” WNV infection. Serum PCR WNV was performed in one patient and was undetectable. Serum arbovirus panels were obtained in six patients and were negative. In the WNND group, a serum WNV IgM test was positive in 35 patients, negative in 2, and not obtained in 6 (including the two with positive total unfractionated WNV antibody). Serum WNV PCR was not obtained in any WNND patient. However, all had clinical neurological findings compatible with WNND, as defined by CDC clinical criteria (Table 3). Fortythree patients underwent lumbar puncture. Cell counts were available on 42, and 37 had pleocytosis. In the WNND group, cell counts were available in 37, and 35 had pleocytosis. Thirtytwo patients had CSF analysis for WNV IgM, and 19 had detectable CSF WNV IgM antibodies. Three had a positive CSF WNV PCR, but the test was only ordered in 14. CSF WNV IgG antibody testing was performed in 8 of the 43 patients; only one patient tested positive. Thirty-two patients (25 WNND) were initially admitted to a medicine floor; 19 (17 WNND) to the intensive care unit, and 4 (1 WNND) were seen and discharged in the emergency department. The mean length of stay for all was 7.7 days (WNND, 8.9 days; WNF, 3.2 days). In the WNF group, 11 were discharged home and one to a rehabilitation facility. In contrast, for WNND, 23 were discharged home, 7 to a rehabilitation unit, 2 to a long-term acute care facility, 2 to a skilled nursing facility, and 9 died. The mortality rate was 21%. Of all 292 Table 1. Demographic characteristics of 55 West Nile patients treated at Baylor University Medical Center in 2012 Category Age (years) Race Variable N % 18–30 5 9% 31–40 10 18% 41–50 9 16% 51–60 13 24% 61–70 6 11% 71–80 10 18% 80+ 2 4% White 30 55% Black 11 20% Hispanic 14 26% Asian 0 0% Sex Male 36 65% Female 19 35% Body mass index <18.5 3 6% 18.5–24.9 14 26% 25–29.9 17 31% 30–24.9 Length of stay (days) Admission status Discharge status 10 18% >35 6 11% Not done 5 9% 0 4 7% 1–3 12 22% 4–6 14 26% 7–10 10 18% 11–14 10 18% 15–21 1 2% 21+ 4 7% Emergency room 4 7% Medical/surgical floor 32 58% Intensive care unit 19 35% Home 34 62% Long-term acute care 2 Skilled nursing facility 2 4% Rehabilitation unit 8 15% Died, no autopsy 5 9% Died, with autopsy History 4 7% Hypertension 33 60% Diabetes 38 69% Transplant 1 2% Chronic kidney disease 6 11% Immunocompromised Current conditions Baylor University Medical Center Proceedings 4% 7 13% Hypertension 22 40% Diabetes mellitus 17 31% Transplant recipient 1 2% Chronic kidney disease/ end-stage renal disease 6 11% Immunocompromised 7 13% Volume 28, Number 3 Table 2. Signs and symptoms and laboratory data for 55 West Nile patients treated at Baylor University Medical Center in 2012 Table 3. Comparison of cases with West Nile fever and West Nile neuroinvasive disease WNF WNND Confirmed cases 0 7 Probable cases 7 29 Possible cases 5 7 Positive Total reported Percent* Subjective fevers 52 55 95% Objective fever >100.4°F 42 55 76% Any fever 42 55 76% Total 12 43 Elevated WBC on CSF 37 42 88% Mean age (years) 44.5 55.8 Headache 32 49 65% Mean body mass index (kg/m2) 30.1 28.6 AMS/encephalopathy 28 52 54% Symptoms Acute flaccid paralysis 4 16 25% Fever 5 35 Myoclonus 3 11 27% Headache 6 26 Tremors 3 11 27% Gastrointestinal illness 5 19 Rhabdomyolysis 3 12 25% Altered mental status 1 27 Atrial fibrillation 2 14 13% Seizures 0 11 Elevated total bilirubin 5 50 10% Acute flaccid paralysis 0 3 11 54 20% Serum WNV IgM positive 11 35 Acute respiratory failure 9 55 16% Serum WNV IgM negative 1 2 Transaminitis 8 52 15% Serum WNV IgM not drawn 0 6 Gastroenteritis 24 42 57% CSF WNV IgM positive 0 19 1 11 9% CSF WNV IgM negative 4 9 CSF WNV IgM not drawn 8 15 Serum sodium <120 mEq/L 0 55 0% CSF WNV PCR positive 0 3 Sodium 120–124 mEq/L 1 55 2% CSF WNV PCR negative 1 28 Sodium 125–129 mEq/L 5 55 9% Mean length of stay (days) 3.2 Sodium 130–134 mEq/L 20 55 36% Sodium 135–145 mEq/L 23 55 42% Home 6 55 11% Variable Acute kidney injury Epididymitis Hyponatremia Sodium >145 mEq/L Laboratory results Serum antibody screen 2 2 100% Serum IgM 46 49 94% Serum IgG 26 42 62% Serum PCR 0 1 0% Serum arbovirus 0 6 0% CSF IgM 19 33 58% CSF IgG 1 8 13% CSF PCR 3 15 20% CSF arbovirus 0 6 0% *The percentage reflects the total number of positive responses among those for whom data were available (which was not always the full group of 55 patients). AMS indicates altered mental status; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; WBC, white blood cells. WNV deaths in the four-county area, 24% were hospitalized at BUMC. Among the 9 patients who died, 8 were older than 50 years of age; 6 were men, 4 were white, 3 were Hispanic, and 2 were black. Six had hypertension, 6 had diabetes mellitus, 5 had chronic or end-stage renal disease, and 3 were immunoJuly 2015 8.9 Discharge status 11 23 Rehabilitation facility 1 7 Long-term care facility 0 2 Skilled nursing facility 0 2 Death 0 9 Mortality rate (%) 0% 21% compromised. Several patients had multiple comorbidities. All presented with altered mental status and subjective fever (8 documented a fever of ≥100.4°F). Eight were admitted to the intensive care unit. Seven had acute respiratory failure requiring mechanical ventilation, and six had seizures. DISCUSSION This study highlights WNV outbreak challenges. One challenge was related to case classification, given strict CDC criteria (14). Twenty-two percent of patients didn’t fulfill CDC case definitions for confirmed or probable WNND or WNF (Table 3). They lacked a documented fever >100.4°F and/or specific confirmatory testing. Elderly patients and those with renal failure or receiving corticosteroids may have had compromised febrile response mechanisms (15, 16). Another challenge was underutilization of nucleic acid amplification techniques early in West Nile virus and the 2012 outbreak: The Baylor University Medical Center experience 293 acute illness or in immunosuppressed populations. Such testing can be costly, and with decreasing reimbursement, physicians may be reluctant to order molecular diagnostics when effective therapeutic options are lacking. Additionally, tests measuring neutralizing antibodies aren’t widely available (limited to state departments of health and the CDC). Physician unfamiliarity with the presentations of WNV illness, coupled with the lack of standardized testing protocols for suspected disease, contributed to uncertainty in the classification of some cases. To avoid excluding potential cases, we employed a category of “possible” WNV infection as described previously. We suggest the CDC adopt a definition of “possible WNV infection” for reporting and potentially therapeutic purposes. For case definition, arboviral testing should be limited to known regional endemic viruses. The presence of endemic viruses in sentinel populations could be utilized in CDC case definitions. In the absence of active endemic viruses in humans or sentinel populations, no further arboviral testing is necessary. For example, St. Louis encephalitis virus infections previously endemic to our area were not detected in humans, sentinel flocks, or mosquito pools during the 2012 season (17, 18). We suggest the CDC laboratory diagnostic criterion “negative arboviral serologies for endemic arboviruses” be revised to reflect the absence of other endemic arboviruses in mosquitoes and sentinel birds in the affected geographic area during an epidemic. Additional difficulties involved distinguishing between true WNND and WNF with nonspecific neurologic symptoms. Determining whether WNV infection was a primary or contributory cause of death was problematic. Although most of the autopsied patients had CNS lesions that were clearly sufficient to explain death, one patient did not have well-developed CNS pathology. The literature cites evidence that systemic WNV infection may cause direct injury to organs, exacerbating preexisting diseases (19–21). This may complicate the diagnostic evaluation when attempting to decipher what is or is not attributable to WNV infection. WNV may contribute to the death of patients with significant underlying comorbidities in the absence of definitive CNS involvement. Data published by Schanzer et al reviewed the potential contributory role of influenza and found many comorbidities to be associated with influenza-attributed deaths, particularly pulmonary and cardiac diseases (21). It is important to realize that WNV may have systemic implications. We caution that misidentification of potentially treatable conditions could delay appropriate therapy. Furthermore, historical data review found distribution differences in WNF and WNND cases in 2003 versus 2012 (22, 23). In 2003, the WNF:WNND ratio was approximately 2.4:1; in 2012, this ratio was approximately 1:1. Both observations raise the possibility that the virus may have become more neurotropic due to viral mutation and genetic drift. Other possibilities include changes in testing patterns with improved detection related to patient and physician awareness and immunity of the population at risk. Of concern, despite increased awareness and prevention with DEET, mortality has not substantially decreased. 294 Data analysis suggests opportunities to improve our response to outbreaks. Lessons learned include the need to 1) remain vigilant for the diagnosis of WNV; 2) educate staff in recognizing real-world manifestations of WNV infection, which doesn’t neatly lend itself to published criteria for diagnosis; 3) develop standardized diagnostic testing algorithms; 4) develop recommendations for multisystem supportive care in WNF and WNND patients; and 5) research strategies for better detection, prevention, and treatment, including refined molecular tools for viral identification. Plans are currently under way at BUMC to optimize response to future outbreaks. Some activities involve developing standardized testing protocols and guidelines for the care of patients with possible WNV infection. However, further studies are needed as we search for more effective diagnostic, supportive, and therapeutic measures. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Smithburn KC, Hughes TP, Burke AW, Paul JH. A neurotropic virus isolated from the blood of a native of Uganda. Am J Trop Med Hyg 1940;20:471–492. Petersen LR, Roehrig JT. West Nile virus: a reemerging global pathogen. Emerg Infect Dis 2001;7(4):611–614. Murgue B, Murri S, Triki H, Deubel V, Zeller HG. West Nile in the Mediterranean basin: 1950–2000. Ann N Y Acad Sci 2001;951:117– 126. Klein C, Kimiagar I, Pollak L, Gandelman-Marton R, Itzhaki A, Milo R, Rabey JM. Neurological features of West Nile virus infection during the 2000 outbreak in a regional hospital in Israel. J Neurol Sci 2002; 200(1–2):63–66. Nash D, Mostashari F, Fine A, Miller J, O’Leary D, Murray K, Huang A, Rosenberg A, Greenberg A, Sherman M, Wong S, Layton M; 1999 West Nile Outbreak Response Working Group. The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med 2001;344(24):1807–1814. Watson JT, Pertel PE, Jones RC, Siston AM, Paul WS, Austin CC, Gerber SI. Clinical characteristics and functional outcomes of West Nile fever. Ann Intern Med 2004;141(5):360–365. Sejvar JJ, Marfin AA. Manifestations of West Nile neuroinvasive disease. Rev Med Virol 2006;16(4):209–224. Crichlow R, Bailey J, Gardner C. Cerebrospinal fluid neutrophilic pleocytosis in hospitalized West Nile virus patients. J Am Board Fam Pract 2004;17(6):470–472. Sejvar JJ, Haddad MB, Tierney BC, Campbell GL, Marfin AA, Van Gerpen JA, Fleischauer A, Leis AA, Stokic DS, Petersen LR. Neurologic manifestations and outcome of West Nile virus infection. JAMA 2003;290(4):511–515. Gandelman-Marton R, Kimiagar I, Itzhaki A, Klein C, Theitler J, Rabey JM. Electroencephalography findings in adult patients with West Nile virus-associated meningitis and meningoencephalitis. Clin Infect Dis 2003;37(11):1573–1578. Kanagarajan K, Ganesh S, Alakhras M, Go ES, Recco RA, Zaman MM. West Nile virus infection presenting as cerebellar ataxia and fever: case report. South Med J 2003;96(6):600–601. Sejvar JJ. The long-term outcomes of human West Nile virus infection. Clin Infect Dis 2007;44(12):1617–1624. ARUP Laboratory. Laboratory test directory: West Nile virus RNA by RT-PCR. Available at http://www.aruplab.com/guides/ug/tests/0050229. jsp; accessed April 28, 2015. National Notifiable Diseases Surveillance Systems. Arboviral diseases, neuroinvasive and non-neuroinvasive. Available at http://wwwn.cdc. gov/NNDSS/script/casedef.aspx?CondYrID=616&DatePub=1/1/2011; accessed April 28, 2015. Norman DC. Fever in the elderly. Clin Infect Dis 2000;31(1):148–151. Roghmann MC, Warner J, Mackowiak PA. The relationship between age and fever magnitude. Am J Med Sci 2001;322(2):68–70. Baylor University Medical Center Proceedings Volume 28, Number 3 17. Unites States Geological Survey. St. Louis encephalitis, human, Texas, 2012. Available at http://diseasemaps.usgs.gov/2012/sle_tx_human.html; retrieved April 28, 2015. 18. Unites States Geological Survey. St. Louis encephalitis, sentinel, Texas, 2012. Available at http://diseasemaps.usgs.gov/2012/sle_tx_sentinel.html; retrieved April 28, 2015. 19. Pergam SA, DeLong CE, Echevarria L, Scully G, Goade DE. Myocarditis in West Nile virus infection. Am J Trop Med Hyg 2006;75(6):1232–1233. 20. Georges AJ, Lesbordes JL, Georges-Courbot MC, Meunier DMY, Gonzalez JP. Fatal hepatitis from West Nile virus. Ann Inst Pasteur Virol 1987;138(2):237–244. 21. Schanzer DL, Tam TW, Langley JM, Winchester BT. Influenza-attributable deaths, Canada 1990–1999. Epidemiol Infect 2007;135(7):1109–1116. 22. Centers for Disease Control and Prevention. West Nile virus disease cases and presumptive viremic blood donors reported to ArboNET, United States, 2003. Available at http://www.cdc.gov/westnile/statsMaps/finalMapsData/data/2003WNVHumanInfectionsbyState.pdf; accessed April 28, 2015. 23. Centers for Disease Control and Prevention. West Nile virus disease cases and presumptive viremic blood donors reported to ArboNET, United States, 2012. Available at http://www.cdc.gov/westnile/statsMaps/finalMapsData/ data/2012WNVHumanInfectionsbyState.pdf; accessed April 28, 2015. Acknowledgment of contributors B aylor University Medical Center Proceedings couldn’t exist without writers or without readers, but it also couldn’t exist without financial support. Here we wish to acknowledge our individual donors who sent in gifts between August 7, 2014, and May 6, 2015. Leadership Gifts ($500+) Pierce M. Allman James W. Choi Roger S. Khetan Göran B. Klintmalm Michael A. Ramsay William C. Roberts Barbara Glazer Rosenblatt and Randall Lee Rosenblatt Family F. David Winter Scott W. Yates Benefactor ($250 to $499) Evangeline T. Cayton David L. Glancy Zelig H. Lieberman Marvin J. Stone Carlos E. Velasco Associate ($100 to $249) Peter A. Alivizatos Edward P. Allen Gayle Allison Anonymous Larry J. Barker Patricia L. Blanton Christopher J. Bolton Robert S. Capper July 2015 John C. Carson Christ Medical Center DOM Barry Cooper Andrew Z. Fenves Steve M. Frost Gary N. Gross Robert D. Gross Joseph M. Guileyardo H. A. T. Hein D. M. Highbaugh Ronald C. Jones Kari M. Klaskin John R. Krause Millie H. Lathan Harold M. Mims John C. O’Brien Steven J. Phillips Daniel E. Polter Patrick H. Pownell Irving D. Prengler Mrs. Maruf A. Razzuk Stewart R. Roberts Andrew C. Sambell Robert F. Sanford Steve P. Schoettle Scruggs Family Charitable Fund Craig A. Troop Barry N. Wilcox Friend (to $99) Anonymous Zaven H. Chakmakjian John E. Eisenlohr George P. Fosmire Frisco Medical Center, LLP Gabriele B. Gruschkus Maria Kalman Frederick J. Koberg Marion Luecke Thomas W. Newsome Ali A. Shams Curtis L. Studey Joan Windmiller Jean Woods The total amount raised this period from individual donors was $15,151. Any additional donations can be sent to the editorial office or the BHCS Foundation office and will be acknowledged in the July 2016 issue. West Nile virus and the 2012 outbreak: The Baylor University Medical Center experience 295 Comparison of long-term follow up of laparoscopic versus open colectomy for transverse colon cancer Samir Agarwal, MD, Mikhail Gincherman, MD, Elisa Birnbaum, MD, James W. Fleshman, MD, and Matthew Mutch, MD Clinical Outcomes of Surgical Therapy (COST) was a landmark study demonstrating that laparoscopic-assisted colectomy had oncologic outcomes similar to those of open colectomy for colon cancer, but transverse colon cancers (TCCs) were excluded from that study. Oncologic results of a laparoscopic resection for TCC are unknown. This single-institution retrospective 3:1 case-matched review examined patients treated for TCC from January 1, 1996, to April 15, 2009. Laparoscopic colectomy (LC) and open colectomy (OC; extended right, extended left, and total abdominal) cases completed for Stage I to III adenocarcinoma of the transverse colon (hepatic flexure, transverse colon, and splenic flexure) were analyzed. Patients were matched for age, tumor location, and stage. Primary endpoints were overall survival and disease-free survival. Secondary endpoints were length of stay and pathologic parameters. One hundred and twenty-three OC cases were matched with 41 LC cases. There were four conversions (9.7%) in the LC group. Length of stay was reduced by 28% in the LC group (P = 0.02). Complication rate and severity were similar between the two groups (29% vs 24%; P = 0.68). Lymph node harvest was higher in the LC group than in the OC group (23.3 vs 18.6; P = 0.03). All pathologic margins were clear, and no local recurrence was found in either group. Five-year overall survival (61% vs 59%; P = 0.39) and disease-free survival (88% vs 82%; P = 0.23) were similar in the two groups. Short-term recovery was faster and lymph node harvest was improved in the LC group. Thus, laparoscopic management of TCC is a safe and feasible procedure. T he Clinical Outcomes of Surgical Therapy (COST) trial demonstrated the oncological equivalence of laparoscopic surgery and open surgery in the treatment of colon cancer (1). Transverse colon cancers were excluded from the COST trial. It is well known that the laparoscopic management of transverse colon cancers is more challenging than other cancers of the colon. This is primarily due to anatomic reasons. The transverse colon has at least two collateralizing sources of blood flow and therefore multiple possibilities of divergent lymphatic drainage. The transverse (middle colic) mesentery is short over the anterior surface of the pancreas, and the venous drainage is fragile at the base of the mesentery. Consideration of tumor site along the transverse colon will influence which operation will provide the appropriate extent of mesenteric resection. There are no data regarding the appropriateness of laparoscopic resec296 tion for curable cancer from the randomized controlled trials published to date since all excluded transverse colon cancer in their protocols (2). The question of whether laparoscopic surgery is equivalent to open surgery in the management of transverse colon cancer should be addressed before assuming the appropriateness of this technique. Specifically, evaluation of 5-year overall survival and disease-free survival for patients undergoing a laparoscopic approach to curable transverse colon cancer is needed. METHODS The colorectal cancer database containing over 3000 patients at Washington University in St. Louis was queried to obtain patients that would be suitable for our retrospective comparison. The study was approved by the institutional review board at Washington University in St. Louis/Barnes Jewish Hospital. All operations were performed by surgeons in the Section of Colon and Rectal Surgery at Washington University in St. Louis from January 1, 1996, to April 15, 2009. A retrospective review of 164 patients with curable (Stage I–III) transverse colon cancer was performed. Complete removal of the colon mesentery and high ligation of major feeding vessels was performed in all cases according to practice parameter recommendations of the American Society of Colon and Rectal Surgeons. All patients treated laparoscopically for a curable transverse colon cancer (41) were matched 3:1 with 123 patients who underwent an open operation. Patients were matched according to age, gender, tumor location, and pathologic stage (I–III). All patients had histologically confirmed adenocarcinoma between the hepatic and splenic flexures found on colonoscopy and confirmed at the time of surgery. Patients with Stage IV disease, perforated cancers, and emergency operations were excluded from the study. From the George Washington University Hospital, Washington, DC (Agarwal); the Division of Colon and Rectal Surgery, Washington University in St. Louis, St. Louis, Missouri (Gincherman, Birnbaum, Mutch); and the Department of Surgery, Baylor University Medical Center at Dallas, Dallas, Texas (Fleshman). Presented in poster form at the 2009 meeting of the American Society of Colon and Rectal Surgeons in Minneapolis, Minnesota. Corresponding author: James W. Fleshman, MD, Department of Surgery, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: james.fleshman@baylorhealth.edu). Proc (Bayl Univ Med Cent) 2015;28(3):296–299 Patients underwent extended right colectomy (removal of right and transverse colon), extended left colectomy (removal of left and transverse colon), or total abdominal colectomy based on patient characteristics and tumor location to remove the colon and blood supply to the affected area. No segmental, wedge resections were performed for transverse colon cancer. The omentum was removed in all patients with transaction of the gastrocolic ligament outside the gastroepiploic arcade along the greater curvature of the stomach. The laparoscopic group included laparoscopic-assisted procedures (with intracorporeal dissection and vessel ligation with extraction and anastomosis through a 5 cm midline umbilical incision) and hand-assisted laparoscopic procedures (with the hand port placed at the suprapubic transverse incision used to extract and anastomose the bowel). Postoperative complications occurring within 30 days of the operation were classified according to the Accordion Severity Grading System of Surgical Complications (ASGS) (3). Mild complications are those that only require a minor procedure at the bedside to resolve. Examples of these include drainage of wound infections and nasogastric tubes. Moderate complications are those that require more aggressive intervention, such as antibiotics, blood transfusions, or total parenteral nutrition. Severe complications are those that require some form of intervention such as an endoscopic procedure, interventional radiologic procedure, or operation. Additionally, severe complications are those that result in the failure of one or more organ system. The final classification in the ASGS is death. Primary endpoints of our study were 5-year overall and disease-free survival. Secondary endpoints were length of stay, complications, and quantity of lymph node retrieval. Patients were followed by the Section of Colon and Rectal Surgery every 3 months with physical exam and carcinoembryonic antigen level for the first year, at which time colonoscopy and computed tomography (CT) was performed. Patients were followed every 6 months with physical exam and carcinoembryonic antigen level until 5 years. CT scan and colonoscopy were repeated as indicated. Stage III and some stage II patients received adjuvant chemotherapy with 5-flurouracil–based therapy. Comparisons were made between the laparoscopic and open groups using unpaired two-tailed t tests for continuous variables and chi-square or Fisher’s exact test for categorical variables. Survival was estimated using the Kaplan-Meier method with log rank estimation used to assess differences in survival between the two groups. Statistical significance was set at P < 0.05 and results are presented as mean ± standard deviation for continuous variables and as percentages for categorical variables. Statistical analysis was performed using GraphPad 5 Prism Software (San Diego, CA). RESULTS Patient demographics and tumor characteristics are shown in Table 1 for the matched groups. No statistically significant differences were found in age or gender between the laparoscopic and open surgical groups. Stratifying the two groups July 2015 according to American Society of Anesthesiologists score >3 or <3 revealed similar groups. Comparison of tumor location along the transverse colon revealed no significant differences. The tumors were considered hepatic flexure tumors if they were in the proximal one-third of the transverse colon and were considered splenic flexure tumors if they were in the distal one-third of the transverse colon. There were four conversions to open surgery (9.7%) in the laparoscopic group (poor visualization = 3, body habitus = 1). Length of stay was shortened by 28% in the laparoscopic surgery group (P = 0.02) (Table 1). Complication rate and severity of complications were similar between the two groups (29% vs 24%; P = 0.68). There were 4 (3.3%) anastomotic leaks in the open group and 2 (4.9%) in the laparoscopic group, and no perioperative deaths. Lymph node harvest was significantly higher in the laparoscopic group than in the open group (23.3 vs Table 1. Demographic characteristics and outcomes of the laparoscopic and open surgery groups Variable Laparoscopic (n = 41) Open (n = 123) P value 67.0 ± 13.7 68.6 ± 12.7 0.51 62% 49% Demographic characteristics Age (years) Men ASA classification 0.19 0.53 <3 88% 92% >3 12% 8% Tumor location 0.47 Hepatic flexure 40% 33% Transverse colon 49% 48% Splenic flexure 11% 19% I 38% 38% II 35% 35% III 27% 27% Pathologic stage 1.0 Outcomes 5-year survival 61% 59% 0.39 Stage I 55% 75% 0.80 Stage II 83% 61% 0.19 Stage III 58% 35% 0.82 88% 82% 0.23 Lymph node retrieval 23.3 ± 12.9 18.6 ± 10.7 0.03 Length of stay (days) 6.8 ± 2.9 9.4 ± 6.3 0.02 24% 29% 0.68 Mild 44% 50% Moderate 22% 16% Severe 34% 34% Death 0% 0% 5-year disease-free survival Complication rate ASA indicates American Society of Anesthesiologists. Comparison of long-term follow up of laparoscopic versus open colectomy for transverse colon cancer 297 a b c d Figure 1. Overall survival for (a) all patients, (b) patients with Stage I disease; (c) patients with Stage II disease; and (d) patients with Stage III disease receiving either a laparoscopic procedure (solid line) or open procedure (dashed line). 18.6; P = 0.03). All pathologic margins were clear. There were no perforations of the cancer or violation of the tumor during the procedure. Operative times were longer for the laparoscopic group. Five-year overall survival was similar between the laparoscopic group and open group (61% vs 59%, respectively; P = 0.39) (Figure 1a). There was no local recurrence in either group. No differences were found when comparing the stage of disease and the method of resection (Figure 1b, 1c, 1d). Disease-free 5-year survival, comparing all stages together, was 88% and 82% for the laparoscopic and open groups, respectively (P = 0.23) (Figure 2). DISCUSSION The COST trial excluded patients with transverse colon lesions from its analysis (1). The purpose of this paper was to retrospectively analyze our outcomes for laparoscopic resection of transverse colon cancers when compared to the previous gold standard of open resection. Only three other reports have addressed this issue (4–7). Our data represent the largest review 298 of laparoscopic versus open surgery for transverse colon cancer with long-term follow up. The data presented here support the supposition that laparoscopic resection of transverse colon cancer is feasible and similar to open surgery in experienced hands. Hospital stay is shortened and oncologic outcomes are the same as for open resection. The benefits of laparoscopic resection are less pain, better cosmesis, improved quality of life, and a shorter recovery without an oncologic or long-term survival detriment. These long-term survival data are consistent with previous data on other site colon resections (2). The complication rate for transverse colectomy is the same for laparoscopic and open techniques (24% vs 29%), and there is no difference in the frequency of moderate or severe events. The rate of anastomotic leak was also similar. Laparoscopic resection of transverse colon cancers is considered challenging for laparoscopic surgeons. Exposure at the base of the mesentery is difficult. Multiple vessels must be controlled, and vessel-sealing instrumentation has reduced this problem. Injury to the superior mesenteric artery can result from excessive Baylor University Medical Center Proceedings Volume 28, Number 3 Figure 2. Disease-free survival for all patients receiving either a laparoscopic procedure (solid line) or open procedure (dashed line). retraction of the colon to expose the base of the middle colic arteries. It is usually during this excessive retraction to obtain exposure that bleeding occurs. This was not a problem in this group of patients, and bleeding did not result in an increased conversion to open operation. It is helpful to approach the middle colic vessels from the avascular windows on either side of the middle colic vessels. A familiarity with upper abdominal anatomy is essential. This maneuver is facilitated by a hand assist approach. An interesting result of our study was the statistically significant finding of a greater lymph node harvest with the laparoscopic approach, 23.3 vs 18.6 lymph nodes (P = 0.03). This may reflect a greater number of total colectomy procedures in the laparoscopic group. This could also be a result of better visualization of the base of the middle colic vessels and ligation at a level closer to the surface of the pancreas compared with open surgery. The significance of these findings is unclear. The higher ligation of the vessels was not associated with an increase in bleeding. The four conversions in the laparoscopic group were primarily a result of poor visualization. One was done for large body habitus. We feel that as we became more adept in laparoscopic July 2015 resection of transverse colon cancers, our skills allowed us to approach more difficult resections without the need for conversion. A conversion rate of 10% is compatible with expected conversion rates for elective laparoscopic colectomy and is less than the rate reported by the COST trial (2). This report was limited by its retrospective nature and the inherent selection bias that occurs without a randomization process. The selection of patients for laparoscopic resection of a transverse colon cancer will be influenced by the appearance of the tumor on staging CT. Less advanced tumors will naturally be selected for laparoscopic approaches, and this may influence the oncologic outcomes of the patients. In conclusion, laparoscopic colectomy performed by experienced surgeons for transverse colon cancer is oncologically similar to open colectomy with no significant difference in long-term overall or disease-free survival. Short-term recovery and lymph node harvest are improved in the laparoscopic group compared to the open group. Laparoscopic colectomy for transverse colon cancer seems safe and feasible in expert hands, and there is no difference in oncologic outcomes. 1. Clinical Outcomes of Surgical Therapy Study Group. A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 2004;350(20):2050–2059. 2. Fleshman J, Sargent DJ, Green E, Anvari M, Stryker SJ, Beart RW Jr, Hellinger M, Flanagan R Jr, Peters W, Nelson H; Clinical Outcomes of Surgical Therapy Study Group. Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg 2007;246(4):655–662; discussion 662–664. 3. Strasberg SM, Linehan DC, Hawkins WG. The accordion severity grading system of surgical complications. Ann Surg 2009;250(2):177–186. 4. Lee YS, Lee IK, Kang WK, Cho HM, Park JK, Oh ST, Kim JG, Kim YH. Surgical and pathological outcomes of laparoscopic surgery for transverse colon cancer. Int J Colorectal Dis 2008;23(7):669–673. 5. Zmora O, Bar-Dayan A, Khaikin M, Lebeydev A, Shabtai M, Ayalon A, Rosin D. Laparoscopic colectomy for transverse colon carcinoma. Tech Coloproctol 2010;14(1):25–30. 6. Kim HJ, Lee IK, Lee YS, Kang WK, Park JK, Oh ST, Kim JG, Kim YH. A comparative study on the short-term clinicopathologic outcomes of laparoscopic surgery versus conventional open surgery for transverse colon cancer. Surg Endosc 2009;23(8):1812–1817. 7. Akiyoshi T, Kuroyanagi H, Fujimoto Y, Konishi T, Ueno M, Oya M, Yamaguchi T. Short-term outcomes of laparoscopic colectomy for transverse colon cancer. J Gastrointest Surg 2010;14(5):818–823. Comparison of long-term follow up of laparoscopic versus open colectomy for transverse colon cancer 299 Mortality by treatment in patients ≥80 years of age with gastroesophageal cancer seen in a 20-year period at a single medical center Tara Barnett, MD, James Mason, DO, Yolanda Munoz Maldonado, PhD, and Lucas Wong, MD The treatment approach to patients 80 years of age and older with gastroesophageal cancer at Baylor Scott and White in Temple, Texas, has historically favored conservative measures in the form of palliation and observation. To evaluate this trend in practice, the administered treatments and subsequent patient outcomes of this group were retrospectively reviewed. The study group included all patients 80 years of age and older with a diagnosis of gastroesophageal cancer seen at our facility between 1991 and 2010. Of the 117 cases, 49% received none of the available treatment modalities. The median overall survival (OS) of patients who received treatment, however, was significantly longer than the OS of those who did not, regardless of modality. Specifically, surgical intervention offered an almost double median OS compared with no therapy (6.8 vs. 3.9 months, respectively; P = 0.02); chemotherapy, an almost 4-fold OS benefit (14.8 vs. 3.9 months; P = 0.03); and radiation therapy, a >3-fold OS benefit (11.1 vs. 3.5 months; P = 0.04). These results further substantiate chronological age as an inaccurate predictor of treatment benefit, and age alone should not dictate the administration or withholding of available treatment options. T he treatment approach to patients 80 years of age and older with gastroesophageal cancer at Baylor Scott and White in Temple, Texas, has historically favored conservative measures in the form of palliation and observation. To evaluate this trend in practice, the administered treatment(s) and subsequent patient outcomes of this group were retrospectively reviewed. METHODS The study group included all patients 80 years of age and older with a diagnosis of gastroesophageal cancer, regardless of stage (I–IV) or performance status (Eastern Cooperative Oncology Group 0–4), seen in our facility from 1991 to 2010. The treatment course (i.e., surgery, chemotherapy, radiation therapy, or any combination of these modalities) and overall survival in months were retrospectively reviewed. Descriptive statistics were reported using minimum, 25th percentile, median (or 50th percentile), mean, 75th percentile, maximum, and standard deviation for continuous variables. Categorical variables were described as counts and percentages. Kaplan-Meier curves were constructed for gender, age group, 300 chemotherapy, radiation, and surgery. Cox proportional hazard models were fitted to the data. The variables included in the model were all variables with a P value < 0.25 in the univariate survival analysis. Residual diagnostics indicated a good fit of the model and no significant deviations from the model assumptions. A level of 0.05 was considered statistically significant for all other tests. SAS 9.2 was used for the statistical analysis. R software version 3.1.0 was used for the survival curves. RESULTS Between 1991 and 2010, a total of 117 patients over the age of 80 were diagnosed with gastroesophageal cancer at our facility. Table 1 depicts overall demographic and baseline characteristic information, highlighting the heterogeneity in presentation and treatment approach of gastroesophageal cancer, even in this highly specific age group. Of note, 62% of the study population was male, and 62% were between the ages of 80 and 84 at the time of inclusion. Only 29 patients (31%) presented with stage I disease, while stages II, III, and IV comprised 10%, 25%, and 34%, respectively. The most common site of primary malignancy was the gastric fundus (50%), followed by esophageal (30%) and gastric cardia (20%). Table 2 details the frequency of treatment modalities administered. Interestingly, 57 (49%) patients received no treatment; 25% of patients underwent surgery, 11% received chemotherapy, and 27% received radiation therapy, alone or in combination with another modality. Table 3 illustrates the effects baseline characteristics may have had on treatment decisions, demonstrating that most patients who received at least one of the available treatments were between the ages of 80 and 84 and had more advanced (stage 3–4) or aggressive (grade III) disease. The median overall survival for patients who received treatment was significantly longer relative to those without treatment, regardless of modality (Figure 1). Specifically, the median From the Division of Hematology and Oncology (Barnett, Wong), the Department of Internal Medicine (Mason), and the Office of Biostatistics (Munoz Maldonado), Baylor Scott & White Health, Scott & White Memorial Hospital, Temple, Texas. Corresponding author: Tara Barnett, MD, Baylor Scott & White Health, Scott & White Memorial Hospital, MS-01-692, 2401 South 31st Street, Temple, TX 76508 (e-mail: tabarnett@sw.org). Proc (Bayl Univ Med Cent) 2015;28(3):300–303 Table 1. Patient characteristics for 117 patients with gastroesophageal cancer over the age of 80 treated at a single institution* Variable N (%) Hazard ratio (95% CI) Table 3. Patient characteristics by treatment for patients with gastroesophageal cancer over the age of 80 treated at a single institution* P value Variable Demographics Gender Female 44 (38%) Male 73 (62%) Age (years) 80–84 Race 72 (62%) 85+ 45 (38%) White 102 (87%) 1.6 (1.04, 2.39) 0.31 0.04 Age (years) 0.6 (0.33, 1.11) 0.14 15 (13%) Race 0–1 29 (31%) 0.24 (0.13, 0.44) <0.001 2 10 (10%) 0.41 (0.78, 0.87) 0.03 Follow-up, months: mean, SD 3 24 (25%) 0.54 (0.30, 0.94) 0.03 4 32 (34%) I–II 22 (23%) 0.27 (0.12, 0.64) 0.002 III 63 (67%) 0.65 (0.18, 0.78) 0.005 Nonwhite Grade IV Site Treatment 10 (35%) 2 (15%) 8 (26%) 19 (65%) 11 (85%) 23 (74%) 80–84 20 (69%) 10 (77%) 17 (55%) 85+ 9 (31%) 3 (23%) 14 (45%) White 27 (93%) 10 (77%) 24 (77%) 2 (7%) 3 (23) 7 (23%) 6.3 (0.33, 173.5) 14.1 (3.0, 48.0) 10.2 (2.2, 48.0) 0–1 9 (33%) 2 (20%) 10 (38%) 2 3 (11%) 1 (10%) 3 (12%) 3 9 (33%) 3 (30%) 10 (38%) 4 6 (23%) 4 (40%) 3 (12%) Esophagus I–II 3 (13%) 4 (40%) 6 (24%) III 19 (79%) 6 (60%) 16 (64%) IV 2 (8%) 0 (0%) 3 (12%) Esophagus 6 (21%) 3 (23%) 18 (58%) Gastric 20 (69%) 5 (38%) 6 (19%) Cardia 3 (10%) 5 (38%) 7 (23%) Classification Stage 9 (10%) 35 (30%) Gastric 58 (50%) Cardia 24 (20%) Surgery 29 (25%) 0.99 (0.56, 1.79) 1.25 (0.75, 2.20) 1.76 (1.1, 2.9) 0.97 0.02 Chemotherapy 13 (11%) 0.48 (0.23, 0.89) 0.03 Radiotherapy 31 (27%) 1.57 (1.02, 2.48) 0.047 overall survival for patients who underwent surgical intervention was nearly double that of those who did not (6.8 months [95% confidence interval (CI) 3.9–19.9] vs. 3.9 months [95% CI 2.8–6.3]; P = 0.02; Figure 1a); chemotherapy offered an almost 4-fold overall survival benefit (14.8 months [95% CI 5.3– 30.6] vs. 3.9 months [95% CI 3.0–5.8]; P = 0.03; Figure 1b); Table 2. Frequency of treatment modalities administered for 117 patients with gastroesophageal cancer over the age of 80 treated at a single institution Treatment modality Frequency Percent No treatment 57 49% Surgery alone 25 21% 3 3% Chemotherapy alone Radiation alone Grade 0.41 *Univariate hazard ratios compared with overall mortality. Baseline references for variables with more than one level in the hazard ratio are always the last level. CI indicates confidence interval. 22 19% Surgery and chemotherapy 1 <1% Chemotherapy and radiation 6 5% Surgery, chemotherapy, and radiation 3 3% July 2015 Female Male Nonwhite Classification Stage Chemotherapy Radiation (N = 13) (N = 31) Demographics Gender 0.7 (0.44, 0.98) Surgery (N = 29) Site *Tests between the treatments could not be performed since any given patient could have one or more treatment modality. and radiation therapy, a greater than 3-fold overall survival benefit (11.1 months [95% CI 6.3–15.0] vs. 3.5 months [95% CI 2.4–4.6]; P = 0.04; Figure 1c). A Cox proportional hazards model was fitted to the data. Backward, forward, and stepwise variable selection procedures chose gender, stage, and treatment with chemotherapy to be part of the model. Age group was also included in the reduced model. The model was statistically significant (P < 0.0001). Stage and chemotherapy had coefficient estimates significantly different than 0 (Table 4). Gender and age group were not significant. Patients without chemotherapy treatment were 2.4 times more likely to die than patients treated with chemotherapy. Patients with stage 4 disease were 5 times more likely to die than patients with stage 1, but otherwise no higher hazards for other stage combinations was identified. A Cox model was fitted to the data stratified by age group. Although this model seemed to indicate an interaction between age group and gender, this interaction could not be explored due to the small sample size. DISCUSSION The complexity of gastrointestinal oncologic resection imposes significant morbidity and mortality. A recently published study found that increasing age independently impacted Mortality by treatment in patients ≥80 years of age with gastroesophageal cancer 301 No Surgery Surgery 0.0 0.2 0.4 0.6 Survival Rate 0.8 1.0 a 0 3 6 9 15 21 27 33 39 45 51 57 63 69 45 51 57 63 69 51 57 63 69 Time(months) 0.4 0.6 0.8 No Chemo Chemo 0.0 0.2 Survival Rate 1.0 b 0 3 6 9 15 21 27 33 39 Time(months) 0.8 0.4 0.6 No Radiation Radiation 0.0 0.2 Survival Rate 1.0 c 0 3 6 9 15 21 27 33 39 45 Time(months) Figure 1. Kaplan-Meier estimates of survival for patients who did and did not receive (a) surgery, (b) chemotherapy, and (c) radiation. Table 4. Coefficient estimators for the final model using all patients in a Cox proportional hazard model* Parameter Age group (80–84) Parameter Standard Hazard 95% CI for estimate error P value ratio hazard ratio –0.34 0.24 0.17 0.71 0.45, 1.16 0.45 0.26 0.08 1.56 0.94, 2.58 Stage (0–1) –1.65 0.33 <.001 0.19 0.09, 0.36 Stage (2) –0.90 0.41 0.03 0.41 0.17, 0.88 Stage (3) –0.62 0.30 0.04 0.54 0.30, 0.96 Chemotherapy –0.89 0.39 0.02 0.41 0.18, 0.83 Gender (Female) *Analysis of maximum likelihood estimates. The final model considered mortality as a function of age group, gender, stage, and chemotherapy. The model was significant with a P < 0.001. Variables were selected using backward, forward, and stepwise selection. All three methods agreed on the final model. All regression diagnoses were checked and model assumptions satisfied. CI indicates confidence interval. 302 outcome following esophagectomy, particularly mortality and discharge disposition, and patients who are at least 80 years of age considering esophagectomy should be recognized as a high-risk cohort (1). The same study also concluded that age should not necessarily be a contraindication for esophagectomy, but patients over the age of 80 must be carefully selected on a case-by-case basis and serious consideration of nonoperative treatment is warranted. Similarly, a systematic review published in 2007 found no evidence of inferior survival or increased treatment-related mortality in the elderly with experimental treatments compared with younger patients (2). The available data also suggest that older patients are just as willing to undergo chemotherapy as their younger counterparts, although less willing to endure severe treatment-related side effects (3). This perspective, however, is uncommonly the standpoint from which treatment strategies for older patients are formulated. In reviewing our data, almost 50% of patients 80 years of age or older with a diagnosis of gastroesophageal cancer did not receive any of the three available modalities of treatment, even though patients who received treatment fared far better. This study had limitations. It failed to consider treatment bias, in that perhaps those patients selected to undergo treatment fared better because they were “healthy” enough to undergo treatment, while those who were not offered, or opted against, treatment had inferior survival because they were more “sick” as a cohort and not candidates for therapy. It also did not reflect quality of life during the gained months of survival in those who underwent treatment. Safety data and side effects were also not discussed. With over 20 years of data, we hoped to also identify trends in mortality among the treatment and nontreatment groups over time, to perhaps demonstrate the effectiveness of modern therapies compared to those used 20 years ago. Unfortunately, our sample size was not sufficient for such an analysis, but the question would be an interesting avenue of future study. Of note, within the timeframe studied, there were no major advances largely affecting overall survival. The development of minimally invasive approaches to gastroesophageal cancer resection offered an attractive alternative to traditional transthoracic open surgery, although retrospective evaluation demonstrated identical mortality and overall surgical morbidity (4). To date, there remains no standard chemotherapy regimen for use in the neoadjuvant, combined modality setting (4). In addition, targeted therapies with known survival benefit in gastroesophageal cancer are currently limited to trastuzumab and ramucirumab, although both were approved for use after the close of our study (5). These data represent a significant contribution to the ongoing debate over treatment strategies for those over the age of 80 diagnosed with gastroesophageal cancer. Based on these findings, while age is an important predictor of overall outcome and should play a substantial role in the decision making on approach to treatment, age alone should not be the deciding factor, but one of many patient-specific variables that warrant consideration. As our institution, the treatment of patients over the age of 80 with gastroesophageal cancer should be considered Baylor University Medical Center Proceedings Volume 28, Number 3 more frequently and advocated with proper selection and appropriate counseling. Acknowledgments The authors acknowledge the contributions of Alejandro Arroliga, MD, and Mark Holguin, MD. 1. 2. Stahl CC, Hanseman DJ, Wima K, Suton JM, Wilson GC, Hohmann SF, Shah SA, Abbott DE. Increasing age is a predictor of short-term outcomes in esophagectomy: a propensity score adjusted analysis. J Gastrointest Surg 2014;18(8):1423–1428. Kumar A, Soares HP, Balducci B; National Cancer Institute. Treatment tolerance and efficacy in geriatric oncology: a systematic review of phase III 3. 4. 5. randomized trials conducted by five National Cancer Institute–sponsored cooperative groups. J Clin Oncol 2007;25(10):1272–1276. Yellen SB, Cella DF, Leslie WT. Age and clinical decision making in oncology patients. J Natl Cancer Inst 1994;86(23):1766–1770. Lockhart CA, El-Khoueiry AB, Krasna M. Update on upper gastrointestinal cancers: what’s new since the 2009 ASCO annual meeting? ASCO University 2010 Education Book. Category: Gastrointestinal (Noncolorectal) Cancer. Available at http://meetinglibrary.asco.org/content/34-74; accessed April 20, 2015. Burtness B, Ilson D, Iqbal S. New directions in perioperative management of locally advanced esophagogastric cancer. ASCO University 2014 Education Book. Category: Gastrointestinal (Noncolorectal) Cancer. Available at http://meetinglibrary.asco.org/EdBookTracks/2014%20 ASCO%Annual%20Meeting; accessed April 29, 2015. Proceedings’ annual editorial board meeting B aylor University Medical Center Proceedings held its annual editorial board meeting on April 2, 2015. Some of the points discussed were as follows: • In 2014, Proceedings published 125 manuscripts and 396 pages (Table), with an acceptance rate of 80%. The number of manuscripts was at an all-time high. • A little over half (52%) of the manuscripts were submitted by Baylor Scott and White physicians—an all-time low since we are receiving more submissions from outside the system. • In response to the merger, we modified the tagline and images on the cover and have published several articles from Baylor Scott & White physicians in Temple. In addition, two board members now represent the Central Division. • New electronic options were added in 2014, including an ePub version and an improved eTOC. • A reader survey was conducted in spring 2014. • For 2014, 6800 copies of each issue were printed, and the eTOC was sent to 500 individuals. • There were 2.1 million visits to the journal’s PubMed Central website in 2014 (plus more for the BaylorHealth.edu/ Proceedings site). July 2015 Table. Numbers of articles and pages published in BUMC Proceedings in 2014 Jan 14 Apr 14 Jul 14 Oct 14 Content Art Pp Art Pp Art Pp Art Pp Case reports 12 30 19 15 40 17 37 50 Total Art Pp 63 157 Original articles 2 12 8 29 3 11 4 22 17 74 Editorials, tributes 4 10 7 19 3 11 3 6 17 46 Interviews 1 1 13 1 8 3 28 Facts and ideas Reviews Miscellaneous* Total 7 1 6 4 11 24 76 1 11 6 24 39 120 1 8 4 7 31 100 1 10 4 35 1 4 1 4 6 10 20 52 31 100 125 396 *Miscellaneous includes the copyright page, Baylor news, obituaries, journal notices, abstracts, guidelines for authors, ads, and publications list. Not included are items that appear at the end of articles. The miscellany items are not included in the total article count. Mortality by treatment in patients ≥80 years of age with gastroesophageal cancer 303 Trends in the neonatal mortality rate in the last decade with respect to demographic factors and health care resources Vinayak Govande, MBBS, Amy R. Ballard, MD, Madhavi Koneru, MD, and Madhava Beeram, MD To understand factors contributing to the neonatal mortality rate (NMR), we studied trends in the NMR during 2000 to 2009 with respect to demographic factors and health care resources. Birth- and death-linked mortality data for 14,168 neonatal deaths that occurred between 2000 and 2009 were obtained from the Texas Department of Health and Human Services. Demographic factors and health care resource data were analyzed using analysis of variance, chi-square tests, and linear regression analysis. The average NMR increased from 3.37 in 2000 to 3.77 in 2009. The NMR in blacks ranged from 6.57 to 8.97 during the study period. Among the babies who died, the mean birthweight decreased from 1505 to 1275 g (P < 0.001) and the mean gestational age decreased from 28.4 to 27.8 weeks (P < 0.001). Cesarean section deliveries increased from 32.7% to 44.9% (P < 0.001). The percentage of mothers receiving prenatal care increased from 81.4% to 86.6% (P < 0.001). Mothers with a college education increased from 8.8% to 20.5% (P < 0.001). The median household income increased from $41,047 to $49,189 (P < 0.001). The number of neonatal intensive care unit beds increased from 33.4 to 56 per 10,000 births, and the number of neonatologists increased from 0.27 to 0.40 per 10,000 women of 15 to 44 years of age. In conclusion, the NMR didn’t improve despite improvements in demographic factors and health care resources. Racial disparities persist, with a high NMR in the black population. We speculate a possible genetic predisposition related to ethnicity, and a potentially higher rate of extreme prematurity might have contributed to a high NMR in the study population. T he neonatal mortality rate (NMR) and the infant mortality rate are often used to indicate the effectiveness of maternal and child health care services (1, 2). In the United States, neonatal mortality has decreased steadily during the previous three decades. However, in the last 10 years, the decrease has been marginal. The US NMR was 4.19 in 2009 (3). Texas is the second-largest state in population, and in 2009, it ranked 18th regarding NMR in the USA (3). Because it is a large state with diverse sociodemographic factors and has a high NMR, Texas is an important context in which to study the effectiveness of maternal and child health care services. This study examined trends in the NMR and their relation to underlying variables such as maternal sociodemographic factors and available health care resources in the state of Texas from 2000 to 2009. 304 METHODS In this study, we used publicly available information obtained from the Texas Department of Health and Human Services (TDHHS). The study received approval from the institutional review board of Baylor Scott and White Healthcare. Data for neonates who died under the age of 28 days were collected from TDHHS for the period of 2000 to 2009. Birth and death certificate data were linked by TDHHS during the study period. The number of obstetrics and gynecology providers and neonatologists, along with the number of beds available in neonatal intensive care units (NICU), was also obtained from TDHHS. Important outcome variables studied included NMR, ethnicity (white, black, Hispanic, and other), and key demographic determinants of NMR including maternal age, birthweight, educational level, socioeconomic status, gestational age, prenatal care, cause of death, method of delivery, and maternal smoking. Variables regarding health care included number of available beds in the NICU and number of obstetrics providers and neonatologists. The NMR is the number of neonatal deaths during a year, divided by the number of live births during the same year, expressed per 1000 live births. Characteristics were summarized according to ethnicity and year by descriptive statistics: mean (± standard deviation) for continuous variables and frequency (percent) for categorical variables. Multivariable Poisson regression analysis and multivariable negative binomial regression analysis were utilized to investigate the significance of ethnicity, median income, and year on NMR. Proportion comparisons were assessed utilizing chi-square test. Linear regression analysis or the CochranArmitage trend test was used for trend analysis. A P value of < 0.05 indicates statistical significance. SAS 9.2 (SAS Institute Inc, Cary, NC) was used for data analysis. RESULTS Between 2000 and 2009, a total of 14,168 death records of neonates younger than 28 days old and associated birth records From the Department of Pediatrics, McLane Children’s Hospital at Baylor Scott and White, Temple, Texas. Corresponding author: Vinayak Govande, MBBS, Department of Pediatrics, Baylor Scott and White Health, Texas A&M College of Medicine, 2401 S. 31st Street, Temple, TX 76508 (e-mail: vgovande@sw.org). Proc (Bayl Univ Med Cent) 2015;28(3):304–306 Table 1. The neonatal mortality rate in Texas and accompanying socioeconomic factors from 2000 to 2009 using information collected from records of 14,168 neonatal deaths Variables 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 NMR (all) 3.37 3.71 3.90 4.37 4.13 4.10 3.97 3.81 3.81 3.77 NMR (blacks) 6.61 7.17 8.36 8.97 8.17 8.81 7.63 7.53 6.57 6.57 NMR (whites) 2.83 3.25 3.34 3.69 3.54 3.05 3.44 2.97 3.21 3.32 Mean birthweight (g)* 1505 1436 1358 1310 1333 1217 1270 1295 1268 1275 Mean GA (weeks)* 28.4 28.4 27.8 27.4 27.5 27.4 27.7 27.7 27.5 27.8 Mode of delivery (cesarian section)* 32.7% 30.2% 28.9% 27.5% 29.0% 41.9% 42.6% 44.1% 41.9% 44.9% Prenatal care 81.4% 80.0% 80.1% 80.9% 82.2% 85.1% 87.1% 85.0% 84.5% 86.6% Maternal age (years) 26.4 26.7 26.5 26.8 27.0 27.2 26.9 27.1 27.2 27.7 Maternal education (college)* 8.8% 7.5% 7.6% 7.9% 8.9% 17.8% 17.7% 18.6% 17.6% 20.5% Smokers 8.4% 8.2% 7.0% 8.0% 6.7% 8.9% 8.6% 9.6% 7.0% 7.6% Median household income* (thousands/year) 41.0 41.0 40.9 41.4 42.0 43.2 45.8 48.8 50.7 49.2 NICU beds/10,000 births 33.4 34.9 35.7 38.1 40.4 42.3 43.6 48.9 52.2 56.0 Neonatologists/10,000 females of 15–44 yr 0.27 0.28 0.29 0.32 0.35 0.35 0.34 0.37 0.39 0.40 Obstetricians/10,000 females of 15–44 yr 0.05 0.04 0.04 0.04 0.06 0.06 0.06 0.06 0.05 0.04 NMR indicates neonatal mortality rate; GA, gestational age; NICU, neonatal intensive care unit. *P < 0.001. were obtained and the characteristics of neonatal death were assessed. The NMR according to ethnicity, mean birthweight, mean gestational age, mode of delivery, prenatal care, maternal age, maternal education, incidence of smoking, median household income, number of NICU beds per 10,000 births, and number of neonatal providers and obstetricians per 10,000 females of 15 to 44 years are shown in Table 1. Figures 1 to 3 highlight the NMR by ethnicity and by cause and the growing number of resources over the time period. DISCUSSION The NMR declined from 15.1 in the 1970s to about 6.1 in the 1990s due to advances in neonatal critical care; however, the NMR has remained relatively unchanged in recent years (4). Advances in the care of sick neonates did not impact the NMR, unlike the previous few decades (4). In our study, we found similar results, suggesting the NMR did not change significantly from 2000 to 2009. In 2009, the NMR was 3.78 in Texas, compared with 2.69 in Minnesota (3). Texas ranked 18th in the USA in NMR (3). In the black population in Texas, the NMR remained relatively unchanged and high (6.61 in 2000 and 6.57 in 2009). These findings are consistent with current neonatal outcomes in the USA (5). The percentage of women receiving prenatal care and average maternal age remained the same over the period of 9.5 25 8.5 20 Percetange NMR according to ethnicity 30 7.5 6.5 5.5 15 10 4.5 5 3.5 0 2000 2.5 2001 2002 2003 2004 2005 2006 2007 2008 2009 Years 1.5 2000 2001 Total 2002 2003 Black 2004 White 2005 2006 Hispanics 2007 2008 2009 Others Figure 1. Neonatal mortality rate among various ethnicities from 2000 to 2009 in Texas. July 2015 ELBW, 500-749 grams ELBW, 750-999 grams Extreme prematurity (Total) RDS Figure 2. Leading causes of neonatal deaths from 2000 to 2009 in Texas. ELBW indicates extremely low birthweight; RDS, respiratory distress syndrome. Trends in the neonatal mortality rate in the last decade with respect to demographic factors and health care resources 305 Figure 3. Number of neonatal intensive care unit beds per 10,000 births and number of perinatal providers in Texas per 10,000 females 15 to 44 years of age from 2000 to 2009. the study. We noticed an increasing trend of mothers with a college education. This trend is similar to the trend found in the country as a whole by Hamilton et al (6). There is also an increasing trend for cesarean deliveries. Multiple studies have shown a negative relation between cesarean section rates and neonatal outcomes (7). The cesarean section rate increase can be correlated with decreased gestational age and birthweight, as more premature and sicker babies tend to be born via cesarean section. In our study, cesarean section rates increased from 32.7% to 44.9%. Our study did not show a similar correlation. In our study, the median household income increased from $41,000 to $49,200 from 2000 to 2009. In spite of increasing median household income, the NMR remained relatively unchanged. Olson et al documented a negative association between median family income and all birth outcomes (8). Subramanian et al (9) and Shmueli (10) have shown an inverse association between median income and health disparities. We were unable to show a similar trend in our study. Advances in neonatal critical care medicine, and better resource availability as evidenced by higher numbers of neonatologists, obstetricians, and available NICU beds, did not have an effect on the NMR. These findings correlate with the findings of Thompson et al (11), who found that in spite of having greater resources regarding neonatal care per capita compared with Canada, the United Kingdom, and Australia, neonatal outcomes in the US are lagging. This may suggest that neonatal care providers, NICU beds, and hospitals are one part of the health care delivery system, and it may suggest a need to focus on sociodemographic factors. The mean birthweight and gestational age showed decreasing trends in our analysis. Extremely low birthweight infants 306 with a birthweight of 500 to 999 g and respiratory distress syndrome or respiratory failure were leading causes of mortality in the study group. This finding suggests that extreme prematurity and its complications are still leading contributors to the NMR. Efforts targeted against extreme prematurity may help to decrease the NMR. We obtained our data set from TDHHS and thus were dependent on the accuracy of data reporting. The data set could have been limited by poor reporting and the misclassification of births as stillbirths. In conclusion, in our study, NMR did not change significantly from 2000 to 2009 despite improvements in maternal age, decreased smoking, improved education, higher median household income, and an increased number of NICU beds and perinatal providers. Racial disparities persist, with a high NMR in the black population. We speculate that a possible genetic predisposition related to ethnicity and a potentially higher rate of extreme prematurity might have contributed to a high NMR in the study population. However, additional studies are needed to explore these factors. Heisler EJ. The U.S. Infant Mortality Rate: International Comparisons, Underlying Factors, and Federal Programs [CRS Report for Congress]. Washington, DC: Congressional Research Service, April 4, 2012. Available at https://www.fas.org/sgp/crs/misc/R41378.pdf; accessed March 30, 2015. 2. MacDorman MF, Mathews TJ. Behind International Rankings of Infant Mortality: How the United States Compares with Europe [NCHS Data Brief No. 23]. Hyattsville, MD: National Center for Health Statistics, 2009. Available at http://www.cdc.gov/nchs/data/databriefs/db23.htm; accessed March 30, 2015. 3. Kochanek KD, Kirmeyer SE, Martin JA, Strobino DM, Guyer B. Annual summary of vital statistics: 2009. Pediatrics 2012;129(2):338–348. 4. MacDorman MF, Mathews TJ. Recent Trends in Infant Mortality in the United States [NCHS Data Brief No. 9]. Hyattsville, MD: National Center for Health Statistics, 2008. Available at http://www.cdc.gov/nchs/data/ databriefs/db09.htm; accessed March 30, 2015. 5. Collins JW Jr, David RJ. Racial disparity in low birth weight and infant mortality. Clin Perinatol 2009;36(1):63–73. 6. Hamilton BE, Hoyert DL, Martin JA, Strobino DM, Guyer B. Annual summary of vital statistics: 2010–2011. Pediatrics 2013;131(3):548–558. 7. MacDorman MF, Declercq E, Menacker F, Malloy MH. Neonatal mortality for primary cesarean and vaginal births to low-risk women: application of an “intention-to-treat” model. Birth 2008;35(1):3–8. 8. Olson ME, Diekema D, Elliott BA, Renier CM. Impact of income and income inequality on infant health outcomes in the United States. Pediatrics 2010;126(6):1165–1173. 9. Subramanian SV, Kawachi I. Income inequality and health: what have we learned so far? Epidemiol Rev 2004;26(1):78–91. 10. Shmueli A. Cost-effective outlays for better health outcomes. World Health Forum 1995;16(3):287–292. 11. Thompson LA, Goodman DC, Little GA. Is more neonatal intensive care always better? Insights from a cross-national comparison of reproductive care. Pediatrics 2002;109(6):1036–1043. 1. Baylor University Medical Center Proceedings Volume 28, Number 3 Effect of adding tetracaine to bupivacaine on duration of analgesia in supraclavicular brachial plexus nerve blocks for ambulatory shoulder surgery Linda T. Pearson, MD, Benjamin P. Lowry, MD, William C. Culp Jr., MD, Olen E. Kitchings, MD, Tricia A. Meyer, PharmD, Russell K. McAllister, MD, Charles R. Roberson, MD, and Christopher J. Burnett, MD The objective of this study was to determine if the addition of 1% tetracaine to 0.25% bupivacaine prolonged the duration of postoperative analgesia of supraclavicular brachial plexus nerve blockade for patients undergoing ambulatory shoulder surgery. We conducted a prospective, double-blinded, randomized controlled clinical study at an ambulatory surgery center utilizing ultrasound- and nerve stimulation-guided supraclavicular nerve blockade for postoperative analgesia. The control group received 30 mL of 0.25% bupivacaine plus 4 mL preservative-free saline. The study group received 30 mL of 0.25% bupivacaine plus 4 mL of 1% tetracaine. Patients documented their visual analog scale scores and intake of pain medications for 3 days. Primary outcomes included time of first postoperative pain, time of first postoperative pain pill, and time of return of motor and sensory function. Secondary outcomes included pain score and pain medication intake trends and adverse events secondary to the nerve block. A total of 84 patients completed the study, 42 patients in each group. The study group was statistically significantly older than the control group (mean age, 54 vs 48 years; P = 0.04). The mean duration of analgesia was 16.6 ± 8.3 h for the control group and 17.1 ± 7.3 h for the study group (P = 0.69). No outcomes were statistically different. In conclusion, there was no significant difference in duration of postoperative analgesia with the addition of 1% tetracaine to 0.25% bupivacaine in supraclavicular brachial plexus nerve blockade. No differences were identified in postoperative pain medications, pain scores, or complications. B rachial plexus blockade for upper-extremity surgery has been shown to be an effective form of postoperative analgesia, resulting in reduced opioid requirements, length of stay in the postanesthetic care unit, and time to discharge in the ambulatory surgery setting (1–3). Numerous studies have described the addition of adjunctive agents to a primary local anesthetic for peripheral nerve blockade resulting in longer duration of analgesia and decreased opioid requirements (4–10). Adjunctive agents include rapid-onset local anesthetics, sedative hypnotics, opioids, tramadol, and dexamethasone. A few studies have evaluated the addition of the long-acting amino-ester local anesthetic tetracaine to peripheral nerve blockade to prolong duration of anesthesia and analgesia (6, 11, 12). Tetracaine hydrochloride has a duration of action similar to that of the amino amide local anesthetic bupivacaine, both averaging 3 to 10 hours Proc (Bayl Univ Med Cent) 2015;28(3):307–311 (13). Pflug et al and Van Gessel et al reported a similar duration of action between tetracaine and bupivacaine for spinal anesthesia (14, 15). Several studies have utilized tetracaine as the primary local anesthetic for trigeminal neuralgia and peripheral nerve blockade (5, 16–18). Moore reported a duration of analgesia of 4 to 10 hours utilizing tetracaine as a sole anesthetic in peripheral nerve blocks (16, 17). Moore et al compared sensory anesthesia between bupivacaine, mepivacaine, lidocaine, and tetracaine in peripheral nerve blocks and found that sensory anesthesia with bupivacaine was 20% to 30% longer than that of tetracaine (19). Sensory anesthesia with tetracaine was approximately twice as long as that of lidocaine or mepivacaine. At our institution, it is routine practice to combine tetracaine with other local anesthetics for peripheral nerve blocks in an effort to prolong anesthesia and analgesia. This practice is based on many years of anecdotal evidence from patient reports of prolonged analgesia (often >24 hours) and no reports of adverse events. Therefore, we hypothesized that the addition of 1% tetracaine to 0.25% bupivacaine for supraclavicular nerve blockade would significantly prolong the duration of postoperative analgesia after shoulder surgery in the ambulatory setting. METHODS After obtaining approval from the local institutional review board, informed consent was obtained from 100 patients. Selection criteria included patients 1) who were 18 years and older; 2) who had an American Society of Anesthesiologists (ASA) physical status of I, II, or III; 3) who were undergoing shoulder surgery at the ambulatory surgery center; and 4) who preferred regional anesthesia for postoperative pain control. Patients provided informed consent for general anesthesia for the surgical procedure, as well as regional anesthesia for postoperative pain control. Patients were randomly allocated to one of two groups. The control group received a supraclavicular nerve block containing 30 mL of 0.25% bupivacaine plus 4 mL preservative-free From the Department of Anesthesiology, Baylor Scott and White Health, and the Texas A&M University System Health Science Center College of Medicine, Temple, Texas. Corresponding author: Christopher J. Burnett, MD, Scott and White Pain Clinic Pavilion, 2401 South 31st Street, MS 32-P2032, Temple, TX 76508 (e-mail: cburnett@sw.org). 307 saline (34 mL total). The study group received a supraclavicular nerve block containing 30 mL of 0.25% bupivacaine plus 4 mL of 1% tetracaine (34 mL total). The dose and amount of medications assigned were based on the routine practice at the institution’s ambulatory surgery center. A pharmacist filled empty vials with either 4 mL of 1% tetracaine or 4 mL of preservative-free saline and labeled the vials with a study identification number according to a randomization log. The pharmacist had no direct patient interaction or access to the collected data. To minimize the technique variability, only five attending physician anesthesiologists and two anesthesiology pain fellows performed the supraclavicular nerve blocks using a protocoled approach. Following placement of a peripheral intravenous line, each patient received 2 mg of midazolam intravenously prior to the performance of the supraclavicular nerve block. All nerve blocks were conducted utilizing a nerve-stimulating needle (Braun Stimuplex® A; Bethlehem, PA) and under direct sonographic guidance (Sonosite M-Turbo™ Ultrasound System; Bothell, WA) with a 10 to 13 MHz linear array transducer. The minimum amplitude when motor stimulation could no longer be identified ranged from 0.3 to 0.8 mA. After negative aspiration for blood, incremental doses of the local anesthetic solution were injected around nerve trunks consisting of the radial, ulnar, median, and musculocutaneous nerves. All images using the ultrasound machine were documented in the patient’s medical record. After completion of the regional anesthetic in the preoperative area, all patients received a general anesthetic for the surgical procedure. No limitations were placed on the intraoperative use of opioids and/or adjuncts that could be utilized. All intraoperative medications were documented and utilized in the analysis. Postoperatively, patient pain scores were assessed and managed according to routine practice with intravenous or oral medications in the postanesthesia care unit. No limitations were placed on the use of opioids and/or adjuncts in the postanesthesia care unit. All postanesthesia care unit medications were documented and utilized in the analysis. As per local standard practice, patients reporting pain in the shoulder in the postanesthesia care unit were evaluated by a physician and could receive a supplemental superficial cervical plexus nerve block if appropriate. The supplemental superficial cervical plexus nerve block was performed in a subset of patients (n = 23) who experienced significant postoperative pain along the superior and anterior aspect of the shoulder. These patients received a solution of 8 mL of 0.25% bupivacaine distributed along the superficial cervical plexus using a 25-gauge needle. At the time of discharge, patients received a pain diary to document their pain scores using an 11-point visual analog scale. Pain scores were documented every 2 hours while awake from the time of discharge to the end of postoperative day 2. Patients were instructed not to take pain medications until they started to feel pain in the operated shoulder. They were also instructed to document when and how many pain pills they consumed during this period. Patients were issued 308 a questionnaire to rate their satisfaction with the regional anesthetic for their postoperative pain control. Study personnel contacted patients via telephone on postoperative days 1 and 2 to verify their continued participation and to answer any questions. Subjects were required to return their completed pain diaries and questionnaires for inclusion in the final analysis of the study. It was determined that 74 subjects (37 in each group) would be required using a two-tailed sample t test to achieve 80% power to detect a 4-hour difference in duration of analgesia between the two groups. The estimation assumed a group standard deviation of 6 hours with an alpha of 0.05. One hundred subjects were enrolled to account for an expected 25% attrition rate. To compare the duration of analgesia, the Wilcoxon rank-sum test was chosen. Linear regression analysis was used to compare duration of analgesia when there were significant differences between the groups in other variables. Significant variables were adjusted as covariates in the regression models. To assess all the variables related to quality of analgesia, need for additional pain medications, side effects, and/or complications between the two groups, the two-tailed sample t test and Wilcoxon rank-sum test were used for mean comparisons and the chi-square test or Fisher’s exact test for proportion comparisons. A P value of <0.05 indicated statistical significance. SAS 9.2 (SAS Institute Inc.; Cary, NC) was used for data analysis. RESULTS Of the 100 patients initially enrolled, 84 completed and returned the pain diary and questionnaire. Two patients from the experimental group reported a failed block, as they had no analgesia or anesthesia immediately postoperatively. All results were similar when excluding the two patients who had a failed nerve block. Analysis of the demographic data revealed that the study group was significantly older than the control group (mean age, 54 vs 49 years; P = 0.04). No significant differences were detected with regard to gender, body mass index, or ASA classification scores (Table 1). There was no statistically significant difference between the groups with regard to preexisting diabetes mellitus or resultant neuropathy of the operative extremity. Preoperative pain score was reported on an 11-point visual analog scale with an average score of 3 out of 10 for both groups. No significant difference was noted in the preoperative consumption of opioids, neuropathic medications, or daily nonsteroidal antiinflammatory use between the two groups. The surgical approach (arthroscopic vs open) and the different types of surgical repairs and/or procedures were not significantly different between the two groups (Table 2). Total opioid and adjunctive pain medications administered during the intraoperative and postoperative period were similar in both groups, with no significant differences (Tables 2 and 3). Supplemental superficial cervical plexus blocks were provided for 27% of all patients: 29% in the control group and 26% in the study group (P = 0.80) (Table 3). Visual analog pain scores at the time of discharge were similarly low (1 out of 10) for both groups. There were no significant Baylor University Medical Center Proceedings Volume 28, Number 3 Table 1. Demographics and preoperative data Saline (N = 42) Variable Patient age (years), mean ± SD Gender: Female Body mass index (kg/m2), mean ± SD ASA class I II III Preexisting neuropathy Preexisting diabetes mellitus Prenerve block pain score, mean ± SD Premedication with midazolam Preop opioids: pills daily, mean ± SD Preop neuropathics: pills daily, mean ± SD Preop NSAIDS: pills daily, mean ± SD Tetracaine (N = 42) Total (N = 84) P value 48.7 ± 13.8 54.1 ± 15.4 51.4 ± 14.8 0.04† 16 (38%) 19 (45%) 35 (42%) 0.51‡ 30.2 ± 5.7 30.6 ± 5.7 30.4 ± 5.7 0.74† 0.89* 4 (10%) 4 (10%) 8 (10%) 26 (62%) 23 (55%) 49 (58%) 12 (29%) 15 (36%) 27 (32%) 6 (14%) 9 (21%) 15 (18%) 0.39‡ 8 (19%) 10 (24%) 18 (21%) 0.59‡ 0.76† 3.2 ± 2.9 3.0 ± 2.9 3.1 ± 2.9 42 (100%) 42 (100%) 84 (100%) NA 0.50† 3.5 ± 2.5 4.5 ± 3.2 4.1 ± 3.0 0.49† 2.3 ± 3.2 2.8 ± 1.6 2.7 ± 1.9 0.98† 2.2 ± 1.9 2.0 ± 1.4 2.1 ± 1.7 Fisher’s exact test was used. rank-sum test was used. ‡ Chi-square test was used. ASA indicates American Society of Anesthesiologists; NSAIDs, nonsteroidal antiinflammatory agents. † Wilcoxon Table 2. Surgical and intraoperative data Variable Surgical approach Arthroscopic Open Major surgical repair type Labral reconstructions Rotator cuff repair Both Other Additional procedures: shoulder Acromioplasty Coracoplasty Debridement Subacromial decompression None Additional procedures: clavicle Distal clavicle excision None Additional procedures: biceps Biceps tenodesis Biceps tenotomy None Total narcotic dose and adjuncts during surgery Intraop fentanyl (mcg), mean ± SD Intraop ketorolac (mg), mean ± SD * Fisher’s exact test was used. rank-sum test was used. ‡ Chi-square test was used. † Wilcoxon July 2015 Saline (N = 42) Tetracaine (N = 42) Total (N = 84) 31 (74%) 11 (26%) 33 (79%) 9 (21%) 64 (76%) 20 (24%) P value 0.61‡ 0.67* 13 (31%) 23 (55%) 2 (5%) 4 (10%) 8 (19%) 26 (62%) 3 (7%) 5 (12%) 21 (25%) 49 (58%) 5 (6%) 9 (11%) 0.37‡ 11 (26%) 1 (2%) 11 (26%) 7 (17%) 12 (29%) 5 (12%) 4 (10%) 13 (31%) 7 (17%) 13 (31%) 16 (19%) 5 (6%) 24 (29%) 14 (17%) 25 (30%) 1.00‡ 11 (26%) 31 (74%) 11 (26%) 31 (74%) 22 (26%) 62 (74%) 1.00* 2 (5%) 4 (10%) 36 (86%) 3 (7%) 4 (10%) 35 (83%) 103 ± 52 12 ± 16 99 ± 48 12 ± 15 5 (6%) 8 (10%) 71 (85%) 101 ± 50 0.62† 12 ± 15 1.00† differences in the average surgery time or in the average time to discharge home (Table 3). Patient satisfaction with the nerve block was favorable, with 90% of all patients stating they would undergo the same nerve block for any subsequent surgeries and would recommend the nerve block to a family member. There were no patient reports of permanent paresthesia from the nerve block. One patient from the study group reported dissatisfaction with temporary paresthesia from a dense nerve block on postoperative day 1. This sensation resolved with the return of motor function after about 24 hours. One patient from the control group reported flushing and mild itching on postoperative day 2, which resolved with oral diphenhydramine. Among patients in the control group, 53% reported being awakened from sleep by pain on the first night home, while 37% from the study group reported the same (P = 0.33). Similarly, 55% of the control group and 70% of the study group reported pain that awakened them from sleep on the second night home (P = 1.00). Average pain scores during the study time period were similar between both groups, with no significant difference identified (Figure 1a). The mean duration of analgesia was 16.6 hours for the control group and 17.1 hours for the study group (P = 0.69). The time to return of motor function was 21 hours in both groups (P = 0.88). The time to first pain pill was 11.6 hours in the control group and 10.5 hours in the study group (P = 0.76); Figure 1b shows the total number of pills taken in each group. DISCUSSION There is an ongoing search to identify adjunct medications to add to local anesthetics in order to prolong the anesthetic and analgesic effect to improve postoperative pain experiences. Reviews of additives to local anesthetics for peripheral nerve blocks provide insight on the efficacy of these additives along with their potential safety risks and neurotoxic effects (20, 21). Few studies have added the longacting amino ester tetracaine to a long-acting amino amide such as bupivacaine to prolong anesthesia and analgesia. The purpose of this study was to identify differences in duration of analgesia of supraclavicular nerve blocks with the addition of tetracaine. No significant difference was identified in the duration of postoperative analgesia with the addition of 1% tetracaine to 0.25% bupivacaine in supraclavicular nerve blocks. There were no significant Effect of adding tetracaine to bupivacaine on duration of analgesia in supraclavicular brachial plexus nerve blocks 309 Table 3. Postoperative data Variable Saline (N = 42) Tetracaine (N = 42) Total narcotic dose and adjuncts postoperatively Hydromorphone (mg), mean ± SD 0.7 ± 0.6 0.6 ± 0.7 Acetaminophen (mg), mean ± SD 386 ± 296 356 ± 307 No 30 (71%) 31 (74%) Yes 12 (29%) 11 (26%) Pain score at discharge, mean ± SD 1.1 ± 1.6 1.3 ± 1.9 Average surgery time (hours), mean ± SD 1.2 ± 0.9 1.4 ± 0.9 Average time in PACU (hours), mean ± SD 1.5 ± 0.6 1.5 ± 0.5 Supplemental superficial cervical plexus block *Fisher’s exact test was used. †Wilcoxon rank-sum test was used. ‡Chi-square test was used. PACU indicates postanesthesia care unit. differences in postoperative pain medication intake, pain scores, or complications between the two groups either. The safety of utilizing tetracaine in peripheral nerve blockade was a theoretical concern based on prior literature. Previous animal studies have shown neurotoxicity from the intrathecal administration of tetracaine (22, 23). However, there was minimal toxicity when ≤1% tetracaine was administered (23). Subsequent animal studies have shown similar neurotoxicity a with intrathecal administration of lidocaine, bupivacaine, and ropivacaine (24). Kitawaga et al reported that the mechanism of action is Total P hypothesized to be secondary to the detergent(N = 84) value like properties of the local anesthetics (25). These were all animal studies focused on intra0.6 ± 0.6 0.49† thecal administration of the local anesthetics. 369 ± 298 0.80† No studies have shown any clinically relevant 0.81‡ neurological sequelae from intrathecal or peripherally administered tetracaine in humans. 61 (73%) Leonard et al reported that intrathecal admin23 (27%) istration of tetracaine produced a longer and † 1.2 ± 1.7 0.62 denser motor blockade (40–50 minutes) than 1.3 ± 0.9 0.33 intrathecal bupivacaine (26). In this study, 1.5 ± 0.5 0.73 no persistent paresthesias, prolonged block, or other neurological sequelae were observed or reported. Limitations of this study include a relatively small sample size in conjunction with the inability to directly observe patients following discharge home. Neurologic exams were not performed on these patients at the time of discharge. Return of motor function was determined by the patient reporting the ability to make a full fist. Furthermore, the study was limited by the subjective nature of patients’ self-reporting their pain scores. An additional confounding variable was the timing of the first onset of postoperative pain. The average time of first pain was reported between 16 and 17 hours after placement of the nerve block, and most of these outpatient cases were performed between 7:30 am and 4:00 pm. Consequently, many patients would have experienced first pain during the late night or early morning hours, making it difficult to ascertain the exact time of the onset of this pain. Additionally, patients were instructed to take pain medication only at the time of first pain; however, some patients likely took pain medication as a preemptive measure. Acknowledgments The investigators would like to thank Jared E. Anderson, MD, Rodney Lange, MD, Andrew L. Barker, MD, Adam M. Savage, MD, Juhee Song, PhD, and Ying Fang, MS, MPH, for their contributions to this study. This study was supported by funding from the Scott and White Office of Academic Research Development and the Department of Anesthesiology. b 1. Figure 1. (a) Mean pain scores and (b) total number of pain pills over 3 days. Blue = control group (saline; 42 patients); Red = experimental group (tetracaine; 42 patients). 310 Brown AR, Weiss R, Greenberg C, Flatow EL, Bigliani LU. Interscalene block for shoulder arthroscopy: comparison with general anesthesia. Arthroscopy 1993;9(3):295–300. 2. D’Alessio JG, Rosenblum M, Shea KP, Freitas DG. A retrospective comparison of interscalene block and general anesthesia for ambulatory surgery shoulder arthroscopy. Reg Anesth 1995;20(1):62–68. 3. Mariano ER, Chu LF, Peinado CR, Mazzei WJ. Anesthesia-controlled time and turnover time for ambulatory upper extremity surgery performed with regional versus general anesthesia. J Clin Anesth 2009;21(4):253–257. 4. Bourke DL, Furman WR. Improved postoperative analgesia with morphine added to axillary block solution. J Clin Anesth 1993;5(2): 114–117. Baylor University Medical Center Proceedings Volume 28, Number 3 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Candido KD, Franco CD, Khan MA, Winnie AP, Raja DS. Buprenorphine added to the local anesthetic for brachial plexus block to provide postoperative analgesia in outpatients. Reg Anesth Pain Med 2001;26(4):352–356. Gadsden J, Hadzic A, Gandhi K, Shariat A, Xu D, Maliakal T, Patel V. The effect of mixing 1.5% mepivacaine and 0.5% bupivacaine on duration of analgesia and latency of block onset in ultrasound-guided interscalene block. Anesth Analg 2011;112(2):471–476. Jarbo K, Batra YK, Panda NB. Brachial plexus block with midazolam and bupivacaine improves analgesia. Can J Anaesth 2005;52(8):822–826. Shrestha BR, Maharjan SK, Shrestha S, Gautam B, Thapa C, Thapa PB, Joshi MR. Comparative study between tramadol and dexamethasone as an admixture to bupivacaine in supraclavicular brachial plexus block. JNMA J Nepal Med Assoc 2007;46(168):158–164. Tandoc MN, Fan L, Kolesnikov S, Kruglov A, Nader ND. Adjuvant dexamethasone with bupivacaine prolongs the duration of interscalene block: a prospective randomized trial. J Anesth 2011;25(5):704–709. Vieira PA, Pulai I, Tsao GC, Manikantan P, Keller B, Connelly NR. Dexamethasone with bupivacaine increases duration of analgesia in ultrasound-guided interscalene brachial plexus blockade. Eur J Anaesthesiol 2010;27(3):285–288. Berry JS, Heindel L. Evaluation of lidocaine and tetracaine mixture in axillary brachial plexus block. AANA J 1999;67(4):329–334. Goto F, Ishizaki K, Yoshikawa D, Obata H, Arii H, Terada M. The long lasting effects of peripheral nerve blocks for trigeminal neuralgia using high concentration of tetracaine dissolved in bupivacaine. Pain 1999;79(1):101–103. Covino BG. Physiology and pharmacology of local anesthetic agents. Anesth Prog 1981;28(4):98–104. Pflug EA, Aasheim GM, Beck HA. Spinal anesthesia: bupivacaine versus tetracaine. Anesth Analg 1976;55(4):489–492. Van Gessel EF, Miege B, Forster A, Salvaj G, Fathi M, Gamulin Z. Comparison of hyperbaric solutions of bupivacaine and tetracaine during continuous spinal anaesthesia. Can J Anaesth 1992;39(4):323–329. July 2015 16. Moore DC. Pontocaine hydrochloride for brachial block analgesia; 150 cases. Anesthesiology 1948;9(3):281–284. 17. Moore DC. The use of pontocaine hydrochloride for nerve block and infiltration analgesia, therapeutic, and diagnostic blocks; 1004 cases. Anesthesiology 1950;11(1):65–75. 18. Radwan IA, Saito S, Goto F. High-concentration tetracaine for the management of trigeminal neuralgia: quantitative assessment of sensory function after peripheral nerve block. Clin J Pain 2001;17(4):323–326. 19. Moore DC, Bridenbaugh LD, Bridenbaugh PO, Tucker GT. Bupivacaine for peripheral nerve block: A comparison with mepivacaine, lidocaine, and tetracaine. Anesthesiology 1970;32(5):460–463. 20. Bailard NS, Ortiz J, Flores RA. Additives to local anesthetics for peripheral nerve blocks: Evidence, limitations, and recommendations. Am J Health Syst Pharm 2014;71(5):373–385. 21. Brummett CM, Hong EK, Janda AM, Amodeo FS, Lydic R. Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarizationactivated cation current. Anesthesiology 2011;115(4):836–843. 22. Saito S, Radwan I, Obata H, Takahashi K, Goto F. Direct neurotoxicity of tetracaine on growth cones and neurites of growing neurons in vitro. Anesthesiology 2001;95(3):726–733. 23. Takenami T, Yagishita S, Asato F, Hoka S. Neurotoxicity of intrathecally administered tetracaine commences at the posterior roots near entry into the spinal cord. Reg Anesth Pain Med 2000;25(4):372–379. 24. Yamashita A, Matsumoto M, Matsumoto S, Itoh M, Kawai K, Sakabe T. A comparison of the neurotoxic effects on the spinal cord of tetracaine, lidocaine, bupivacaine, and ropivacaine administered intrathecally in rabbits. Anesth Analg 2003;97(2):512–519. 25. Kitagawa N, Oda M, Totoki T. Possible mechanism of irreversible nerve injury caused by local anesthetics: detergent properties of local anesthetics and membrane disruption. Anesthesiology 2004;100(4):962–967. 26. Leonard M, Moore L, Algozzine R, Gregorino J, Giles B. Recovery times from subarachnoid blocks using bupivacaine hydrochloride and tetracaine hydrochloride with and without epinephrine. AANA J 1997;65(3):260–264. Effect of adding tetracaine to bupivacaine on duration of analgesia in supraclavicular brachial plexus nerve blocks 311 Comparison of documentation and evidence-based medicine use for non–ST-segment elevation myocardial infarction among cardiology, teaching, and nonteaching teams Austin Metting, MD, Daniel Binz, MD, Colleen Y. Colbert, PhD, Juhee Song, PhD, Chris Chiles, MD, and Curtis Mirkes, DO Non–ST-segment elevation myocardial infarctions (NSTEMI) are common and cause significant morbidity and mortality. Following evidence-based medicine (EBM) guidelines is one way to ensure that these patients are cared for appropriately. This pilot study examined data from patients with NSTEMI to assess both documentation quality and use of EBM across multiple teams. Medical records were reviewed for significant differences in documentation quality in areas including history and physical exam, treatment, and inpatient mortality. While total documentation quality and mortality were not significantly different between groups, cardiology teams adhered to evidence-based recommendations more often than other teams. L ack of proper documentation has been associated with poor patient outcomes. Cox et al found that documentation of cardiac risk factors was quite poor when reviewing history and physical documentation for patients hospitalized for myocardial infarction and congestive heart failure. It was even worse in the elderly and females (1). The absence of documented cardiovascular risk factors has led to higher mortality in non–ST-segment elevation myocardial infarctions (NSTEMI) (2). It was unknown locally how well physicians at Scott & White Memorial Hospital, part of the Baylor Scott & White Health system, document in these situations. This quality improvement study examined medical record documentation associated with three types of inpatient medicine treatment teams to determine if there were differences in documentation and use of evidence-based medicine (EBM) across provider teams. METHODS This study was approved by the institutional review board at Scott & White Healthcare. This was a retrospective chart review designed to examine the following questions: 1) In a comparison of cardiology, nonteaching, and teaching teams, which team scored higher in the quality of the medical record documentation and EBM use? 2) Does better physician documentation translate into a decrease in patient mortality at our institution? The study took place at Scott & White Memorial Hospital in Temple, Texas, a 636-bed hospital part of an integrated health care system in Central Texas. Medical records of patients aged 18 312 to 99 with a primary diagnosis of NSTEMI who were admitted to our teaching, nonteaching, or cardiology teams between January 1, 2006, and December 31, 2009, were eligible for inclusion. Inclusion dates were chosen by the research team based upon when team structure, guidelines, and medical record systems were the most stable. After this timeframe, many changes in the institution occurred that did not allow for a long enough period of stability. Exclusion criteria included sepsis, demand infarction, NSTEMI as a secondary diagnosis, admission to a non–internal medicine team, and a troponin level <0.04 ng/mL. Based upon these criteria, 442 patients with a diagnosis of NSTEMI were initially included in this study. Teaching teams comprised internal medicine residents and a hospitalist attending; nonteaching teams comprised a midlevel provider and a hospitalist; and cardiology teams comprised residents, fellows, and cardiology attendings. As part of a mentored research grant at Scott & White/ Texas A&M Health Sciences Center College of Medicine, the first author, who was an internal medicine resident at the time, conducted a retrospective chart review to examine the quality of medical record documentation and use of EBM across teams that cared for NSTEMI patients. The authors compared teams’ use of EBM and documentation in the history, physical exam, lab findings, and tests performed. The purpose of this quality improvement project was to determine which team (cardiology, teaching, nonteaching inpatient team) needed the most improvement in documentation and EBM use. The history and physical checklist used in this study was based upon a 20-point rating scale developed by Dunlay et al (3). The scale was modified to include 25 items evaluating the history and physical, as well as five items designed to evaluate the use of EBM. The modified scale included an expanded history and physical checklist, with a maximum score of 30, compared From Scott & White Healthcare and Texas A&M Health Science Center College of Medicine. Dr. Binz is currently with the University of Oklahoma Health Sciences Center, Tulsa, Oklahoma; Dr. Colbert is currently with the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio; and Dr. Song is currently with MD Anderson Cancer Center, Houston, Texas. Corresponding author: Austin Metting, MD, Assistant Professor, Scott & White Healthcare, Texas A&M Health Science Center College of Medicine, 2401 South 31st Street, Temple, TX 76508 (e-mail: ametting@sw.org). Proc (Bayl Univ Med Cent) 2015;28(3):312–316 to 20 in the Dunlay study. The additional items covered were EBM, history of present illness, chief complaint, type and duration of pain, past medical history including lipids or previous cardiac imaging, family history, social history including drug and activity, and adding electrocardiogram and chest x-ray to studies. We excluded creatinine from labs and removed the problem list. Unlike the Dunlay study, partial credit for items was not given in this quality improvement study. Charts were reviewed and scored using the initial history and physical. Each chart was reviewed and the history and physical was evaluated using the 30-point checklist described above. Use of EBM was determined on a 5-point scale and inpatient mortality was recorded. Patient team data (teaching, nonteaching, cardiology) and demographics were also recorded for each patient. For patients who were admitted overnight by hospitalists, the team recorded was the team to which they were assigned. Specific criteria were used when examining each variable within the history and physical. For example, the chief complaint must have been listed specifically. A description of the type and duration of the complaint must have been listed, as well as any associated symptoms. The history of present illness was also inspected for mention of prior events like the current one. The medical history was reviewed for mention of current medical problems, recent lipid panels or hemoglobin A1C, or previous stress tests or angiograms or lack thereof. In the family history, the physician must have discussed the age at which a relative had a myocardial infarction, and other family history was counted as a separate item. Documentation of social history must have contained a positive or negative response to any drug, which includes alcohol, tobacco, and illegal drugs. A separate point was given if physical activity was included. Individual portions of the physical exam included vital signs, cardiovascular exam, respiratory exam, and peripheral vascular exam (peripheral pulses). For labs and studies, we concentrated on cardiac enzymes, electrocardiogram, chest x-ray, and hemoglobin. We also examined lipid, glucose, and hemoglobin A1C values. The assessment and plan were reviewed for a differential diagnosis, five specific evidence-based therapies for NSTEMI, and treatments of other comorbidities. We reviewed for the following five specific therapies: aspirin, beta-blockers, heparin or a heparinoid, statin on discharge, and glycoprotein IIb/IIIa inhibitors. One point each was given if these were mentioned in the assessment and plan by documenting use or reason for not using. Angiotensin-converting enzyme inhibitors were not included due to specific requirements about ejection fraction. Clopidogrel was not included on the checklist since eptifibatide was the preferred agent when providers anticipated invasive management during this time period. All variables, including 30 checklist items, overall checklist scores, and patient demographics, were summarized according to care team using descriptive statistics: mean for continuous variables and frequency for categorical variables. The three care teams were compared utilizing analysis of variance or KruskalWallis test for continuous variables. Chi-square test or Fisher’s exact test was used to compare groups of categorical variables. Pairwise comparisons utilized Bonferroni adjustment or Tukey’s July 2015 pairwise comparison when significant differences were detected. A P value of <0.05 was the threshold for statistical significance. SAS version 9.2 (SAS Institute Inc., Cary, NC) was used for data analysis. RESULTS Based upon a retrospective review of 442 charts of patients with a diagnosis of NSTEMI and a troponin level >0.04 ng/ mL, 252 (57.0%) were NSTEMI cases that had been treated by one of the three teams. Excluded were 91 cases (20.6%) with ST-elevation myocardial infarctions, 59 cases (12%) treated by teams not in the study, and 40 cases (9%) wherein myocardial infarction was a secondary diagnosis. Among patients with NSTEMI as a primary diagnosis (N = 252), 151 cases (60%) were treated by a cardiology team, 60 cases (24%) were treated by a teaching team, and 41 cases (16%) were treated by a nonteaching team. Based on pairwise comparisons, the nonteaching team had older patients than the cardiology team, who had significantly more male patients than the teaching team. There were no significant differences in other demographics across teams (Table 1). The three teams differed significantly on EBM use (P < 0.0001). Based on Bonferroni-adjusted pairwise comparisons, cardiology had a significantly higher mean EBM score than the other teams. No significant differences were detected among the three teams in total history and physical score (0–25) or the 30-item total score (Table 2, Figure 1). Significant differences were also found on eight of 30 history and physical checklist items (Table 3). Teams differed significantly on documentation of the following items: type and duration of pain; whether the pain had ever occurred before; social history of activity; chest x-ray results; whether lipids, glucose, or A1C were mentioned; differential diagnosis; treatment of other comorbidities; and the use of glycoprotein IIb/ IIIa inhibitors. No significant differences were detected across teams on other items. Social history of activity and differential diagnosis were found in only 45 subjects (18%), and those items were documented least often. Pulmonary exam was listed for all subjects in the cohort, and it was most often documented. DISCUSSION The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) initiative is being conducted at multiple institutions across the country and deals with the care of patients with unstable angina and NSTEMI. Several studies that referenced the CRUSADE database analyzed the quality of medical record documentation and EBM use within their own institutions (4). Dunlay et al utilized CRUSADE data to evaluate the quality of documentation, use of EBM, and mortality rates when comparing academic versus nonacademic hospitals, and cardiologists versus noncardiologists. Results showed that academic institutions and cardiologists scored higher than their counterparts, and these higher scores demonstrated better use of EBM Comparison of documentation and evidence-based medicine use for NSTEMI 313 adherence to guidelines drastically improved. One study showed that institutions that were accredited by the Society of Chest Pain Centers had better Cardiology Teaching Nonteaching Entire cohort P outcomes due to an improved use of EBM (9). Variable (N = 151) (N = 60) (N = 41) (N = 252) value* These studies inspired us to assess documentation b 0.01 Age (years), mean ± SD 64 ± 13 67 ± 13 72 ± 14 66 ± 14 and EBM use within our institution and compare Female 50 (33%) 32 (53%) 21 (51%) 103 (41%) 0.009a outcomes across care teams. Male 101 (67%) 28 (47%) 20 (49%) 149 (59%) Based upon the results of our study, cardiolRace ogy teams performed better than teaching and Black 16 (11%) 11 (18%) 5 (12%) 32 (13%) 0.63 nonteaching teams in giving glycoprotein IIb/IIIa inhibitors. However, teaching teams performed Hispanic 18 (12%) 9 (15%) 4 (10%) 31 (12%) better in discussing the results of chest x-rays and Unknown 3 (2%) 0 (0%) 0 3 (1%) evaluating other comorbidities in the assessment White 114 (76%) 40 (67%) 32 (78%) 186 (74%) and plan. Findings also indicated that nonteachComorbidity ing teams scored lower than cardiology teams in Diabetes mellitus 63 (42%) 27 (45%) 21 (51%) 111 (44%) 0.55 discussing the symptom type and duration, if the 106 (70%) 50 (83%) 33 (80%) 189 (75%) 0.09 Hypertensione symptoms had ever occurred before, and use of gly83 (55%) 26 (43%) 22 (54%) 131 (52%) 0.30 Coronary artery coprotein IIb/IIIa inhibitors. Nonteaching teams diseasee performed better than cardiology teams at documenting a differential diagnosis. The only difference Congestive heart 25 (17%) 11 (18%) 7 (17%) 43 (17%) 0.95 failure noted between teaching and nonteaching teams was the discussion of other comorbidities in the Hyperlipidemiae 92 (61%) 35 (58%) 22 (54%) 149 (59%) 0.70 assessment and plan. Sleep apnea 4 (3%) 4 (7%) 3 (7%) 11 (4%) 0.20 The present study design differed from previous Current smoker 44 (29%) 19 (32%) 7 (17%) 70 (28%) 0.23 studies in that we compared different teams within 3 (2%) 1 (2%) 0 4 (2%) 1.00 Current drug used the same hospital to determine if there were differInpatient death 3 (2%) 3 (5%) 0 6 (2%) 0.35 ences in quality of care and documentation. Also, aSignificant difference between Cardiology vs. Teaching. while CRUSADE studies included patients with unbSignificant difference between Cardiology vs. Nonteaching. stable angina, transient ST elevations, and NSTEMI cSignificant difference between Teaching vs. Nonteaching. who presented within 24 hours, our study included dCurrent drug use is defined as the use of any illegal drugs found in the history and physical. eHypertension, hyperlipidemia, and coronary artery disease are defined as a history of these diagnoses only NSTEMI whenever it presented. in their medical chart. Our results differed from other studies (10–12) in that we found no difference in medical record total scores or mortality among groups. Detecting differences in mortality between groups was difficult due to and improved mortality rates (3). Patel et al (5) and O’Brien the small total number of deaths (N = 6). While other studies et al (6) found that academic institutions were better at folhave found that teaching hospitals adhere to guidelines more lowing guidelines than nonacademic institutions, but they did frequently than nonteaching hospitals (5, 13, 14), our findings not examine specific history and physical exam documentation. indicated there was no significant difference between our teachBottorff et al (7) found that academic institutions were better at ing and nonteaching teams in EBM use. Overall documentation prescribing antiplatelet agents in the hospital than nonacademic did not seem to influence EBM use. The quality of documentainstitutions. Mehta et al (8) reported that once groups were in tion on medicine teams at our institution appears to be similar the CRUSADE trial and were notified of their own results, to that reported in the Dunlay study (3). In our facility, mean scores were 17.7/25 (70.8%) for the Table 2. Score comparison according to care team history and physical score and 21.8/30 (72.6%) for history and physical score with EBM added. Score Cardiology Teaching Nonteaching Entire cohort Dunlay et al (3) reported a mean score of 12.5/20 (mean ± SD) (N = 151) (N = 60) (N = 41) (N = 252) P value (62.5%). History and physical 17.7 ± 2.9 18.2 ± 2.6 17.2 ± 2.6 0.20 17.7 ± 2.8 Our findings appear to mirror those of Dunlay (25 items) et al (3) in that cardiology teams adhered to EBM Evidence-based <.0001a,b 4.3 ± 1.0 3.8 ± 1.1 3.7 ± 0.9 4.1 ± 1.0 guidelines significantly more than other teams. medicine (5 items) However, this difference appears to be due to the Total (30 items) 0.08 21.9 ± 3.4 22.0 ± 2.9 20.9 ± 2.8 21.8 ± 3.2 use of glycoprotein IIb/IIIa inhibitors, which was aSignificant difference between Cardiology vs. Teaching. also found in another study (7). The reason may be bSignificant difference between Cardiology vs. Nonteaching. lack of knowledge of this particular guideline or a cSignificant difference between Teaching vs. Nonteaching. discomfort in prescribing additional blood thinners. Table 1. Patient characteristics of the entire cohort and according to care team 314 Baylor University Medical Center Proceedings Volume 28, Number 3 a b Figure 1. Distribution of history and physical scores (a) with and (b) without the evidence-based medicine score added. Table 3. Inclusion of each item according to care team Variable Cardiology (N = 151) Teaching (N = 60) Nonteaching Entire cohort (N = 41) (N = 252) P value Chief complaint 119 (79%) 53 (88%) 29 (71%) 201 (80%) 0.09 Type and duration of pain 128 (85%) 46 (77%) 28 (68%) 202 (80%) 0.05b Associated symptoms 124 (82%) 51 (85%) 33 (80%) 208 (83%) 0.82 Previous occurrence 78 (52%) 22 (37%) 10 (24%) 110 (44%) 0.004b Past medical history 149 (99%) 59 (98%) 40 (98%) 248 (98%) 0.79 Recent lipids or A1C 27 (18%) 19 (32%) 11 (27%) 57 (23%) 0.08 Previous stress test or angiogram 52 (34%) 18 (30%) 9 (22%) 79 (31%) 0.30 Medications 149 (99%) 59 (98%) 40 (98%) 248 (98%) 0.79 Allergies 145 (96%) 55 (92%) 40 (98%) 240 (95%) 0.41 Family history of CAD 88 (58%) 34 (57%) 22 (54%) 144 (57%) 0.87 Other family history 79 (52%) 37 (62%) 20 (49%) 136 (54%) 0.36 145 (96%) 54 (90%) 38 (93%) 237 (94%) 0.23 34 (23%) 8 (13%) 3 (7%) 45 (18%) 147 (97%) 60 (100%) 40 (98%) 247 (98%) 0.55 Cardiovascular exam 150 (99%) 60 (100%) 41 (100%) 251 (100%) 1.00 Pulmonary exam 151 (100%) 60 (100%) 41 (100%) 252 (100%) – Peripheral vascular exam 115 (76%) 41 (68%) 28 (68%) 184 (73%) 0.39 Cardiac enzymes 146 (97%) 57 (95%) 41 (100%) 244 (97%) 0.45 Electrocardiogram 137 (91%) 55 (92%) 34 (83%) 226 (90%) 0.29 Chest x-ray 80 (53%) 43 (72%) 27 (66%) 150 (60%) 0.03a Hemoglobin 118 (78%) 52 (87%) 37 (90%) 207 (82%) 0.12 Lipids, glucose, or A1C 93 (62%) 47 (78%) 31 (76%) 171 (68%) 0.03a,b Differential diagnosis 19 (13%) 14 (23%) 12 (29%) 45 (18%) 0.02b 120 (79%) 59 (98%) 34 (83%) 213 (85%) 0.003a,c Social history of any drugs Social history of activity Vitals documented Other comorbidities and treatment TIMI score done 0.046a,b 75 (50%) 27 (45%) 15 (37%) 117 (46%) 0.32 Aspirin 140 (93%) 57 (95%) 36 (88%) 233 (92%) 0.44 Beta-blocker 141 (93%) 55 (92%) 37 (90%) 233 (92%) 0.71 Statin on discharge 140 (93%) 54 (90%) 40 (98%) 234 (93%) 0.40 Anticoagulation 133 (88%) 49 (82%) 31 (76%) 213 (85%) 0.12 90 (60%) 14 (23%) 9 (22%) 113 (45%) <.0001a,b Glycoprotein IIb/IIIa inhibitors aSignificant difference between Cardiology vs. Teaching. difference between Cardiology vs. Nonteaching. cSignificant difference between Teaching vs. Nonteaching. CAD indicates coronary artery disease; TIMI, Thrombolysis in Myocardial Infarction. bSignificant July 2015 We also found that patients treated by the cardiology team were significantly younger and more often male than those served by noncardiology teams, which is similar to demographics seen in other studies (5, 11, 12). Differences from the Dunlay study include that this retrospective study was performed at one site with a small population. Only NSTEMI patients confirmed with a troponin level >0.04 ng/mL were included in our study. The small sample size could inhibit our ability to detect differences among the teams. Another factor is that other teams in our facility had patients with NSTEMI, but these were excluded in order to compare only medicine teams. Our rating scale was based upon a scale used in the Dunlay study, but was not validated, which could be a limitation. In an attempt to improve the overall quality of patient care, medicine teams have been notified of the results, and we will reevaluate the documentation and use of EBM across provider teams. Since the onset of the study, the use of certain medications upon admission to the hospital for NSTEMI patients has changed. The frequency of glycoprotein IIb/IIIa inhibitor use decreased during the study period, and it will be removed from future checklists. We believe this may be related to results of the ACUITY Timing trial (15) and EARLY ACS study (16), as well as the increasing use of bivalirudin in the catheterization lab. Most NSTEMI patients at our institution undergo an early invasive strategy and now receive clopidogrel, ticagrelor, or prasugrel as a second antiplatelet agent. Use of Comparison of documentation and evidence-based medicine use for NSTEMI 315 these medications will be tracked in future studies. To enhance generalizability of findings, we hope to collaborate with other teaching institutions. Our quality improvement study demonstrated that cardiology teams at Scott & White/Texas A&M adhered to EBM guidelines more frequently than other medicine teams. Statistically significant differences in mortality rates or documentation were not found. This study appears to be only the second to examine the influence of documentation on patient care in myocardial infarction (3). A small improvement in mortality in a disease this common can translate to a large effect. Studies with an increased sample size may find a difference related to documentation alone. Recent events in our institution have included the integration of a new electronic health record and the merger between Scott & White and Baylor Health Care Systems. These two changes will allow for a larger study to be performed and likely an intervention including a standardized history and physical with order set to ensure appropriate use of EBM. 1. 2. 3. 4. 5. 6. 316 Cox JL, Zitner D, Courtney KD, MacDonald DL, Paterson G, Cochrane B, Mathers J, Merry H, Flowerdew G, Johnstone DE. Undocumented patient information: an impediment to quality of care. Am J Med 2003;114(3):211–216. Roe MT, Halabi AR, Mehta RH, Chen AY, Newby LK, Harrington RA, Smith SC Jr, Ohman EM, Gibler WB, Peterson ED. Documented traditional cardiovascular risk factors and mortality in non-ST-segment elevation myocardial infarction. Am Heart J 2007;153(4):507–514. Dunlay SM, Alexander KP, Melloni C, Kraschnewski JL, Liang L, Gibler WB, Roe MT, Ohman EM, Peterson ED. Medical records and quality of care in acute coronary syndromes: results from CRUSADE. Arch Intern Med 2008;168(15):1692–1698. Ohman EM, Roe MT, Smith SC Jr, Brindis RG, Christenson RH, Harrington RA, Gibler WB, Peterson ED; CRUSADE Investigators. Care of non-ST-segment elevation patients: insights from the CRUSADE national quality improvement initiative. Am Heart J 2004;148(5 Suppl):S34–S39. Patel MR, Chen AY, Roe MT, Ohman EM, Newby LK, Harrington RA, Smith SC Jr, Gibler WB, Calvin JE, Peterson ED. A comparison of acute coronary syndrome care at academic and nonacademic hospitals. Am J Med 2007;120(1):40–46. O’Brien E, Subherwal S, Roe MT, Holmes DN, Thomas L, Alexander KP, Wang TY, Peterson ED. Do patients treated at academic hospitals have better longitudinal outcomes after admission for non-ST-elevation myocardial infarction? Am Heart J 2014;167(5):762–769. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Bottorff MB, Nutescu EA, Spinler S. Antiplatelet therapy in patients with unstable angina and non-ST-segment-elevation myocardial infarction: findings from the CRUSADE national quality improvement initiative. Pharmacotherapy 2007;27(8):1145–1162. Mehta RH, Roe MT, Chen AY, Lytle BL, Pollack CV Jr, Brindis RG, Smith SC Jr, Harrington RA, Fintel D, Fraulo ES, Califf RM, Gibler WB, Ohman EM, Peterson ED. Recent trends in the care of patients with non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE initiative. Arch Intern Med 2006;166(18):2027–2034. Chandra A, Glickman SW, Ou FS, Peacock WF, McCord JK, Cairns CB, Peterson ED, Ohman EM, Gibler WB, Roe MT. An analysis of the Association of Society of Chest Pain Centers Accreditation to American College of Cardiology/American Heart Association non-ST-segment elevation myocardial infarction guideline adherence. Ann Emerg Med 2009;54(1):17–25. Allison JJ, Kiefe CI, Weissman NW, Person SD, Rousculp M, Canto JG, Bae S, Williams OD, Farmer R, Centor RM. Relationship of hospital teaching status with quality of care and mortality for Medicare patients with acute MI. JAMA 2000;284(10):1256–1262. Casale PN, Jones JL, Wolf FE, Pei Y, Eby LM. Patients treated by cardiologists have a lower in-hospital mortality for acute myocardial infarction. J Am Coll Cardiol 1998;32(4):885–889. Jollis JG, DeLong ER, Peterson ED, Muhlbaier LH, Fortin DF, Califf RM, Mark DB. Outcome of acute myocardial infarction according to the specialty of the admitting physician. N Engl J Med 1996;335(25):1880–1887. Peterson ED, Roe MT, Mulgund J, DeLong ER, Lytle BL, Brindis RG, Smith SC Jr, Pollack CV Jr, Newby LK, Harrington RA, Gibler WB, Ohman EM. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA 2006;295(16):1912–1920. Tricoci P, Peterson ED, Roe MT; CRUSADE Quality Improvement Initiative. Patterns of guideline adherence and care delivery for patients with unstable angina and non-ST-segment elevation myocardial infarction (from the CRUSADE Quality Improvement Initiative). Am J Cardiol 2006;98(12A):30Q–35Q. Stone GW, Bertrand ME, Moses JW, Ohman EM, Lincoff AM, Ware JH, Pocock SJ, McLaurin BT, Cox DA, Jafar MZ, Chandna H, Hartmann F, Leisch F, Strasser RH, Desaga M, Stuckey TD, Zelman RB, Lieber IH, Cohen DJ, Mehran R, White HD; ACUITY Investigators. Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY Timing trial. JAMA 2007;297(6):591–602. Giugliano RP, White JA, Bode C, Armstrong PW, Montalescot G, Lewis BS, van ‘t Hof A, Berdan LG, Lee KL, Strony JT, Hildemann S, Veltri E, Van de Werf F, Braunwald E, Harrington RA, Califf RM, Newby LK; EARLY ACS Investigators. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009;360(21):2176–2190. Baylor University Medical Center Proceedings Volume 28, Number 3 Assessment of leadership training needs of internal medicine residents at the Massachusetts General Hospital Traci N. Fraser, MD, Daniel M. Blumenthal, MD, MBA, Kenneth Bernard, MD, MBA, and Christiana Iyasere, MD, MBA Internal medicine (IM) physicians, including residents, assume both formal and informal leadership roles that significantly impact clinical and organizational outcomes. However, most internists lack formal leadership training. In 2013 and 2014, we surveyed all rising secondyear IM residents at a large northeastern academic medical center about their need for, and preferences regarding, leadership training. Fifty-five of 113 residents (49%) completed the survey. Forty-four residents (80% of respondents) reported a need for additional formal leadership training. A self-reported need for leadership training was not associated with respondents’ gender or previous leadership training and experience. Commonly cited leadership skill needs included “leading a team” (98% of residents), “confronting problem employees” (93%), “coaching and developing others” (93%), and “resolving interpersonal conflict” (84%). Respondents preferred to learn about leadership using multiple teaching modalities. Fifty residents (91%) preferred to have a physician teach them about leadership, while 19 (35%) wanted instruction from a hospital manager. IM residents may not receive adequate leadership development education during pregraduate and postgraduate training. IM residents may be more likely to benefit from leadership training interventions that are physician-led, multimodal, and occur during the second year of residency. These findings can help inform the design of effective leadership development programs for physician trainees. E ffective clinical leadership is critical to the success of cost control and quality improvement efforts (1). Although no universal definition of leadership exists, effective leaders articulate and build consensus around a vision and empower their team members (2). For physicians in the modern interdisciplinary practice environment, clinical leadership is crucial to health care quality and organizational performance (2). Evidence suggests that leadership training can improve leadership quality (3–5). However, medical schools and residency programs do not emphasize leadership training (2, 6). Moreover, we know little about the leadership development needs of internal medicine (IM) residents, and a paucity of quantitative data exists to guide the development of leadership training programs for them. We report the results of a leadership needs assessment survey of IM residents at an academic medical center. Proc (Bayl Univ Med Cent) 2015;28(3):317–320 METHODS The Massachusetts General Hospital is a 1057-bed teaching hospital affiliated with Harvard Medical School. The Department of Medicine residency program at Massachusetts General Hospital includes approximately 55 categorical, primary care, and medicine-pediatrics residents in each residency class. A Leadership Needs Assessment Survey (LNAS) was designed by IM residents at Massachusetts General Hospital to characterize residents’ need for and preferences regarding leadership training. Several survey questions were adapted from a previously published needs assessment survey of Dutch IM residents (7). Answers to LNAS questions were structured on a 5-point Likert scale, yes/no, “choose all that apply,” “choose only one,” or free-text format. The LNAS was reviewed by Dr. Eric Campbell, a professor of medicine at Harvard Medical School and an expert in survey design, for face and content validity and by two IM residents for clarity. The LNAS contained questions about resident demographics and leadership experience, perceived need for leadership training, and content and format of desired leadership training. In May 2013 and 2014, we administered surveys to rising junior residents in the categorical, primary care, and combined medicine-pediatrics programs. Participants were given 2 months to respond to the survey, and e-mail reminders were sent bimonthly. To motivate survey participation, participants received a $5 gift card for completing the LNAS. Survey responses were deidentified. We administered all surveys through RED Cap, a secure online data repository (REDCap; Vanderbilt University, Nashville, TN). Data were analyzed using JMP Pro 11 (SAS Inc.; Cary, NC) and Microsoft Excel (Microsoft Inc.; Redmond, WA). We summarized data by count and percentage for categorical outcomes and used the Fisher’s exact test to compare the perceived need for leadership training among subgroups of residents. This study was deemed exempt by our institution’s institutional review board. From the Department of Medicine (Fraser, Blumenthal, Iyasere), Division of Cardiology (Blumenthal), and Department of Emergency Medicine (Bernard), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Corresponding author: Traci Fraser, MD, Massachusetts General Hospital, 55 Fruit Street, GRB 740, Boston, MA 02114 (e-mail: tnfraser@partners.org). 317 Table 1. Characteristics of 55 survey participants at Massachusetts General Hospital in 2013 and 2014 Characteristic Gender Male Female Residency program Primary care Categorical Medicine-pediatrics Marital status Single Married Time offa Advanced degree MBA or MPH MPP PhD Military training Prior leadership trainingb Through employer During medical school Through college Through extracurricular organization Prior leadership experienceb During medical school During college Led a team Career plansc Basic science Clinical research Clinical fellowship General medical fellowship Health care administration Health policy fellowship Hospitalist Primary care Private industry Translational research Undecided 2013–14 2014–15 interns interns Total Characteristic 13 (48%) 16 (57%) 29 (53%) 14 (52%) 12 (43%) 26 (47%) I have a need for training in leadership competencies. 2013–14 interns 2014–15 interns Total 22 (81%) 22 (79%) 44 (80%) I would like training in the following competencies: 5 (19%) 7 (25%) 12 (22%) 20 (74%) 19 (68%) 39 (71%) 2 (7%) 2 (7%) 4 (7%) 18 (67%) 9 (33%) 13 (48%) 3 (11%) 0 3 (11%) 0 0 10 (37%) 3 (11%) 3 (11%) 5 (19%) 3 (11%) 22 (81%) 18 (67%) 19 (70%) 20 (74%) 17 (61%) 11 (39%) 16 (57%) 4 (14%) 0 3 (11%) 1 (4%) 0 9 (32%) 3 (11%) 3 (11%) 4 (14%) 4 (14%) 23 (82%) 21 (75%) 20 (71%) 22 (79%) 35 (64%) 20 (36%) 29 (53%) 7 (13%) 0 6 (11%) 1 (2%) 0 19 (35%) 6 (11%) 6 (11%) 9 (16%) 7 (13%) 45 (82%) 39 (71%) 39 (71%) 42 (76%) 4 (15%) 4 (14%) 8 (15%) 8 (30%) 6 (21%) 14 (25%) 19 (70%) 20 (71%) 39 (71%) 4 (15%) 7 (25%) 11 (20%) 2 (7%) 7 (25%) 9 (16%) 4 (15%) 9 (32%) 13 (24%) 6 (22%) 5 (18%) 11 (20%) 5 (19%) 5 (18%) 10 (18%) 1 (4%) 6 (21%) 6 (11%) 2 (7%) 5 (18%) 7 (13%) 3 (11%) 3 (11%) 6 (11%) a Time off indicates residents who took at least 1 year off between medical school and residency. b Respondents could check off more than one type of leadership training or experience. The numbers and percentages in “prior leadership training” and “prior leadership experience” rows correspond to the total number of respondents who reported any kind of leadership training or experience. c Respondents were asked to check off all potential career options that they planned to pursue, and many respondents checked more than one response. RESULTS Fifty-five of 113 eligible residents (49%) completed the survey. While 45 survey respondents (82%) had prior leadership experience, only 6 (11%) had received focused leader318 Table 2. Characteristics of leadership training desired by the 55 survey participants at Massachusetts General Hospital in 2013 and 2014 Leading with purpose 26 (96%) 25 (89%) 51 (93%) Problem solving 27 (100%) 25 (89%) 52 (95%) Coaching others 27 (100%) 24 (86%) 51 (93%) Leading a team 27 (100%) 27 (96%) 54 (98%) Confronting problem employees 25 (93%) 51 (93%) 26 (93%) If I were to go through leadership training, I would want the training to occur in the following location: Workplace 24 (89%) 28 (100%) 52 (95%) Medical school 1 (4%) 4 (14%) 5 (9%) University 4 (15%) 5 (18%) 9 (16%) If I were to go through leadership training during residency, I would want the training to occur over the following time period: Intern year Second year 8 (30%) 7 (25%) 15 (27%) 15 (56%) 16 (57%) 31 (56%) Third year 1 (4%) 2 (7%) 3 (5%) Any time during residency 2 (7%) 2 (7%) 4 (7%) If I were to go through leadership training, I would want to be taught by the following people: Physician 24 (89%) 26 (93%) 50 (91%) Business school professor 11 (41%) 20 (71%) 31 (56%) Hospital manager 6 (22%) 13 (46%) 19 (35%) Private industry leader 4 (15%) 13 (46%) 17 (31%) If I were to go through leadership training, I would want to be taught using the following methods: Health care case discussion 14 (52%) 19 (68%) 33 (60%) 9 (33%) 13 (46%) 22 (40%) 12 (44%) 10 (36%) 22 (40%) Large group discussion 9 (33%) 14 (50%) 23 (42%) Small group discussion 20 (74%) 22 (79%) 42 (76%) Simulation 15 (56%) 20 (71%) 35 (64%) Role play 6 (22%) 8 (29%) 14 (25%) Web training 7 (25%) 10 (36%) 17 (31%) Non–health care case discussion Lectures ship training in either medical school or residency (Table 1). Forty-eight residents (87%) somewhat or strongly agreed that the quality of clinical leadership impacts the care they deliver, and 44 survey participants (80%) agreed that there is a need for additional formal leadership training. Residents’ perceived need for additional formal leadership training did not vary by gender (P = 0.74), residency track (P = 0.48), receipt of prior leadership training (P = 0.73), or prior leadership experience (P = 0.59). Baylor University Medical Center Proceedings Volume 28, Number 3 Figure 1. Internal medicine residents’ self-reported leadership skill needs. Residents believed that they would benefit from additional training to develop a number of specific leadership skills, including leading a team (98% of residents), coaching and developing others (93%), confronting problem employees (93%), self-management (84%), resolving interpersonal conflict (84%), and understanding different leadership styles (84%) (Figure 1). Respondents preferred a multimodal approach to leadership training that included teaching methods such as small group discussion, case studies, and simulations (Table 2). Over 90% of respondents wanted leadership training to take place in an environment that was convenient to access from work and for sessions to be taught by a physician rather than a business school professor, hospital manager, or private industry leader. Fifty-six percent of residents preferred to go through leadership training during the second year of residency, while 15% wanted training to occur during internship. DISCUSSION To our knowledge, ours is the first published documentation of US IM residents’ leadership training needs. Most survey respondents agreed that the quality of clinical leadership impacts clinical care quality and affirmed a need for additional formal leadership training during residency. A review of the literature indicates that this need is not met by traditional teaching methods at our institution or by the majority of medical schools or residency programs around the country (2). Our results also indicated that leadership experiences and formal leadership training prior to entering residency may not obviate IM residents’ needs for leadership training and may not adequately prepare them for the leadership roles that they assume as practicing clinicians. For example, while IM residents in most training programs, including ours, lead clinical teams, 98% of residents surveyed reported a need for focused team leadership training. This result raises questions about whether July 2015 or not trainees have been equipped with the nonclinical (i.e., managerial) skills necessary to effectively lead clinical teams. Survey respondents may have been more interested in learning about leadership from physicians—rather than from business school professors (content experts) or managers of hospitals or private corporations—for a few reasons. First, physicians may better understand the particular leadership challenges faced by IM trainees and are more likely to have the clinical experience necessary to teach residents to apply leadership skills in clinical settings. Second, residents may feel more comfortable around, and learning from, other physicians. Our findings also have significant implications for the design of effective leadership development interventions. For example, while residents may prefer to learn about leadership from other physicians, many physicians lack experience teaching leadership, so curriculum development may require collaboration with content experts. In addition, IM residents appear to prefer that leadership training take place during the second year of residency and in an environment that is convenient to access from work. Successful implementation of leadership training programs therefore requires a commitment from residency program administrators in order to coordinate residents’ schedules and meeting locations. This analysis has a number of limitations. Our analysis may have been underpowered to identify associations between resident characteristics and specific leadership training needs. Selection bias may have been introduced by the low response rate, as residents who were more interested in leadership training may have been more likely to complete the survey. Moreover, our findings may not be generalizable to attending physicians, residents at other institutions, or specialties other than IM. While our survey was determined to have good content and face validity, it has not undergone assessments of criterion or content validity. Assessment of leadership training needs of internal medicine residents at the Massachusetts General Hospital 319 Bohmer RMJ. Designing Care. Boston: Harvard Business Press, 2009:22– 23, 173–174. 2. Blumenthal DM, Bernard K, Bohnen J, Bohmer R. Addressing the leadership gap in medicine: residents’ need for systematic leadership development training. Acad Med 2012;87(4):513–522. 3. Donnithorne LR. The West Point Way of Leadership: From Learning Principled Leadership to Practicing It. New York: Doubleday, 1993: 1–85. 4. Snook SA. Leader(ship) Development. Boston: Harvard Business School Publishing, 2008. 1. 5. 6. 7. Stoller JK, Rose M, Lee R, Dolgan C, Hoogwerf BJ. Teambuilding and leadership training in an internal medicine residency training program. J Gen Intern Med 2004;19(6):692–697. Ackerly DC, Sangvai DG, Udayakumar K, Shah BR, Kalman NS, Cho AH, Schulman KA, Fulkerson WJ Jr, Dzau VJ. Training the next generation of physician-executives: an innovative residency pathway in management and leadership. Acad Med 2011;86(5):575–579. Brouns JW, Berkenbosch L, Ploemen-Suijker FD, Heyligers I, Busari JO. Medical residents’ perceptions of the need for management education in the postgraduate curriculum: a preliminary study. Int J Med Educ 2010;1:76–82. Avocations Easter lily. Photo copyright © Rolando M. Solis, MD. Dr. Solis (e-mail: rmsolis@mac.com) is an interventional cardiologist with Baylor Scott and White Health and practices at Baylor Medical Center at Garland and The Heart Hospital Baylor Plano. 320 Baylor University Medical Center Proceedings Volume 28, Number 3 Abstracts from the First Annual Scholarly Day The Department of Medical Education at Baylor University Medical Center at Dallas hosted its first annual Scholarly Day to showcase the research efforts of medical students, residents, and fellows. Hania Wehbe-Janek, PhD, vice president for academic research integration for Baylor Scott and White Health Central Texas, shared the plenary session, “Building a Culture of Research at Academic Medical Centers: Impact on Medical Education and Recommended Practices.” Stuart Black, MD, John Fordtran, MD, Ronald C. Jones, MD, Michael A. Ramsay, MD, William C. Roberts, MD, and Hania Wehbe-Janek, PhD, served as judges of the posters and the oral presentations. Winners in each category were as follows: best fellow poster, “Diet pattern and cardiovascular disease among women with type 2 diabetes mellitus,” by Hyun Joon Shin, MD; best resident poster, “Oral squamous cell carcinoma: current concepts in imaging, staging, and fibular osteocutaneous free-flap reconstruction,” by R. Evans Heithaus, MD; best medical student poster, “Neuromyelitis optica,” by Elizabeth Coffee; and best oral presentation, “Transarterial chemoembolization with smaller beads: midterm clinical outcomes,” by R. Evans Heithaus, MD. Overall, participants in the inaugural event presented more than 40 posters and six oral presentations. This article reprints a selection of the abstracts. Cutaneous metastasis from hepatocellular carcinoma to the abdomen Jamil Alsahhar, MD (e-mail: JamilS.Alsahhar@baylorhealth.edu) Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third leading cause of cancer mortality worldwide. Patients with cirrhosis are at highest risk of developing this malignant disease. Metastases are most commonly seen in the lung, abdominal lymph nodes, and bones. Cutaneous metastases of HCC are uncommon. We report a case of a 54-year-old Caucasian man with a history of HCC treated with six rounds of transarterial chemoembolization followed by CyberKnife therapy, as well as a history of hepatitis C cirrhosis and diabetes mellitus, who presented with complaints of abdominal rash and pain. Examination revealed multiple erythematous, firm, well-circumscribed, dry, subcutaneous nodules surrounding the umbilicus and left abdomen. The nodules were tender to palpation. The patient was initially started on antibiotics, as the rash was concerning for cellulitis. A histopathological analysis of the nodules was consistent with high-grade adenocarcinoma of hepatobiliary origin. Electron beam therapy was utilized for palliation. HCC Proc (Bayl Univ Med Cent) 2015;28(3):321–324 often metastasizes to the lungs, abdominal lymph nodes, and bones. A literature review showed that cutaneous metastasis of HCC to the abdomen is rare, with most cases occurring at sites of previous biliary drains or biopsies. Cutaneous nodules presenting in patients with HCC or hepatobiliary malignancies should be biopsied to assess for possible metastases. Formalized resident training in code blue execution in a simulation lab improves immediate post-code survival Adan Mora Jr., MD, Benjamin Bijas, MD, Britton Smialek, MD, Bradley Christensen,* Jennifer Duewall, MD, and Cristie Columbus, MD (*e-mail: christensen@medicine.tamhsc.edu) Although residents complete advance cardiac life support (ACLS) training, they rarely receive formal instruction in the practical elements of leading and executing a code blue in a hospital setting. This study tested whether code simulation could facilitate residents’ formal training and improve code blue execution and postcode outcomes. Internal medicine residents at Baylor University Medical Center were trained for a 10-month period in a simulation lab on a 3G version SimMan. Residents were exposed to progressively more challenging arrhythmias and code scenarios in which ACLS was implemented and were observed by internal medicine and critical care faculty. The hospital’s code blue data for a 12-month historical period were then compared with the 10-month intervention period during which simulation training was implemented. There were 107 codes (an average of 8.9 per month) during the historical control period, with immediate postcode survival noted in 72 codes (67.3%), and 180 codes (an average of 16.4 per month) during the intervention period, with immediate postcode survival noted in 128 codes (71.1%). The hospital census during the 22-month study period was stable. Twenty-five patients (23.4%) survived to discharge in the control period, compared with 40 patients (22.2%) in the intervention period (P = .82; NS). While formal resident training in code execution in a simulation lab may improve immediate postcode survival in hospitalized patients, the trend seen in immediate postcode survival did not translate to discharge. This may be a result of improved ACLS execution of patients in whom successful resuscitation would not have previously been achieved. Further study is needed to determine whether or not the observed trend in immediate postcode survival is significant. 321 Neuromyelitis optica heralded by intractable hiccups, nausea, and vomiting Elizabeth Coffee* and Chaouki Khoury, MD (*e-mail: coffee@medicine. tamhsc.edu) A 19-year-old woman presented to the emergency department with vertigo, dysphonia, dysphagia, right tongue deviation, left hemiataxia, left hemiparesis, and vertical oscillopsia. Upon further questioning, it was revealed that the patient had experienced intractable hiccups, nausea, and vomiting (IHN) 3 weeks earlier that was treated as an acute gastroenteritis. She then developed wheezing, which was treated as reactive airways disease, and progressed to the previously listed symptoms. On admission she was found to have a single right dorsal medullary lesion on magnetic resonance imaging (MRI) and was later determined to be seropositive for aquaporin-4 antibody. Thus, a diagnosis of neuromyelitis optica (NMO) was made. NMO is a rare inflammatory demyelinating disease of the central nervous system. Current diagnostic criteria for NMO require both optic neuritis and acute myelitis and at least two of the following: contiguous spinal cord lesion, MRI that does not meet criteria for multiple sclerosis, and seropositive NMO IgG. However, IHN is increasingly recognized as an early presentation of NMO that distinguishes it from multiple sclerosis. This distinction is crucial in order to avoid potentially harmful treatments for patients with NMO mistaken for multiple sclerosis. This report suggests that an indepth assessment of IHN, including a brain MRI, is needed for a prompt and accurate diagnosis of NMO. Continuous renal replacement therapy to treat severe metformin-induced lactic acidosis Jeffrey Klein, MD,* and Harold Szerlip, MD (*e-mail: Jeffrey.Klein@ baylorhealth.edu) Chronic metformin ingestion rarely causes lactic acidosis, but the risk is increased in chronic kidney disease. We present a case of severe lactic acidosis in a patient with diabetes treated with metformin, complicated by acute on chronic renal failure. A 54-year-old African American man with hypertension, insulindependent diabetes mellitus, chronic kidney disease (serum creatinine 1.5 mg/dL), and bilateral above-the-knee amputations presented to the emergency department with a 3-day history of lethargy and pruritus. The patient was taking insulin, simvastatin, and metformin (500 mg twice a day). Initial laboratory evaluation revealed leukocytosis (11,000/mm3) and severe renal failure (blood urea nitrogen 89 mg/dL; creatinine, 10.2 mg/dL), as well as a potassium level of 6.2 mmol/L, anion gap of 24, and glucose of 198 mg/dL. His lactate was 11 mmol/L with an arterial blood gas of pH 6.5 and CO2 <5. Since there was no clear source of infection, suspicion was raised for metformin-associated lactic acidosis (MALA). The patient required emergent hemodialysis due to profound metabolic acidosis and electrocardiographic changes. Marked hypotension ensued within minutes on conventional hemodialysis and required dual vasopressor support. After 3.5 hours of hemodialysis, his lactate level was 17.5 mmol/L, and continuous venovenous hemodialysis (CVVHD) was initiated for ongoing clearance of lactatemia and metformin. Dialysate 322 ran at 30 mL/kg/h with bicarbonate 35 mEq/L, and vasopressor support was weaned. His lactate reduced to 3.2 mmol/L after 24 hours of CVVHD. Ultrafiltration increased to 250 mL/h on the second day of CVVHD and was transitioned off after 4 days. Two additional intermittent conventional hemodialysis sessions were required. His creatinine was 2.3 mg/dL upon discharge and 1.4 two weeks later. His metformin level was 38 mcg/mL (therapeutic level 1–2) upon admission and 8.6 mcg/mL after 10 hours of continuous replacement therapy. Our patient had findings consistent with MALA. Continuous renal replacement therapy effectively cleared both lactate and metformin. Early initiation of continuous renal replacement therapy should be considered in the setting of suspected severe MALA. Acute coronary syndrome and androgenic anabolic steroids Rosemary Nustas, MD,* and Stuart Lander, MD (*e-mail: Rosemary.Nustas@ baylorhealth.edu) Many side effects of androgenic anabolic steroids (AAS) are well reported. This report highlights the cardiovascular consequences of abusing AAS on healthy adults and presents the effect of a proper medical intervention. A 55-year-old man who was an active body builder for over 20 years presented to a local emergency department with severe chest pain that started during his routine gym workout. He was found to have marked ST segment elevations in the inferior leads and was transferred to our center for urgent cardiac catheterization. En route, he received aspirin, heparin, and clopidogrel. His history was significant for controlled hypertension but no previous angina symptoms or family history of cardiac disease. He never consumed alcohol or used tobacco. He was on a high-protein diet and performed regular endurance exercise to participate in weight-lifting tournaments. Upon further questioning, he revealed consistent use of injectable testosterone derivatives for performance enhancement. His physical exam was remarkable for a generalized muscular appearance, baldness, and small testicular size. The rest of his exam was unremarkable. Laboratory results showed very low high-density lipoprotein and slightly elevated low-density lipoprotein. Echocardiogram demonstrated depressed systolic function. Percutaneous coronary intervention revealed multiple lesions and stenosis, necessitating stent placement in the right coronary artery. The patient tolerated the procedure and remained symptom-free. He was discharged the next day on dual antiplatelet therapy, appropriate medications, and a follow-up appointment after intensive counseling on abstaining from further steroid use. A follow-up echocardiogram at 3 months showed improved left ventricular function. This case illustrates that the widely used AAS are becoming a public health issue, calling for increased awareness of the evidence implicating their life-threatening dyslipidemia and cardiovascular effects. A rapidly fatal case of acute myeloid leukemia Jacque Rampy, MD (e-mail: Jacqueline.Rampy@baylorhealth.edu) Acute myeloid leukemia (AML) is the most common acute leukemia in adults. This case describes a patient who presented with newly diagnosed AML with hyperleukocytosis and shortness of breath. A 55-year-old Caucasian woman with a past medical history Baylor University Medical Center Proceedings Volume 28, Number 3 of multiple deep vein thromboses and pulmonary embolisms dating back to 1996 was transferred to Baylor University Medical Center via air ambulance with newly diagnosed acute leukemia. One week prior to admission, she presented to her primary care physician with a painful and swollen left leg and was told all of her labs were “normal” and no further testing was performed. Two days prior to admission, she developed severe dyspnea. Computed tomographic angiogram of the chest at an outside hospital showed bilateral emboli in the proximal pulmonary arteries, and Doppler ultrasound showed deep vein thromboses in the bilateral lower extremities. Laboratory tests showed a white blood cell count of 190,000/μL with 91% blasts. Heparin was started, and she was transferred to Baylor Dallas. She was admitted with disseminated intravascular coagulation and bilateral pulmonary embolisms and the plan was to start hydroxyurea and stabilize her for leukapheresis. Shortly after admission, she became acutely short of breath and required emergent intubation. She then suffered bradycardiac arrest and code blue was called. Throughout the code she had pulseless electrical activity, with only brief periods of a thready pulse. Venous blood gas showed an oxygen partial pressure of 28 and saturation of 19. The patient died shortly after. An autopsy revealed deep leg vein thrombosis and massive pulmonary thromboembolism as well as extensive leukemic infiltrates in the lungs, kidneys, peripheral nerves, and muscles. In conclusion, leukostasis (symptomatic hyperleukocytosis) is a medical emergency with a high mortality rate within the first week of presentation if not treated. Treatment includes cytoreduction through the use of chemotherapy and leukapheresis. Is there a relationship between psoas impingement and increased trochanteric retroversion? Manoj Reddy,* Juan Gomez-Hoyos, Ricardo Schroder, Ian J. Palmer, Anthony Khoury, and Hal David Martin, DO (*e-mail: mreddy@medicine.tamhsc.edu) Iliopsoas impingement refers to an anterior labral injury due to the direct contact by the iliopsoas tendon at the nonarticular side. Although a tight psoas is a common finding during hip arthroscopy in patients with symptomatic psoas impingement, the cause of the tightening has not yet been explored. Previous studies of iliopsoas impingement have found inferior clinical outcomes in patients with increased femoral neck version (FNV); however, lesser trochanteric version (LTV) was not assessed. This study assessed the amount of LTV in patients with symptomatic psoas impingement and compared that to patients with asymptomatic hips. The FNV and LTV were evaluated on axial magnetic resonance imaging, as well as the angle between LTV and FNV. Data from 12 symptomatic patients and 250 asymptomatic patients were analyzed. The mean, range, and standard deviations were calculated. Independent t tests were used to determine differences between groups. The lesser trochanteric retroversion was significantly increased in patients with psoas impingement compared with asymptomatic patients in degrees (–31.1 ± 6.5 vs –24.2 ± 11.5, P < 0.05). The FNV (9 ± 8.8 vs 14.1 ± 10.7, P > 0.05) and the angle between FNV and LTV (40.2 ± 9.7 vs 38.3 ± 9.6, P > 0.05) were not significantly different between groups. In conclusion, the lesser trochanteric retroversion is significantly increased in patients with psoas impingement compared with patients with asymptomatic hips. July 2015 Beyond Typhoid Mary: the sophistication of Salmonella typhi Charis Santini,* Curtis R, Mirkes, DO, and Cedric Spak, MD (*e-mail: santini@ medicine.tamhsc.edu) As resistant strains of Salmonella typhi are increasing worldwide, a clinician in the United States may find it more difficult to treat typhoid fever in returning travelers. This case demonstrates the variability within which typhoid fever can present. A 20-yearold formerly healthy man presented with an 18-day history of intermittent fever and myalgia. The fever spiked to approximately 104°F in the late afternoons. Associated symptoms included chills, headache, weakness, nausea/vomiting, and occasional loose stools. The patient returned from Bangladesh 5 days prior to symptom onset. He denied contact with contaminated food, sick contacts, bloody diarrhea, constipation, or rashes. His laboratory results were significant for a white blood cell count of 4.7 × 109/L with 37% bands, thrombocytopenia (109 × 109/L), hyponatremia (129 mmol/L), and elevated transaminases (aspartate transaminase [AST] and alanine transaminase [ALT], 157 and 138 U/L). Cultures were obtained and the patient was placed empirically on vancomycin and piperacillin/tazobactam. Serum cultures were positive after 48 h for gram-negative rods. After 3 days of treatment, the patient’s symptoms did not improve. His liver transaminases continued to increase to a maximum AST/ALT of 301/245 U/L. Also, his hemoglobin and hematocrit levels dropped, with laboratory values consistent with intravascular hemolysis. The patient improved on ceftriaxone. Culture growth further revealed S. typhi group D with intermediate sensitivity to ciprofloxacin. He was discharged on oral antibiotics. This case of typhoid fever was not the straightforward picture of enteritis, bloody diarrhea/constipation, and salmon-colored macules. Once typhoid fever is diagnosed, a new difficulty arises with the changing resistance patterns; selecting appropriate antibiotic therapy is of the utmost importance. Fluoroquinolones for 7 to 10 days is the recommended treatment. However, in certain regions, including South Asia, fluoroquinolone resistance is becoming more prevalent. Therefore, in cases of known fluoroquinolone resistance, recommendations promote the use of a third-generation cephalosporin or azithromycin. Delaying appropriate therapy increases the risk of relapse and can result in a mortality rate of 10% to 20%. Acute enlargement and dysfunction of the exocrine glands of the head Avery Smith, MD,* and Alan Hise (*e-mail: Avery.Smith@baylorhealth.edu) We present a case of immunoglobulin G4-related disease (IgG4-RD), a recently recognized syndrome. Diagnosis generally requires elevated serum IgG4 levels, biopsy-proven elevation in IgG4, and a rapid response to steroid treatment. A 23-yearold Ethiopian man presented with 2 weeks of facial swelling of his upper eyelids, submandibular area, and cheeks. He endorsed visual impairment, nasal stuffiness, dry mouth/eyes, and odynophagia. Laboratory values were normal except for eosinophilia. Magnetic resonance imaging of the head demonstrated significant bilateral lacrimal gland swelling and buccal lymphadenopathy. The patient began to have a sensation that his throat was “closing up” so was given high-dose intravenous dexamethasone. Abstracts from the First Annual Scholarly Day 323 Subsequently, he had dramatic improvement. A bilateral lacrimal gland biopsy showed many B and T lymphocytes mixed with eosinophils. The lymphocytes were prominently positive for IgG. Only 1% of the lymphocytes were positive for IgG4, but his serum IgG4 level was slightly elevated at 97 mg/dL. He was transitioned to oral prednisone. After completing the steroid taper, his facial features were normal, eosinophilia resolved, and he was asymptomatic. He has not had a relapse to date. Enlargement of the lacrimal and salivary glands, known as Mikulicz’s disease, was once considered a subtype of Sjögren syndrome. This disease has since been reclassified as falling within the IgG4-RD spectrum. This case had many features of IgG4-RD but did not meet strict diagnostic criteria. However, suspicion for IgG4-RD remains high based upon his presentation, response to treatment, and exclusion of other diagnoses. Antinuclear antibody and anti-Ro/SSA and anti-La/SSB antibodies were negative. The marked peripheral eosinophilia and prominent eosinophils in his lacrimal gland biopsy suggested an allergic etiology. However, serum IgE levels were normal. Thus, his peripheral and biopsy-proven eosinophilia was attributed to a reactive process secondary to the recruitment of T lymphocytes, a well-recognized feature of IgG4-RD. The patient’s dramatic response to dexamethasone and the eventual resolution of his dry eyes/mouth support IgG4-RD over Sjögren syndrome. Thus, it appears that intensive steroid treatment can markedly decrease peripheral and glandular IgG4 levels, and this may have accounted for his negative results. A rare case of recurrent focal myositis and an associated coagulopathy Avery Smith, MD,* and Carolyn Quan, MD (*e-mail: Avery.Smith@ baylorhealth.edu) Focal myositis is a rare disorder with less than 50 cases reported to date. It typically presents as localized swelling, pain, and skin discoloration over a muscle group of an extremity. We present a case of recurring focal myositis complicated by an autoimmune coagulopathy. A 74-year-old African American man presented to the emergency department with a 3-day history of right calf swelling, dark discoloration, and pain, which started abruptly without inciting trauma. He denied fever, chills, or night sweats, but did note a similar presentation 2 months earlier in his left upper extremity. Based on magnetic resonance imaging, myositis was diagnosed, and the patient was treated with antibiotics despite negative cultures. He improved but then returned with the right calf pain. Laboratory results showed markedly positive antinuclear antibody, positive anti-centromere antibody, and an elevated erythrocyte sedimentation rate/C-reactive protein. Surgical muscle biopsy showed necrosis and muscle regeneration but no infection, dermatomyositis, polymyositis, or inclusion body myositis. The procedure was complicated by significant bleeding. Studies showed an isolated prolongation of the partial thromboplastin time, which led to the diagnosis of a factor VIII inhibitor. 324 Electromyography performed to evaluate for subclinical weakness had unremarkable results. However, his myositis recurred at the electromyography insertion sites. He was then treated with high-dose prednisone, rituximab, and cyclophosphamide. He improved without further bleeding or recurrence of his myositis. This case is unique because the patient experienced recurrent focal myositis as well as the development of a rare autoimmune-driven coagulopathy. Heffner’s theory regarding micro-trauma as an inciting factor was supported by this patient’s recurrent myositis following the electromyography study. Focal myositis is an atypical, rheumatologic syndrome that can mimic infections of other rheumatologic entities. It is presumably secondary to an autoimmune response against a muscular antigen, but the specific antibody remains unknown, with negative myositis panels, antistriated muscle antibody, and paraneoplastic panel. Delayed treatment for herpes zoster resulting in disabling plexopathy in the immunosuppressed patient Anwar Y. Zaman, MD,* Sridevi Mukkamala, MD, and Matt Bayazitoglu, MD (*e-mail: Anwar.Zaman@baylorhealth.edu) Here we report two cases of adults on chronic immunosuppressive therapy who were diagnosed with herpes zoster and treated with oral steroids alone. Both patients developed focal weakness in the affected limb. A 63-year-old man on chronic immunosuppression after liver transplantation presented to his primary care physician with a left lower extremity vesicular rash and pain. He was initially started on oral steroids and within 5 weeks developed left lower extremity weakness with foot drop. He subsequently was admitted to the hospital and started on antiviral treatment. The second patient was a 66-yearold man with rheumatoid arthritis on chronic immunosuppression who presented to his primary care physician with a right thigh vesicular rash and pain. He was started on oral steroids and 1 month later developed progressive right lower extremity weakness. Nerve conduction studies and electromyography were performed on the patients more than a month after onset of symptoms. Each patient had electrodiagnostic evidence of lumbosacral plexopathy with significant motor denervations that matched clinical findings. Lumbosacral plexopathy with motor involvement occurring in the context of herpes zoster is rare and underrecognized. The patients each developed severe weakness with minimal recovery at 2-month follow-up. The patients did not receive antiviral treatment at the time of initial rash presentation. The delay in antiviral treatment may have contributed to dissemination of the infection and extensive motor involvement. In conclusion, patients on chronic immunosuppressive therapy can be at higher risk of developing plexopathy or polyradiculopathy secondary to herpes zoster. In this patient population, early disease recognition and treatment with antiviral medication may help prevent plexopathy and subsequent disability. Baylor University Medical Center Proceedings Volume 28, Number 3 Uses, limitations, and complications of endobronchial ultrasound Bilal A. Jalil, MD, Kazuhiro Yasufuku, MD, PhD, and Amir Maqbul Khan, MD, MSc Endobronchial ultrasound (EBUS) plays a pivotal role in the minimally invasive staging of non–small cell lung cancer. The role of EBUS is progressively expanding to include the evaluation of peribronchial lesions, pulmonary nodules, and other mediastinal abnormalities. Recently, EBUS has assisted in the diagnosis of many other disease entities, including malignancies and various infections such as tuberculosis and sarcoidosis. This article reviews the indications and contraindications of EBUS, with emphasis on the technique and complications encountered during the procedure. E ndobronchial ultrasound (EBUS) combines bronchoscopy with ultrasound to enhance the definition of mediastinal structures and aid in visualization of parabronchial anatomy, reducing biopsy sampling errors due to superior site selection for transbronchial sampling (1). Over the last two decades, EBUS has emerged as a highly effective and minimally invasive technique for sampling peribronchial, mediastinal, and lung masses for pathologic examination. EBUS may provide rapid on-site results with relatively less expertise and has a very safe profile. It has been shown to be significantly cost-effective compared with prior gold standard techniques (2). EBUS plays a role in the staging of non–small cell lung cancer (NSCLC) and the diagnostic evaluation of endobronchial lesions, peripheral pulmonary nodules, and mediastinal abnormalities (3, 4). Recently, use of EBUS has expanded for patients with sarcoidosis, tuberculosis, and lymphoma and in the workup of nonspecific mediastinal adenopathy (5–7). As chest computed tomography (CT) scans are being performed much more frequently than before, benign diseases and incidentalomas are being detected as well as early stage lung cancer (8). Benign diseases warrant the need for the least invasive technique of obtaining histologic diagnosis. For this reason, EBUS has become the staging tool of choice for mediastinal NSCLC and is currently being explored for many other disease entities. As medical diagnosis and therapy move towards less-invasive procedures that provide results equal or superior to those of more invasive procedures, additional uses of EBUS are emerging on a daily basis. EBUS can be used to characterize suspicious mucosal lesions, determine the extension of early lung cancer, and assess Proc (Bayl Univ Med Cent) 2015;28(3):325–330 the involvement of the tracheobronchial wall or mediastinum in cases of advanced malignancy. TECHNIQUE EBUS may be performed under conscious sedation or general anesthesia depending on the anticipated length of the procedure. Local anesthetic may be administered to minimize cough, and the flexible bronchoscope is advanced for an initial airway exam. Bronchial segments and subsegments are identified, secretions are suctioned, and 1% to 2% lidocaine is administered to further minimize cough. After initial airway examination, the flexible bronchoscope is removed and the EBUS bronchoscope is advanced. While EBUS is performed, the bronchoscopist simultaneously visualizes the ultrasonic and bronchoscopic views on display. EBUS can help differentiate normal parenchyma from malignant tissue by its sonographic appearance. The sonographic visualization of normal alveolar tissue is described as a “snowstorm” appearance (Figure 1). Figure 2a is a sonographic view of the peripheral pulmonary nodule visualized on the CT scan in Figure 2b. After sonographic confirmation of the biopsy site, the transbronchial needle aspiration (TBNA) needle is advanced through a 2.2 mm working channel on the bronchoscope (Figure 3a). This needle may be 21 or 22 gauge and can be advanced up to 40 mm. A stylet or wire is present in the needle at the time of insertion to clear tissue that may have collected while crossing the bronchial or tracheal wall. The distal end of the needle is grooved, rendering it hyperechoic and improving ultrasound visualization (Figure 3b). After the lymph node or tumor is punctured, the needle is connected to suction and excursions are made in the lymph node. Multiple punctures have been recommended to decrease sampling error. The samples obtained can either be analyzed on site by the use of rapid on-site evaluation (ROSE) or collected in saline or cell culture media. The application of ROSE has been shown to significantly lower the need for additional bronchoscopic proceFrom the Department of Pulmonary and Critical Care Medicine, Baylor Scott and White Medical Center, Waxahachie, Texas (Jalil, Khan), and Interventional Thoracic Surgery, University of Toronto, Canada (Yasufuku). Corresponding author: Amir Maqbul Khan, MD, MSc, 1328 West Highway 287 Bypass, Waxahachie, TX 75165 (e-mail: dramirkhan@yahoo.com). 325 tage of EBUS is the accessibility of stations 10R, 10L, 11R, and 11L, which are inaccessible by other invasive techniques (10). Endoscopic ultrasound (EUS) also provides access to 7, but in addition lymph node stations 8 and 9 can be accessed. EBUS may be performed safely in a single session alongside EUS (11, 12). Lymph node stations not accessible by EBUS are shown in Figure 4b. EBUS is preferred as a primary procedure when EUS is performed in the same session (13). INDICATIONS The role of diagnostic bronchoscopy has expanded with the introduction and rapid institution of ultrasound, giving the bronchologist vision beyond what the bronchoscope can see. EBUS was initially developed for the diagnosis and staging of NSCLC but is increasingly involved in nononcologic pulmonary disease states. The following are some of the indications and applications of EBUS. Figure 1. Endobronchial ultrasound of normal alveolar tissue described as a “snowstorm” appearance. dures and puncture number (9). ROSE is particularly beneficial when performing EBUS in the operating room with an expected need for further invasive exploration or surgical resection. Procedure length varies by the number of lymph node stations sampled. When EBUS is performed in the outpatient setting, patients can be discharged home after they regain their gag reflex. The anatomical lymph node stations that are accessible via EBUS are 2R, 2L, 3P, 4R, 4L and 7 (Figure 4a). A unique advana Diagnosis, staging, and restaging of lung cancer Mediastinoscopy has been the historic gold standard in lung cancer staging. Lung cancer staging has progressed from mediastinoscopy in the early 1950s to video-assisted thoracic surgery, video-assisted mediastinal lymphadenectomy, transcervical extended mediastinal lymphadenectomy, and TBNA (14). The introduction of EBUS improves the sensitivity and reliability of TBNA in the staging of lung cancer (1). Appropriate staging of lung cancer is of utmost importance before initiation of treatment. Computed tomography (CT) and positron emission tomography (PET) have been inconsistent at accurately staging the mediastinum (15). Identification of suspicious mediastinal metastases by CT or PET should always b Figure 2. (a) Imaging of a pulmonary nodule through endobronchial ultrasound, with a so-called “blizzard” appearance. (b) Axial CT of the lung nodule (arrow). 326 Baylor University Medical Center Proceedings Volume 28, Number 3 a c b Figure 3. Endobronchial ultrasound (EBUS) bronchoscope. (a) The inflated balloon over the ultrasound transducer and a protracted biopsy needle through the EBUS working channel. (b) An EBUS biopsy needle with dimples for better sonographic visualization (arrow). (c) Real-time visualization of EBUS transbronchial aspiration needle advancement into the lymph node. a b Figure 4. Anatomical depiction of lymph node stations (a) accessible by EBUS and (b) not accessible by EBUS. Reproduced with permission from the American College of Chest Physicians via the Copyright Clearance Center: Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111:1718–1723. July 2015 Uses, limitations, and complications of endobronchial ultrasound 327 be followed by histologic assessment of mediastinal and hilar lymph nodes for accurate staging. Minimally invasive modalities are preferred over more invasive modalities for the initial biopsy. However, sometimes more than one procedure will be necessary, particularly when initial tissue sampling provides inconclusive results or is insufficient for molecular characterization. Histologic diagnosis is prudent in the diagnosis of NSCLC, as is disease staging, as therapy depends on the stage. In the absence of obvious metastatic disease, it may be important to biopsy mediastinal lymph nodes to accurately determine node status. The 5-year survival rate of 16% for bronchogenic carcinoma with lymph node metastases is very low compared to the rate of 49% in lung cancer without lymph node involvement (16). Randomized trials have reported a low prevalence of metastatic disease in patients with suspected stage 1A NSCLC with peripheral tumors <3 cm. These patients may undergo primary tumor resection, and the need for preoperative mediastinal sampling is not well defined (17–20). Patients with suspected NSCLC stages IB, II, and III should undergo mediastinal sampling, the timing of which should be individualized according to patient characteristics and radiographic stage. EBUS-TBNA is the preferred first step for large, centrally located tumors and for suspicious nodal involvement in the mediastinum. The most recent American College of Chest Physicians guidelines on the management and treatment of lung cancer recommend EBUS as the initial step in the diagnostic staging of lung cancer (21). The European Society of Thoracic Surgeons also recommends EBUS as a first choice for mediastinal staging in patients with NSCLC (14). EBUS-TBNA has a reported high sensitivity to stage and diagnose NSCLC and is able to access more nodal stations than the prior gold standard, cervical mediastinoscopy (22). EBUS cannot sample all mediastinal lymph node stations and is usually combined with EUS for a more thorough and systematic sampling of the mediastinum. EBUS can access the anterosuperior mediastinum while EUS can access the posteroinferior mediastinum (23). Prior to the development of EBUS, mediastinoscopy was used to sample the mediastinum. Mediastinoscopy is an invasive procedure requiring general anesthesia, while EBUS can be performed as an outpatient procedure with conscious sedation and usually does not require postprocedure hospitalization. EBUS combined with EUS is essentially a less-invasive alternative to mediastinoscopy. The mediastinum is restaged after induction therapy in patients with stage III NSCLC, as those with persistent mediastinal involvement have a worse prognosis than those with proven mediastinal downstaging. In the absence of an experienced surgeon, it is technically challenging and difficult to restage the mediastinum with mediastinoscopy in patients who had undergone a prior mediastinoscopy, as tissue planes are obliterated by fibrosis. EBUS is less invasive, more accurate, and can be performed time and time again without the limitations that prevent mediastinal restaging by mediastinoscopy. EBUS-TBNA is highly specific and sensitive in restaging the mediastinum after neoadjuvant chemotherapy. 328 EBUS is also able to obtain adequate samples to run immunohistochemistry and DNA analysis on the tissue obtained. There is a need to further subclassify cancer by driving mutations. Anaplastic lymphoma tyrosine kinase (ALK) and c-ros oncogene 1 receptor kinase (ROS1) are examples that can be specifically treated with targeted agents. Flow-cytometric analysis, DNA point mutations, and RNA analysis can be run on tissue specimens obtained by EBUS sampling to help individualize therapy for lung cancer with genetically based chemotherapy regimens (24). Endobronchial lesions EBUS allows for diagnosis and treatment as well as surveillance follow-up of pathologic processes. It extends the endoscopist’s vision to allow evaluation of the tracheobronchial wall and parabronchial anatomy. Radiographically inapparent endobronchial lesions may be detected during bronchoscopy or by newer methods being developed to screen high-risk patients for lung cancer, such as autofluorescence bronchoscopy and confocal microscopic bronchoscopy (25, 26). EBUS has been shown to more accurately predict malignancy in endobronchial lesions. In a trial of 105 patients with central thoracic malignancies, EBUS was superior to chest CT in differentiating tumor invasion of the airway from tumor compression (25). EBUS not only provides a more accurate classification of mucosal lesions, but also contributes to therapy decisions (16). Mediastinal and hilar lymphadenopathy The most common indication for hilar or mediastinal lymph node sampling is as previously described: to assess lymph node involvement in lung cancer. There are many infectious, noninfectious, and malignant causes of hilar and mediastinal lymphadenopathy, such as sarcoidosis, reactive lymphadenopathy, and tuberculosis. Metastatic primary cancers, thymomas, and lymphoma are some malignant causes of hilar and mediastinal lymphadenopathy. The incidence of sarcoidosis in the United States is high, and sarcoidosis-related mortality is increasing (27, 28). Currently, conventional bronchoscopy is regarded as the standard to demonstrate noncaseating granulomas in patients with suspected sarcoidosis. EBUS-TBNA has been used in patients with suspected sarcoidosis to obtain tissue diagnosis as well as exclude other pathologies such as tuberculosis and malignancy. Studies have shown a higher diagnostic yield and a lower complication rate in favor of EBUS-TBNA. It has also been shown that use of EBUSTBNA can avoid further invasive procedures in patients with suspected sarcoidosis (29). EBUS-TBNA is critical in confirming a diagnosis of sarcoidosis as well as excluding other pathology that may require prompt initiation of therapy. Compared with conventional transbronchial biopsy, the use of EBUS has also resulted in greater diagnostic yield (30). EBUS-TBNA is a safe procedure with a high yield for the diagnosis of sarcoidosis (31). Lymphoma Mediastinoscopies or thoracotomies have been performed as the standard procedure to obtain a histologic diagnosis in Baylor University Medical Center Proceedings Volume 28, Number 3 patients with mediastinal lymphadenopathy and suspected lymphoma. These procedures require general anesthesia and carry immense risks. Mediastinoscopy also has limited access to perihilar lymph nodes. Conventional TBNA, though superior to mediastinoscopy, has been shown to be inferior to EBUSTBNA due to a lower specificity and sensitivity (5). EBUS can be performed for a histologic diagnosis in suspected lymphoma, and fluorescence in situ hybridization can also be done on the samples obtained by EBUS to further characterize lymphoma subtypes (32). LIMITATIONS OF EBUS As with all medical technologic advances, EBUS has its limitations. In the instance of mediastinal staging in lung cancer, EBUS is not able to stage the entire mediastinum. EBUS is limited to the anterosuperior mediastinum, and EUS is often utilized to sample the posteroinferior mediastinum. EBUS and EUS can often be performed in the same session consecutively. EBUS is technically difficult to perform in some anatomic locations, such as the upper lobes, as scope angulation is required. Multiple studies have reported a good experience with the use of electromagnetic navigational bronchoscopy with EBUS in upper lobe lesions (33, 34). Needle puncture can be technically difficult, specifically in the elderly who have narrow intercartilaginous spaces and cartilage calcification. A significant cough can limit the success of the procedure in patients undergoing bronchoscopy under conscious sedation. With the growing development and application of EBUS, many chest physicians lack adequate training and experience. This may be influenced by the fact that a fully equipped EBUS bronchoscopy suite may cost several thousand dollars to establish. For this fairly large investment, there is minimal additional professional fee reimbursement and no additional facility fee reimbursement above standard bronchoscopy (35). CONTRAINDICATIONS Contraindications to EBUS are similar to those of bronchoscopy in general. Recent myocardial infarction or ischemia, poorly controlled heart failure, significant hemodynamic instability, chronic obstructive pulmonary disease or asthma exacerbations, or life-threatening cardiac dysrhythmias should delay an endobronchial procedure. Contraindications particular to EBUS-TBNA are related to coagulopathies (medication induced or inherent). The recommendation is to hold antiplatelet and anticoagulation agents prior to endoscopy to reduce bleeding risk (36). COMPLICATIONS Bronchoscopy is generally a safe procedure with a reported low complication rate (37–39). Complications related to the bronchoscopy procedure can be related to sedation for the procedure or directly from the bronchoscope. Complications related to sedation are hypoxemia and hypotension, while those related to bronchoscopy are bronchospasm, laryngospasm, nausea, vomiting, bleeding due to scope trauma, cardiac arrhythJuly 2015 mias, and vasovagal syncope. Complications specifically related to EBUS-TBNA are pneumothorax and bleeding. There has been a single reported case of EBUS-TBNA needle breakage without event (40). In summary, EBUS has become the standard of care and has rapidly attained a key status in the diagnosis and staging of various lung cancers, but in addition is also aiding and helping manage other pulmonary pathologies such as sarcoidosis, lymphoma, and in situ endobronchial lesions. The ability of EBUS to help perform mediastinal and transbronchial biopsies less invasively and with better sensitivity and specificity makes it more favorable than mediastinoscopy. EBUS and EBUS-TBNA, with convex probe or radial probe, have galvanized pulmonologists further into the care of thoracic malignancies, improving treatment selection based on genetics and helping stage the mediastinum in a minimally invasive, safer, and more effective fashion. 1. Jiang J, Browning R, Lechtzin N, Huang J, Terry P, Wang KP. TBNA with and without EBUS: a comparative efficacy study for the diagnosis and staging of lung cancer. J Thorac Dis 2014;6(5):416–420. 2. Navani N, Lawrence DR, Kolvekar S, Hayward M, McAsey D, Kocjan G, Falzon M, Capitanio A, Shaw P, Morris S, Omar RZ, Janes SM; REMEDY Trial Investigators. Endobronchial ultrasound-guided transbronchial needle aspiration prevents mediastinoscopies in the diagnosis of isolated mediastinal lymphadenopathy: a prospective trial. Am J Respir Crit Care Med 2012;186(3):255–260. 3. Yasufuku K, Chiyo M, Sekine Y, Chhajed PN, Shibuya K, Iizasa T, Fujisawa T. Real-time endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal and hilar lymph nodes. Chest 2004;126(1):122– 128. 4. Yasufuku K, Chiyo M, Koh E, Moriya Y, Iyoda A, Sekine Y, Shibuya K, Iizasa T, Fujisawa T. Endobronchial ultrasound guided transbronchial needle aspiration for staging of lung cancer. Lung Cancer 2005;50(3):347– 354. 5. Steinfort DP, Conron M, Tsui A, Pasricha SR, Renwick WE, Antippa P, Irving LB. Endobronchial ultrasound-guided transbronchial needle aspiration for the evaluation of suspected lymphoma. J Thorac Oncol 2010;5(6):804–809. 6. Ribeiro C, Oliveira A, Neves S, Campainha S, Nogueira C, Torres S, Brito MC, Almeida J, e Sá JM. Diagnosis of sarcoidosis in the endobronchial ultrasound-guided transbronchial needle aspiration era. Rev Port Pneumol 2014;20(5):237–241. 7. Low SY, Koh MS, Ong TH, Phua GC, Anantham D. Use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of granulomatous mediastinal lymphadenopathy. Ann Acad Med Singapore 2014;43(5):250–254. 8. Sarma A, Heilbrun ME, Conner KE, Stevens SM, Woller SC, Elliott CG. Radiation and chest CT scan examinations: what do we know? Chest 2012;142(3):750–760. 9. Oki M, Saka H, Kitagawa C, Kogure Y, Murata N, Adachi T, Ando M. 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Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest 2006;130(3):710–718. Goeckenjan G, Sitter H, Thomas M, Branscheid D, Flentje M, Griesinger F, Niederle N, Stuschke M, Blum T, Deppermann KM, et al.; German Respiratory Society; German Cancer Society. Prevention, diagnosis, therapy, and follow-up of lung cancer. Interdisciplinary guideline of the German Respiratory Society and the German Cancer Society—abridged version. Pneumologie 2011;65(8):e51–e75. Gómez-Caro A, Garcia S, Reguart N, Arguis P, Sanchez M, Gimferrer JM, Marrades R, Lomeña F. Incidence of occult mediastinal node involvement in cN0 non-small-cell lung cancer patients after negative uptake of positron emission tomography/computer tomography scan. Eur J Cardiothorac Surg 2010;37(5):1168–1174. Pozo-Rodríguez F, Martín de Nicolás JL, Sánchez-Nistal MA, Maldonado A, García de Barajas S, Calero-García R, Pozo MA, Martín-Escribano P, Martín-García I, García-Lujan R, Lopez-Encuentra A, Arenas de Pablo A. Accuracy of helical computed tomography and 18F-fluorodeoxyglucose positron emission tomography for identifying lymph node mediastinal metastases in potentially resectable non-small-cell lung cancer. J Clin Oncol 2005;23(33):8348–8356. Verhagen AF, Bootsma GP, Tjan-Heijnen VC, van der Wilt GJ, Cox AL, Brouwer MH, Corstens FH, Oyen WJ. FDG-PET in staging lung cancer: how does it change the algorithm? Lung Cancer 2004;44(2):175–181. Freixinet Gilart J, García PG, de Castro FR, Suárez PR, Rodríguez NS, de Ugarte AV. Extended cervical mediastinoscopy in the staging of bronchogenic carcinoma. Ann Thorac Surg 2000;70(5):1641–1643. Detterbeck FC, Lewis SZ, Diekemper R, Addrizzo-Harris D, Alberts WM. 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Carr IM, Koegelenberg CF, von Groote-Bidlingmaier F, Mowlana A, Silos K, Haverman T, Diacon AH, Bolliger CT. Blood loss during flexible bronchoscopy: a prospective observational study. Respiration 2012;84(4):312–318. 40. Özgül MA, Çetinkaya E, Tutar N, Özgül G. An unusual complication of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA): the needle breakage. Ann Thorac Cardiovasc Surg 2014;20(Suppl):567–569. Baylor University Medical Center Proceedings Volume 28, Number 3 Recurrent hospitalization for self-injuries and suicide attempts: case study of a super-utilizer Jacob W. Roden-Foreman, Ann Marie Warren, PhD, Megan Reynolds, MS, and Michael L. Foreman, MD Super-utilizers, patients who amass disproportionately large occurrences of emergency department visits and hospital admissions, are increasingly recognized as a significant and potentially preventable resource consumer. A comprehensive understanding of these individuals and their situations may prove useful in preventing unnecessary admissions and improving patient care and outcomes. While most super-utilizers suffer from chronic medical issues, this patient is an unusual variant, as his super-utilization stemmed from mental health problems leading to serial self-injury. Between January 2010 and October 2014, the patient performed 49 acts of self-harm resulting in 27 acute hospital admissions and 17 additional admissions secondary to complications. In addition to documented injuries, he and his family reported up to 50 additional self-injuries since his first episode 34 years earlier. It was concluded that the patient’s pattern of self-injury resulted from a combination of factors, including underlying psychiatric conditions, chronic noncompliance with medications, and potentially unavoidable behavioral reinforcement from health care professionals. A ccording to the Centers for Disease Control and Prevention, in 2010 suicide was the 10th leading cause of death among all ages in the United States, with more than 38,000 fatalities. More than 1 million people reported attempting suicide in the past year, and twice as many adults reported making plans to commit suicide within the past year (1). Between 2005 and 2009, the greatest percentage of fatal self-harm injuries occurred by firearm (47%), while self-inflicted abdominal stabbings accounted for a very small fraction of injuries (2). Among patients with intentional selfinflicted abdominal stab wounds, 70% were adult men, 74% had a psychiatric history, and 41% had prior suicide attempts (3, 4). Therefore, it is likely that many of these individuals have been admitted to hospitals multiple times and are potential “super-utilizers” of health care resources, patients who amass disproportionately large occurrences of emergency department visits and hospital admissions (5). The present case describes one such super-utilizer, a 51-year-old divorced Caucasian man with a pattern of serial self-injurious behavior and suicide attempts, which required multiple hospitalizations and operations. After obtaining the patient’s consent for multi-institutional release of information from area hospitals where he received care, Proc (Bayl Univ Med Cent) 2015;28(3):331–333 records were obtained for all hospital admissions from 2001 to October 2014. Charts were reviewed and demographic information, hospital charges, psychiatric diagnoses and interventions, substance use, circumstantial aspects of the injury resulting in hospital admission, and discharge disposition were recorded. CASE DESCRIPTION Since 2010, the patient performed 49 documented acts of self-harm resulting in 27 acute hospital admissions. These admissions included three overdoses, one episode of jumping from a moving car, two episodes of cutting at his wound site, three lacerations to his neck, three stab wounds to his chest, and 37 stab wounds to his abdomen. In addition to these documented injuries, the patient and his family reported as many as 50 additional self-injuries since his initial episode of selfinjury at age 17. These documented admissions and reported self-injuries are detailed in Table 1. As an indicator of his level of super-utilizing, charges of nearly $1 million were incurred at a single hospital between 2011 and 2012, which was one of his less active periods. The patient reported beginning his pattern of self-harm at age 17 when, following a breakup with his girlfriend, he shot himself in the right shoulder. His self-injurious behavior continued and usually began with an emotional trigger that led to a pattern of increased anxiety, manic behavior, and insomnia and ended with an act of self-injury, most commonly by stabbing himself one or more times in the abdomen and characteristically leaving the object in place. However, the impetus and mechanism of self-harm varied. In one episode, the patient reportedly slit both wrists after his grandfather died; on other occasions, he attempted an overdose. Additionally, in several of his more recent episodes of self-harm, he reported auditory hallucinations of voices he believed were trying to harm him and explained that he acted to harm himself before the voices could do so. In nearly every occurrence, his chronic and recurrent noncompliance with his psychiatric medications was a factor. From the Division of Trauma, Critical Care, and Acute Care Surgery, Baylor University Medical Center at Dallas, Texas. Corresponding author: Michael L. Foreman, MD, Chief, Division of Trauma, Critical Care, and Acute Care Surgery, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: MichaeFo@baylorhealth.edu). 331 Table 1. Self-injuries by region Purported injuries Documented injuries* Per region total Right neck 0 2 2 Left neck 0 1 1 Right shoulder 0 1 1 Mid, upper thorax 0 2 2 Epigastrium 0 3 3 Umbilical region 0 24 24 Region Hypogastrium 0 3 3 Abdomen, unspecified 47 9 56 Total, abdomen 47 37 84 Other or general 3† 4‡ 7 Total self-injuries 50 49 99 *Over the course of 27 acute admissions from January 2010 to October 2014. †Slit both wrists and cut himself in an unspecified location. ‡Jumped from a car and three overdoses. With repeated injury and repair, medical management of his injuries became increasingly difficult, and it is now considered impossible to surgically address his abdominal injuries due to the degree of scarring and adhesions caused by repeated injury, exploration, and complications, including wound infections and multiple enterocutaneous fistulas. Therefore, his more recent stab wounds have been managed nonoperatively, despite almost certain visceral injuries (Figure 1). In addition to his abdomen being regarded as inoperable, the patient has also been deemed psychiatrically futile (i.e., further treatment will not improve his underlying psychiatric condition and will be of little if any benefit to him). During his hospitalizations, a psychologist or psychiatrist typically assessed him to determine his level of functioning and identify stressors that led to the self-harm. Typically, he denied suicidal or homicidal ideations and voiced that he used self-injury as a coping mechanism. In one interview, he stated that, after an argument with his then wife, he stabbed himself to “relieve the pressure in my life.” On another occasion, he stated that his self-stabbing was not a suicide attempt but that “it’s just something I do to release the tension, like other people make little cuts on themselves.” Such statements are congruent with the reasons that people give for engaging in nonsuicidal selfinjury behaviors such as cutting one’s arms or inner thighs (6). He also occasionally cited an inability to live with his chronic pain, both physical and emotional, as a reason to end his life. However, regardless of any suicidal intent, the patient always expressed regret over harming himself and voiced his sons as important reasons to continue living. The psychologist or psychiatrist then provided the patient with other methods of coping to replace his current, maladaptive one and reminded him of the importance of maintaining his medication schedule. Based on the recommendations of the psychologist or psychiatrist, he was commonly transferred to an inpatient psychiatric hospital for ongoing mental health care or occasionally to a skilled nursing facility for continued wound care. DISCUSSION The patient had received multiple psychiatric diagnoses throughout his life, including bipolar disorder, posttraumatic stress disorder, borderline personality disorder, schizophrenia, schizoaffective disorder, REM sleep behavior disorder with comorbid narcolepsy, and dissociative identity disorder. The last two diagnoses were thought to explain his occasional amnesia and vehement denial of having stabbed himself; however, posttraumatic retrograde amnesia or amnesia related to his other diagnoses seem to be more likely explanations. This is because there was no evidence to suggest the patient was sleeping prior to or during his self-harm, nor was there evidence of multiple distinct personality states or dissociative fugues occurring separately from the self-harm episodes reported by him or his family. Beyond these diagnoses, he reported a history of physical and emotional abuse from his father as a child, and an unspecified psychiatric disorder in his mother. Figure 1. Lateral and anterior CT images of self-inflicted stab wound. 332 Baylor University Medical Center Proceedings Volume 28, Number 3 In addition to reinforcing his self-harm behavior by temporarily substituting acute injury for his chronic mental and physical pain, his behaviors were likely secondarily reinforced, albeit unintentionally. Given his increased social isolation, the attention he received from caregivers during his hospitalizations may have positively reinforced his self-injurious behaviors, as the caregivers were one of his only sources of support. Despite ongoing outpatient counseling and multiple inpatient stays at psychiatric facilities—both voluntary and involuntary—recurrent noncompliance with his psychiatric mediations may be the most important and potentially modifiable contributor to the patient’s recurring behavior pattern. While this issue comes in part from financial difficulties and from his increasing isolation, attempts at providing him with medications and visiting care providers have not been successful. While the patient clearly remains a hazard to himself, the very limited availability of inpatient long-term psychiatric placement, both voluntary and involuntary, has made this alternative effectively impossible. Given the complexity and long-term, recurrent nature of this case, it is perhaps not surprising that health care professionals have been largely unsuccessful in modifying the patient’s behavior. A primary constraint is the limited availability of extended mental health care secondary to monetary and statutory restrictions. While the legal issues relating to the availability of chronic mental health placements are beyond the scope of July 2015 this manuscript, the financial costs of institutionalization or other creative care options are likely to be favorable compared to the funds that continue to be expended in multiple acute hospitalizations, not to mention the likely improvement in his quality of life. Ultimately, while it might seem obvious, mental and behavioral pathology can have profound influences on super-utilizer encounters for physical illnesses and must be addressed as part of their overall treatment plans and when designing programs specifically to reduce their admissions. 1. 2. 3. 4. 5. 6. Centers for Disease Control and Prevention. Suicide: Facts at a Glance 2012. Available at http://www.cdc.gov/violenceprevention/pdf/suicide_ datasheet_2012-a.pdf; accessed June 9, 2014. Centers for Disease Control and Prevention. Web-Based Injury Statistics Query and Reporting System (WISQARS): Fatal Injury Reports and Nonfatal Injury Reports. Atlanta, GA: National Center for Injury Prevention and Control. Available at http://www.cdc.gov/injury/wisqars/index.html. Last accessed March 09, 2014 Abdullah F, Nuernberg A, Rabinovici R. Self-inflicted abdominal stab wounds. Injury 2003;34(1):35–39. Badger JM, Gregg SC, Adams CA Jr. Non-fatal suicide attempt by intentional stab wound: Clinical management, psychiatric assessment, and multidisciplinary considerations. J Emerg Trauma Shock 2012;5(3):228–232. Gawande A. The hot spotters. The New Yorker, January 24, 2011. Available at http://www.newyorker.com/magazine/2011/01/24/the-hot-spotters; accessed August 20, 2014. Klonsky ED. The functions of deliberate self-injury: a review of the evidence. Clin Psychol Rev 2007;27(2):226–239. Recurrent hospitalization for self-injuries and suicide attempts: case study of a super-utilizer 333 Radiographic findings in the nail-patella syndrome James A. West, MD, and Thomas H. Louis, MD Nail-patella syndrome is a rare disorder characterized classically by the tetrad of nail hypoplasia or aplasia, aplastic or hypoplastic patellae, elbow dysplasia, and the presence of iliac horns. Iliac horns are considered pathognomonic, and the presence of hypoplastic or aplastic patellae in conjunction with nail abnormalities is a cardinal feature of diagnosis. Elbow dysplasia is present in most cases and can exhibit features typical of the syndrome. Herein we present the radiographic findings of the elbows, knees, and pelvis of a woman with nail-patella syndrome. N ail-patella syndrome (NPS), a hereditary disorder that occurs in approximately 1 in 50,000 newborns (1), is known by many other names, including hereditary onycho-osteodysplasia (HOOD), TurnerKeiser syndrome, and Fong disease (2). It is characterized by nail hypoplasia or aplasia, aplastic or hypoplastic patellae, elbow dysplasia, and the presence of iliac horns (2). The earliest description of a nail dysplasia being associated with knee and elbow dysplasia dates back to 1820 by Chatelain (3). The familial and hereditary nature of the disorder was recognized by Pye-Smith and Little in 1883 and 1897, respectively (4). A few years after Fong described the incidental finding of “iliac horns” in 1946 during a routine pyelogram, they became associated with the syndrome and are now considered pathognomonic (4, 5). Identifying the common radiographic manifestations of the pelvis, knees, and elbows can aid in establishing the diagnosis of NPS. CASE STUDY A 70-year-old woman presented to the emergency department complaining of hip pain. An anteroposterior radiograph of the pelvis was obtained and demonstrated no acute abnormality and only mild osteoarthritic degenerative changes of the hips bilaterally. Incidentally, there were bilateral, triangular osseous excrescences extending from the posterior aspect of the ilia (Figure 1a). Review of the patient’s prior imaging studies revealed multiple musculoskeletal studies in addition to computed tomography (CT) of the abdomen and pelvis. CT of the abdomen and pelvis showed the bilateral posterior iliac osseous excrescences to 334 involve the origin of the gluteus medius muscles (Figure 1b). An anteroposterior view of the bilateral femurs demonstrated both patellae to be hypoplastic (Figure 2). Anteroposterior and lateral radiographs of the right elbow showed an abnormal configuration of the capitulum, lateral epicondyle, and radial head as well as posterior inferior dislocation of the radial head (Figure 3). Radiographic features of the left elbow were similar though less pronounced, and the left radial head was also posteriorly and inferiorly dislocated. Review of the patient’s records revealed a standing diagnosis of NPS. DISCUSSION NPS exhibits full genetic penetrance but an unpredictable degree of expression, even within families (1, 6). No clinical diagnostic criteria exist for NPS; however, a combination of clinical and imaging features seen with this condition are characteristic (6). Genetic testing can be performed if findings are ambiguous (6). NPS results from loss of function mutations of transcription factor LMX1B located on chromosome 9, which is a member of the LIM-homeodomain family of transcription factors involved in ventral-dorsal body-pattern formation during development (7). Nail dysplasia and patellar aplasia or hypoplasia are cardinal features in the diagnosis of NPS (4). Nail anomalies predominantly involve the fingernails, with the thumbs most severely affected. The toenails are rarely involved and the presence of triangular nail lunulae is considered pathognomonic (4). The nails may be absent, hypoplastic, or dystrophic, with some of the various nail dysplasia including horizontal or longitudinal ridging, pitting, or the presence of a longitudinal cleft that separates them in half. Patellar abnormalities are present in >90% of cases and include aplasia or, more frequently, patellar hypoplasia (4). Recurrent superolateral subluxation or dislocation is common. Even when not displaced, the hypoplastic patellae tend to be positioned more superolateral than normal (6). There can also From the Department of Diagnostic Radiology, Baylor University Medical Center at Dallas, Dallas, Texas. Corresponding author: James A. West, MD, Department of Diagnostic Radiology, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: james.west@baylorhealth.edu). Proc (Bayl Univ Med Cent) 2015;28(3):334–336 a b Figure 1. Imaging of the pelvis. (a) Radiograph of the anteroposterior pelvis demonstrates the presence of bilateral triangular osseous excrescences from the posterior aspect of the ilia, known as iliac horns (arrows). (b) CT of the pelvis shows the bilateral iliac osseous excrescences (arrows) to emanate from the posterior body of the ilia at the origin of the gluteus medius muscles. Figure 2. Anteroposterior radiograph of the bilateral femurs shows both patellae to be hypoplastic (arrows). July 2015 be hypoplasia of the lateral femoral condyle resulting in a genu valgus deformity. Elbow dysplasia is also frequently encountered in NPS, having been described in >90% of patients (4). Most frequently the radial heads, lateral epicondyles, and capitula are dysplastic with recurrent, typically posterolateral, displacement of the radial heads occurring in 61% of patients (4). Pterygia (webbing) may also occur across the elbow. Iliac horns, which are pathognomonic for NPS, only occur in 70% to 80% of patients (2, 5). They are most often bilateral, conical osseous excrescences that typically project dorsolaterally from the posterior ilia and serve as the origin of the gluteus medius muscles (5). On physical exam, these processes may be palpable, although they are typically asymptomatic and have no effect on gait (4). They can be identified as early as the third trimester on a fetal ultrasound (6). Other frequently encountered orthopedic features of NPS that do not contribute to the diagnosis are shoulder girdle dysplasia, short stature, talipes equinovarus (club foot), calcaneovalgus feet, dislocation of the hips, Madelung’s deformity, and large joint contractures. Besides physical manifestations, there is also a strong association with open-angle glaucoma and progressive nephropathy (7). Nephropathy is reported to be present in 30% to 60% of patients, with progression to nephrotic syndrome in 20% and renal failure requiring dialysis and/or transplant in approximately 10% (8). Open-angle glaucoma occurs in 10% and ocular hypertension in 7% (4). There is no cure for NPS, and treatment is directed towards addressing the various orthopedic and nonorthopedic manifestations of the disorder. Radiographic findings in the nail-patella syndrome 335 a b Figure 3. Radiograph of the right elbow. (a) Anteroposterior radiograph demonstrates dysplasia of the radial head (arrow), capitulum (asterisk), and lateral epicondyle (arrowhead). (b) Lateral radiograph shows the radial head (arrow) to be inferiorly and posteriorly dislocated. 1. Levy M, Feingold J. Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 2000;58(3):925–943. 2. Mankin H. Nail-patella syndrome: hereditary onycho-osteodysplasia. In Mankin H, ed. Pathophysiology of Orthopaedic Diseases. Rosemont, IL: American Academy of Orthopaedic Surgeons, 2009:191–196. 3. Thompson EA, Walker ET, Weens HS. Iliac horns: an osseous manifestation of hereditary arthrodysplasia associated with dystrophy of the fingernails. Radiology 1949;53(1):88–92. 4. Bongers EM, Gubler MC, Knoers NV. Nail-patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol 2002;17(9):703–712. 5. Fong EE. Iliac horns (symmetrical bilateral central posterior iliac processes). Radiology 1946;47(5):517. 336 6. Sweeney E, Hoover-Fong JE, McIntosh I. Nail-patella syndrome. 2003 [updated 2014 Nov 13]. In Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, 1993-2015. Available at http://www.ncbi. nlm.nih.gov/books/NBK1132/ 7. McIntosh I, Dunston JA, Liu L, Hoover-Fong JE, Sweeney E. Nail patella syndrome revisited: 50 years after linkage. Ann Hum Genet 2005;69(Pt 4):349–363. 8. Granata A, Nori G, Ravazzolo R, Marini M, Castellino S, Sicurezza E, Fiore CE, Mignani R. Nail-patella syndrome and renal involvement. Description of three cases and literature review. Clin Nephrol 2008;69(5):377–382. Baylor University Medical Center Proceedings Volume 28, Number 3 Solitary supratentorial Listeria monocytogenes brain abscess in an immunocompromised patient James A. West, MD, Anthony R. Onofrio, MD, Lauren C. Martinez, MD, Michael J. Opatowsky, MD, MBA, Cedric W. Spak, MD, MPH, and Kennith F. Layton, MD, MS We describe an 81-year-old man receiving azacitidine monotherapy for myelodysplastic syndrome who was improving from Listeria monocytogenes bacteremia after receiving antibiotic therapy during an earlier hospital admission. Shortly after discharge he developed new-onset seizure activity, with brain imaging on subsequent admissions demonstrating a posterior right frontal lobe mass. Specimen cultures after resection of the mass revealed this to be a cerebral abscess related to L. monocytogenes. Brain abscesses related to this organism are rare. L isteria monocytogenes is a ubiquitous, opportunistic pathogen that rarely causes illness in healthy individuals. The immunocompromised and those with underlying illness are at greater risk for serious and potentially fatal infection. Approximately 20% of all listeriosis patients succumb to infection despite early aggressive treatment, with particularly elevated case fatality rates in those with comorbid illnesses and in immunocompromised states (1–4). While L. monocytogenes is a well-known cause of meningitis and encephalitis, brain abscesses related to this organism are rare and reported to occur in only 10% of all Listeria central nervous system (CNS) infections (4). Here we present the case of an immunocompromised man who developed L. monocytogenes bacteremia and a subsequent single supratentorial brain abscess. CASE DESCRIPTION An 81-year-old man with myelodysplastic syndrome was being treated with azacitidine monotherapy. He also had a remote history of acute myelogenous leukemia in remission, medically controlled atrial fibrillation, basal cell skin carcinoma resection, and treated prostate cancer. For 1 week, the patient complained only of intermittent fevers, reaching a maximum temperature of 102.4°F, and mild fatigue. Four days after the onset of fevers, blood cultures were drawn and he was started on levofloxacin and later on amoxicillin clavulanate once Gram-positive rods were isolated. Blood cultures grew L. monocytogenes, and the patient was hospitalized. He received intravenous piperacillin-tazobactam for 2 days. When sensitivity tests revealed susceptibility to ampicillin, penicillin G, and trimethoprim sulfamethoxazole, the treatment was changed to intravenous ampicillin, which continued for Proc (Bayl Univ Med Cent) 2015;28(3):337–339 his remaining 2 days in the hospital. Repeat blood cultures were negative at the time of discharge and he was afebrile. The patient was discharged home on continuous intravenous penicillin infusion. During the hospital admission there were no specific neurologic complaints, headaches, or altered sensorium. The morning after discharge, the patient had generalized jerking movements and left facial droop that lasted approximately 10 minutes while he remained lucid. Two additional seizure-like episodes occurred during transport to the emergency department. Noncontrast head computed tomography (CT) demonstrated a mass in the right frontoparietal region. Treatment with lorazepam and dexamethasone was initiated. Subsequent contrast-enhanced magnetic resonance imaging (MRI) of the brain showed a 2.2 cm rim-enhancing mass within the posterior right frontal lobe with mild surrounding edema (Figure 1). Intravenous ampicillin was restarted and levetiracetam treatment initiated. A 2-day posttreatment contrast-enhanced brain MRI demonstrated a slightly decreased volume of the mass, a similar degree of edema, and imaging characteristics most suggestive of an isolated cerebral abscess. A right frontal craniotomy was performed and a purulent cavity in the posterior right frontal lobe was resected. Specimens revealed acute inflammation consistent with cerebritis/abscess, although no organisms were identified by microscopy. Cultures of the abscess fluid were positive for L. monocytogenes susceptible to ampicillin, penicillin G, and trimethoprim sulfamethoxazole. No additional seizures occurred, and the patient was discharged on long-term intravenous ampicillin therapy, with surveillance imaging 7 days after the abscess was resected. DISCUSSION L. monocytogenes is a ubiquitous, Gram-positive, facultative intracellular bacterium that is typically acquired via food contamination (4). The groups considered at risk for listeriosis are pregnant women and neonates, the elderly, and immunocompromised or From the Department of Diagnostic Radiology (West, Onofrio, Opatowsky, Layton), the Department of Internal Medicine (Martinez), and the Division of Infectious Diseases (Spak), Baylor University Medical Center at Dallas. Corresponding author: James A. West, MD, Department of Diagnostic Radiology, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: james.west@baylorhealth.edu). 337 a b c Figure 1. Baseline contrast-enhanced brain MRI. (a) T1 post-gadolinium image shows a 2.2 cm rim-enhancing mass within the posterior right frontal lobe (arrow) with surrounding edema. (b) Fluid-attenuated inversion recovery (FLAIR) image shows the rim of the mass to be hypointense (arrow) with a central core of heterogeneous signal. Increased signal within the subcortical white matter surrounding the mass reflects reactive vasogenic edema (arrowhead) that contributes to mild local mass effect with partial sulcul effacement. (c) Diffusion-weighted imaging reveals restricted diffusion predominantly within the rim of the mass (arrow), with less pronounced heterogeneous central diffusion restriction. (The confirmatory apparent diffusion coefficient [ADC] map is not shown.) debilitated adults with underlying diseases (5). In nonpregnant adults, most cases have been associated with solid and hematologic malignancies, antineoplastic chemotherapy, immunosuppressant therapy, chronic liver disease, kidney disease, diabetes, collagen diseases, and HIV infection (5). In the immunocompetent, gastrointestinal exposure to a high inoculum of L. monocytogenes can result in a self-limited, febrile diarrheal gastroenteritis with a median duration of 27 to 42 hours (6). In the immunocompromised, gastrointestinal invasion can lead to bacteremia and seeding to various organs, with a particular predilection and invasive efficiency for the CNS, where it can cause meningitis, meningoencephalitis, rhombencephalitis, or, much less commonly, brain abscesses (5). Brain abscesses constitute approximately 10% of all L. monocytogenes CNS infections (4). Bacteremia is almost always present, and concomitant meningitis with isolation of L. monocytogenes from the cerebrospinal fluid occurs in 25% to 40% of brain abscess cases (4). Little information was available regarding the relative incidence of L. monocytogenes as the causative bacterium of cerebral abscesses in general. In an 8-year prospective multiinstitutional study by Prasad et al, L. monocytogenes was isolated from 0.8% of brain abscesses; however, this study did not include an organ transplant population, which could potentially constitute a significant number of patients who acquire Listeria brain abscesses (7). A retrospective study by Tattevin et al showed that L. monocytogenes accounted for 9% of brain abscesses in patients admitted to the intensive care unit, although patients with HIV were excluded from this study (8). While L. monocytogenes is not the most common cause of CNS infections, an epidemiologic study of bacterial meningitis in the US in 1995 found that it is nearly 10-fold more efficient than other neuroinvasive Gram-positive bacteria at invading 338 the CNS (9, 10). L. monocytogenes gains access to the CNS by transporting across the blood-brain or blood-choroid barriers within circulating leukocytes by a phagocyte-facilitated (Trojan horse) mechanism, direct invasion of blood-brain or blood-choroid endothelial cells by extracellular blood-borne bacteria, or retrograde migration into the brain within the axons of cranial nerves (9). Approximately 20% of all listeriosis patients succumb to infection despite early aggressive treatment, with particularly elevated case fatality rates in those who are immunocompromised or have an underlying illness or malignancy (1–4). Skogberg et al demonstrated a 32% mortality in those with underlying disease or in those receiving immunosuppressant medication, while no deaths were observed in healthy patients (3). Goulet et al demonstrated up to 40% mortality among those with L. monocytogenes bacteremia complicating a malignancy, with the highest incidence of infection occurring in patients with chronic lymphocytic leukemia and liver cancer and the highest case fatality rate in those with lung and pancreatic cancers (1). This high mortality rate is at least in part due to L. monocytogenes being a facultative intracellular pathogen with the capability to infect adjacent cells by direct extension through filopodia formation within the host cell, allowing the bacterium to circumvent extended exposure to the humoral immune response (9). This leaves the critical role of pathogen elimination to T lymphocyte–mediated cytotoxicity, which is typically impaired in various physiologically and pathologically immunocompromised states (9). There are currently no large controlled trials comparing treatments for listeriosis. Generally, ampicillin is considered the treatment of choice (4). Gentamicin is often added to ampicillin due to synergy that has been observed in vitro and in animal models; however, its use in clinical practice is often debated (11). In those with a penicillin allergy, trimethoprim sulfamethoxazole Baylor University Medical Center Proceedings Volume 28, Number 3 is considered an acceptable second-line treatment (12). Listeria is often in part or fully resistant to cephalosporins, so they are not typically recommended (13). Patients with a Listeria brain abscess should receive treatment for at least 6 weeks and be followed by serial neurological imaging, with MRI as the preferred modality (4). 6. 7. 8. 1. 2. 3. 4. 5. Goulet V, Hebert M, Hedberg C, Laurent E, Vaillant V, De Valk H, Desenclos JC. Incidence of listeriosis and related mortality among groups at risk of acquiring listeriosis. Clin Infect Dis 2012;54(5):652–660. Mylonakis E, Hohmann EL, Calderwood SB. Central nervous system infection with Listeria monocytogenes. 33 years’ experience at a general hospital and review of 776 episodes from the literature. Medicine (Baltimore) 1998;77(5):313–336. Skogberg K, Syrjänen J, Jahkola M, Renkonen OV, Paavonen J, Ahonen J, Kontiainen S, Ruutu P, Valtonen V. Clinical presentation and outcome of listeriosis in patients with and without immunosuppressive therapy. Clin Infect Dis 1992;14(4):815–821. Lorber B. Listeria monocytogenes. In Bennett J, Dolin R, Blaser M, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th ed. Philadelphia, PA: Elsevier/Saunders, 2015:2383–2390. Vázquez-Boland JA, Kuhn M, Berche P, Chakraborty T, DomínguezBernal G, Goebel W, González-Zorn B, Wehland J, Kreft J. Listeria pathogenesis and molecular virulence determinants. Clin Microbiol Rev 2001;14(3):584–640. July 2015 9. 10. 11. 12. 13. Dalton CB, Austin CC, Sobel J, Hayes PS, Bibb WF, Graves LM, Swaminathan B, Proctor ME, Griffin PM. An outbreak of gastroenteritis and fever due to Listeria monocytogenes in milk. N Engl J Med 1997;336(2):100–105. Prasad KN, Mishra AM, Gupta D, Husain N, Husain M, Gupta RK. Analysis of microbial etiology and mortality in patients with brain abscess. J Infect 2006;53(4):221–227. Tattevin P, Bruneel F, Clair B, Lellouche F, de Broucker T, Chevret S, Bédos JP, Wolff M, Régnier B. Bacterial brain abscesses: a retrospective study of 94 patients admitted to an intensive care unit (1980 to 1999). Am J Med 2003;115(2):143–146. Drevets DA, Bronze MS. Listeria monocytogenes: epidemiology, human disease, and mechanisms of brain invasion. FEMS Immunol Med Microbiol 2008;53(2):151–165. Schuchat A, Robinson K, Wenger JD, Harrison LH, Farley M, Reingold AL, Lefkowitz L, Perkins BA; Active Surveillance Team. Bacterial meningitis in the United States in 1995. N Engl J Med 1997; 337(14):970–976. Edmiston CE Jr, Gordon RC. Evaluation of gentamicin and penicillin as a synergistic combination in experimental murine listeriosis. Antimicrob Agents Chemother 1979;16(6):862–863. Michelet C, Avril JL, Cartier F, Berche P. Inhibition of intracellular growth of Listeria monocytogenes by antibiotics. Antimicrob Agents Chemother 1994;38(3):438–446. Hof H, Nichterlein T, Kretschmar M. Management of listeriosis. Clin Microbiol Rev 1997;10(2):345–357. Solitary supratentorial Listeria monocytogenes brain abscess in an immunocompromised patient 339 Asplenia and fever Mitchell L. Huebner, MD, and Kristin A. Milota, RN, MSN A 45-year-old-man presented with the abrupt onset of a fever over 30 years after surgical splenectomy. He presented with symptoms and findings that seemed consistent with influenza. He rapidly developed fulminant meningitis that resulted in his death. P neumococcal meningitis remains a devastating illness with high mortality and morbidity despite all of the advances in medical care. Pneumococcal meningitis has been found in some studies to be over four times deadlier than other causes of bacterial meningitis in adults, and over six times more likely to cause other poor outcomes (1). Survivors of meningitis frequently are left with chronic neurologic deficits. Streptococcus pneumoniae, otherwise known as pneumococcus, is an encapsulated bacterial organism. Individuals who lack a functional spleen are at higher risk for infection from encapsulated organisms. A person without a functional spleen is at risk for postsplenectomy sepsis (PSS) and overwhelming infection, including pneumococcal meningitis. They are also more likely to have a devastating outcome despite current treatment options. Physicians and caregivers in the outpatient clinic setting will rarely, if ever, see a patient presenting with PSS. As such, primary caregivers are less familiar with the best practice guidelines associated with PSS than caregivers in the hospital setting. CASE DESCRIPTION A 45-year-old man who had a history of a splenectomy at age 13 secondary to idiopathic thrombocytopenic purpura presented with the abrupt onset of a high fever, myalgias, fatigue, loose stools, and headache. He had received an influenza vaccine about 2 months earlier. His temperature was 102.3°F and blood pressure, 110/74 mm Hg. He appeared sick, answered questions appropriately, and had no nuchal rigidity; head, ear, eye, nose, or throat abnormalities; rales or rhonchi; abdominal abnormalities; or evidence of dermal cellulitis. A rapid influenza test was negative. He was sent home on oseltamivir with instructions to call back if his clinical situation changed. The next day his temperature was 99.4°F. He still had myalgias and mild diarrhea and had developed a “puffiness” in his hands. He became confused that night at home and was taken to the emergency department. His blood pressure was 129/80 mm Hg 340 and heart rate, 76 beats per minute. He was in distress, moaning, combative, and not following commands, but had reactive pupils, a supple neck, and no other abnormalities. Computed tomographic scan of the head revealed no apparent disease. A lumbar puncture was described by the emergency room physician as having high opening pressure with cloudy fluid, and specifically that the cerebrospinal fluid (CSF) “flew 3 feet with patient lying on side.” The CSF had a protein of 425 mg/dL and a glucose of <5 mg/dL. Gram stain revealed Gram-positive cocci in pairs. Pneumococcal antigen was present. Intravenous antibiotics (vancomycin and cephtriaxone) were immediately started. He experienced respiratory arrest nearly 6 hours after arrival to the emergency department. He was intubated and ventilated, but cardiac arrest occurred. After several rounds of cardiopulmonary resuscitation and the addition of multiple cardiac vasopressor medications, his pulse was stable. He was given ventilator support and intensive therapy, but never regained consciousness and died 3 days later. DISCUSSION Streptococcus pneumoniae is the most common bacteria implicated in overwhelming PSS. Some studies have suggested it might be responsible for as many as 90% of these devastating infections (2). The initial infection leading to pneumococcal meningitis usually presents with vague symptoms such as fever, chills, malaise, headache, and various gastrointestinal symptoms. Bacterial meningitis often presents with only one of the classic meningitis triad: a) fever, b) neck stiffness (i.e., nuchal rigidity), and c) altered mental status. A delay in diagnosis and treatment of meningitis can be devastating and fatal. Studies have shown a triphasic progression to bacterial meningitis: from a nonspecific illness phase to a bacteremic phase to finally bacteremic seeding of the CNS and the meningitic phase (3). Bonadio explained: Symptoms characterizing each phase can be heterogenous, can vary in type and duration, and are often of a ‘nonspecific’ nature From Dallas Diagnostic Association Park Cities, Dallas, Texas (Huebner) and the Department of Critical Care Services, Children’s Health System, Dallas, Texas (Milota). Corresponding author: Mitchell L. Huebner, MD, Dallas Diagnostic Association Park Cities, Health Texas Provider Network, 9101 N. Central Expressway, Suite 300, Dallas, TX 75231 (e-mail: mitchell.huebner@baylorhealth.org). Proc (Bayl Univ Med Cent) 2015;28(3):340–341 (e.g. fever, vomiting, alterations in behavior and activity) that can mimic those indicative of less serious, nonmeningitic illnesses. The relatively more ‘specific’ symptoms of meningitis (e.g. nuchal rigidity, bulging fontanelle, altered mental status/ neurologic deficit) are not invariably present, especially early in the course of the infection (3). These phases can progress more rapidly in patients without a functional spleen, sometimes over the course of a few hours rather than days. Our patient presented with only one symptom of the classic meningitis triad (fever). He began showing mental status changes about 36 hours after initial presentation. He was never reported to have nuchal rigidity. The patient was initially thought to have influenza. The presentation of a variety of infections can mimic influenza, especially in early phases. If the patient has not received an influenza vaccine or has a positive rapid influenza test, one can be more confident of the diagnosis; however, the absence of either of these two does not rule out influenza as the causative agent. The influenza vaccine’s effectiveness against influenza A and B varies from 50% to 90%. The rapid influenza antigen tests that are used in most primary care offices range in sensitivity from 10% to 70%. The Centers for Disease Control and Prevention stated: Negative results of [rapid influenza diagnostic tests] do not exclude influenza virus infection in patients with signs and symptoms suggestive of influenza. Therefore, antiviral treatment should not be withheld from patients with suspected influenza, even if they test negative. While influenza vaccine is the best way to prevent influenza, a history of influenza vaccination does not rule out influenza virus infection in an ill patient with clinical signs and symptoms compatible with influenza (4). Our patient had a splenectomy as a child, increasing his risk of serious infection in the setting of a febrile illness. PSS is most common in the first few years after a splenectomy, but may appear even decades later. Current recommendations for vaccines prior to a splenectomy call for a patient to receive a 13-valent pneumococcal conjugate vaccine (PCV13) 8 weeks prior, and then a pneumococcal polysaccharide vaccine (PPSV23) at least 14 days prior to the surgery. A Haemophilus influenza type b vaccine (Hib) and a quadrivalent meningococcal conjugate vaccine (MenACWY) should be given at least 14 days prior to the procedure in those who have not previously been vaccinated for either of these organisms. It is also recommended that both children and adults without a functional spleen be reimmunized 5 years after their initial vaccination with a PPSV23, and again at the age of 65 (5). The MenACWY should be repeated every 5 years after the splenectomy (5). Yearly influenza immunizations are recommended. Asplenic adults are not recommended to take prophylactic antibiotics, but should have antibiotics available to them to “be taken at the first sign of infection (increase in body temperature, malaise or shivering) if the patient is unable to obtain prompt medical attention. However, in such situations medical help should still July 2015 be sought without delay” (6). “Prompt” medical attention is defined as less than 2 hours (5). In an emergency room or hospital setting, appropriate evaluation and treatment for an asplenic febrile patient should include a complete blood count with differential, blood culture with Gram stain, arterial blood gas analysis, chest x-ray, and consideration for lumbar puncture with CSF studies. None of these evaluations should delay the initiation of appropriate broad-spectrum intravenous antibiotics. The Surviving Sepsis Campaign guidelines state that antibiotics should be administered in a patient suspected of sepsis within 1 hour of presentation (7). Delay in starting antibiotics for any reason is associated with a poor outcome. There is fairly clear understanding of the risks to asplenic patients and of PSS among hospital specialists and hospitalbased physicians, most likely because of the frequency with which they encounter these patients. Conversely, in the primary care setting, experience and familiarity with these patients is lower. A study published in the Journal of Clinical Pathology “suggests a continuing broad failure to attain currently accepted best practice in the management of asplenic patients” (8). Primary care literature has published very few articles reviewing the risks to asplenic patients and of PSS. A review of the New England Journal of Medicine and the Journal of the American Medical Association found only two articles related to PSS published in the last 10 years (5, 9). The overwhelming majority of articles related to these topics are published in surgical or specialty literature. In this time of avoiding the overuse of antibiotics due to the development of resistance, it is important to know this important exception. 1. 2. 3. 4. 5. 6. 7. 8. 9. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004;351(18):1849–1859. Moffett SL. Overwhelming postsplenectomy infection: managing patients at risk. JAAPA 2009;22(7):36–39, 45. Bonadio WA. Medical-legal considerations related to symptom duration and patient outcome after bacterial meningitis. Am J Emerg Med 1997;15(4):420–423. Centers for Disease Control and Prevention. Notice to Clinicians: Early Reports of pH1N1-Associated Illnesses for the 2013-14 Influenza Season. CDC Health Alert Network, December 24, 2013. Available at http:// emergency.cdc.gov/han/han00359.asp; accessed April 27, 2015. Rubin LG, Schaffner W. Clinical practice. Care of the asplenic patient. N Engl J Med 2014;371(4):349–356. Melles DC, de Marie S. Prevention of infections in hyposplenic and asplenic patients: an update. Neth J Med 2004;62(2):45–52. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41(2):580–637. Waghorn DJ. Overwhelming infection in asplenic patients: current best practice prevention measures are not being followed. J Clin Pathol 2001;54(3):214–218. Gandhi TK, Zuccotti G, Lee TH. Incomplete care—on the trail of flaws in the system. N Engl J Med 2011;365(6):486–488. Asplenia and fever 341 Myroides odoratimimus bacteremia in a diabetic patient Tiana R. Endicott-Yazdani, Neelam Dhiman, PhD, Raul Benavides, MD, and Cedric W. Spak, MD, MPH Myroides species are a rare source of human infection. Though not part of the human microbiota, Myroides species are commonly found in the environment. Myroides infections are typically attributed to contact with contaminated water; the most common presentation is in immunocompromised patients. We present a patient with a diabetic foot ulcer who subsequently developed Myroides odoratimimus bacteremia and bone abscess. M yroides odoratum and odoratimimus are gram-negative, nonmotile, obligate aerobic bacilli with yellow pigmentation and a distinct fruity odor (1). Myroides species infect primarily immunocompromised patients, often with diabetes mellitus, cirrhosis, chronic obstructive pulmonary disease, or prolonged corticosteroid therapy (2–6); they are infrequent sources of bloodstream infections (1, 7). This case describes Myroides odoratimimus bloodstream infection in a patient with a chronic diabetic foot ulcer who was exposed to freshwater sources. CLINICAL PRESENTATION A 75-year-old white man presented to the emergency department with a 2-day history of fever, chills, and concern of an infected wound on his arm. The patient had taken a recent trip to Colorado, where he went whitewater rafting and spent time in a mineral spa. During the trip he slipped on a rock and fell on his arm, causing an abrasion. Five days later, after returning home, he developed a fever (up to 102°F), fatigue, and malaise, treated with acetaminophen. He became concerned that his arm could be the source of his infection. His temperature was 98.8°F; blood pressure, 118/57 mm Hg (sitting); heart rate, 62 beats/minute; and respiratory rate, 18 breaths/minute. Physical exam revealed a 3 cm abrasion on the right forearm with mild erythema, minimal warmth, and no swelling or exudate and a nontender ulcerated lesion on the right second toe with no exudate. His white blood cell count was 12.5 K/µl. He received a 1 L 0.9% saline bolus, and blood cultures were collected. Lactate results were initially 3.0 mmol/L and decreased to 2.0 mmol/L when redrawn following the fluid bolus. He was discharged with directions to follow up with his primary care physician. Two days after discharge from the emergency department, the blood cultures demonstrated gram-negative rods. The initial 342 identification of the culture revealed Myroides species. The patient was contacted and instructed to return to the hospital. He was started on intravenous meropenem 500 mg every 6 hours and vancomycin 1500 mg every 12 hours. The patient improved on the antibiotic regimen. He was also found to have a chronic, nonhealing ulcer on his left second toe. The toe was excised prior to discharge and cultures showed polymicrobial growth of Myroides species along with multiple morphotypes of coagulase-negative Staphylococcus species. He was discharged 2 days following his toe amputation. Initial identification of Myroides species was performed using Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) on a VITEK MS system (bioMerieux, Nürtingen, Germany). Briefly, isolated bacterial colonies from blood agar plates were smeared on the VITEK MS-DS target slide. The smear was overlaid with 1 µL matrix solution and allowed to air dry completely. Composite mass spectra of over 100 spectral profiles were generated within the range of 2 to 20 kilodaltons and probed using the Research-Use Only version of the VITEK MS Plus database (SARAMISTM Knowledge Base v4.12) that includes M. odoratimimus and M. odoratus. Species-level–only identification was obtained at a 92.8% to 99.9% confidence level at four different attempts. Definitive identification of M. odoratimimus was accomplished via 16S rRNA sequencing using subcultured isolates from the same plate at the reference testing facility (ARUP Laboratories, Salt Lake City, UT). DISCUSSION The two most common Myroides species seen in humans are odoratus and odoratimimus (8). The most common clinical presentations are bacteremia, cellulitis, and isolated outbreaks of urinary tract infections following exposure to a contaminated water source or in the setting of trauma (8, 9). Infections are rare but can occasionally be life-threatening (8). The less common Myroides species pelagicus, profundi, and marinus have been From the Department of Internal Medicine (Endicott-Yazdani), the Department of Pathology (Benavides), and the Division of Infectious Diseases (Spak), Baylor University Medical Center at Dallas; and med fusion and ClearPoint Diagnostic Laboratories, Lewisville, Texas (Dhiman, Benavides). Corresponding author: Cedric W. Spak, MD, MPH, 3409 Worth Street, Suite 600, Dallas, TX 75246 (e-mail: CedricS@BaylorHealth.edu). Proc (Bayl Univ Med Cent) 2015;28(3):342–343 isolated from various seawater sources but have not to date been documented as a source of infections in humans (10–12). The traditional epidemiology of Myroides involves infection of an immunocompromised host. While our patient appeared clinically well, patients with diabetes are well documented to be relatively immunocompromised compared with nondiabetic patients. The most common types of patients infected with Myroides species (M. odoratus and odoratimimus) are immunocompromised or have end-stage renal disease, cirrhosis, chronic obstructive pulmonary disease, neoplasms, or heart diseases (4–7, 9, 13–16). While M. odoratus infections in diabetics have been documented, to our knowledge, ours is the first documented case of M. odoratimimus in a diabetic patient (14, 16). Of the five documented reports of M. odoratimimus infections, two involved nosocomial outbreaks of urinary tract infections in the setting of urinary stones or cancer (9, 17). Another report documented bacteremia and cellulitis in a patient with alcoholic cirrhosis (13). The next report involved an otherwise healthy elderly man who experienced severe trauma from a farming accident that caused septic shock, pneumonia, and soft tissue infection (8). The last report was of a child who suffered a pig bite and subsequently developed cellulitis (1). In our case, the primary portal of entry and source of infection was felt to be the second left toe, after exposure of that open wound to a presumably contaminated water source, either the natural thermal mineral spa or the river. Subsequently, there was hematogenous spread of M. odoratimimus from the infected nonhealing chronic ulcer. Although antibiotics appeared to clinically resolve the Myroides bloodstream infection, the patient’s left second toe was still amputated due to a chronic nonhealing ulcer that was felt to pose a risk for future infections. Cultures of the left toe revealed Staphylococcus epidermidis in the bone as well as coagulase-negative Staphylococcus and Myroides spp. from an abscess in the toe. While the patient was initially concerned that the arm abrasion was the cause of infection, that was unlikely given the Myroides abscess found in the left second toe. 1. Maraki S, Sarchianaki E, Barbagadakis S. Myroides odoratimimus soft tissue infection in an immunocompetent child following a pig bite: case report and literature review. Braz J Infect Dis 2012;16(4):390–392. July 2015 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Holmes B, Snell JJ, Lapage SP. Flavobacterium odoratum: a species resistant to a wide range of antimicrobial agents. J Clin Pathol 1979;32(1):73–77. Winn WC, Koneman EW, Allen SD, Procop GW, Janda WM, Schreckenberger PC. The nonfermentative gram-negative bacilli. In Koneman’s Colour Atlas and Textbook of Diagnostic Microbiology. Philadelphia: Lippincott Williams and Wilkins, 2006:304–391. Hsueh PR, Wu JJ, Hsiue TR, Hsieh WC. Bacteremic necrotizing fasciitis due to Flavobacterium odoratum. Clin Infect Dis 1995;21(5):1337–1338. Bachman KH, Sewell DL, Strausbaugh LJ. Recurrent cellulitis and bacteremia caused by Flavobacterium odoratum. Clin Infect Dis 1996;22(6):1112– 1113. Green BT, Green K, Nolan PE. Myroides odoratus cellulitis and bacteremia: case report and review. Scand J Infect Dis 2001;33(12):932–934. Ferrer C, Jakob E, Pastorino G, Juncos LI. Right-sided bacterial endocarditis due to Flavobacterium odoratum in a patient on chronic hemodialysis. Am J Nephrol 1995;15(1):82–84. Benedetti P, Rassu M, Pavan G, Sefton A, Pellizzer G. Septic shock, pneumonia, and soft tissue infection due to Myroides odoratimimus: report of a case and review of Myroides infections. Infection 2011;39(2):161–165. Yağci A, Cerikçioğlu N, Kaufmann ME, Malnick H, Söyletir G, Babacan F, Pitt TL. Molecular typing of Myroides odoratimimus (Flavobacterium odoratum) urinary tract infections in a Turkish hospital. Eur J Clin Microbiol Infect Dis 2000;19(9):731–732. Yoon J, Maneerat S, Kawai F, Yokota A. Myroides pelagicus sp. nov., isolated from seawater in Thailand. Int J Syst Evol Microbiol 2006;56(Pt 8):1917–1920. Zhang XY, Zhang YJ, Chen XL, Qin QL, Zhao DL, Li TG, Dang HY, Zhang YZ. Myroides profundi sp. nov., isolated from deep-sea sediment of the southern Okinawa Trough. FEMS Microbiol Lett 2008;287(1):108– 112. Cho SH, Chae SH, Im WT, Kim SB. Myroides marinus sp. nov., a member of the family Flavobacteriaceae, isolated from seawater. Int J Syst Evol Microbiol 2011;61(Pt 4):938–941. Bachmeyer C, Entressengle H, Khosrotehrani K, Goldman G, Delisle F, Arlet G, Grateau G. Cellulitis due to Myroides odoratimimus in a patient with alcoholic cirrhosis. Clin Exp Dermatol 2008;33(1):97–98. Motwani B, Krezolek D, Symeonides S, Khayr W. Myroides odoratum cellulitis and bacteremia: a case report. Infect Dis Clin Pract 2004; 12(6):343–344. Spanik S, Trupl J, Krcmery V. Nosocomial catheter-associated Flavobacterium odoratum bacteraemia in cancer patients. J Med Microbiol 1998;47(2):183. Prieur D, Colombani JC, Michelon G. Bacteriemie a Flavobacterium odoratum. Med Mal Infect 1988;18(10):466–467. Ktari S, Mnif B, Koubaa M, Mahjoubi F, Ben Jemaa M, Mhiri MN, Hammami A. Nosocomial outbreak of Myroides odoratimimus urinary tract infection in a Tunisian hospital. J Hosp Infect 2012;80(1):77–81. Myroides odoratimimus bacteremia in a diabetic patient 343 Right-sided hydropneumothorax as a presenting symptom of Boerhaave’s syndrome (spontaneous esophageal rupture) Supannee Rassameehiran, MD, Saranapoom Klomjit, MD, and Kenneth Nugent, MD Boerhaave’s syndrome, or spontaneous esophageal rupture, is a rare condition that classically presents with Mackler’s triad of vomiting, subcutaneous emphysema, and severe sudden onset of chest pain and requires immediate medical attention. Approximately 90% of the perforations occur at the left lateral aspect of the distal esophagus, causing a left-sided pleural effusion. Less than 10% of patients have bilateral effusions, and few patients have a right-sided pleural effusion only. We present the case of a 59-year-old man with spontaneous esophageal rupture. His clinical presentation is of interest since he had no inciting event for spontaneous esophageal rupture and had a delayed presentation with a right-sided hydropneumothorax. B oerhaave’s syndrome, or spontaneous esophageal rupture, is a life-threatening condition that requires prompt diagnosis and treatment. Delayed diagnosis may result in serious complications, including mediastinitis, pneumonitis, pericarditis, empyema, and death. We report an atypical presentation of Boerhaave’s syndrome with no vomiting, with progressive right-sided chest pain and shortness of breath of 2 weeks’ duration, and with a right-sided hydropneumothorax. CASE REPORT A 59-year-old man with a history of hypertension presented with worsening right-sided chest pain and progressive shortness of breath of 2 weeks’ duration. The patient had reported mild constant right-sided chest pain over the past year. The chest pain was pleuritic in nature. He denied fevers, chills, productive cough, nausea, and vomiting. The patient had a history of upper gastrointestinal bleeding 4 months prior to presentation while taking meloxicam. He underwent esophagogastroduodenoscopy, which showed benign esophageal ulcers in the middle thoracic esophagus from 26 to 29 cm and in the distal esophagus from 33 to 36 cm, as well as chronic gastritis. He took oral omeprazole 20 mg twice a day and stopped taking meloxicam. He started to take one or two 7.5 mg tablets of meloxicam a day to relieve the chest pain without taking omeprazole for 1 week before his current presentation. He denied reflux symptoms, a history of heavy lifting or straining, a history of chest trauma, peptic ulcer disease, or alcohol or steroid use. 344 His blood pressure was 114/66 mm Hg; heart rate, 123 beats/ min; respiratory rate, 21 breaths/min; and temperature, 36.7°C (98°F). His body mass index was 20.3 kg/m2. The jugular veins were not distended. Breath sounds were decreased in the right lower field, with corresponding dullness on percussion. There was no murmur, subcutaneous emphysema, or Hamman’s crunch. The abdomen was soft without tenderness. The bowel sounds were normal. Initial laboratory tests revealed the following: white blood cell count, 26,570/μL with 95% polymorphonuclear cells; hemoglobin, 10.7 g/dL; blood urea nitrogen, 31 mg/dL; creatinine, 0.9 mg/dL; and albumin, 2.7 g/dL. All other laboratory results were unremarkable. His initial chest radiograph revealed a right-sided hydropneumothorax (Figure 1). A thoracostomy tube was placed into the right chest, resulting in the drainage of 1 L of brownish purulent material. Pleural fluid analysis showed a pH of 7.2. Gram stain of the pleural fluid showed a few white blood cells; many Gram-positive cocci in pairs, chains, and clusters; moderate Gram-positive rods; few Gram-negative rods; and few yeast. Computed tomography (CT) of the chest revealed moderate right pleural effusion, small right pneumothorax, consolidation/atelectasis in the right lower lobe with air bronchograms, and thickening of the distal esophagus and gastroesophageal junction. The patient had video-assisted thorascopic surgery 2 days after admission. Gastrointestinal contents were found in the pleural cavity. At this point, the diagnosis of Boerhaave’s syndrome was suspected, and the procedure was converted to an open thoracotomy. The patient had a hiatal hernia and a distal esophagus perforation measuring approximately 2.5 cm. A distal esophageal resection and gastrostomy tube placement were performed. The biopsy report of the distal esophagus showed intestinal metaplasia and ulcer without dysplasia or malignancy. The patient’s postoperative course was complicated by sepsis and acute renal failure. The pleural culture grew Citrobacter freundii; blood cultures were negative. He was continued on meropenem and fluconazole. His renal function returned to From the Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas. Corresponding author: Supannee Rassameehiran, MD, Department of Internal Medicine, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430 (e-mail: Supannee.Rassameehiran@ttuhsc.edu). Proc (Bayl Univ Med Cent) 2015;28(3):344–346 Figure 1. Chest radiograph demonstrates right hydropneumothorax. normal. The chest tubes, drains, and gastrostomy tube were discontinued, and the patient was discharged on day 19 of admission. DISCUSSION Boerhaave’s syndrome is a rare condition, with an incidence of 7.4 per 10 million per year (1). It is associated with substantial morbidity and has a mortality rate of at least 20% (1–3). This condition is caused by an acute increase in intraluminal esophageal pressure as the result of retching or vomiting causing perforation at the weak point of the esophageal wall, which is the left posterolateral wall of the distal esophagus (4). There are anatomical reasons to explain this location, including thinning of the muscle in the distal esophagus, weakening of its wall as a result of vessels and nerves entering it, anterior angulation at the left diaphragmatic crus, and lack of adjacent support- ing structures (5). The classical clinical presentation, Meckler’s triad, is severe vomiting and retching followed by severe sudden onset of chest pain and subcutaneous emphysema (6). However, some reviews point out that the presence of the entire triad is rare, and reliance on a classic presentation may lead to delayed diagnosis, resulting in mediastinitis, pneumonitis, pericarditis, empyema, and increased mortality (5, 7). Mediastinal pleura rupture from acute intraabdominal pressure elevation or digestion by gastric contents will lead to leakage of air and fluid into the pleural space, causing pleural effusion, pneumothorax, or hydropneumothorax. Approximately 90% of patients have left-sided pleural effusions, 5% to 10% of patients have bilateral effusions, and few patients have an effusion on the right side only (8). Only five cases have been reported to present with right-sided effusions in the past 10 years (Table 1) (9–12). Table 1. Patients with spontaneous esophageal perforation who presented with right-sided pleural effusions, 2005 to 2015 First author, year of publication (ref) Age (years) Gender Underlying disease Vomiting Days from prior to Perforation presentation presentation length to diagnosis Treatment Outcome Rokszin, 2011 (9) 53 Male GERD, BE, rectal cancer Yes 5–7 mm – Endoscopic closure Survived Hingston, 2010 (10) 84 Female Osteopenia treated with alendronic acid 5 h before presentation Yes 6 cm 3 Gastric port and bilateral chest tube drainage Survived Cascio, 2010 (11) 45 Female Alcoholism, pregnancy No – 8 Right chest tube drainage; Died primary repair of esophagus Khan, 2005 (12) 61 Male Spontaneous esophageal rupture 26 mo earlier, BE Yes 2 cm – Primary repair of esophagus Survived Khan, 2005 (12) 51 Male Spontaneous esophageal rupture 27 mo earlier, BE Yes 3 cm – Conservative treatment Survived BE indicates Barrett esophagus; GE, gastroesophageal; GERD, gastroesophageal reflux disease; –, no information available. July 2015 Right-sided hydropneumothorax as a presenting symptom of Boerhaave’s syndrome 345 The diagnosis of Boerhaave’s syndrome is made primarily from clinical presentation and radiographic evidence. A posteroanterior and lateral chest radiograph is the best method to see indirect signs of esophageal perforation, since up to 90% of patients have abnormal chest x-ray findings, including pleural effusion, pneumothorax, hydropneumothorax, pneumomediastinum, widening mediastinum, and subcutaneous emphysema. However, an immediate chest x-ray after esophageal perforation may be normal, as a pneumomediastinum will take at least an hour to develop and a pleural effusion may take several hours to become discernable (13). A water-soluble contrast swallow study is recommended to confirm the diagnosis by showing leakage of contrast into the mediastinum and/or pleural cavity and to identify the anatomical site of perforation. CT of the chest and upper abdomen with oral contrast can also show the site of perforation and the degree of contamination. Given current access to CT and oral contrast studies, the diagnosis of esophageal rupture was missed and found only at autopsy in only 17% of patients in a recent study (1). Early recognition and operative repair are the mainstays of treatment and provide better outcomes. Dasari and colleagues summarized 27 case series using esophageal stents in patients with esophageal anastomotic leaks and benign perforations. These series included 340 patients, and technical and clinical success rates with stenting were 91% and 81%, respectively. However, 187 patients required thoracotomy procedures, including chest tubes and surgery (14). Salo reported his experience with Boerhaave’s syndrome over a three-decade period. His approach includes early antibiotics, a CT study of the thorax and upper abdomen, emergency endoscopy to evaluate the rupture and tissue vitality, and primary esophageal repair with fundic reinforcement when possible. Mortality has fallen from 50% to 5%; all aspects of current management appear to have contributed to this improvement (15). Conservative treatment can be an option for selected patients with small and contained intrathoracic esophageal ruptures (16). Unusual presentations should be kept in mind while evaluating patients with hydropneumothorax, even on the right side. The only risk factor that might explain esophageal rupture in our patient is nonsteroidal antiinflammatory drug use with a history of esophageal ulcer when he was taking this drug in the 346 past. Our patient had a delayed presentation with a right-sided hydropneumothorax, required surgery, and had a prolonged 19-day hospital course. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Vidarsdottir H, Blondal S, Alfredsson H, Geirsson A, Gudbjartsson T. Oesophageal perforations in Iceland: a whole population study on incidence, aetiology and surgical outcome. Thorac Cardiovasc Surg 2010;58(8):476–480. Ryom P, Ravn JB, Penninga L, Schmidt S, Iversen MG, Skov-Olsen P, Kehlet H. Aetiology, treatment and mortality after oesophageal perforation in Denmark. Dan Med Bull 2011;58(5):A4267. Bhatia P, Fortin D, Inculet RI, Malthaner RA. Current concepts in the management of esophageal perforations: a twenty-seven year Canadian experience. Ann Thorac Surg 2011;92(1):209–215. Garas G, Zarogoulidis P, Efthymiou A, Athanasiou T, Tsakiridis K, Mpaka S, Zacharakis E. Spontaneous esophageal rupture as the underlying cause of pneumothorax: early recognition is crucial. J Thorac Dis 2014;6(12):1655–1658. Jagminas L, Silverman RA. Boerhaave’s syndrome presenting with abdominal pain and right hydropneumothorax. Am J Emerg Med 1996;14(1):53–56. Curci JJ, Horman MJ. Boerhaave’s syndrome: the importance of early diagnosis and treatment. Ann Surg 1976;183(4):401–408. Jones WG 2nd, Ginsberg RJ. Esophageal perforation: a continuing challenge. Ann Thorac Surg 1992;53(3):534–543. Janjua KJ. Boerhaave’s syndrome. Postgrad Med J 1997;73(859):265–270. Rokszin R, Simonka Z, Paszt A, Szepes A, Kucsa K, Lazar G. Successful endoscopic clipping in the early treatment of spontaneous esophageal perforation. Surg Laparosc Endosc Percutan Tech 2011;21(6):e311–312. Hingston CD, Saayman AG, Frost PJ, Wise MP. Boerhaave’s syndrome— rapidly evolving pleural effusion: a radiographic clue. Minerva Anestesiol 2010;76(10):865–867. Cascio A, Barone M, Micali V, Iaria C, Delfino D, David A, Monaco M, Monaco F. On a fatal case of Candida krusei pleural empyema in a pregnant woman with spontaneous esophagus perforation. Mycopathologia 2010;169(6):451–455. Khan OA, Barlow CW, Weeden DF, Amer KM. Recurrent spontaneous esophageal rupture. Eur J Cardiothorac Surg 2005;28(1):178–179. Wu JT, Mattox KL, Wall MJ Jr. Esophageal perforations: new perspectives and treatment paradigms. J Trauma 2007;63(5):1173–1184. Dasari BV, Neely D, Kennedy A, Spence G, Rice P, Mackle E, Epanomeritakis E. The role of esophageal stents in the management of esophageal anastomotic leaks and benign esophageal perforations. Ann Surg 2014;259(5):852–860. Salo J, Sihvo E, Kauppi J, Rasanen J. Boerhaave’s syndrome: lessons learned from 83 cases over three decades. Scand J Surg 2013;102(4):271–273. Cameron JL, Kieffer RF, Hendrix TR, Mehigan DG, Baker RR. Selective nonoperative management of contained intrathoracic esophageal disruptions. Ann Thorac Surg 1979;27(5):404–408. Baylor University Medical Center Proceedings Volume 28, Number 3 Pneumomediastinum in inflammatory bowel disease Nino Mihatov, MD, and Andrew Z. Fenves, MD A 28-year-old man with a history of inflammatory bowel disease (IBD) developed sudden-onset chest pain and dyspnea 9 days after esophagogastroduodenoscopy and colonoscopy. A chest radiograph demonstrated pneumomediastinum tracking along the left heart border. The spontaneous pneumomediastinum was presumed to be a complication of his severe colitis. The severity of our patient’s symptoms ultimately necessitated a subtotal colectomy, a decision unrelated to the pneumomediastinum. IBD-associated pneumomediastinum can be attributed to retroperitoneal air leakage from severe colitis and usually resolves with conservative management. P neumomediastinum, often associated with diseases of or traumatic injury to the airway, is a rare complication of inflammatory bowel disease (IBD). In IBD, pneumomediastinum is most frequently a procedural complication associated with esophageal microperforation during esophagogastroduodenoscopy or colonic perforation during colonoscopy (1). We present a patient with severe IBD who developed spontaneous pneumomediastinum. CASE REPORT A 28-year-old man with an 11-month history of IBD presented to an outside hospital with 6 weeks of fatigue, severe abdominal pain, diarrhea, and hematochezia. He was treated for an IBD flare with corticosteroids, mesalamine, and infliximab. He underwent a flexible sigmoidoscopy that demonstrated extensive rectal inflammation and ulceration suggestive of ulcerative colitis. After 3 weeks of persistent symptoms, he was transferred to our hospital for further management and surgical evaluation. Prior to his admission, he was taking mesalamine, prednisone, and hydrocortisone enemas. He was a graduate student who occasionally drank alcohol but had never smoked or used illicit substances. He had no known drug allergies. His family history was notable for colon cancer in his paternal grandfather and liver cancer in his maternal uncle. On admission to our hospital, he was afebrile, with a heart rate of 84 beats/minute, blood pressure of 100/60 mm Hg, and oxygen saturation of 94% on room air. He appeared uncomfortable and was vomiting. His cardiopulmonary examination disclosed no abnormalities. His abdomen was mildly distended and tender to palpation without organomegaly. Rectal examination revealed few external hemorrhoids without fissures or masses. Proc (Bayl Univ Med Cent) 2015;28(3):347–349 The patient’s hemoglobin was 8.1 g/dL and the hematocrit was 24.5%. His white blood cell count, platelet count, basic chemistries, prothrombin time, and partial thromboplastin time were normal. The serum albumin was 2.5 g/dL. The serum iron was 17 mcg/dL, iron binding capacity was 212 mcg/dL, and ferritin was 16 ng/mL. A chest radiograph was normal. On hospital day 2, the patient underwent an esophagogastroduodenoscopy that demonstrated a normal esophagus, stomach, and duodenum. Colonoscopy with biopsy revealed severe inflammation from the rectum to the transverse colon and discontinuously in the cecum in a pattern suggestive of Crohn’s disease. Corticosteroids and infliximab were continued. On day 11 of hospitalization, 9 days after the procedure, the patient developed sudden-onset chest pain and dyspnea. He was no longer vomiting and had not been retching or coughing. The chest pain worsened with positional changes and inspiration. He remained hemodynamically stable. Examination of the chest revealed palpable subcutaneous crepitus over both sternoclavicular joints. Lungs were clear to auscultation bilaterally. An anteroposterior chest radiograph showed pneumomediastinum tracking along the left cardiac border and superiorly in the bilateral soft tissues of the upper mediastinum and neck (Figure 1a). A barium swallow study revealed a normally distensible esophagus with no areas of abnormal contrast retention or extravasation (Figure 2). Computed tomography (CT) of the chest with oral contrast demonstrated contrast in the esophagus without obvious defect of the esophageal wall or extravasation of esophageal contrast (Figure 3). Further CT of the abdomen with oral and intravenous contrast demonstrated mild wall thickening of the distal descending and rectosigmoid colon with pericolonic stranding consistent with inflammatory bowel disease. The small bowel was normal. There was no evidence of toxic megacolon or retroperitoneal free air. With cessation of oral intake and intravenous broadspectrum antibiotics, the chest pain and dyspnea decreased. Radiographically, the patient had progressive reduction in the From the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Corresponding author: Nino Mihatov, MD, Massachusetts General Hospital, Harvard Medical School, Department of Medicine, 55 Fruit Street, GRB 740, Boston, MA 02114 (e-mail: nmihatov@partners.org). 347 a b Figure 1. Chest radiograph (a) at the onset of symptoms, with mediastinal air (white arrows) evident along the left heart border and upper mediastinum, and (b) 9 days later, with resolution of the previously demonstrated pneumomediastinum. degree of mediastinal air with resolution by day 9 following the onset of symptoms (Figure 1b). The patient continued to have abdominal pain refractory to medical therapy. A repeat flexible sigmoidoscopy demonstrated worse colitis compared to the prior colonoscopy. The patient underwent an uncomplicated laparoscopic subtotal colectomy with ileostomy on hospital day 16. He was discharged on day 21. Pathology of the excised colon revealed severely active chronic colitis without dysplasia or granulomas. There was no evidence of colonic perforation. Figure 2. Barium swallow study at the time of symptom onset demonstrating contrast in the esophagus and gastric fundus without evidence of contrast extravasation or esophageal wall defect. 348 DISCUSSION Pneumomediastinum is an overall rare finding characterized by free air within the mediastinum. Some principal causes include 1) blunt trauma to the chest; 2) increased alveolar pressure and rupture from coughing, straining, emesis, or positive pressure ventilation; 3) gas-forming organisms driving an infectious process in the neck, chest, or oropharynx; and 4) a complication from esophageal or colonic instrumentation and subsequent perforation (1–4). Spontaneous pneumomediastinum is defined by the absence of a clear inciting cause for mediastinal air accumulation. There are nine reported cases of spontaneous pneumomediastinum in association with inflammatory bowel disease, most commonly ulcerative colitis, and in the absence of evidence of perforation (5–12). In our patient who was not coughing or actively vomiting and had no underlying lung disease or perforation of a viscous, the spontaneous pneumomediastinum was thought to be a complication of his severe colitis. Symptoms of pneumomediastinum include dyspnea, chest pain, and neck pain. Examination often reveals subcutaneous crackling in the neck and cervical soft tissue reflective of free air (13). Pneumomediastinum can be diagnosed with plain chest radiographs and confirmatory CT. Identifying the cause of the pneumomediastinum can prove difficult. In IBD, severe inflammation facilitates forcible herniation of colonic mucosa, allowing microscopic perforations to develop that are permeable to air (7). The risk of colonic perforation in patients with ulcerative colitis, in particular, has been correlated to the severity of symptoms (14). The retroperitoneum communicates with the mediastinum and subcutaneous tissue through the visceral space, one of three described compartments of the neck (4). The visceral space follows the trachea and esophagus into the chest and creates a tract for air between the mediastinum and the neck. The space continues inferiorly through the diaphragmatic hiatus into the retroperitoneum. Baylor University Medical Center Proceedings Volume 28, Number 3 a b Figure 3. (a) Axial and (b) coronally reformatted CT images of the chest with intravenous contrast and oral contrast ingested at the time of image acquisition. Oral contrast is seen in the distal esophagus with no evidence of extravasation (black arrow). Mediastinal air is seen throughout the mediastinum, particularly along the heart border with extension to the soft tissue of the neck (white arrows). The overall rarity of pneumomediastinum makes validating an optimal management strategy difficult. In general, management of pneumomediastinum requires surgical correction of any mucosal disruption, treatment of any infectious causes, and elimination of contributors to increased alveolar pressure such as bronchospasm or positive-pressure ventilation (4). In spontaneous pneumomediastinum, nonoperative management is often most effective (2, 15, 16). In IBD-associated pneumomediastinum, management of IBD symptoms has been reported to result in resolution of mediastinal air (6, 8, 11, 12). Although the decision to pursue surgery in this case was unrelated to the pneumomediastinum, persistent pneumomediastinum may reflect a severe degree of colitis that may necessitate surgical intervention. Pneumomediastinum should be considered in a patient with severe IBD symptoms who acutely develops pleuritic chest pain and dyspnea. An exhaustive search for a primary cause of pneumomediastinum, most notably colonic or esophageal perforation following instrumentation, should be undertaken. In the absence of a clear cause, pneumomediastinum can be attributed to retroperitoneal air leakage from severe colitis and should resolve with conservative management. 1. 2. 3. Cappello M, Randazzo C, Peralta S, Cocorullo G. Subcutaneous emphysema, pneumomediastinum and pneumoperitoneum after diagnostic colonoscopy for ulcerative colitis: a rare but possible complication in patients with multiple risk factors. Int J Colorectal Dis 2011;26(3):393–394. Park NS, Choi JH, Lee DH, Kim YJ, Kim ES, Jung SW, Koo JS, Lee HS, Lee SW. Pneumoretroperitoneum, pneumomediastinum, pneumopericardium, and subcutaneous emphysema after colonoscopic examination. Gut Liver 2007;1(1):79–81. Dehal A, Tessier DJ. Intraperitoneal and extraperitoneal colonic perforation following diagnostic colonoscopy. JSLS 2014;18(1):136–141. July 2015 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Maunder RJ, Pierson DJ, Hudson LD. Subcutaneous and mediastinal emphysema. Pathophysiology, diagnosis, and management. Arch Intern Med 1984;144(7):1447–1453. Mogan GR, Sachar DB, Bauer J, Salky B, Janowitz HD. Toxic megacolon in ulcerative colitis complicated by pneumomediastinum: report of two cases. Gastroenterology 1980;79(3):559–562. Annaházi A, Polyák I, Nagy F, Wittmann T, Molnár T. “Ulcerative crepitus”—a case with subcutaneous emphysema and pneumomediastinum without colonic perforation or toxic megacolon in ulcerative colitis successfully treated conservatively. J Crohns Colitis 2012;6(6):717–719. Cohen ME, Kleinman MS. Pneumomediastinum during relapse of ulcerative colitis. Am J Gastroenterol 1997;92(12):2306–2307. Martín Castillo A, Pons Miñano JA, Riquelme Riquelme J, Parrilla Paricio P. Retroperitoneal perforation, pneumomediastinum and subcutaneous emphysema in severe ulcerative colitis. Gastroenterol Hepatol 2003;26(4):275. Badina L, Ferrara G, Guastalla P, Barbi E. A precordial rub in a boy with a severe attack of ulcerative colitis. Pediatr Emerg Care 2014;30(4):268. Blanchet E, Kull E, Beau P. Pneumomediastinum without colonic perforation during a severe attack of ulcerative colitis. Gastroenterol Clin Biol 2001;25(12):1121–1123. Alvares JF, Dhawan PS, Tibrewala S, Shankaran K, Kulkarni SG, Rananavare R, Kalro RH. Retroperitoneal perforation in ulcerative colitis with mediastinal and subcutaneous emphysema. J Clin Gastroenterol 1997;25(2):453–455. Cooke AA, Deshpande AV, Shun A, O’Loughlin EV. Pneumomediastinum and subcutaneous emphysema in a child with ulcerative colitis. Pediatr Emerg Care 2010;26(2):129–131. Baumann MH, Sahn SA. Hamman’s sign revisited. Pneumothorax or pneumomediastinum? Chest 1992;102(4):1281–1282. De Dombal FT, Watts JM, Watkinson G, Goligher JC. Intraperitoneal perforation of the colon in ulcerative colitis. Proc R Soc Med 1965;58(9):713–715. Waye JD, Kahn O, Auerbach ME. Complications of colonoscopy and flexible sigmoidoscopy. Gastrointest Endosc Clin N Am 1996;6(2):343–377. Winek TG, Mosely HS, Grout G, Luallin D. Pneumoperitoneum and its association with ruptured abdominal viscus. Arch Surg 1988;123(6): 709–712. Pneumomediastinum in inflammatory bowel disease 349 Pulmonary veno-occlusive disease as a cause of pulmonary arterial hypertension Mateo Porres-Aguilar, MD, Ihsan Al-Bayati, MD, Mateo Porres-Muñoz, MD, Osvaldo Padilla, MD, Saad H. Syed, MD, Kevin Lowder, Komola Azimova, Jerry Fan, Debabrata Mukherjee, MD, and Aamer Abbas, MD Pulmonary veno-occlusive disease (PVOD) represents a rare form of precapillary pulmonary arterial hypertension. We present a young patient hospitalized with progressive dyspnea, with initial workup suggestive of pulmonary hypertension and unexplained noncardiogenic pulmonary edema. His subsequent clinical course was consistent with the diagnosis of PVOD. Pulmonary veno-occlusive disease (PVOD) represents an uncommon form of pulmonary arterial hypertension (PAH) characterized by progressive obliteration of the pulmonary venules, elevation of pulmonary arterial pressures, and increased pulmonary vascular resistance, leading to right ventricular failure and death (1–3). PVOD shares similar characteristics with idiopathic PAH, which can easily lead to misdiagnosis among these two entities. Based on data from the French pulmonary hypertension registry, the annual incidence of PVOD is low (4). A less-invasive diagnostic approach utilizing high-resolution computed tomography (CT) of the chest, arterial blood gases, pulmonary function tests, and appropriate hemodynamic interpretation of right-sided heart catheterization could be useful for the detection of PVOD (2). CASE PRESENTATION A 19-year-old man was brought to the hospital by his mother in an acute confusional state after being found lying on the floor and responding slowly to verbal and tactile stimuli. According to his mother, the patient had smoked spice (herbal mixtures of synthetic cannabinoid compounds) and complained of progressive dyspnea for the past 3 months. He smoked cigarettes, weed, and spice and drank alcohol. On admission he was hypoxic, with an oxygen saturation of 84% on room air. He had clubbing of fingernails and an accentuated second pulmonic heart sound. A chest radiograph showed enlarged pulmonary arteries and mild interstitial prominence (early pulmonary edema). A 12lead electrocardiogram showed right axis deviation, incomplete right bundle branch block, and right ventricular hypertrophy. A CT scan of the chest with contrast showed diffuse bilateral confluent ground-glass opacities, septal line thickening with bilateral small pleural effusions, a mildly enlarged right atrium, mildly enlarged mediastinal and hilar lymphadenopathies, and 350 a dilated pulmonary trunk (Figure 1). A transthoracic echocardiogram showed a severely dilated right atrium and ventricle, a flattened ventricular septum, and an estimated right ventricular systolic peak pressure of 79 mm Hg. A ventilation/perfusion lung scan was negative for chronic thromboembolic pulmonary hypertension. Right-sided heart catheterization showed severe PAH with a mean pulmonary artery pressure of 56 mm Hg, pulmonary arterial occlusion pressure measured in different lung zones at 3 to 4 mm Hg, cardiac output of 4.2 L/min, and calculated pulmonary vascular resistance of 13.32 Wood units (Figure 2). The patient was discharged on oral diuretics, home oxygen, and low-dose warfarin. DISCUSSION The annual incidence of PVOD is approximately 0.1 to 0.2 cases per million in the general population per year. However, since 5% to 10% of PVOD cases are misdiagnosed as idiopathic PAH, the actual incidence rate may be higher (1). PVOD poses a diagnostic challenge given the overlapping features and similarities with idiopathic PAH (Table 1). Hemodynamic evaluation is necessary to differentiate between suspected cases of PAH and PVOD. Both of these conditions show evidence of severe PAH with an elevated resting mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery occlusion pressure ≤15 mm Hg (2). While the right atrial pressure is higher in idiopathic PAH, it is lower in PVOD. Another distinguishing finding in PVOD is normal or low pulmonary artery occlusion pressure (5, 6). The use of pulmonary vasodilators does not appear to help in the management of PVOD or in predicting the risk From the Department of Internal Medicine (Porres-Aguilar, Al-Bayati, Syed), Department of Pathology (Padilla), Division of Cardiovascular Diseases (Mukherjee, Abbas), and medical student (Lowder, Azimova, Fan), Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, Texas; and Universidad Autonoma de Tamaulipas School of Medicine and Division of General Internal Medicine, Beneficencia Española de Tampico, Tampico, Mexico (Porres-Muñoz). Corresponding author: Mateo Porres-Aguilar, MD, Department of Internal Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, 4800 Alberta Avenue, El Paso, TX 79905 (e-mail: mateo.porres@ttuhsc.edu). Proc (Bayl Univ Med Cent) 2015;28(3):350–352 Figure 1. CT scan of the thorax with intravenous contrast showing confluent groundglass opacities (white arrow), thickened septal lines (top black arrow), and mild bilateral pleural effusion (bottom black arrow), which are highly suggestive of PVOD. of pulmonary edema in the long term (7). One exception to this may be the use of intravenous epoprostenol, which led to significant improvements in symptoms, exercise capacity, quality of life, cardiopulmonary hemodynamics, and survival without significant development of pulmonary edema in a few studies of patients with PVOD (8). Histological analysis of lung biopsy is the “gold standard” for definitive diagnosis of PVOD (1). However, since this invasive procedure poses many risks, it is important to seek alternative, less-invasive tools, such as high-resolution CT and right-sided heart catheterization, which may be utilized to make an accurate diagnosis and distinguish PVOD from PAH. High-resolution CT of the chest in PVOD is characterized by 1) centrilobular ground-glass opacities, 2) septal lines, and 3) mediastinal lymphadenopathy. In contrast, normal lung parenchyma is noted among patients with idiopathic PAH (2, 5). The combination of these three CT findings is present in up to 75% of histologically proven cases, with a sensitivity of 75% and specificity of 84.6% (1). Hence, CT represents an important diagnostic tool. PVOD is a progressive condition that is managed symptomatically. The prognosis appears to be more dismal than for idiopathic PAH, with a 1-year mortality rate as high as 75% (2). Studies have shown that the average time from first symptom onset to death or lung transplantation was significantly Figure 2. Hemodynamic tracings during right heart catheterization. (a) Pulmonary arterial occlusion pressure of 1 to 2 mm Hg. (b) Mean pulmonary arterial pressure of 56 mm Hg. July 2015 Pulmonary veno-occlusive disease as a cause of pulmonary arterial hypertension 351 Table 1. A comparison of selected characteristics of idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease Characteristic Idiopathic pulmonary arterial hypertension Pulmonary veno-occlusive disease Anatomic site affected Precapillary arteriolar vascular remodeling Postcapillary venular proliferation Gender predominance Female predominance Female:Male ≈ 1:1 Tobacco exposure Unrelated More frequent/higher exposure High-resolution chest computed tomography Normal findings Ground-glass opacities, thickening of septal lines, mediastinal lymphadenopathies, bilateral pleural effusions Hemodynamics RAP is usually high (≥10 mm Hg), PAOP is usually low (≤15 mm Hg) RAP is usually lower (<5 mm Hg), as is PAOP (≤5 mm Hg) Response to pulmonary vasodilators Improves hemodynamics, functional status, and survival Increased risk of pulmonary edema RAP indicates right atrial pressure; PAOP, pulmonary artery occlusion pressure. lower in severe PVOD cases than in idiopathic PAH cases, indicating that PVOD is more severe and progressive. Therapy is primarily focused on symptomatic management due to limited definitive treatment options for PVOD. Lung transplantation represents the treatment of choice and is the only therapeutic option capable of improving survival in patients with PVOD. Single- and double-lung transplantation procedures have both been used. Therefore, early diagnosis and lung transplantation are key prognostic factors in PVOD. 1. 2. 3. 352 Montani D, Price LC, Dorfmuller P, Achouh L, Jaïs X, Yaïci A, Sitbon O, Musset D, Simonneau G, Humbert M. Pulmonary veno-occlusive disease. Eur Respir J 2009;33(1):189–200. Huertas A, Girerd B, Dorfmuller P, O’Callaghan D, Humbert M, Montani D. Pulmonary veno-occlusive disease: advances in clinical management and treatments. Expert Rev Respir Med 2011;5(2):217–229. Dai Z, Matsui Y. Pulmonary veno-occlusive disease: an 80-year-old mystery. Respiration 2014;88(2):148–157. 4. Montani D, Achouh L, Dorfmüller P, Le Pavec J, Sztrymf B, Tchérakian C, Rabiller A, Haque R, Sitbon O, Jaïs X, Dartevelle P, Maître S, Capron F, Musset D, Simonneau G, Humbert M. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore) 2008;87(4):220–233. 5. Frazier AA, Franks TJ, Mohammed TL, Ozbudak IH, Galvin JR. From the Archives of the AFIP: pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Radiographics 2007;27(3):867–882. 6. El-Gabaly M, Farver CF, Budev MA, Mohammed TL. Pulmonary capillary hemangiomatosis imaging findings and literature update. J Comput Assist Tomogr 2007;31(4):608–610. 7. Kothari SS, Jagia P, Gupta A, Singh N, Ray R. Images in cardiovascular medicine. Pulmonary capillary hemangiomatosis. Circulation 2009;120(4):352–354. 8. Montani D, O’Callaghan DS, Savale L, Jaïs X, Yaïci A, Maitre S, Dorfmuller P, Sitbon O, Simonneau G, Humbert M. Pulmonary venoocclusive disease: recent progress and current challenges. Respir Med 2010;104(Suppl 1):S23–S32. Baylor University Medical Center Proceedings Volume 28, Number 3 Pulmonary artery catheter–induced perforation treated with coil embolization Darpan S. Kumar, MD, Christopher Trotter, MD, Douglas McDonald, MD, and Timothy A. Mixon, MD The past 40 years have taught us much about the use of pulmonary artery catheters and their complications. Pulmonary artery rupture carries high morbidity and mortality, and therefore a high index of suspicion and timely management are key to the survival of patients who suffer from this rare complication. While surgical therapy has been considered the mainstay of treatment, endovascular therapy is feasible when surgery is not possible or desirable, as demonstrated in our patient. It is unknown which approach is optimal. W e present a case describing the diagnosis and management of a woman who underwent diagnostic right-sided heart catheterization resulting in iatrogenic left lower lobe pulmonary artery (PA) branch perforation managed utilizing endovascular coil embolization. Figure 1. Development of large left-sided hemothorax noted on fluoroscopy. CASE HISTORY A 74-year-old woman was admitted to the hospital with dyspnea and volume overload, as evidenced by pulmonary vascular congestion on chest x-ray, as well as a B-type natriuretic peptide level of 376 pg/mL and lower extremity edema on examination. She had a body mass index of 45 kg/m2 and a history of cerebrovascular accident, coronary artery disease, and atrial fibrillation treated with warfarin. A transthoracic echocardiogram revealed an ejection fraction of 65% with increased right atrial and right ventricular sizes and a right ventricular peak systolic pressure of 60 mm Hg. Despite aggressive diuresis, the patient remained dyspneic and therefore the decision was made to perform diagnostic heart catheterization. The patient’s anticoagulation was discontinued and the international normalized ratio was 1.8 on the day of the procedure. Right-sided heart catheterization via a right femoral vein approach revealed a right atrial pressure of 29/27, right ventricle pressure of 84/17, PA systolic pressure of 78/39, and PA wedge pressure of 36 mm Hg. The PA catheter balloon was wedged in the left lobe without incident, but it was noted upon deflation of the balloon that the PA catheter dove deep into the left lower lobe lung field, and this was subsequently pulled back. Given the elevated pulmonary wedge pressure in the presence of normal systolic function, we then proceeded with left-sided heart catheterization via a right femoral artery approach. Once the left ventricle was entered with Proc (Bayl Univ Med Cent) 2015;28(3):353–354 a pigtail catheter, we proceeded with reinflation of the PA catheter balloon to obtain simultaneous wedge and left ventricular diastolic pressures to evaluate for possible mitral valve disease. At this time the patient was noted to have a small amount of hemoptysis, which subsequently progressed to massive hemoptysis. The patient was emergently intubated with a dual lumen endotracheal tube. Fluoroscopy of the chest wall revealed a large left-sided hemothorax (Figure 1). Immediate administration of fresh frozen plasma and blood products was initiated. Vasopressor support was administered with multiple rounds of intravenous epinephrine followed by a norepinephrine infusion. Selective arteriography of the left PA revealed an actively extravasating branch in the left lower lobe (Figure 2a). The branch was embolized with four 5/3 0.035 Tornado Platinum coils (Cook Medical, Bloomington, IN), which resulted in cessation of flow on postembolization arteriography (Figure 2b). The left hemothorax was treated with fluoroscopic-guided chest tube placement at the same time. From the Division of Cardiology (Kumar, Trotter, Mixon) and the Department of Radiology (McDonald), Baylor Scott & White Healthcare, Temple, Texas. Corresponding author: Darpan S. Kumar, MD, Division of Cardiology, Baylor Scott & White Healthcare, 2401 S. 31st Street, Temple, TX 76508 (e-mail: DKumar@ sw.org). 353 b a Figure 2. Arteriography images (a) showing the actively extravasating branch of the left lower lobe pulmonary artery subselected during pulmonary arteriography and (b) after coil embolization of the previously extravasating branch of the left lower lobe pulmonary artery. The patient was subsequently transferred to the intensive care unit (ICU) where her stay was further complicated by the development of loculations consisting of pus and blood in the left lower lobe, resulting in concomitant pneumonia and acute respiratory distress syndrome. Subsequent fiberoptic bronchoscopy with clot evacuation was then performed with placement of a second chest tube. She remained in the ICU for approximately 7 days, after which she was successfully extubated and transferred to the medical floor in stable condition. Although she suffered great morbidity as a result of a rare complication that occurred during her catheterization procedure, emergent coil embolization saved her life and led to her eventual discharge from the hospital on day 14. surgical management of PA rupture utilizing lobectomy, pneumonectomy, and hilar clamping with direct arterial repair or PA ligation are some of the options available to the surgeon (6). More recently a less invasive option for treatment that has emerged is transcatheter embolization utilizing steel coils, liquids (sobutyl-2-cyano-acrylate), absorbable gelatin sponges, or detachable balloons (7). The stainless steel coil, introduced in 1975 by Gianturco et al, was initially intended for arterial occlusions, control of hemorrhage, and management of arteriovenous fistulas, malformations, and aneurysms (8). While catheter-based embolization has been used extensively for these indications, it has only recently been described for the treatment of PA perforation (9). DISCUSSION The use of PA catheters to estimate right-sided heart and PA pressures was first described in 1970 and expanded our understanding and guided our therapies of the most complex cardiovascular patients (1). Documented complications including venous damage, valvular damage, arrhythmias, catheter knotting, balloon rupture, pulmonary embolism, pulmonary hemorrhage, PA rupture, bacteremia, and death usually arise either as a result of insertion or of maintenance of the catheter (2–4). While the rate of major/potentially life-threatening complications (ventricular arrhythmias, endocarditis, valve rupture, septicemia, pulmonary hemorrhage/infiltrates) and minor complications of this procedure has been reported to be as high as 23%, a retrospective chart review involving 32,442 inpatients revealed an observed PA rupture rate of 0.031% of catheter insertions (5, 6). The most common risk factors leading to PA rupture, all of which were present in our patient, include systemic anticoagulation, pulmonary hypertension, female gender, and age >60 years. The overall mortality rate from PA rupture approaches 70% (6). In the intraoperative setting (e.g., coronary artery bypass surgery), 1. 354 2. 3. 4. 5. 6. 7. 8. 9. Swan HJ, Ganz W, Forrester J, Marcus H, Diamond G, Chonette D. Catheterization of the heart in man with use of a flow-directed balloontipped catheter. N Engl J Med 1970;283(9):447–451. Sprung CL, Elser B, Schein RM, Marcial EH, Schrager BR. Risk of right bundle-branch block and complete heart block during pulmonary artery catheterization. Crit Care Med 1989;17(1):1–3. Lipp H, O’Donoghue K, Resnekov L. Intracardiac knotting of a flowdirected balloon catheter. N Engl J Med 1971;284(4):220. Boscoe MJ, de Lange S. Damage to the tricuspid valve with a Swann-Ganz catheter. Br Med J (Clin Res Ed) 1981;283(6287):346–347. Boyd KD, Thomas SJ, Gold J, Boyd AD. A prospective study of complications of pulmonary artery catheterizations in 500 consecutive patients. Chest 1983;84(3):245–249. Kearney TJ, Shabot MM. Pulmonary artery rupture associated with the Swan-Ganz catheter. Chest 1995;108(5):1349–1352. Abreu AR, Campos MA, Krieger BP. Pulmonary artery rupture induced by a pulmonary artery catheter: a case report and review of the literature. J Intensive Care Med 2004;19(5):291–296. Chuang VP, Wallace S, Gianturco C, Soo CS. Complications of coil embolization: prevention and management. AJR Am J Roentgenol 1981;137(4):809–813. Gottwalles Y, Wunschel-Joseph ME, Hanssen M. Coil embolization treatment in pulmonary artery branch rupture during Swan-Ganz catheterization. Cardiovasc Intervent Radiol 2000;23(6):477–479. Baylor University Medical Center Proceedings Volume 28, Number 3 A hybrid repair of a superior mesenteric artery pseudoaneurysm using open mesenteric bypass and endovascular exclusion Todd A. Cumbie, MD, John C. Kedora, MD, Gregory J. Pearl, MD, and William P. Shutze, MD Superior mesenteric artery (SMA) aneurysms and pseudoaneurysms are uncommonly encountered in vascular surgery practice, but they typically require repair. Historically, they have been repaired with open aneurysmorrhaphy, bypass and exclusion, or simple ligation. More recently, endovascular repair with coil embolization and stent graft exclusion have been advocated. We present a repair of an SMA pseudoaneurysm via a hybrid approach with common hepatic artery to SMA bypass, exclusion of the pseudoaneurysm with ligation of the SMA proximal to the bypass, plug occlusion of the proximal SMA, and coil embolization of the pseudoaneurysm. S uperior mesenteric artery (SMA) aneurysms and pseudoaneurysms are rare entities being encountered more frequently secondary to increased utilization of abdominal imaging (1, 2). When SMA aneurysms and pseudoaneurysms are discovered, most surgeons elect to repair them because of the 35% mortality rate associated with rupture, acute thrombosis, or embolization to the small bowel (3). Traditionally, repair has consisted of open SMA bypass with exclusion of the aneurysm or aneurysmorrhaphy. There have been multiple recent reports of endovascular repair either by stent graft exclusion or coil embolization of the aneurysm. We report a case of a 4.5-cm mid-SMA pseudoaneurysm repaired by a hybrid technique with open bypass and endovascular exclusion. CASE DESCRIPTION In 2008, a 76-year-old woman presented to an outside hospital with ischemic colitis. At that time, she underwent a total abdominal colectomy with end ileostomy followed by a complicated SMA stenting procedure. The patient had a long segment chronic dissection of the SMA that was treated with three 6 × 20 mm balloon expandable stents from the ostium of the SMA to mid-SMA. This procedure was complicated by the most proximal stent being misdeployed, with half of the stent residing outside the SMA in the aorta. Ultimately, this stent was snared and removed via an open femoral cutdown. The patient subsequently came under our care for right lower extremity tissue loss in December 2011. An angiogram was performed that incidentally demonstrated a large mesenteric aneurysm. Computed tomography (CT) angiogram delineated Proc (Bayl Univ Med Cent) 2015;28(3):355–357 Figure 1. Preoperative CT angiogram demonstrating a 4.5-cm superior mesenteric artery pseudoaneurysm (arrow). the anatomy most clearly (Figure 1). An abdominal aortogram showed the large aneurysm involving the origin of the SMA and the stents (Figure 2). The patient was then sent to the operating room for a hybrid open/endovascular repair of this pseudoaneurysm. We performed a common hepatic artery (CHA) to mid-SMA bypass with reversed greater saphenous vein. The SMA distal to the aneurysm, but proximal to the bypass anastomosis, was ligated to occlude the outflow of the pseudoaneurysm. The proximal SMA stent was cannulated from a femoral approach using a renal doublecurve guiding catheter, and using the telescope technique, we advanced the guide catheter over a glide catheter and Bentson wire (Olympus America, Center Valley, PA) into the aneurysm. We then deployed an 8-mm Amplatzer plug (St. Jude Medical, St. Paul, MN) within the proximal stent after withdrawing the guide sheath into the aorta. This effectively occluded the inflow into the pseudoaneurysm. The exposed pseudoaneurysm was From Waco Surgical Group, Waco, Texas (Cumbie) and the Division of Vascular Surgery, Baylor University Medical Center at Dallas (Kedora, Pearl, Shutze). Corresponding author: William P. Shutze, MD, Texas Vascular Associates, 621 N. Hall Street, Suite 100, Dallas, TX 75226 (e-mail: willshut@sbcglobal.net). 355 Figure 2. Abdominal aortogram demonstrating a very large aneurysm involving the origin of the superior mesenteric artery (SMA) and the SMA stents (arrow). The SMA can be seen filling distal to the aneurysm. accessed from the abdomen with a 5 French sheath and the pseudoaneurysm was evacuated. Several intravascular coils were deployed into the pseudoaneurysm sac through the 5 French sheath (Boston Scientific, Marlborough, MA). The sheath was removed and the access site oversewn with 5-0 Prolene (Ethicon US, Somerville, NJ). The completion angiogram showed exclusion of the pseudoaneurysm sac with excellent filling of the distal SMA via the CHA-to-SMA bypass (Figure 3). The patient recovered uneventfully and was discharged home on postoperative day 7. CT angiogram was performed prior to discharge and confirmed exclusion of the pseudoaneurysm with sac shrinkage and patency of the CHA-to-SMA bypass (Figure 4). At 3-month follow-up, the patient continued to be asymptomatic. She died at another facility 4 months after the procedure due to line sepsis. DISCUSSION SMA pseudoaneurysms and aneurysms are rarely encountered but can potentially lead to significant morbidity and mortality (4). Historically, SMA aneurysms resulted from infections. However, more recently, atherosclerosis and collagen vascular disease have been reported as more common etiologies. Additionally, SMA pseudoaneurysms can occur from arterial dissection, pancreatitis, trauma, and iatrogenic sources (3). Typically, SMA aneurysms affect the proximal 5 cm of the SMA. Approximately 90% of patients are symptomatic with abdominal pain or nausea and vomiting. They may also present with gastrointestinal hemorrhage. Half of patients will have a pulsatile mass or bruit (5). SMA aneurysms and pseudoaneurysms have usually been repaired with aneurysmorrhaphy, exclusion, and bypass or, in some cases, ligation. The perioperative mortality ranges from 1.3% to 5%, with morbidity rates close to 10% (6, 7). Excellent 356 Figure 3. Intraoperative completion sagittal angiogram demonstrating the proximal superior mesenteric artery (SMA) stent occluded by an Amplatzer plug (thin white arrow), the stent within the SMA as it exits the pseudoaneurysm (thick black arrow), the clip occluding SMA outflow (thin black arrow), and coils within the pseudoaneurysm sac. long-term results have been achieved, with surgical repair providing good survival rates and protection from late aneurysmrelated adverse events (6, 7). More recently, endovascular means to treat these aneurysms have been employed, with case reports and case series detailing both endovascular stent graft exclusion and coil embolization (3, 7). The ability to use endovascular techniques is limited by challenging target vessel access, arterial tortuosity, and the necessity to preserve side branches at or near Figure 4. Postoperative CT angiogram demonstrating the excluded superior mesenteric artery pseudoaneurysm without flow (arrow). Baylor University Medical Center Proceedings Volume 28, Number 3 the repair site; therefore, only a few totally endovascular repairs have been reported (7). Long-term follow-up in the endovascularly treated patients is not available, and the durability of these repairs is not firmly established. Our patient’s SMA pseudoaneurysm likely arose from previous manipulation with balloon-expandable stents within a chronic dissection. A totally endovascular repair was considered but abandoned due to the angulation constraints of the proximal inflow of the pseudoaneurysm and the outflow vessel. It did not appear that the anatomy of the SMA would accommodate a covered stent graft without causing significant kinking of the stent graft (Figure 2). A totally open operative repair of the SMA pseudoaneurysm was considered. However, because of the close proximity of the SMA pseudoaneurysm to the aorta, proximal control would have been obtained on the supraceliac aorta before opening the aneurysm, and an aorto-mesenteric bypass would have been necessary. Therefore, we chose a hybrid approach for this particular anatomy. The inflow to the pseudoaneurysm was excluded by an endovascular plug, avoiding the morbidity associated with supraceliac aortic cross-clamping. The SMA was ligated and revascularized distally with an extra-anatomic bypass. Coils were placed directly into the sac to ensure sac thrombosis. Complications of endovascular therapy can lead to challenging anatomic situations. Pure endovascular or surgical rescue July 2015 will often suffice. At times, a combination of these modalities is the best approach, as exemplified by this case. Utilizing both endovascular and open techniques can minimize the complexity and morbidity of the open procedure while maintaining the durability of the pseudoaneurysm repair. 1. 2. 3. 4. 5. 6. 7. Dasari BV, Mullan M, Lau L, Loan W, Lee B. A 6.5-cm pseudoaneurysm of the superior mesenteric artery managed by primary surgical repair. Vascular 2011;21(1):39–42. Díaz E, Lozano FS, González S, Alcázar JA, Torres JA, Gónzalez-Porras JR, Gómez-Alonso A. Open and endovascular treatment of pseudoaneurysms of the superior mesenteric artery. Ann Vasc Surg 2010;24(5):690.e9–e12. Stone WM, Abbas M, Cherry KJ, Fowl RJ, Gloviczki P. Superior mesenteric artery aneurysms: is presence an indication for intervention? J Vasc Surg 2002;36(2):234–237; discussion 237. Shrikhande GV, Khan SZ, Gallagher K, Morrissey NJ. Endovascular management of superior mesenteric artery pseudoaneurysm. J Vasc Surg 2011;53(1):209–211. Nosher JL, Chung J, Brevetti LS, Graham AM, Siegel RL. Visceral and renal artery aneurysms: a pictorial essay on endovascular therapy. Radiographics 2006;26(6):1687–1704; quiz 1687. Pulli R, Dorigo W, Troisi N, Pratesi G, Innocenti AA, Pratesi C. Surgical treatment of visceral artery aneurysms: a 25-year experience. J Vasc Surg 2008;48(2):334–342. Marone EM, Mascia D, Kahlberg A, Brioschi C, Tshomba Y, Chiesa R. Is open repair still the gold standard in visceral artery aneurysm management? Ann Vasc Surg 2011;25(7):936–946. A hybrid repair of a superior mesenteric artery pseudoaneurysm using open mesenteric bypass and endovascular exclusion 357 Allergic acute coronary syndrome (Kounis syndrome) Sarfaraz Memon, MD, Lovely Chhabra, MD, Shihab Masrur, MD, and Matthew W. Parker, MD Anaphylaxis rarely manifests as a vasospastic acute coronary syndrome with or without the presence of underlying coronary artery disease. The variability in the underlying pathogenesis produces a wide clinical spectrum of this syndrome. We present three cases of anaphylactic acute coronary syndrome that display different clinical variants of this phenomenon. The main pathophysiological mechanism of the allergic anginal syndromes is the inflammatory mediators released during a hypersensitivity reaction triggered by food, insect bites, or drugs. It is important to appropriately recognize and treat Kounis syndrome in patients with exposure to a documented allergen. A cute coronary syndrome accompanying mast cell activation from allergic, hypersensitivity, or anaphylactoid reactions was first described by Kounis and Zavras in 1991 and has been referred to as “allergic angina” or “allergic myocardial infarction” (1, 2). The mechanism of Kounis syndrome (KS) involves release of inflammatory cytokines through mast cell activation, which leads to coronary artery vasospasm and/or atheromatous plaque erosion or rupture (2). KS has been described with multiple conditions, including a variety of environmental exposures and drugs (3). More recently, variant presentations of allergic angina have been described. In this case series, we describe three variable case presentations of anaphylactic ST elevations, which include ST-elevation myocardial infarction (MI) in the presence of underlying coronary artery disease and ST-elevation MI without underlying coronary artery disease (pure vasospasm). We also briefly review the existing literature on KS. CASE PRESENTATIONS Case 1 A 64-year-old man with known peripheral arterial disease, chronic obstructive pulmonary disease, coronary artery disease, dyslipidemia, and hypertension presented with pruritus, chest pain, dyspnea, and nausea immediately after having dinner at a restaurant including pea salad. The initial electrocardiogram demonstrated ST-segment elevations in leads II, III, and aVF (Figure 1a). The patient had a prior known allergic reaction (type 1) to peas and peanuts. His initial vital signs were a tem- 358 perature of 98°F, blood pressure of 81/60 mm Hg, respiration rate of 20 breaths/minute, and pulse of 91 beats/minute. Examination disclosed wheezing, generalized erythema, and weak peripheral pulses. His hemogram and basic chemistry panel were unremarkable except for a white blood cell count of 19,500/uL. Both the creatinine kinase and troponin I levels were normal (145 U/L, normal 24–204 U/L; and <0.30 ng/ mL, normal <0.30 ng/mL, respectively). Emergent coronary angiogram demonstrated moderate stenosis of the proximal and mid left anterior descending artery and the right coronary artery, with evidence of improvement in the stenosis with administration of intracoronary nitroglycerine (Figure 2). Diagnosis of coronary vasospasm was made secondary to anaphylactic reaction from pea ingestion. Treatment for anaphylaxis was initiated with intravenous hydrocortisone, diphenhydramine, and famotidine with improvement in pruritus, dyspnea, and chest discomfort. The patient’s blood pressure also improved to 120/60 mm Hg. Repeat electrocardiogram showed resolution of ST segment elevations (Figure 1b). He was discharged home. Case 2 A 54-year-old man with past Lyme disease, hypertension, hyperlipidemia, and gastroesophageal reflux disease presented after he was stung by a bee while working in the yard. He developed facial swelling and hypotension. Emergency medical services found him to be in respiratory distress associated with facial swelling. He was intubated and was administered intravenous diphenhydramine and methylprednisolone and inhaled albuterol. The initial electrocardiogram demonstrated ST elevations in the inferior leads (Figure 3a). The patient was started on intravenous fluids and heparin and was transferred to our hospital. On arrival, he was found to have transient complete heart block, which resolved after administration of diphenhydramine and methylprednisolone. Coronary angiography revealed severe 3-vessel disease but no acute culprit lesion (Figure 4). Based on the clinical data, coronary vasospasm as From the Department of Cardiovascular Medicine, Hartford Hospital, University of Connecticut School of Medicine, Hartford, Connecticut. Corresponding author: Sarfaraz Memon, MD, 80 Seymour Street, Hartford, CT 06102 (e-mail: sarfarazmemon.md@gmail.com). Proc (Bayl Univ Med Cent) 2015;28(3):358–362 a b Figure 1. Electrocardiograms in case 1. (a) Initial electrocardiogram demonstrates an ectopic atrial rhythm with an isolated sinus beat (third beat), inferior Q waves, and ST elevation in the inferior leads. (b) Repeat electrocardiogram shows Q waves in the inferior leads and resolution of inferior ST elevations. There is limb lead reversal. a b c Figure 2. Coronary angiogram in case 1. (a) A left anterior oblique cranial view shows left main coronary artery (LM), left circumflex artery (LCx) and left anterior descending artery (LAD). The arrow points to significant proximal LAD stenosis (a nonculprit lesion for the presentation). (b) The right coronary artery (RCA) shows evidence of distal stenosis (black arrow). (c) After administration of intracoronary nitroglycerine, the RCA stenosis demonstrated resolution consistent with coronary vasospasm (white arrow). July 2015 Allergic acute coronary syndrome (Kounis syndrome) 359 a b Figure 3. Electrocardiograms in case 2. (a) Initial electrocardiogram demonstrates ST elevations in the inferior leads. (b) Repeat electrocardiogram demonstrates resolution of ST elevations. a b Figure 4. Coronary angiogram in case 2. (a) Posteroanterior caudal view shows chronic multivessel coronary artery disease of the left main (LM) coronary artery, left anterior descending (LAD) artery, and left circumflex (LCx) artery (arrows). There was no acute culprit lesion. (b) Left anterior oblique projection of the right coronary artery (RCA) shows focal severe stenosis in the mid and distal RCA and mild to moderate atherosclerotic disease at other locations. 360 Baylor University Medical Center Proceedings Volume 28, Number 3 a b Figure 5. Electrocardiograms in case 3. (a) Initial electrocardiogram shows inferior lead ST elevations and premature ventricular complexes. (b) Repeat electrocardiogram demonstrates resolution of inferior lead ST elevations. Premature ventricular complexes and widespread T wave inversions are additional notable findings. the likely cause was considered in retrospect. The ST elevations resolved on a repeat electrocardiogram (Figure 3b). He was seen by a cardiothoracic surgery team and was scheduled for elective bypass surgery. Case 3 A 75-year-old man with known diabetes mellitus, hypertension, hyperlipidemia, and abdominal aortic aneurysm presented to our hospital with dysuria and fever. His urinalysis was positive for leukocyte esterase, a few red blood cells, and multiple leucocytes. He was given intravenous ceftriaxone for suspected urinary tract infection. After the administration of ceftriaxone, he immediately developed a generalized erythematous macular rash, hypotension, and tachycardia followed by pulseless electrical activity and cardiac arrest. Advanced cardiovascular life support was employed, including the use of intravenous July 2015 epinephrine per protocol. He had return of spontaneous circulation with complete neurological recovery. The electrocardiogram after return of the patient’s spontaneous circulation revealed ST segment elevations in inferior leads (II, III, and aVF) (Figure 5a), leading to activation of the cardiac catheterization laboratory team. The patient also received intravenous diphenhydramine, famotidine, and methylprednisolone. Subsequent electrocardiograms taken 5 and 15 minutes later showed normalization of ST segments (Figure 5b). His hemogram and basic chemistry panel were normal; the creatinine kinase was 145 U/L, and troponin I, <0.30 ng/mL. The patient was admitted and successfully extubated after a day. His urinary tract infection resolved, and he was discharged home in a stable condition. Prior to discharge, he underwent an elective nuclear stress test, which showed a small fixed apical anterolateral wall defect with no evidence of ischemia. Allergic acute coronary syndrome (Kounis syndrome) 361 DISCUSSION Three types of KS have been previously described (4). Type I includes patients with normal coronary arteries without predisposing factors for coronary artery disease in whom the acute allergic insult leads to coronary artery spasm with normal cardiac biomarkers or infarction with positive cardiac biomarkers. This variant represents a manifestation of endothelial dysfunction or microvascular angina (5). The type II variant includes patients with culprit but inactive preexisting atheromatous disease, in whom the allergic insult leads to plaque erosion or rupture, leading to acute myocardial infarction or coronary vasospasm with normal cardiac enzymes (4). The type III variant includes coronary artery stent thrombosis secondary to allergic reaction (4). The ischemia in allergic reaction is secondary to the release of inflammatory mediators, including histamine, tryptase, chymase, platelet-activating factor, cytokines, and prostaglandins, and leukotriene synthesis, which leads to coronary vasospasm (2). Vigorito et al previously reported a paradoxical vasoconstriction mediated by histamine-1 receptors (6). Multiple cases of KS have been reported in the literature (7). Our first two cases were a form of type 2 KS, and the third case represented a form of type 1 KS. The second patient experienced transient complete heart block with anaphylaxis and is the second such report of KS associated with complete heart block described in the literature (8). Our cases further support KS as a distinct phenomenon. Some authors have argued against the vasospastic process being the dominant underlying pathophysiological explanation for KS. It is well known that anaphylaxis causes systemic vasodilation and decreased venous return secondary to increased vascular permeability and subsequently may lead to a depressed cardiac output, resulting in coronary hypoperfusion and myocardial damage. Thus, differentiating primary myocardial damage secondary to mast cell activation from global myocardial hypoperfusion can be challenging and remains an alternative potential explanation for allergic acute coronary syndrome (elec- 362 trocardiographic ST elevations) (4). It is important to recognize these forms of KS to provide appropriate management and care. The diagnosis and treatment of KS can be indeed challenging, requiring attention to both the cardiac and anaphylactic pathophysiology concurrently. Treatment of KS requires thoughtful use of several common drugs. Morphine, an important drug for treating acute chest pain, should be avoided in KS, as it may potentially stimulate histamine release and exacerbate the pathologic cascade in KS. Beta-blockers also may potentiate coronary vasospasm if used in an acute exacerbation of KS due to an unopposed alpha adrenergic action. Epinephrine, which is used routinely for the treatment of anaphylaxis, should also be used with cautionary monitoring, as it may potentially worsen coronary vasospasm and aggravate coronary ischemia in KS (4). The primary focus of treatment of KS should be directed towards the allergic insult and removal of the offending allergens. 1. 2. 3. 4. 5. 6. 7. 8. Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract 1991;45(2):121–128. Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 2006;110(1):7–14. Rodrigues MC, Coelho D, Granja C. Drugs that may provoke Kounis syndrome. Braz J Anesthesiol 2013;63(5):426–428. Kounis NG. Coronary hypersensitivity disorder: the Kounis syndrome. Clin Ther 2013;35(5):563–571. Nikolaidis LA, Kounis NG, Gradman AH. Allergic angina and allergic myocardial infarction: a new twist on an old syndrome. Can J Cardiol 2002;18(5):508–511. Vigorito C, Poto S, Picotti GB, Triggiani M, Marone G. Effect of activation of the H1 receptor on coronary hemodynamics in man. Circulation 1986;73(6):1175–1182. Caglar FN, Caglar IM, Coskun U, Ugurlucan M, Okcun B. Kounis syndrome: myocardial infarction secondary to an allergic insult—a rare clinical entity. Acta Cardiol 2011;66(4):559–562. Kounis NG. Caspofungin-induced fatal complete heart block: Another manifestation of Kounis syndrome. J Pharmacol Pharmacother 2013;4(2):161–162. Baylor University Medical Center Proceedings Volume 28, Number 3 Blood cyst of the anterior mitral leaflet causing severe mitral regurgitation Suresh Madhavan, MD, DM, K. Jayaprakash, MD, DM, N. Jayaprasad, MD, DM, Gargi Sathish, DO, MS, and Raju George, MD, DM We report a case of blood cyst of the anterior mitral leaflet leading to severe mitral regurgitation and heart failure in a 70-year-old woman with no other factors that could explain the severe mitral regurgitation. B lood cysts of the cardiac valves are rare. They are relatively common in newborns, but disappear spontaneously during infancy in most cases. Finding a blood cyst on the mitral valve in an older adult prompted this case report. CASE REPORT A 70-year-old woman was admitted for progressive effort dyspnea and palpitation of 5 years’ duration and orthopnea and paroxysmal dyspnea for 6 months. She had no history of rheumatic fever. She had acute loss of vision in her left eye, diagnosed as retinal artery occlusion 3 weeks prior to the present admission. On examination, she was dyspneic and tachypneic, with a heart rate of 98 beats per minute. Her jugular venous pressure was 8 cm above the sternal angle. Both ankles were edematous, and her blood pressure was 100/80 mm Hg. Her heart was enlarged, and a systolic thrill and left parasternal heave were palpated. The first heart sound was soft, the second heart sound was widely split with an accentuated pulmonary component, and the left ventricular third heart sound was heard over the apex. There was a grade 4/6 pansystolic murmur at the apex, and it radiated to the back. An electrocardiogram showed sinus rhythm with a right axis deviation and left ventricular volume overload pattern. A chest radiograph showed cardiomegaly with pulmonary venous and arterial enlargement. A transthoracic echocardiogram showed a dilated left ventricle and a left atrium with an ejection fraction of 55%. A cystic swelling was attached to the atrial aspect of the anterior mitral leaflet, present during both systole and diastole (Figure 1a). The chordae and papillary muscles were normal. Severe mitral regurgitation was observed (Figure 1b). There was no regional wall motion abnormality or mitral annular calcium. Pulmonary arterial hypertension was estimated to be 64 mm Hg. Transesophageal examination confirmed the cystic swelling in the anterior mitral leaflet (Figure 1c) with severe mitral regurgitation (Figure 1d), with no other morphological changes in the mitral Proc (Bayl Univ Med Cent) 2015;28(3):363–364 valve apparatus (Video supplement). The coronary arteries were normal. The patient was treated with diuretics, digoxin, and vasodilators. Intraoperatively, surgeons noted a 16 mm round, bluish cystic swelling with a broad base attached to the atrial aspect of the anterior mitral leaflet. The patient subsequently underwent successful mitral valve replacement with a TTK Chitra tilting disc prosthesis. Histopathology revealed bloodfilled space lined with a single layer of endothelium consistent with a blood cyst. At 1-year follow up, the patient was clinically stable. DISCUSSION Intracardiac blood cysts are rare. Blood cysts are lined by flattened endothelial cells and filled with nonorganized blood (1). Generally blood cysts are small and round, although giant cysts have been reported. Their etiology is thought to be congenital or acquired. There are various theories regarding the origin of intracardiac blood cysts. Boyd’s theory states that during valvular development, blood is pressed into the crevices on the valvular surfaces of the cusps, which later gets sealed off (2). Kantelip’s theory proposes dilatation of the normal invagination of the valve cusp as the mechanism of genesis of the blood cyst (3). Blood cysts may be derived from ectatic blood vessels or angiomas. Inflammation, vagal stimulation, anoxia, and hemorrhagic diathesis could lead to sudden occlusion of small vascular channels and lead to subsequent hematoma formation in the subvalvular region. Congenital blood cysts of the heart valves are mostly seen on tricuspid and mitral valves of fetuses and infants. Autopsy reports of fetuses and infants have shown a higher occurrence of cardiac blood cysts (4), indicating that severe hypoxia or inflammation may be an etiology for the appearance of this entity. Blood cysts are often found in neonates dying of various causes and probably have no clinical significance. Blood cysts may persist and enlarge to form giant cysts of heart valves. Blood cysts are usually asymptomatic in adults and have often been discovered incidentally during routine echocardiographic From Government Medical College, Kottayam, Kerala State, India. Corresponding author: Suresh Madhavan, MD, DM, Government Medical College, Kottayam, Kerala State, India 686008 (e-mail: drsureshmadhavan76@ gmail.com). 363 a b c d Figure 1. Apical four-chamber echocardiography showing (a) a blood cyst of the anterior mitral leaflet and (b) severe mitral regurgitation. Transesophageal echocardiography showing (c) a blood cyst of the anterior mitral leaflet and (d) severe mitral regurgitation. evaluation. They can cause inflow and outflow obstruction and valvular regurgitation due to incomplete coaptation (5). Mitral regurgitation can also occur due to the mitral paraannular location of the cyst (6). Cysts may be a potential source of cerebrovascular embolism (7). There is not necessarily a correlation between the size of the cyst and hemodynamic consequences; even giant blood cysts can be asymptomatic and may be an incidental finding during echocardiography (8). There is no consensus regarding the management of blood cysts. Pelikan et al suggested that asymptomatic cysts, because of their benign character, can be monitored with echocardiography, and resection should be reserved for cysts that interfere with normal cardiac function (9). Paşaoğlu et al advised surgical excision of all cystic tumors of the heart, especially in a valvular location, because the precise diagnosis can be made only by intraoperative examination (10). Video supplement Transesophageal echocardiography at 130° showing the cyst in the atrial aspect of the anterior mitral valve leaflet (see www. BaylorHealth.edu/Proceedings/Documents/BUMC%20Proceedings/2015%20Vol%2028/No_3/28_3_Jayaprakash.mp4). 364 Burke A, Virmani R. Tumors of the Heart and Great Vessels (Atlas of Tumor Pathology, Third Series, Vol. 15). Washington, DC: American Registry of Pathology, 1996:171–177. 2. Boyd TA. Blood cysts on the heart valves of infants. Am J Pathol 1949;25(4):757–759. 3. Kantelip B, Satge D, Camilleri L, Chenard MP, De Riberolles C. Valvular cyst and atrioventricular canal in a child with trisomy 21. Ann Pathol 1994;14(2):101–107. 4. Zimmerman KG, Paplanus SH, Dong S, Nagle RB. Congenital blood cysts of the heart valves. Hum Pathol 1983;14(8):699–703. 5. Xie SW, Lu OL, Picard MH. Blood cyst of the mitral valve: detection by transthoracic and transesophageal echocardiography. J Am Soc Echocardiogr 1992;5(5):547–550. 6. Sekine S, Abe T, Kuribayashi R, Aida H, Seki K, Shibata Y. Mitral regurgitation caused by mitral paraannular cyst. J Heart Valve Dis 1997;6(1):67–68. 7. Kuvin J, Saha P, Rastegar H, Salomon RN, Pandian N, Denofrio D. Blood cyst of the mitral valve apparatus in a woman with a history of orthotopic liver transplantation. J Am Soc Echocardiogr 2004;17(5):480–482. 8. Abreu A, Galrinho A, Sá EP, Ramos S, Martins AP, Fragata J, Ferreira R. Hamartoma of the mitral valve with blood cysts: a rare tumor detected by echocardiography. J Am Soc Echocardiogr 1998;11(8):832–836. 9. Pelikan HM, Tsang TS, Seward JB. Giant blood cyst of the mitral valve. J Am Soc Echocardiogr 1999;12(11):1005–1007. 10. Paşaoğlu I, Doğan R, Nazli N, Güngen Y, Bozer AY. Blood cyst originating from tricuspid septal leaflet. J Cardiovasc Surg (Torino) 1991;32(5):589– 591. 1. Baylor University Medical Center Proceedings Volume 28, Number 3 Right-sided superior vena cava draining into the left atrium in a patient with persistent left-sided superior vena cava emptying into the right atrium diagnosed by echocardiography Courtney Clark, RDCS, and Lee MacDonald, MD We present a patient with an isolated right-sided superior vena cava draining into the left atrium with a persistent left-sided superior vena cava emptying into the right atrium. During an agitated saline injection into the patient’s right upper extremity intravenous line, the patient suffered an acute transient ischemic attack. To our knowledge, this is the only reported case of this rare anomaly incidentally uncovered during an echocardiogram with saline contrast study. A nomalous systemic venous connection with the left atrium (LA) is an unusual congenital cause of a rightto-left shunt. It is most commonly due to a persistent left-sided superior vena cava (SVC) draining into the LA (1). Less commonly, the right-sided SVC may drain into the LA. This occurrence is rare in the absence of other cardiac abnormalities (2). Here we present a rare cardiac congenital anomaly with double SVC drainage, with a right-sided SVC emptying into the LA and a persistent left-sided SVC emptying into the right atrium (RA). CASE PRESENTATION A 65-year-old man presented to the emergency department with a sudden onset of speech disturbances and left arm weakness. He was known to have had hypertension, pancreatitis, migraines, hyperlipidemia, and a cerebral brain abscess drained at the age of 22, resulting in a seizure disorder. He was not cyanotic. Due to his sudden onset of stroke symptoms, a transthoracic echocardiogram with agitated saline was done. A peripheral intravenous line in the patient’s right antecubital vein was used to inject agitated saline and evaluate for intracardiac shunting. During echocardiographic imaging, the agitated saline immediately entered the LA, bypassing the right side of the heart (Figure 1). Immediately following the injection of agitated saline, the patient had a sudden onset of left-sided weakness and speech disturbances and was ultimately diagnosed with a transient ischemic attack. In preparation for a transesophageal echocardiogram, an additional peripheral intravenous line was placed in the left antecubital vein. When the agitated saline was injected into the left arm, imaging demonstrated that it entered into the RA normally. A computed tomographic angiogram of the chest demonstrated a double SVC. The persistent left SVC Proc (Bayl Univ Med Cent) 2015;28(3):365–366 Figure 1. Echocardiographic apical four-chamber view. The agitated saline completely fills the left heart chambers after right antecubital venous injection. coursed through the left mediastinum and around the left side of the heart, where it emptied into the coronary sinus, which was significantly enlarged. This coronary sinus then emptied into the RA. The right SVC drained the right subclavian vein and coursed along the right mediastinum and emptied into the LA, just superior to the right upper pulmonary vein, producing a large right-to-left shunt (Figure 2). No significant connection From Swedish Medical Center, Englewood, Colorado. Corresponding author: Lee MacDonald, MD, Cardiac Catheterization Laboratory Director, Cardiology Section Chair, Assistant Chair of Medicine, Swedish Medical Center, 501 East Hampden Avenue, Englewood, CO 80113 (e-mail: Leem@ southdenver.com). 365 Figure 2. Chest computed tomography shows the right superior vena cava draining into the left atrium, with the persistent left-sided superior vena cava (filled with contrast) draining into the right atrium inferiorly. or communication was noted between the persistent left SVC and the right SVC. The patient recovered fully and was discharged after 1 week of hospitalization. Surgery was declined by the patient. DISCUSSION Persistent left SVC occurs in about 0.3% of the general population and in about 5% of patients with congenital heart disease. It is the most common form of anomalous systemic venous return (1). A left-sided SVC forms when the left anterior cardinal vein is not obliterated during normal fetal development. The persistent left SVC passes anterior to the left hilum 366 and lateral to the aortic arch before rejoining the circulatory system (3). The persistent left SVC drains into the coronary sinus or RA in 92% of patients. In the remaining 8%, the persistent left SVC drains into the LA. A right-sided SVC is present in 82% to 90% of patients with a persistent left SVC; in about 30% of these patients, the left innominate vein is present (4). This usually drains into the RA. A right-sided SVC that drains into the LA is a rare congenital abnormality, and only a few cases have been reported. In our patient, due to the injection of agitated saline into the right antecubital vein, the agitated saline traveled through the right SVC and then drained directly into the LA. These saline bubbles may have acted as small air emboli, progressing to the brain, resulting in a transient ischemic attack. If the intravenous access would have been in the left arm during the echocardiogram with agitated saline, the anomaly most likely would not have been identified, and the systemic venous-arterial connection may have been missed. When an agitated saline study was performed from the left upper extremity, transesophageal imaging demonstrated normal drainage through the left SVC into the RA. 1. Hulten EA, Pinto G, Weissman G, Fuisz A. Anomalous vena caval return to the left atrium. Circulation 2012;125(13):e525–e528. 2. Baggett C, Skeen SJ, Gantt DS, Trotter BR, Birkemeier KL. Isolated right superior vena cava drainage into the left atrium diagnosed noninvasively in the peripartum period. Tex Heart Inst J 2009; 36(6):611–614. 3. Pahwa R, Kumar A. Persistent left superior vena cava: an intensivist’s experience and review of the literature. South Med J 2003;96(5):528– 529. 4. Pretorius PM, Gleeson FV. Case 74: right-sided superior vena cava draining into left atrium in a patient with persistent left-sided superior vena cava. Radiology 2004;232(3):730–734. Baylor University Medical Center Proceedings Volume 28, Number 3 Spontaneous coronary artery dissection in a 22-year-old man on lisdexamfetamine Aasim M. Afzal, MD, MBA, Syed A. Sarmast, MD, Nicholas A. Weber, BA, and Jeffrey M. Schussler, MD Spontaneous coronary artery dissection (SCAD) is a rare cause of coronary events and sudden cardiac death. SCAD can present with a wide spectrum of clinical presentations and as an entity remains underrecognized. Several risk factors, such as female gender, peripartum and early postpartum state, and atherosclerotic disease, have been attributed to SCAD. Amphetamine use has been attributed to an increased risk for coronary artery events. We present a case of a 22-year-old man on lisdexamfetamine and no other significant medical history who presented with SCAD and was successfully treated with medical management. S pontaneous coronary artery dissection (SCAD) overall remains a relatively rare cause of acute coronary syndromes and tends to affect the young healthy population, with a female preponderance. SCAD resulting in acute coronary events has a high mortality rate, and its prompt recognition and treatment is vital. SCAD should be included as part of a complete differential in a population with identifiable risk factors. Amphetamines and cocaine have been identified as risk factors for SCAD. Lisdexamfetamine is an amphetamine commonly prescribed for the treatment of attention-deficit/ hyperactivity disorder (ADHD). We report a case of a 22-yearold on lisdexamfetamine who presented with SCAD and was successfully treated with medical management. CASE PRESENTATION A 22-year-old white man with ADHD presented to the emergency department with severe substernal chest pain 8 out of 10 on a pain scale with radiation to his left arm and neck associated with dyspnea, nausea, and vomiting. The pain started while he was bicycling and had resolved by the time he arrived at the emergency department. His only home medication was lisdexamfetamine, which he had been taking for about 5 months. He denied any drug or alcohol use, and his drug screen was positive for amphetamines (his prescribed medication). The electrocardiogram was normal and his initial troponin level was <0.05 μg/L. An echocardiogram showed ventricular septal hypokinesis with an ejection fraction of 60%. A second troponin test was positive at 2 μg/L and ultimately peaked at 24 μg/L. The patient was started on heparin, aspirin, metoprolol, and clopidogrel and was evaluated with a gated computed Proc (Bayl Univ Med Cent) 2015;28(3):367–368 tomography coronary angiogram (CTCA). The CTCA showed a density concerning for a dissection, with intramural hematoma within the proximal left anterior descending artery (LAD) (Figure 1a, 1b). Left-sided heart catheterization demonstrated a hazy area in the proximal LAD, consistent with dissection and adherent clot (Figure 1c). Intravascular ultrasound confirmed a dissection in the proximal LAD (Figure 1d). There was TIMI 3 flow in the LAD without evidence of compromised flow. He was medically treated with aspirin, statin, carvedilol, and lisinopril. The lisdexamfetamine was discontinued, and he was cautioned not to start it again. He remained symptom free and was discharged on the above-mentioned medications. At the 1-year mark, he was symptom free and was exercising regularly. Follow-up CTCA at 6 months showed complete resolution of both the dissection and the hematoma. DISCUSSION This is the first reported case of lisdexamfetamine associated with SCAD. It is unusual for young men to present with coronary dissection (which typically has a female predominance), suggesting that the amphetamine derivative played a role in the pathophysiology (1). There are isolated cases of methamphetamine causatively associated with SCAD (2). Lisdexamfetamine, an amphetamine-derived stimulant treatment used for ADHD, has been shown to have a safety profile similar to that of other medications in this group, but has been associated with increased risks of cardiovascular side effects (3, 4). Notable in this case is that CTCA was used as the initial test in evaluating the patient, especially given the low pretest probability for the presence of coronary disease. It can be a valuable tool in evaluating patients with SCAD (5). In this case, as in many cases where SCAD occurs, treatment should be individualized. Patients who are hemodynamically stable, without active symptoms, may be best treated with medications alone. In follow up, as in our case, many of those patients show From the Department of Internal Medicine (Afzal) and Division of Cardiology (Sarmast, Schussler), Baylor University Medical Center at Dallas and Baylor Hamilton Heart and Vascular Hospital; and Texas A&M College of Medicine (Schussler); and the University of Texas at Austin (Weber). Corresponding author: Jeffrey M. Schussler, MD, 621 N. Hall Street, Suite 400, Dallas, TX 75226 (e-mail: Jeffrey.Schussler@Baylorhealth.edu). 367 a b complete angiographic resolution of the dissection and do not need either angioplasty or surgery (6, 7). 1. 2. 3. 4. c d 5. 6. Figure 1. (a, b) Computed tomography coronary angiogram demonstrating an area of decreased density in the proximal left anterior descending artery (LAD) concerning for dissection and intramural hematoma (arrows). (c) Coronary angiogram with hazy area in the proximal LAD, concerning for dissection with thrombus (arrow). (d) Intravascular ultrasound confirming a proximal LAD dissection (arrows). 368 Baylor University Medical Center Proceedings 7. Saw J. Spontaneous coronary artery dissection. Can J Cardiol 2013;29(9):1027–1033. Kanwar M, Gill N. Spontaneous multivessel coronary artery dissection. J Invasive Cardiol 2010;22(1):E5–E6. Weisler R, Young J, Mattingly G, Gao J, Squires L, Adler L; 304 Study Group. Long-term safety and effectiveness of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. CNS Spectr 2009;14(10):573–585. Adler LA, Weisler RH, Goodman DW, Hamdani M, Niebler GE. Short-term effects of lisdexamfetamine dimesylate on cardiovascular parameters in a 4-week clinical trial in adults with attentiondeficit/hyperactivity disorder. J Clin Psychiatry 2009;70(12):1652–1661. Schroder C, Stoler RC, Branning GB, Choi JW. Postpartum multivessel spontaneous coronary artery dissection confirmed by coronary CT angiography. Proc (Bayl Univ Med Cent) 2006;19(4):338–341. Tweet MS, Hayes SN, Pitta SR, Simari RD, Lerman A, Lennon RJ, Gersh BJ, Khambatta S, Best PJ, Rihal CS, Gulati R. Clinical features, management, and prognosis of spontaneous coronary artery dissection. Circulation 2012;126(5):579–588. Maeder M, Ammann P, Angehrn W, Rickli H. Idiopathic spontaneous coronary artery dissection: incidence, diagnosis and treatment. Int J Cardiol 2005;101(3):363–369. Volume 28, Number 3 Worsening dyspnea in a 38-year-old woman D. Luke Glancy, MD, Douglas K. Mendoza, MD, and Radhakrishnan G. Nair, MD Figure 1. Electrocardiogram soon after admission showed left atrial enlargement (negative terminal P-wave deflection in lead V1 ≥ 0.1 mV and 0.04 s in duration) (2) and right ventricular enlargement (right axis deviation of the QRS complex and R/S ratio V1 > 1.0 with a negative T V1) (3). A 38-year-old Hispanic woman with longstanding exertional dyspnea sought medical attention because of the recent onset of paroxysmal nocturnal dyspnea. Cardiac physical examination revealed murmurs of mitral stenosis and regurgitation, a prominent a wave in the jugular venous pulse, and a loud pulmonic valvular closure sound. An electrocardiogram showed sinus rhythm, left atrial enlargement, right axis deviation of the QRS complex, and an R/S ratio in lead V1 > 1.0 with a negative T V1, suggesting right ventricular hypertrophy (Figure 1). At cardiac catheterization, the pressures (mm Hg) were 64/30 in the pulmonary artery, 65/8 in the right ventricle, a mean of 7 in the right atrium with a waves of 10 and v waves of 7, a mean of 26 with a waves of 17 and v waves of 38 in the pulmonary arterial wedge position, and 96/6 in the left ventricle. The cardiac output by thermodilution was 3.4 L/ min, which together with a 16 mm Hg mean diastolic pressure gradient between pulmonary arterial wedge and left ventricle gave a calculated mitral valve area of 0.7 cm2 (Figure 2). Angiocardiography revealed mild mitral regurgitation, trivial tricuspid regurgitation, and no aortic regurgitation. Rheumatic heart disease is the cause of mitral stenosis in most adults. Because of the steady decrease in the incidence of acute rheumatic fever over the past 75 years in the United States, Proc (Bayl Univ Med Cent) 2015;28(3):369–370 Figure 2. Simultaneous pulmonary arterial wedge and left ventricular pressure tracings showing a 16 mm Hg mean diastolic pressure gradient across the mitral valve (MVG). The pressure scale on each side of the tracing is in mm Hg. DFP indicates diastolic filling period. From the Sections of Cardiology, Department of Medicine, Louisiana State University Health Sciences Center and the Interim LSU Hospital, New Orleans, Louisiana. Currently, Dr. Mendoza is a cardiologist in Baton Rouge, Louisiana, and Dr. Nair is a cardiologist in Plano, Texas. Corresponding author: D. Luke Glancy, MD, 1203 West Cherry Hill Loop, Folsom, LA 70437 (e-mail: dglanc@lsuhsc.edu). 369 mitral stenosis is now uncommon here and is most often seen in older patients and, as in this patient, in immigrants from less developed countries (1). Clinical evaluation is usually sufficient for making a diagnosis of mitral stenosis (1). The electrocardiogram can be helpful in this regard, but the history, physical exam, chest radiograph, and especially the echocardiogram are usually more helpful. Nevertheless, electrocardiographic evidence of left atrial enlargement and right ventricular hypertrophy in a dyspneic young immigrant woman from an underdeveloped country puts mitral stenosis toward the top of the list of diagnostic possibilities. 1. 2. 3. Rahimtoola SH. Mitral stenosis. In Fuster V, Walsh RA, O’Rourke RA, Poole-Wilson P, eds. Hurst’s The Heart, 12th ed. New York: McGraw Hill Medical, 2008:1757–1769. Morris JJ Jr, Estes EH Jr, Whalen RE, Thompson HK Jr, McIntosh HD. P-wave analysis in valvular heart disease. Circulation 1964;29:242–252. Milliken JA, Macfarlane PW, Lawrie TDV. Enlargement and hypertrophy. In Macfarlane PW, Lawrie TDV, eds. Comprehensive Electrocardiology. Theory and Practice in Health and Disease, Vol. 1. New York: Pergamon Press, 1989:631–670. Avocations Cheetah and cub, Tanzania. Photo copyright © Jed Rosenthal, MD. Dr. Rosenthal is a cardiologist in Dallas, Texas (e-mail: jedr2@sbcglobal.net). 370 Baylor University Medical Center Proceedings Volume 28, Number 3 Chronic pulmonary embolism in a young athletic woman Timothy R. Larsen, DO, and Timothy C. Ball, MD, PhD Exercise-induced dyspnea (EID) is a common complaint in young athletes. Exercise-induced bronchospasm (EIB) is the most common cause of EID in healthy athletes, but it is important to recognize more serious pathology. Herein we present the case of an 18-year-old woman with a 1.5-year history of EID. She had been treated for EIB without relief. Her arterial oxygen saturation was 88% during exercise testing. Computed tomographic angiography to assess for vascular abnormalities identified a large thrombus in the main pulmonary trunk. Symptoms markedly improved with therapeutic anticoagulation. Massive pulmonary embolus is an exceedingly rare etiology of exertional dyspnea in young athletes. Hypoxemia during exercise testing was an important clue that something more ominous was lurking that required definitive diagnosis. E xercise-induced dyspnea (EID) is a common complaint in young athletes. Exertional dyspnea in young, otherwise healthy and active individuals can be challenging to diagnose and treat. Exercise-induced bronchospasm (EIB) is recognized as the most common cause of EID in otherwise healthy athletes (1). Patients with EIB typically experience wheezing, chest tightness, coughing, and dyspnea that is due to transient narrowing of the airways (bronchospasm) during or shortly after exercise (2). EIB affects approximately 10% to 15% (3) of the general population. Athletes (particularly varsity and elite athletes) show a much higher prevalence, around 40% (4, 5). The diagnosis of EIB is often made on the basis of self-reported symptoms without objective testing. This approach is neither sensitive nor specific (6). It is important for clinicians to recognize that EID in healthy adolescent athletes may have causes other than asthma (7). Alternative causes of EID should be sought when other symptoms of asthma are not present, bronchodilators do not completely prevent or promptly relieve EID, and baseline pulmonary function is normal (8). Correct diagnosis will not only prevent the use of medications destined to fail but will occasionally uncover potentially life-threatening disease. Herein we present a case of a young athlete with EID who was initially misdiagnosed and treated empirically for EIB, which led to delayed diagnosis of a life-threatening disease. CASE DESCRIPTION An 18-year-old woman presented to an outpatient cardiology clinic for evaluation of exertional dyspnea worsening over the past Proc (Bayl Univ Med Cent) 2015;28(3):371–374 1.5 years. Her medical history was significant for the diagnosis of exercise-induced asthma treated with as-needed short-acting bronchodilators. Her only other medication was an oral contraceptive (desogestrel-ethinyl estradiol 0.15–30 mg–mcg). She did not use tobacco, alcohol, or recreational or performanceenhancing drugs. She was an active athlete participating in varsity basketball, volleyball, and track. Approximately 1.5 years prior to presentation, she developed sudden worsening dyspnea with minimal exertion and associated presyncope. Symptoms were provoked by 5 minutes of aerobic exertion and relieved with <5 minutes of rest. She did not experience wheezing, and albuterol did not provide relief. Her blood pressure was 102/56 mm Hg; heart rate, 52 beats/minute; respiratory rate, 18 breaths/minute; resting oxygen saturation, 99% breathing ambient air; and body mass index, 21.3 kg/m2. She was physically fit, in no distress, and had no conversational dyspnea. Cardiac and pulmonary exams were normal. Her abdomen was soft, nontender, nondistended, and without masses or organomegaly. There was no peripheral edema; peripheral pulses were full and equal bilaterally. Further, there was no calf tenderness, and Homman’s sign was absent. Initial laboratory data revealed normal serum electrolytes, blood counts, and renal and liver function. Quantitative D-dimer was 0.42 ug FEU/mL (normal <0.48 ug FEU/mL). Chest x-ray showed subtle findings, including elevation of the left hemidiaphragm and a Westermark sign (cutoff of the left main pulmonary artery) (Figure 1). An electrocardiogram showed sinus bradycardia, normal intervals and voltage, and no ST segment abnormalities (Figure 2). Pulmonary function testing showed normal spirometry, lung volumes, and diffusing capacity; there was no change with bronchodilator. Resting transthoracic echocardiogram showed the left ventricular ejection fraction to be 60% to 65%. There was mild tricuspid regurgitation (maximum regurgitant velocity of 2.26 m/s), and the estimated pulmonary artery systolic pressure was 25 mm Hg. Right ventricular basal diameter was 42 mm (normal ≤ 42 mm); From the Section of Cardiology, Department of Internal Medicine, Virginia TechCarilion School of Medicine, Roanoke, Virginia. Corresponding author: Timothy R. Larsen, DO, Section of Cardiology, Department of Internal Medicine, Carilion Clinic, Virginia Tech Carilion School of Medicine, 2001 Crystal Spring Avenue, Suite 203, Roanoke, VA 24014 (e-mail: tlarsen17@ gmail.com). 371 was 170 beats/min (84% of her age-predicted maximum). Arterial oxygen saturation was 88% at peak exercise. Computed tomography (CT) angiogram of the chest showed a large intraluminal thrombus within the left main pulmonary artery extending into the right and left pulmonary arteries (Figure 4). The left pulmonary artery was completely occluded (Figure 5). Protein C activity was 116% (normal 70%–130%), protein S activity was 70% (normal 55%–123%), and antithrombin III activity was 92% (normal 80%–120%). Assays for cardiolipin IgG, IgM, and IgA were within the normal range. Two tests for lupus anticoagulant were negative (DRVVT screen and PTTLupus reagent). There was no evidence of activated protein C resistance. DNA testing for Factor V Leiden and prothrombin II gene mutations were negative. Therapeutic anticoagulation was started with warfarin. After 6 weeks of anticoagulation, she noted marked improvement in functional capacity, nearly back to previous baseline. A followup CT angiogram at 8 weeks showed marked improvement in thrombus burden. Figure 1. Chest x-ray showing cutoff of the left pulmonary artery, Westermark sign (arrow), and elevation of the left hemidiaphragm. mid ventricle, 32 mm (normal ≤ 35 mm); and longitudinal length, 56 mm (normal ≤ 86 mm) (Figure 3). Tricuspid annular plane systolic excursion (TAPSE) was 16.4 mm (abnormal ≤ 16 mm), and systolic excursion velocity was 10.57 cm/s (abnormal ≤ 10 cm/s). The patient exercised for 5:32 minutes on a Bruce treadmill protocol (maximum speed 3.4 mph, 14% grade). She reached 6.2 metabolic equivalents. Her maximum heart rate DISCUSSION Massive pulmonary embolus (PE) is an exceedingly rare etiology for exertional dyspnea in young athletes. Young athletes often do not present with classic symptoms associated with PE; thus, these patients are often treated for a number of other conditions before the correct diagnosis is reached (9). Hypoxemia during exercise testing was an important clue that something more ominous was lurking. Normal pulmonary function testing (spirometry, lung volumes, and diffusing capacity) make primary lung pathology less likely. Figure 2. Electrocardiogram demonstrating sinus bradycardia (heart rate 56 bpm), normal intervals and voltage, and no ST segment or T wave abnormalities. 372 Baylor University Medical Center Proceedings Volume 28, Number 3 Figure 5. CT angiogram with three-dimensional volume rendering in the anterior and posterior view demonstrating the absence of left pulmonary artery (PA) circulation. Figure 3. Transthoracic echocardiogram with an apical four-chamber view at end diastole demonstrating right ventricle (RV) dimensions at the upper limit of normal; an RV diameter at the base of 42 mm; mid ventricle 32 mm; and long axis 56 mm. The function of the left ventricle (LV) was normal. Causes of exertional dyspnea with hypoxia in a young athlete (with healthy lungs) are typically related to vascular abnormalities usually resulting in right-to-left shunting or large ventilation-perfusion defects (functional right-to-left shunt). Important considerations include anomalous venous return (10), intrapulmonary arteriovenous malformations (11), and intravascular obstruction (such as PE). Large occlusive PEs cause a functional right-to-left shunt. Shunting occurs due to severe ventilation-perfusion mismatch, which results in a large increase in total dead space with adjacent areas of excess perfusion (12). Shunting is more pronounced in the presence of an atrial septal defect or patent ductus arteriosus as pulmonary pressure increases (due to increased pulmonary vascular resistance) flow through the defect increases. Figure 4. CT angiogram demonstrating a large intraluminal filling defect in the main pulmonary trunk (arrow) extending into both the right and left pulmonary arteries. Note the paucity of vascular markings over the left lung field. July 2015 The test of choice for the diagnosis of pulmonary vascular disorders is pulmonary angiography and chest CT (13, 14). Once PE has been confirmed, interventions are targeted at disruption of the coagulation cascade to minimize ongoing thrombosis. Therapeutic anticoagulation is the mainstay of therapy. In patients with high-risk PEs (particularly cardiogenic shock and/ or persistent arterial hypotension), thrombolysis, percutaneous catheter embolectomy and fragmentation, and/or surgical embolectomy should be considered. A major clinical decision in our patient is the duration of anticoagulation. Indefinite anticoagulation reduces the risk of subsequent venous thromboembolism by approximately 90%; the major disadvantages are increased risk of bleeding and the inconvenience of anticoagulation over the lifetime of our young patient (15, 16). Plasma levels of D-dimer increase in the presence of acute thrombi. D-dimer has a low positive predictive value but a high negative predictive value. Barring laboratory error, our patient’s negative D-dimer may be due to chronic organized thrombus or may simply be a false negative. Our patient was investigated for hypercoagulable conditions with entirely normal results. The only identifiable risk factor for thromboembolism was the use of a combined oral contraceptive preparation. She had been taking an oral contraceptive prior to symptom onset and continued it until the time of diagnosis. While oral contraceptives increase the risk of venous thromboembolic disease by about 3 to 6 times that of similar patients not taking them, the absolute risk is still quite low, at 3 to 4 per 10,000 woman-years (17). The relative risk of thromboembolism in patients using oral contraceptives is about half that of pregnancy (18). A progestin-only preparation would be an appropriate substitution for future contraception while minimizing the risk of recurrent thromboembolism in a patient such as ours. (Our patient opted to forego hormonal prophylaxis.) While EIB is the most common cause of EID in young athletes, it is imperative that physicians recognize alarming features that may suggest more serious underlying pathology. Massive PE Chronic pulmonary embolism in a young athletic woman 373 is an exceedingly rare etiology of exertional dyspnea in otherwise healthy young athletes. Appropriate and timely intervention can prevent serious morbidity and mortality. 1. 2. 3. 4. 5. 6. 7. 8. 9. 374 Koehle M, Lloyd-Smith DR, McKenzie DC. Exertional dyspnea in athletes. Br Columbia Med J 2003;45(10):508–514. Godfrey S, Anderson SD, Silverman M. Physiologic aspects of exerciseinduced asthma. Chest 1973,63(Suppl):365–375. Seear M, Wensley D, West N. How accurate is the diagnosis of exercise induced asthma among Vancouver schoolchildren? Arch Dis Child 2005;90(9):898–902. Feinstein RA, LaRussa J, Wang-Dohlman A, Bartolucci AA. Screening adolescent athletes for exercise-induced asthma. Clin J Sport Med 1996;6(2):119–123. Parsons JP, Kaeding C, Phillips G, Jarjoura D, Wadley G, Mastronarde JG. Prevalence of exercise-induced bronchospasm in a cohort of varsity college athletes. Med Sci Sports Exerc 2007;39(9):1487–1492. Rundell KW, Im J, Mayers LB, Wilber RL, Szmedra L, Schmitz HR. Self-reported symptoms and exercise-induced asthma in the elite athlete. Med Sci Sports Exerc 2001;33(2):208–213. Löwhagen O, Arvidsson M, Bjärneman P, Jörgensen N. Exercise-induced respiratory symptoms are not always asthma. Respir Med 1999;93(10):734– 738. Abu-Hasan M, Tannous B, Weinberger M. Exercise-induced dyspnea in children and adolescents: if not asthma then what? Ann Allergy Asthma Immunol 2005;94(3):366–371. Koehle M, Lloyd-Smith DR, McKenzie DC. Exertional dyspnea in athletes. Br Columbia Med J 2003;45(10):508–514. 10. Valencia PA, Oeckler RA, Taggart NW, Bonnichsen CR. Levoatriocardinal vein: an unusual cause of hypoxemia in the intensive care unit. Am J Respir Crit Care Med 2014;A4842. 11. Weiss P, Rundell KW. Imitators of exercise-induced bronchoconstriction. Allergy Asthma Clin Immunol 2009;5(1):7–15. 12. Goldhaber SZ, Elliott CG. Acute pulmonary embolism: part I: epidemiology, pathophysiology, and diagnosis. Circulation 2003;108(22):2726– 2729. 13. Remy J, Remy-Jardin M, Giraud F, Wattinne L. Angioarchitecture of pulmonary arteriovenous malformations: clinical utility of three-dimensional helical CT. Radiology 1994;191(3):657–664. 14. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP; ESC Committee for Practice Guidelines (CPG). Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29(18):2276–2315. 15. Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet 1992;340(8824):873–876. 16. Schulman S; Duration of Anticoagulation Study Group. The effect of the duration of anticoagulation and other risk factors on the recurrence of venous thromboembolisms. Wien Med Wochenschr 1999;149(2–4):66–69. 17. Vandenbroucke JP, Rosing J, Bloemenkamp KW, Middeldorp S, Helmerhorst FM, Bouma BN, Rosendaal FR. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001;344(20):1527–1535. 18. Weiss G. Risk of venous thromboembolism with third-generation oral contraceptives: A review. Am J Obstet Gynecol 1999;180(2 Pt 2):295–301. Baylor University Medical Center Proceedings Volume 28, Number 3 Nonhepatic hyperammonemic encephalopathy due to undiagnosed urea cycle disorder Tashfeen Mahmood, MD, and Kenneth Nugent, MD Ornithine transcarbamoylase deficiency is the most common inherited urea cycle disorder. In adults, its phenotypes are diverse. In asymptomatic patients with late presentations, symptom onset is often associated with a precipitating factor. We present a case of a woman with urea cycle disorder diagnosed after an acute peptic ulcer bleed and fasting. U rea cycle disorders are commonly seen in the pediatric population. Several enzymes are involved in this cycle, and a defect in any of them can lead to specific laboratory abnormalities and variable clinical presentations. Deficiency of the enzyme ornithine transcarbamoylase (OTC) is the most common inherited urea cycle disorder. In adults, its phenotypes range from severe encephalopathy to subtle psychiatric manifestations to apparently asymptomatic states. Among asymptomatic patients with late presentations, symptom onset may be associated with a precipitating factor, such as trauma, surgery, infection, and/or increased protein intake. We present a case of a woman who had undiagnosed urea cycle disorder that was unmasked by an acute peptic ulcer bleed and fasting for several days. CASE REPORT A 35-year-old white woman with prior peptic ulcer disease and menorrhagia was taken to a local emergency department for an altered level of consciousness and transferred to our medical intensive care unit. She had been alone for 5 days when her family found her lethargic, confused, and minimally responsive. The patient apparently had been withdrawn for 1 year with low self-esteem, occasionally stating that she wished she were dead. Home medications included pantoprazole and norgestimate/ ethinyl estradiol. She was currently single and unemployed and had few friends and no children. Examination disclosed normal vital signs. Neurological examination revealed a minimally responsive woman without apparent focal deficits and normal reflexes. She had no nuchal rigidity. Initial laboratory work showed a normal metabolic panel, thyroid function tests, and liver function tests, including aminotransferases, albumin, bilirubin, and prothrombin time. She had anemia with a hemoglobin of 8.1 g/dL, a guaiac-positive stool, and a ferritin level of 8 ng/mL (reference range, 12–150 ng/mL). A urine drug screen Proc (Bayl Univ Med Cent) 2015;28(3):375–377 was negative; acetaminophen, alcohol, and salicylate levels were undetectable. Computed tomography (CT) and magnetic resonance images of the head were within normal limits. On the night of admission, the patient had an episode of hematemesis, and her hemoglobin dropped to 6.6 g/dL. The next morning she had decerebrate posturing to pain, a decline in responsiveness, twitching movements in her left leg, and plantar flexion of both feet. A repeat CT scan was normal, and electroencephalography did not reveal any subclinical epileptiform discharges. She was intubated, and an esophagogastroduodenoscopy showed an actively bleeding duodenal ulcer that was cauterized. Her ammonia level was 593 mcg/dL (reference range, 15–45 mcg/dL). The patient was started on lactulose, rifaximin, and a low-protein diet. Her subsequent ammonia level in 4 hours dropped to 266 mcg/dL, which continued to improve over the next few hours. A liver ultrasound was within normal limits, and her liver enzymes were normal throughout her hospitalization. She gradually improved, with her ammonia level returning toward normal over the next several days. She had a plasma citrulline of 20 nmol/mL (reference range, 30–45 nmol/mL) and a urine orotic acid level of 1.8 mmol/ mol creatinine (reference range, 0.4–1.2 mmol/mol creatinine), levels consistent with OTC deficiency. She was discharged home on lactulose and a low-protein diet. DISCUSSION The urea cycle is the metabolic pathway that converts nitrogen to urea for excretion from the body (Figure 1). A deficiency in one of the enzymes in this pathway causes a urea cycle disorder (1), and all deficiencies except arginase cause severe hyperammonemia. The amino acid products of endogenous and exogenous protein digestion are degraded by hepatic transamination and oxidative deamination to produce ammonia, which is then converted to urea via the six enzymes of the urea cycle (Table) and excreted by the kidneys (2). The most common genetic disorder of the urea cycle is a deficiency in OTC From the Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas. Corresponding author: Tashfeen Mahmood, MD, 3601 4th Street, Lubbock, TX 79430 (e-mail: tashfeen.mahmood@ttuhsc.edu). 375 Figure 1. Urea cycle disorders. ARG indicates arginase; ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; CPS1, carbamoylphosphate synthetase 1; ORNT1, ornithine transporter 1; OTC, ornithine transcarbamoylase. (3). Partial OTC deficiency has a variable presentation (4), but its symptoms are caused by hyperammonemia secondary to accumulation of precursors of urea, primarily ammonia and glutamine (2). The clinical presentation of hyperammonemia caused by OTC deficiency varies with the age of the patient. In infants, hyperammonemia is associated with lethargy, poor sucking response, vomiting, hypotonia, and seizures (5). In adults, its phenotypes are diverse, ranging from severe encephalopathy to apparently asymptomatic states (6). The OTC gene is encoded on the X chromosome and is expressed in the mitochondrial matrix of the small intestine and liver, where it catalyzes the synthesis of citrulline from carbamoyl phosphate and ornithine (2). OTC deficiency has an estimated incidence of 1 in 82,000 live births in the USA and is the only X-linked urea cycle disorder (2). The biochemical and molecular bases of OTC deficiency have a wide spectrum of genetic defects, resulting in different Table. Urea cycle defects Enzyme deficiency Location Incidence Genetics Presentation ↑↑NH3 in newborns Distinct labs +NH3, low CIT, low ARG, normal urine OA 1. CPS1: Carbamoyl phosphate synthetase Mitochondria 1:1,300,000 AR 2. OTC: Ornithine transcarbamylase Mitochondria 1:56,500 0–30% EA X-linked Risk of ↑NH3 high in dominant pregnancy +OR, +UR, +UOA, low plasma CIT 3. ASS: Argininosuccinic acid synthetase (citrullinemia) Cytosol 1:250,000 AR Some nitrogen incorp in UC ++CIT, absent AS, fibroblast EA 4. ASL: Argininosuccinate lyase (argininosuccinic aciduria) Cytosol 1:218,750 AR Rap in infants, Rx ARG +CIT, +ASA 5. ARG: Arginase (hyperargininemia) Cytosol 1:950,000 AR Often normal NH3, spasticity, ataxia +ARG 7. NAGS: N-acetylglutamate synthetase Mitochondria 1:2,000,000 AR 8. ORNT1: Ornithine transporter Gene mutation ↑NH3 may respond to NAG +NH3 Membrane transporter +NH3,+OR, +homocitrulline AR indicates autosomal recessive; ARG, arginine; AS, argininosuccinate; ASA, argininosuccinate acid; CIT, citrulline; EA, enzyme assay; NAG, N-acetylglutamate; NH3, ammonia; OA, orotic acid; OR, ornithine; UC, urea cycle; UOA, urine orotic acid; UR, uracil. 376 Baylor University Medical Center Proceedings Volume 28, Number 3 phenotypes (7). Mutations that abolish all enzyme activity are found in the neonatal-onset group; mutations causing partial enzyme deficiency are found in the late-onset group (8). Among asymptomatic patients with late presentation, symptom onset is often associated with a precipitating factor, such as infection, trauma, medications (sodium valproate), surgery, pregnancy, excess protein intake, and physiological stress (9, 10). Patients with partial urea cycle disorders may exhibit psychological or cognitive difficulties, presumably due to chronic low-level hyperammonemia, before their presentation with a hyperammonemic crisis (11, 12). Some patients report self-selection of vegetarian diets, stating that high protein intake makes them sick (11). Due to its diverse phenotypic presentations and rarity in the adult population, hyperammonemic crisis resulting from a partial urea cycle disorder is probably underdiagnosed. An elevated serum ammonia level, particularly with normal liver enzymes and the absence of relevant medications, should suggest an inborn error of metabolism and prompt treatment of the hyperammonemic state followed by measurement of plasma amino acid and urine orotic acid levels. There are case reports in which neuropsychiatric and/or neurodevelopmental disturbances represented the initial manifestations and main clinical signs of the disease. Mental retardation, attention-deficit hyperactivity disorder, oppositional defiant disorder, and problems in communication, such as autistic-like behavior, have been reported. Delirium, confusion, and incoherent speech can occur. Moreover, episodes of depressed consciousness were misdiagnosed in one series and erroneously interpreted as psychiatric disorders. These patients responded well to dietary modifications and ammonia-lowering therapy (13). Our patient had recent neuropsychiatric problems, including regression, lack of attention leading to job loss, and introverted behavior, but a formal psychiatric diagnosis was not available. Due to the rarity of these disorders, most physicians have relatively little experience with management. Treatment for acute hyperammonemia should be started before the precise diagnosis is made to reduce production of nitrogenous waste and to lower plasma ammonia levels quickly. This is achieved by withdrawing all protein for 24 to 48 hours, supplying a hypercaloric, protein-free solution with insulin to enhance anabolism (14), infusing arginine, and exploiting alternative pathways for excretion of waste nitrogen. A loading dose of Larginine hydrochloride, sodium benzoate, and sodium phenyl July 2015 acetate is given intravenously over 90 minutes, followed by sustained infusion over 24 hours until the patient is no longer hyperammonemic and oral therapy can be tolerated. Hemodialysis should be considered in patients with persistently high ammonia levels (15). 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Ah Mew N, Lanpher BC, Gropman A, Chapman KA, Simpson KL, Urea Cycle Disorders Consortium, Summar ML. Urea cycle disorders overview. 2003 Apr 29 [updated 2014 Sep 11]. In Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle, 1993–2015. Available at http://www. ncbi.nlm.nih.gov/books/NBK1217/; accessed April 8, 2015. Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 1996;43:127–170. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969–1996. Pediatrics 2000;105(1):e10. Tuchman M, Jaleel N, Morizono H, Sheehy L, Lynch MG. Mutations and polymorphisms in the human ornithine transcarbamylase gene. Hum Mutat 2002;19(2):93–107. Kang ES, Snodgrass PJ, Gerald PS. Ornithine transcarbamylase deficiency in the newborn infant. J Pediatr 1973;82(4):642–649. McCullough BA, Yudkoff M, Batshaw ML, Wilson JM, Raper SE, Tuchman M. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet 2000;93(4):313–319. Tuchman M, McCullough BA, Yudkoff M. The molecular basis of ornithine transcarbamylase deficiency. Eur J Pediatr 2000;159(Suppl 3):S196– S198. Tuchman M, Morizono H, Rajagopal BS, Plante RJ, Allewell NM. The biochemical and molecular spectrum of ornithine transcarbamylase deficiency. J Inherit Metab Dis 1998;21(Suppl 1):40–58. Gordon N. Ornithine transcarbamylase deficiency: a urea cycle defect. Eur J Paediatr Neurol 2003;7(3):115–121. Ellaway CJ, Bennetts B, Tuck RR, Wilcken B. Clumsiness, confusion, coma, and valproate. Lancet 1999;353(9162):1408. Summar ML, Barr F, Dawling S, Smith W, Lee B, Singh RH, Rhead WJ, Sniderman King L, Christman BW. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin 2005;21(4 Suppl):S1–S8. Lien J, Nyhan WL, Barshop BA. Fatal initial adult-onset presentation of urea cycle defect. Arch Neurol 2007;64(12):1777–1779. Serrano M, Martins C, Pérez-Dueñas B, Gómez-López L, Murgui E, Fons C, García-Cazorla A, Artuch R, Jara F, Arranz JA, Häberle J, Briones P, Campistol J, Pineda M, Vilaseca MA. Neuropsychiatric manifestations in late-onset urea cycle disorder patients. J Child Neurol 2010;25(3):352–358. Singh RH. Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis 2007;30(6):880–887. Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 2007;356(22):2282–2292. Nonhepatic hyperammonemic encephalopathy due to undiagnosed urea cycle disorder 377 Anaplastic large-cell lymphoma in AIDS Michael L. Krol, MD, Varsha Podduturi, MD, Abdulla Majid-Moosa, MD, John R. Krause, MD, and Adan Mora Jr., MD AIDS-related malignancies may alter clinical courses and result in death in critically ill patients. We present a case of a newly diagnosed AIDS patient with Pneumocystis jiroveci pneumonia, Epstein-Barr virus, and cytomegalovirus infections who was found to have widely metastatic kinase-negative anaplastic large-cell lymphoma. This case demonstrates the diversity in the malignant presentation of HIV-infected patients, outside of the more commonly observed non-Hodgkin lymphomas. A naplastic large-cell lymphoma (ALCL) is rarely associated with HIV-infected patients. We describe a case of a newly diagnosed HIV-positive man with pathologyconfirmed ALCL and a co-occurring Pneumocystis jiroveci pneumonia, Epstein-Barr virus, and cytomegalovirus infection. CASE PRESENTATION A 55-year-old man with newly diagnosed HIV presented to the hospital for a recent onset of fever and a 1-month history of shortness of breath, fatigue, nonproductive cough, night sweats, dysphagia, and a 20-lb unintentional weight loss. He had only received 2 days of highly active antiretroviral therapy prior to presentation. His CD4 cell count was 5/mm3, with a viral load of 609,639 copies/mL on admission. On physical exam, the patient was tachypneic, with evidence of thrush but no lymphadenopathy or splenomegaly initially noted. He was pancytopenic; his white blood cell count was 4.3 K/uL, with 77% neutrophils and 12% monocytes, his hemoglobin level was 8.7 g/dL, and his platelet count was 124/mcL. He had a lactate of 4.3 mmol/L and an elevated lactate dehydrogenase (LDH) of 900 IU/L and was hypoxic, with arterial oxygen of 40 mm Hg. On admission, a two-view chest x-ray showed a subtle increased density in the right infrahilar region, with no evidence of pleural effusion, adenopathy, or consolidation (Figure 1a). The patient was initially treated for P. jiroveci pneumonia with steroids, Bactrim, and then with addition of pentamidine after limited clinical improvement and persistent elevation in LDH, bandemia, and ongoing lactic acidosis. Over the next few days, he made modest improvement in respiratory function and was able to be weaned from bilevel positive airway pressure to high-flow nasal canula. A cytomega378 lovirus PCR test was positive, and he was started on valganciclovir. On hospital day 10, the patient had an acute worsening hypoxia and became tachycardic and febrile, requiring emergent intubation. He also had a new finding of enlarged inguinal lymph nodes. He was more edematous, precluding appreciation of any additional lymphadenopathy. Abdominal ultrasound at that time showed two hepatic masses and splenomegaly. The patient continued a rapidly progressive decline, with worsening multiorgan failure attributed to sepsis despite negative cultures and precluding additional diagnostic studies due to his hemodynamic instability. All blood cultures obtained had no bacterial growth. He died on hospital day 14. An autopsy was performed. At autopsy, the right and left lungs weighed 1475 and 1175 g, respectively. The lung parenchyma was diffusely consolidated. The pleural surfaces were indurated, with nodules averaging 0.5 cm in diameter. There was splenomegaly (1050 g), hepatomegaly (2000 g), and widespread lymphadenopathy within the chest and abdomen (up to 4.0 cm in greatest diameter). Microscopic evaluations of the lymph nodes revealed architectural effacement, composed of large, atypical lymphoid cells, with prominent nucleoli. Tumor cells were also present in the large upper lobe nodule and the smaller blood vessels throughout the lungs and pleural space (Figure 1b). The bone marrow was devoid of neoplastic cells. Neoplastic lymphoid cells were diffusely immunohistochemically positive for CD30 and focally positive for CD3 (a T-cell marker) and epithelial membrane antigen. Cells were strongly positive by Epstein-Barr virus–encoded RNA (EBER) in situ hybridization. The tumor cells were negative for anaplastic lymphoma kinase (ALK) protein, B-cell markers (BCL6 and CD20), T-cell markers (CD56, TIA-1, CD4, CD5, CD7, CD43), and HHV-8, PAX5, and CD10. Mitotic activity, or Ki-67, measured 20% to 25%, with focal areas of 60% to 65%. T-cell receptor gamma gene rearrangement and IgH receptor From the Department of Internal Medicine (Krol, Majid-Moosa), Department of Pathology (Podduturi, Krause), and Division of Pulmonary Disease (Mora), Baylor University Medical Center at Dallas. Corresponding author: Adan Mora Jr., MD, Division of Pulmonary Disease, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: adam.mora@baylorhealth.edu). Proc (Bayl Univ Med Cent) 2015;28(3):378–380 a c b Figure 1. (a) Posterioanterior chest x-ray showing subtle increased density in the right infrahilar region, with no evidence of pleural effusion, adenopathy, or consolidation. (b) Anaplastic large-cell lymphoma, hematoxylin and eosin, 400×. (c) Pneumocystis jiroveci, Gomori methenamine silver stain, 1000×. Special thanks to Joseph Manuel Guileyardo, MD, for providing the autopsy images. gene rearrangement were unable to yield results due to the poor quality of DNA present in the sample. The final diagnosis was ALK-negative ALCL arising in a setting of HIV. There was widespread lymphomatous involvement of liver, gallbladder, spleen, kidney, lung, stomach, and heart. Other findings included right and left ventricular dilatation, Pneumocystis pneumonia (Figure 1a), bilateral cytomegalovirus adrenalitis, and an incidental appendiceal carcinoid tumor. Postmortem blood cultures were positive for vancomycin-resistant Enterococcus spp. DISCUSSION The World Health Organization (WHO) classification scheme classifies lymphoid neoplasms based on their cell of origin. Peripheral T-cell lymphoma (PTCL) arises from and resembles the phenotype of a mature T cell (1). PTCL accounts for about 5% to 10% of non-Hodgkin lymphomas in the general US population, with an incidence of <1 per 100,000 people (2, 3). PTCL is further subdivided into nodal, extranodal, and leukemic subgroups. ALCL is the least common subtype within the nodal subgroup, representing 12% of the PTCL cases worldwide (4, 5). ALCL is distinguishable based on the strong and diffuse CD30-positive staining of the malignant cells compared to scattered CD30 staining in the more commonly identified PTCL-not otherwise specified (25.9% of PTCL cases). In 2008, the WHO classification further subdivided ALCL based on the presence or absence of an ALK protein (1). On presentation, ALK-negative ALCL is more likely than ALKpositive tumors to be found in older patients, with more advanced (stage 3 or 4) disease and with increased involvement of extranodal sites, including lung, liver, and skin. ALK-negative ALCL is a more aggressive and less responsive disease, with studies suggesting 5-year overall survival rates of 49% vs. 70% for ALK-positive ALCLs (4). In HIV-infected patients, non-Hodgkin lymphoma is the most prevalent malignancy. PTCL is less common, occurring in only 12% to 15% of HIV-affected individuals with lymphoma, of which ALCL only accounts for 28% of cases (6, 7). Thus, with the limited available data, most of our knowledge on ALCL in the HIV patient population is based on a comprehensive review of 37 HIV-associated ALCL patients. This case review demonstrated that ALCL was predominantly ALK July 2015 negative, with an average patient age of 38 years and a mean CD4 count of 83 cells/mm3. Among the cases studied, onethird were EBER positive and 78% of patients presented with advanced lymphoma (stage 3/4), with all showing extranodal involvement including lungs, liver, bone marrow, spleen, and myocardium. The present case furthers the knowledge of HIV-associated ALCL. The patient had a unique presentation, including newly diagnosed HIV. He also had an AIDS-defining illness of P. jiroveci pneumonia on the onset of presentation, along with cytomegalovirus infection and Epstein-Barr virus. In Perez and colleagues’ (2010) review, they found that only 11 of the 37 case reports of ALCL in HIV patients had another underlying AIDS-defining illness. Regarding treatment, chemotherapy options are usually based around CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like therapies. For relapsed/ refractory T-cell lymphomas, preliminary data support the use of autologous stem-cell transplantation to increase progressionfree survival (8). Additional promising research is focused on anti-CD30 monoclonal antibodies, with positive preliminary response in previously treated ALK-negative patients (9, 10). Undoubtedly, the emergence of novel and targeted therapies will increase our ability to treat and manage ALCL in the future. 1. 2. 3. 4. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon, France: International Agency for Research on Cancer Press, 2008:380–428. Ascani S, Zinzani PL, Gherlinzoni F, Sabattini E, Briskomatis A, de Vivo A, Piccioli M, Fraternali Orcioni G, Pieri F, Goldoni A, Piccaluga PP, Zallocco D, Burnelli R, Leoncini L, Falini B, Tura S, Pileri SA. Peripheral T-cell lymphomas. Clinico-pathologic study of 168 cases diagnosed according to the R.E.A.L. classification. Ann Oncol 1997;8(6):583–592. Anderson JR, Armitage JO, Weisenburger DD; Non-Hodgkin’s Lymphoma Classification Project. Epidemiology of the non-Hodgkin’s lymphomas: distributions of the major subtypes differ by geographic locations. Ann Oncol 1998;9(7):717–720. Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, Rimsza L, Pileri SA, Chhanabhai M, Gascoyne RD, Armitage JO, Weisenburger DD; International Peripheral T-Cell Lymphoma Project. ALK– anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008;111(12):5496–5504. Anaplastic large-cell lymphoma in AIDS 379 5. 6. 7. Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008;26(25):4124–4130. Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, Holmberg SD, Brooks JT; Adult and Adolescent Spectrum of Disease Project and HIV Outpatient Study Investigators. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003. Ann Intern Med 2008;148(10):728–736. Perez K, Castillo J, Dezube BJ, Pantanowitz L. Human immunodeficiency virus–associated anaplastic large cell lymphoma. Leuk Lymphoma 2010;51(3):430–438. 8. Reimer P, Rüdiger T, Geissinger E, Weissinger F, Nerl C, Schmitz N, Engert A, Einsele H, Müller-Hermelink HK, Wilhelm M. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol 2009;27(1):106–113. 9. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, Forero-Torres A. Brentuximab vedotin (SGN-35) for relapsed CD30–positive lymphomas. N Engl J Med 2010;363(19):1812–1821. 10. Forero-Torres A, Leonard JP, Younes A, Rosenblatt JD, Brice P, Bartlett NL, Bosly A, Pinter-Brown L, Kennedy D, Sievers EL, Gopal AK. A phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol 2009;146(2):171–179. Avocations Hermits in the Open Hydraulics multiply While muscles atrophy. Through the evolution-scope See the wasted limbs! Creeping concrete around the globe At a dizzying pace. Creatures moving fast and furious Up and down the terrain. Suffocating, burning fossil, Visible air to breath Suspended sewers above the tarmac Rise higher and higher. Menacing soot defaces sun, Vital rays are under siege. Confused are the sunflowers Wondering where to look. Shadows used to embrace strangers In the golden rays–– Masked faces, lost embraces, Hermits in the open. —Amanullah Khan, MD, PhD Copyright © 2013 by Amanullah Khan. Reprinted from Sifting Shades (Dog Ear Publishing, 2013). Dr. Khan (e-mail: aman1963@gmail.com) is an oncologist on the medical staff of Baylor Medical Center at McKinney. 380 Baylor University Medical Center Proceedings Volume 28, Number 3 Primary follicular lymphoma of the duodenum Robbie L. Graham, MD, Mabel A. Mardones, MD, and John R. Krause, MD Follicular lymphoma, a common nodal lymphoma, is rare in the gastrointestinal tract. When seen in this location, duodenal involvement is frequent. Most patients have localized disease, and survival appears to be excellent even without treatment. Although the outcomes are improved, the morphologic, immunophenotypic, and genetic features remain similar to those of nodal follicular lymphomas. We describe a woman with de novo follicular lymphoma of the duodenum and discuss the features of this remarkably indolent variant of follicular lymphoma. P rimary gastrointestinal (GI) follicular lymphoma (FL) is a unique, uncommon variant of FL. Most cases of primary FL of the GI tract occur in the small intestine, with involvement of the second portion of the duodenum predominating (1). Usually an incidental finding on endoscopy for other reasons, FL of the duodenum is a remarkably indolent form of FL that even when left untreated usually does not develop tumorous growth, very rarely disseminates, and does not transform into high-grade disease (2). We report a case of de novo primary FL of the duodenum. CASE PRESENTATION A 52-year-old previously healthy Caucasian woman presented with 2 years of intermittent epigastric abdominal pain associated with nausea and vomiting. These symptoms were typically self-limiting, lasting 3 to 5 days with no clear exacerbating factors. In between her recurrent abdominal pain crises, she remained very healthy and functional. There was no history of foreign travel. She denied any fevers, chills, night sweats, weight loss, diarrhea, or fatigue. She sought care for her symptoms, which initially included a computed tomography (CT) scan of the abdomen. This revealed segmental thickening of the proximal small bowel beginning at the ligament of Treitz with extension over a length of 10 cm with associated mesenteric adenopathy (largest lymph node measuring 3.0 × 1.2 cm). Her blood work, including complete blood count, complete metabolic panel, and peripheral smear, were all unremarkable. She was referred to an outpatient gastroenterologist who performed a small bowel enteroscopy that revealed nodular mucosa with plaque-like lesions present in the second and third part of the duodenum and proximal jejunum. Biopsies of the esophaProc (Bayl Univ Med Cent) 2015;28(3):381–383 gus, stomach, duodenum, and jejunum were taken. A DiffQuik stain of the stomach biopsy was negative for Helicobacter pylori. Morphologically, the duodenal lesions showed an infiltrate within the lamina propria that consisted of small irregular lymphocytes forming large follicles as well as sheets (Figure 1a). Since this finding was highly concerning for lymphoma, immunohistochemical stains were performed and showed the infiltrates to be CD20 strongly positive, CD3/CD5 negative, CD10 weakly positive, and Bcl2 strongly positive (Figure 1b), with a Ki-67 (proliferation index) of 25% to 30%. The findings were consistent with grade 1 to 2 follicular lymphoma of the duodenum, which is a variant of FL also known as primary intestinal follicular lymphoma. Further staging included a positron emission tomography scan, which revealed mild to moderate hypermetabolic activity in the distal duodenum and proximal jejunum and nearby mildly metabolic mesenteric lymph nodes. Additionally, mild hypermetabolic activity was also detected in the gastric fundus, the junction of the second and third portions of the duodenum, and a 3.5 cm area in the proximal transverse colon. Her stage was determined to be stage IIA, E. It remained unclear whether her pain was related to her newly diagnosed lymphoma or an alternative cause, so she underwent a colonoscopy and upper endoscopic ultrasound, which were all unremarkable. Gross abnormalities were not visualized, so biopsies were not taken. Upon further discussion with her oncologist, she decided to pursue active surveillance of her disease, which includes regular radiologic imaging. Her first 6-month follow-up scans showed improving jejunal wall thickening and adjacent mesenteric adenopathy. DISCUSSION The GI tract is the most common site of extranodal lymphoma, accounting for 40% of extranodal lymphomas. Of From the Department of Pathology, Section of Hematopathology (Graham, Krause), and the Department of Hematology/Oncology (Mardones), Baylor University Medical Center at Dallas and Baylor Charles A. Sammons Cancer Center, Dallas, Texas. Corresponding author: Robbie L. Graham, MD, Department of Pathology, Section of Hematopathology, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: robbie.graham@BaylorHealth.edu). 381 a b Figure 1. Morphology of follicular lymphoma in the duodenum. (a) Follicular lymphoma stained with hematoxylin and eosin (original magnification 40×). (b) Follicular lymphoma stained with antibody to Bcl-2 (original magnification 100×). these, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and diffuse large B-cell lymphoma (DLBC lymphoma) are the most common subtypes. Conversely, FL constitutes only 1% to 3% of primary GI lymphomas, despite it being the most common nodal lymphoma in Western populations (3). When FL involves the GI tract, the duodenum is most often affected (89%), while other non–small intestinal portions such as the esophagus (0%), stomach (2%), and colon (1%) are rarely involved. Most patients are asymptomatic at presentation, although abdominal pain, intestinal obstruction, and diarrhea can occasionally occur (4). Endoscopically, most cases of GI FL manifest as multiple white nodules or polyps measuring <10–20 mm, although larger or more diffuse masses have been documented (5). Although most GI lymphomas of types other than FL have been described in patients with inflammatory bowel disease, celiac disease, immunodeficiencies, and after solid organ transplantation, specific risk factors for GI FL have yet to be found (3). The pathologic features of GI FL are similar to nodal FL in that the diagnosis of GI FL requires the identification of a neoplastic infiltrate forming nodular follicles. This differs from other B-cell lymphomas such as MALT lymphoma and DLBC lymphoma, which are typically more diffuse infiltrates that do not routinely form nodules. Malignant follicles in FL are usually enlarged and back to back, with vague borders and scant or absent mantle zones. When involving the GI tract, FL predominantly involves the lamina propria, with occasional involvement of the submucosa. Tumor cells are germinal center–derived B-cells and are composed of small to medium-sized cleaved cells (centrocytes) and large noncleaved cells (centroblasts) (6). Normal follicles have tingible body macrophages, but neoplastic ones of grade 1 or grade 2 lack macrophages and show a monotonous, nonpolarized appearance composed predominantly of centrocytes. If the number of centroblasts is more than 15 per high-powered field, the 382 diagnosis is grade 3. Grade 3a has a mixture of centrocytes, while grade 3b lacks centrocytes and shows a sheet-like proliferation of centroblasts (7). In contrast to nodal FL, FL of the duodenum is unique in that it has always been shown to be low grade (grade 1–2) while nodal FL is grade 3 in 10% to 20% of cases (2). As with low-grade nodal FL, most GI FLs express Bcl-2 and pan B-cell markers such as CD20 and CD79a. Reflecting the germinal center derivation, tumor cells are also positive for CD10 and Bcl-6. They do not usually express CD5, CD23, CD43, or Bcl-1, and T-cell markers are absent (6). In the majority of duodenal tumors, CD21 and CD23 highlight a “hollow” pattern with follicular dendritic cells arranged around the periphery of the neoplastic follicles. This is different than nodal FL, where the follicular dendritic cells are present throughout the follicles (8). Cytogenetic fluorescent in situ hybridization studies show the characteristic IGH/BCL2 translocation, t(14;18) (q32;q21), in up to 90% of duodenal FL. This causes BCL2, an anti-apoptotic protein, to be overexpressed, which is thought to be one of the causes of lymphomagenesis (9). In addition, the neoplastic and clonal nature of the disease can be demonstrated by polymerase chain reaction analysis of IgH and Ig light chain genes in the majority of cases (2). Once a diagnosis of primary GI FL has been made, four general treatment strategies have been used: watch and wait, radiation therapy, rituximab monotherapy, or chemotherapy with or without radiation (10). The largest case series of lowstage GI FL ever assembled included 56 patients who were followed for an average of 77 months. In this study, 24 patients chose watchful waiting. Of these, seven experienced a complete remission and 17 had stable disease. All 19 patients treated with local radiation attained a complete remission. Of the five patients who received rituximab monotherapy, four had complete remission and one had stable disease. All eight patients who were treated with chemotherapy with or without radiation attained Baylor University Medical Center Proceedings Volume 28, Number 3 a complete remission (2). The universal indolent behavior of primary GI follicular lymphoma is quite different from non-GI FL. In non-GI FL, the prognosis can be quite variable, with 5-year survival ranging from 91% to 52% depending on the grade and stage of the tumor (11). 1. 2. 3. 4. Harris NL, Swerdlow SH, Jaffe ES, Ott G, Nathwani BN, de Jong D, Yoshino T, Spagnolo D. Follicular lymphoma. In Jaff ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours. Lyon, France: IARC Press, 2008:220–226. Schmatz A, Streubel B, Kretschmer-Chott E, Puspok A, Jager U, Mannhalter C, Tiemann M, Ott G, Fischbach W, Herzog P, Seitz G, Stolte M, Raderer M, Chott A. Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases. J Clin Oncol 2011;29(11):1445–1451. Misdraji J, Harris NL, Hasserjian RP, Lauwers GY, Ferry JA. Primary follicular lymphoma of the gastrointestinal tract. Am J Surg Pathol 2011;35(9):1255–1263. Takata K, Okada H, Ohmiya N, Nakamura S, Kitadai Y, Tari A, Akamatsu T, Kawai H, Tanaka S, Araki H, Yoshida T. Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: a multicenter retrospective analysis in Japan. Cancer Sci 2011;102(8):1532–1536. 5. Shia J, Teruya-Feldstein J, Pan D, Hegde A, Klimstra D, Chaganti RSK, Qin J, Portlock CS, Filippa DA. Primary follicular lymphoma of the gastrointestinal tract: a clinical and pathologic study of 26 cases. Am J Surg Pathol 2002;26(2):216–224. 6. Medeiros J. Extranodal follicular lymphoma. In Diagnostic Pathology Lymph Nodes and Spleen with Extranodal Lymphomas. Manitoba, Canada: Amirsys Publishing, 2011:712–723. 7. Takata K, Miyata-Takata T, Sato Y, Yoshino T. Pathology of follicular lymphoma. J Clin Exp Hematop 2014;54(1):3–9. 8. Takata K, Sato Y, Nakamura N, Kikuti YY, Ichimura K, Tanaka T, Morito T, Tamura M, Oka T, Kondo E, Okada H, Tari A, Yoshino T. Duodenal and nodal follicular lymphomas are distinct: the former lacks activationinduced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations. Mod Pathol 2009;29:940–949. 9. Albinger-Hegyi A, Hochreutener B, Abdou MT, Hegyi I, DoursZimmermann MT. High frequency of t(14;18) translocation breakpoints outside of major breakpoint and minor cluster regions in follicular lymphomas: improved polymerase chain reaction protocols for their detection. Am J Pathol 2002;3:823–832. 10. Freedman AS. Management of gastrointestinal lymphomas. In Lister A, ed. UpToDate. Waltham, MA: UpToDate, 2013:1–19. 11. Freedman AS, Aster JC. Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma. In Lister A, ed. UpToDate. Waltham, MA: UpToDate, 2014:1–16. In memoriam ALAIN J. MARENGO-ROWE, MD Department of Pathology, Baylor University Medical Center at Dallas Dr. Alain Justice Marengo-Rowe, born on August 20, 1936, died on March 4, 2015, at his home with his family by his side. He spent his early years in Cairo, Egypt, with his French and Italian parents and moved to Ireland at age 11. Deciding to become a physician at a young age, he received his medical degree from the University of London and obtained qualifications in internal medicine, pathology, hematology, and transfusion medicine. He also held positions at The University of Cambridge and The University of Oxford. While at Cambridge, he had great mentors, including the hemoglobin molecular biologists Herman Lehmann and Max Perutz (the latter of whom July 2015 was awarded the Nobel Prize in 1962). Dr. Marengo-Rowe was an officer in the Royal Air Force Medical Corps and served in Southern Arabia for 3 years during the Yemeni revolt under the tutelage of Dr. Perutz. There he defined blood group frequencies in the region and discovered two new hemoglobins. Upon his return to England, he was appointed lecturer in the Department of Hematology at Oxford University. In 1972, Dr. MarengoRowe was recruited to Baylor University Medical Center and began directing the newly established special hematology laboratory, blood bank, and coagulation unit. He also held senior positions at the University of Texas Medical School in San Antonio and wrote over 100 peer-reviewed medical articles. Upon his retirement from Baylor in 2006, he lived at his lake house outside Dallas and made annual visits to Europe and Australia. Primary follicular lymphoma of the duodenum 383 Tubulocystic carcinoma of the kidney Varsha Podduturi, MD, Carol F. Adair, MD, and Haiying Zhang, MD Tubulocystic carcinoma (TCC) of the kidney is a unique, rare, and recently recognized neoplasm. Although originally considered a low-grade collecting duct carcinoma, TCC is now considered to be a distinct entity. TCC should be considered in the differential diagnosis of cystic renal neoplasms. We report a case of TCC arising in the left kidney. K idney cancer accounts for nearly 64,000 new cases and 14,000 deaths per year in the USA. Renal cell carcinomas include various subtypes, including clear cell, papillary, and chromophobe. Tubulocystic carcinoma (TCC) of the kidney is an exceedingly rare, recently recognized subtype of renal cell carcinoma, with <100 cases reported in the literature. Microscopically, it comprises a mixture of tubules and variably sized cysts with low-grade nuclear features. We present the macroscopic, histologic, and immunohistochemical findings of a single case of TCC. CASE REPORT A 57-year-old man with no significant past medical history presented with a 3-month history of abdominal and flank pain. Computed tomography of the abdomen disclosed a mass in the mid to lower pole of the left kidney. Biopsy was performed and showed small fragments of fibrotic and hyalinized stroma containing dilated tubular structures. The tubular structures were lined by highly atypical epithelial cells with nuclear enlargement and prominent nucleoli (Fuhrman nuclear grade 3). The epithelial cells contained abundant eosinophilic cytoplasm and had a hobnailed appearance. The tumor cells were immunohistochemically reactive for RCC antigen, CD10, CK903, P504-S (AMACR), and PAX8. The patient underwent a left radical nephrectomy and periaortic lymph node dissection. Macroscopically, a 2.1 cm tan solid mass was located in the midportion of the kidney grossly abutting the renal sinus fat. Two cortical cysts containing clear fluid were also identified. Microscopically, the tumor contained cystic tubular structures with scant intervening stroma. The tubular structures were lined by a single layer of flattened to cuboidal to hobnail-like cells. The cells had eosinophilic cytoplasm with enlarged nuclei with prominent nucleoli (Figure 1). Focal clear cell features were also identified. Thirty-two months after nephrectomy, the patient was free of metastatic disease. 384 DISCUSSION Originally, TCC was believed to be a subtype of collecting duct carcinoma that was first described by Masson, who coined the moniker “Bellinian epithelioma” or “carcinoma of the collecting ducts” because he thought it originated from collecting ducts of Bellini (1). However, TCC behaved in a low-grade fashion compared to the latter and was termed “low-grade collecting duct carcinoma.” In 1997, MacLennan et al speculated that TCC fell on the low-grade spectrum of collecting duct carcinomas (2). In 2004, Amin et al dubbed the tumor “tubulocystic carcinoma” (3). TCC has a male predominance and occurs in adults with a wide age range. Most patients present in the fifth and sixth decades of life (4). Patients can present with abdominal pain or distension or with hematuria or can be asymptomatic (5). Macroscopically, TCCs are usually small (≤2 cm), circumscribed, and unencapsulated with a white or gray spongy cut surface that is often likened to “bubble wrap” (4). Histologically, the neoplasm comprises variably sized tubules and cysts separated by a thin fibrous septae. The cysts and tubules are lined by a single layer of cuboidal cells with eosinophilic cytoplasm. Hobnailing is a common pattern identified. Nucleoli are often very prominent. TCC are immunohistochemically reactive for CD10, AMACR (P504-S), CK8, CK18, and CK19 (3, 6). These entities can also be positive for PAX2, kidney-specific cadherin, carbonic anhydrase IX, and parvalbumin (3). TCCs are often found coexisting with other papillary renal neoplasms (both type 1 and type 2), including papillary renal cell carcinomas and papillary adenomas. The differential diagnosis for TCC includes collecting duct carcinoma, multilocular cystic renal cell carcinoma, cystic nephroma, and mixed epithelial and stromal tumors. Collecting duct carcinoma is more solid and has higher-grade nuclear features. Multilocular cystic renal cell carcinoma is lined by clear cells and does not have eosinophilic cytoplasm or high-grade nuclei. Cystic nephroma has a female predominance and can be multiloculated; however, it is lined by a single layer of flattened From the Department of Pathology, Baylor University Medical Center at Dallas, Dallas, Texas. Corresponding author: Varsha Podduturi, MD, Department of Pathology, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: Varsha.Podduturi@baylorhealth.edu). Proc (Bayl Univ Med Cent) 2015;28(3):384–385 b a Figure 1. (a) Low-power view of the tumor showing multiple variably sized cystic spaces (hematoxylin and eosin, 40×). (b) Higher-power view of the hobnailed epithelial cells with eosinophilic cytoplasm (hematoxylin and eosin, 400×). epithelium with indistinct nucleoli and has ovarian-like stroma within the septae. Hobnailing can be seen, but is very infrequent (7). Mixed epithelial and stromal tumor has ovarian-type stroma in the septae between the cystic spaces, broad septae (unlike the thin septae in TCC), and solid areas (5). Gene expression microarray analysis by Yang et al demonstrated a unique molecular signature of TCC when compared with other renal tumors and normal renal tissue (4). Clustering analysis of that data revealed that TCC is closely related to papillary renal cell carcinoma. Both type 1 and 2 dimensional clustering placed TCC between low- and high-grade papillary renal cell carcinoma. The most common karyotypic changes seen in papillary renal cell carcinoma are trisomy 7 and 17 with loss of Y chromosome. Yang et al also reported that TCC showed gain of chromosome 17, but not chromosome 7 (4). The findings suggest a strong genetic similarity between TCC and papillary renal cell carcinoma. TCC has been reported with other subtypes of renal cell carcinoma (8). These tumors rarely progress, recur, or metastasize (6). Rare cases have been reported of metastases to lymph node, bone, pleura, and liver (8). 2. 3. 4. 5. 6. 7. 8. 1. Rheault MJ. Pierre Masson: the father of histopathology teaching in Canada. Ann Chir 1991;45(9):833–836. July 2015 MacLennan GT, Farrow GM, Bostwick DG. Low-grade collecting duct carcinoma of the kidney: report of 13 cases of low-grade mucinous tubulocystic renal carcinoma of possible collecting duct origin. Urology 1997;50(5):679–684. Amin MB, MacLennan GT, Gupta R, Grignon D, Paraf F, Vieillefond A, Paner GP, Stovsky M, Young AN, Srigley JR, Cheville JC. Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 31 cases of a distinctive rare subtype of renal cell carcinoma. Am J Surg Pathol 2009;33(3):384–392. Yang XJ, Zhou M, Hes O, Shen S, Li R, Lopez J, Shah RB, Yang Y, Chuang ST, Lin F, Tretiakova MM, Kort EJ, Teh BT. Tubulocystic carcinoma of the kidney: clinicopathologic and molecular characterization. Am J Surg Pathol 2008;32(2):177–187. Alexiev BA, Drachenberg CB. Tubulocystic carcinoma of the kidney: a histologic, immunohistochemical, and ultrastructural study. Virchows Arch 2013;462(5):575–581. Azoulay S, Vieillefond A, Paraf F, Pasquier D, Cussenot O, Callard P, Sibony M. Tubulocystic carcinoma of the kidney: a new entity among renal tumors. Virchows Arch 2007;451(5):905–909. Turbiner J, Amin MB, Humphrey PA, Srigley JR, De Leval L, Radhakrishnan A, Oliva E. Cystic nephroma and mixed epithelial and stromal tumor of kidney: a detailed clinicopathologic analysis of 34 cases and proposal for renal epithelial and stromal tumor (REST) as a unifying term. Am J Surg Pathol 2007;31(4):489–500. Bhullar JS, Varshney N, Bhullar AK, Mittal VK. A new type of renal cancer—tubulocystic carcinoma of the kidney: a review of the literature. Int J Surg Pathol 2013;22(4):297–302. Tubulocystic carcinoma of the kidney 385 Unusual presentation of metastatic ovarian carcinoma as an enlarged intramammary lymph node Callan Mason, MD, Kendall Yokubaitis, MD, Raynal Hamilton, MD, Umesh Oza, MD, Zeeshan Shah, MD, Joseph Spigel, MD, and Jean Wang, MD Metastasis to the breast most commonly arises from a contralateral primary breast malignancy; however, metastatic disease can also result from extramammary malignancies by hematogenous or lymphatic dissemination. This case report reviews an unusual presentation of primary ovarian carcinoma with metastasis to an intramammary lymph node. P rimary breast cancer is one of the most frequently occurring malignancies in women, but metastatic disease to the breast is relatively uncommon. Although malignancies metastatic to the breast parenchyma have no characteristic radiographic presentation, they can present as a rounded or oval mass at the fat-parenchymal interface. Enlarged nonfatty axillary lymph nodes with spiculated or illdefined margins have a strong association with an underlying malignancy. This case report reviews an unusual presentation of primary ovarian carcinoma with metastasis to an intramammary lymph node. Breast or axillary lymph node involvement from a primary ovarian carcinoma is rare, and ovarian carcinoma metastatic to the breast is associated with a poor prognosis, as it is usually related to widespread systemic disease. CASE REPORT An asymptomatic 58-year-old woman with no significant past medical or family history presented for a routine screening mammogram, which revealed a 1.0 cm mass in the upper outer quadrant of the left breast, favored to reflect an enlarging intramammary lymph node (Figure 1a). An additional enlarged lymph node was noted in the right axilla. Further evaluation with bilateral breast ultrasound confirmed a mass in the upper outer quadrant of the left breast, again favored to represent an enlarged intramammary lymph node (Figure 1b), as well as at least two enlarged right axillary lymph nodes. An ultrasound-guided core biopsy of the left intramammary lymph node as well as an additional core biopsy of a right axillary lymph node were performed. Immunohistochemical stains were positive for paired-box gene 8 (PAX8) and Wilm’s tumor gene (WT1), with a final pathologic diagnosis of high-grade serous ovarian carcinoma. Given the unexpected diagnosis of metastatic ovarian carcinoma, further evaluation and staging workup were initiated with 18F-fluoro-2-deoxy-D-glucose positron emission tomog386 raphy/computed tomography (18F-FDG PET-CT). The PETCT confirmed a hypermetabolic mass in the left hemipelvis in close association with the left ovary (Figure 2), corresponding to the pathologic diagnosis of ovarian carcinoma. Multifocal FDG-avid hepatic metastases were also identified, as well as extensive serosal, peritoneal, mesenteric, and omental carcinomatosis (Figure 2b). Intra-abdominal FDG-avid lymphadenopathy, to include portocaval and bilateral common iliac chain lymph nodes, as well as bilateral inguinal lymphadenopathy, was demonstrated and was compatible with additional nodal metastatic disease. PET-CT evaluation of the thorax demonstrated a hypermetabolic mass in the upper outer quadrant of the left breast, corresponding to the biopsy-proven malignancy (Figure 2d), as well as hypermetabolic right axillary lymphadenopathy. The patient’s laboratory values revealed an elevated CA-125 of 900 units/mL. These collective findings were compatible with stage IV metastatic ovarian carcinoma. The patient is currently receiving carboplatin and paclitaxel chemotherapy. DISCUSSION While primary breast cancer is one of the most common malignancies in women, metastatic disease to the breast is relatively rare, accounting for approximately 0.5% to 2.0% of all breast cancer cases (1). Metastatic disease to the breast most often arises from a contralateral primary breast malignancy; however, hematogenous or lymphatic metastasis from extramammary malignancies may also occur. The most common extramammary malignancies known to metastasize to the breast include lymphoma, melanoma, lung, and gynecological primary cancers (1). Studies reveal that axillary nodal metastases also most commonly occur from primary breast cancer, followed by lymphoma, and infrequently from a nonbreast primary site or an unknown primary site (2). Ovarian carcinoma usually presents with intraperitoneal metastases by direct seeding into the peritoneal cavity, and distant metastasis most commonly involves the lung or pleura (3). From the Department of Radiology, Baylor University Medical Center at Dallas. Corresponding author: Callan Mason, MD, Department of Radiology, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: callan. mason@baylorhealth.edu). Proc (Bayl Univ Med Cent) 2015;28(3):386–388 a b Figure 1. (a) Annual screening mammogram of the left breast shows a well-circumscribed dense intramammary lymph node in the upper outer quadrant. (b) Targeted ultrasound of the upper outer quadrant of the left breast demonstrates an enlarged intramammary lymph node with loss of normal fatty hilum. The most frequent sites of lymphatic involvement in ovarian carcinoma are abdominal (47%), para-aortic (38%), mediastinal (29%), and pelvic (17%) lymph nodes (4). Serous ovarian carcinoma is the most common ovarian malignancy to metastasize to the breast, and metastases to the breast parenchyma or axillary lymph nodes are rare and are typically seen in patients with advanced disease (5). Our case is particularly unusual in that an enlarged intramammary lymph node was the patient’s initial presentation of ovarian carcinoma, despite the disease being widespread. Mammographically, metastatic tumors to the breast parenchyma classically present as a rounded or oval noncalcified mass found in the subcutaneous breast tissue at the fat-parenchymal interface. They generally lack the features of primary breast malignancy such as microcalcifications, spiculation, or architectural distortion. Intramammary or axillary lymph node enlargement can also occur, and ill-defined or spiculated nodal margins show a significant association with malignancy (2). a b c d Figure 2. (a) PET-CT image at the level of the pelvis shows moderately intense FDG uptake within a metastatic implant involving the left adnexa (arrow). (b) Multiple regions of hepatic metastatic disease are identified at the level of the upper abdomen, with the most intense lesion in the caudate lobe (arrow). (c) At the level of the iliac crests, there is uptake within the omentum along the anterior abdominal wall extending into an umbilical hernia (arrow). (d) At the level of the mid thorax there is mildly increased FDG uptake in the upper outer quadrant of the left breast (arrow), corresponding to the intramammary lymph node seen on comparison mammogram and ultrasound. July 2015 Unusual presentation of metastatic ovarian carcinoma as an enlarged intramammary lymph node 387 Specifically, ovarian cancer metastatic to the breast parenchyma can present as a focal mass without definite characteristic radiographic features (6); however, a few studies reveal that serous ovarian carcinoma metastatic to axillary lymph nodes can occasionally demonstrate a peripheral amorphous lymph node calcification pattern on a mammogram (7), which is related to psammoma body formation. This calcification pattern could potentially be used to differentiate from metastatic breast carcinoma, which typically demonstrates pleomorphic lymph node calcifications. This case also highlights the utility of PET-CT in detecting suspected metastatic disease such as ovarian carcinoma. PET-CT can be particularly useful for site-specific treatment planning such as biopsy, surgery, or radiotherapy (8). Breast and ovarian tumors can be difficult to pathologically distinguish due to overlapping morphology (9), and immunohistochemistry may be required to distinguish the two. Estrogen and progesterone receptor expression are inadequate markers, as these can be seen in both breast and ovarian neoplasms. PAX8 has been shown to be an excellent distinguishing marker between ovarian and breast carcinoma, as it is positive in nearly all ovarian carcinoma stains and is negative in breast cancer stains (10, 11). WT1 can also be a sensitive marker for serous ovarian carcinoma since it is rarely positive for breast cancer samples but is immunoreactive in up to 85% of ovarian samples (10, 11). Ovarian carcinoma metastatic to the breast is associated with a poor prognosis, largely because it is associated with widespread systemic dissemination of disease (3). On average, ovarian carcinoma metastatic to the breast is diagnosed 2 years following the initial diagnosis of ovarian cancer (12). Several studies have demonstrated survival rates ranging from 13 days to 3.5 years following detection of metastatic disease in the breast (12), and the 1-year survival rate has been reported at 40% (13). With the unanticipated diagnosis of metastatic ovarian carcinoma, this case not only highlights the significance of imaging workup at 388 diagnosis, but also the value of multidisciplinary communication between the radiologist, pathologist, and clinician. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Toombs BD, Klisher L. Metastatic disease to the breast: clinical, pathologic and radiologic features. Am J Roentgenol 1977;129(4):673–676. Walsh R, Kornguth PJ, Soo MS, Bentley R, DeLong DM. Axillary lymph nodes: mammographic, pathologic, and clinical correlation. Am J Roentgenol 1997;168(1):33–38. Goyal H, Mattoo V, Singla U. Isolated axillary lymph node metastasis from serous ovarian cancer. Case Rep Oncol Med 2012:307567. Skagias L, Ntinis A, Vasou O, Kondi-Pafiti A, and Politi E. Ovarian carcinoma presenting with axillary lymph node metastasis: a case documented by fine-needle aspiration and brief review of the literature. Diagn Cytopathol 2008;36(12):891–893. Recine M, Deavers M, Middleton, L, Silva E, Malpica A. Serous carcinoma of the ovary and peritoneum with metastases to the breast and axillary lymph nodes: a potential pitfall. Am J Surg Pathol 2004;28(12):1646– 1651. Moore D, Wilson D, Hurteau J, Look K, Stehman F, Sutton G. Gynecologic cancers metastatic to the breast. J Am Coll Surg 1998;187:178–181. Singer C, Blankstein E, Koenigsberg T, Mercado C, Pile-Spellman E, Smith S. Mammographic appearance of axillary lymph node calcification in patients with metastatic ovarian carcinoma. Am J Roentgenol 2001;176(6):1437–1440. Viswanathan C, Bhosale PR, Shah SN, Vikram R. Positron emission tomography-computed tomography imaging for malignancies in women. Radiol Clin N Am 2013;51(6):1111–1125. Yamasaki H, Saw D, Zdanowitz J, Faltz L. Ovarian carcinoma metastasis to the breast: a case report and review of the literature. Am J Surg Pathol 1993;17(2):193–197. Xiang L, Kong B. PAX8 is a novel marker for differentiating between various types of tumor, particularly ovarian epithelial carcinomas. Oncol Lett 2013;5(3):735–738. DeLair DF, Corben AD, Catalano JP, Vallejo CE, Brogi E, Tan LK. Nonmammary metastases to the breast and axilla: a study of 85 cases. Mod Pathol 2013;26(3):343–349. Ozguroglu M, Ersavasti G, Ilvan S, Hatemi G, Demir G, Demirelli F. Bilateral inflammatory breast metastases of epithelial ovarian cancer. Am J Clin Oncol 1999;22(4):408–410. Loredo D, Powell J, Reed W, Rosenbaum J. Ovarian carcinoma metastatic to breast: a case report and review of the literature. Gynecol Oncol 1990;37(3):432–436. Baylor University Medical Center Proceedings Volume 28, Number 3 Leukoencephalopathic changes on magnetic resonance imaging associated with a thermogenic dietary supplement (Thermatrim) Cristina I. Olivas-Chacon, MD, Manuel Treviño-Garcia, MD, John James Chua-Tuan, MD, Jose M. Rodriguez-Cordero, MD, Alfonso H. Gil-Valadez, MD, Nassim Akle, MD, Jesus E. Calleros, MD, and Luis R. Ramos-Duran, MD Acute toxic leukoencephalopathy can be caused by exposure to many compounds. Reversibility has been described in some cases with prompt recognition and withdrawal of the offending agent. Its association with a thermogenic supplement has never been reported. We describe two such cases in young women taking a commercially available thermogenic dietary supplement who presented with acute neurologic deficits and a common magnetic resonance imaging pattern. D ue to the increasing prevalence of obesity in Western countries, the use of thermogenic dietary supplements is becoming more frequent. Toxic leukoencephalopathy may be caused by exposure to a wide variety of agents, including cranial irradiation, therapeutic agents, illicit drugs, and environmental toxins (1). Its association with a thermogenic supplement has not been reported. Such is the purpose of this report. CASES Pertinent findings for the two patients are summarized in Table 1. Magnetic resonance imaging (MRI) during the acute episode in both patients revealed extensive symmetric restricted diffusion involving the entire corpus callosum, the pons, and subcortical white matter with reduced apparent diffusion coefficient values. No abnormal enhancement was seen (Figures 1 to 3). Both women were using the dietary thermogenic supplement Thermatrim for weight loss. The first patient had taken the supplement within the previous 2 months, and the second patient within the previous 3 weeks. They received supportive therapy and recovered within 2 to 5 days. Both patients had a benign clinical course with progressive clinical improvement and were discharged within the first week of admission. Two-month follow-up MRI of the first patient showed almost complete resolution of the findings. DISCUSSION Leukoencephalopathy describes the structural changes of cerebral white matter in which myelin suffers the most extensive damage (1). The neurological findings in acute toxic leukoencephalopathy can reverse with prompt recognition and withProc (Bayl Univ Med Cent) 2015;28(3):389–391 Table 1. Patient findings Variable Case 1 Case 2 19 17 Headache + + Photophobia + 0 Phonophobia + 0 Blurred vision 0 + Abnormal brain magnetic resonance imaging + + Physical examination + + Neurological examination + + Blood + + Toxicology screening + + Cerebrospinal fluid + + + + Age (years) Presenting symptoms Normal findings Clinical recovery in 2 to 5 days drawal of the offending agent (2). Definite findings on MRI to predict reversible versus irreversible and severe outcomes have not been determined. Similar though less extensive findings have been described in the clinicoradiological syndrome of mild encephalitis/encephalopathy with reversible splenial and white matter lesions (MERS Type II). This entity presents in patients with clinically mild encephalopathy and reversible lesions involving the entire corpus callosum with bilateral extension into the subcortical white matter (3, 4). First reports described this rare entity in patients who had seizures with secondary generalization (5) and in patients with toxicity or drug sensitivity to antiepileptic From the Department of Radiology, Texas Tech University Health Science Center, El Paso, Texas (Olivas-Chacon, Chua-Tuan, Akle, Calleros, Ramos-Duran); the Department of Radiology, Instituto Tecnológico y de Estudios Superiores de Monterrey and TecSalud, Mexico (Treviño-Garcia, Rodriguez-Cordero); Department of Neuroanatomy, Universidad Autónoma de Nuevo León, Mexico (Gil-Valadez). Corresponding author: Cristina Ivette Olivas Chacon, MD, 4800 Alberta Avenue, El Paso, TX 79905 (e-mail: cristina.olivas@ttuhsc.edu). 389 a b c Figure 1. MRI in Case 1. (a) Sagittal fast spin echo T2-weighted image demonstrates diffuse swelling and abnormal hyperintense signal of the entire corpus callosum (arrowheads). There is also abnormal hyperintensity of the pontine tegmentum (arrow). (b) Sagittal T1 contrast-enhanced image shows absence of abnormal enhancement. (c) Follow-up MRI fast spin echo T2-weighted image after 2 months shows resolution of the white matter changes. drugs (6). Subsequently, this entity has widened its spectrum and has been associated with different clinical neurologic and nonneurologic conditions, including postinfectious disorder (7), rapid withdrawal of antiepileptic drugs (8), high-altitude a cerebral edema (9), and various metabolic disorders (hypoglycemia and hypernatremia) (10). Due to the heterogeneous entities linked to mild encephalitis/encephalopathy with reversible splenial and white matter b Figure 2. Axial MRI in Case 1. (a) Fast spin echo T2-weighted imaging, diffusion-weighted imaging (b1000), and apparent diffusion coefficient (ADC) maps demonstrate abnormal T2 hyperintense signal intensity and matching restricted diffusion of the subcortical white matter (top row), corpus callosum (middle row), and the pontine tegmentum (bottom row), as indicated by the arrows. (b) Two-month follow-up imaging utilizing the same sequences shows near complete interval resolution of the white matter changes. 390 Baylor University Medical Center Proceedings Volume 28, Number 3 Thermogenic supplements have been associated with significant side effects, including anxiety, insomnia, cardiovascular disorders, and central nervous system stimulation, among others (15). However, these reports originate from isolated case reports due to the lack of forthcoming users experiencing said adverse effects. This is the first time that reversible white matter lesions have been reported to be associated with a thermogenic dietary supplement. A larger series of patients needs to be studied to assess the specificity and correlation of these findings as a direct cause of acute leukoencephalopathy. Further product-specific research on thermogenic aids is needed to determine levels of effectiveness and safety for consumers. a b 1. 2. 3. c 4. 5. Figure 3. MRI in Case 2. Axial T2-weighted imaging shows abnormal T2 hyperintense signal (arrows) of the (a) subcortical white matter, (b) corpus callosum, and (c) pontine tegmentum. Diffusion-weighted (b1000) imaging and apparent diffusion coefficient (ADC) maps demonstrate restricted diffusion in the same distribution. lesions, there is controversy regarding their pathogenesis. No unequivocal hypothesis has been formulated regarding the nature of the lesions. Several theories have been postulated, including intramyelinic edema due to transient disruption of energy metabolism, which may cause reversible myelin vacuolization (11), antiepileptic drug toxicity-induced reversible demyelination (12), alteration of the arginine-vasopressin system which may affect brain hydric content (13), and development of an inflammatory infiltrate with influx of inflammatory cells and molecules possibly combined with related cytotoxic edema (14). The usage of thermogenic dietary supplements is widespread for augmentation in overall metabolism and “fat burning” in expectation to support weight loss by the consumer. Thermatrim is a thermogenic dietary supplement marketed via the Internet and available to the general public. Its contents profile states it contains garcinia cambogia, chromium picolinate, chitosan, equisetum arvense, momordica charantia, herbal sources of caffeine such as guarana, and other purported metabolic-supporting ingredients such as carnitine and Ilex paraguariensis, though there is a lack of information on the quantities of ingredients and other specific product information. July 2015 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Filley CM, Kleinschmidt-DeMasters BK. Toxic leukoencephalopathy. N Engl J Med 2001;345(6):425–432. McKinney AM, Kieffer SA, Paylor RT, SantaCruz KS, Kendi A, Lucato L. Acute toxic leukoencephalopathy: potential for reversibility clinically and on MRI with diffusion-weighted and FLAIR imaging. AJR Am J Roentgenol 2009;193(1):192–206. Takanashi J, Imamura A, Hayakawa F, Terada H. Differences in the time course of splenial and white matter lesions in clinically mild encephalitis/ encephalopathy with a reversible splenial lesion (MERS). J Neurol Sci 2010;292(1–2):24–27. Takanashi J, Barkovich AJ, Shiihara T, Tada H, Kawatani M, Tsukahara H, Kikuchi M, Maeda M. Widening spectrum of a reversible splenial lesion with transiently reduced diffusion. AJNR Am J Neuroradiol 2006;27(4):836–838. Chason DP, Fleckenstein JL, Ginsburg MI. Transient splenial edema in epilepsy: MR imaging evaluation. In Proceedings of the 34th Annual Meeting of the American Society of Neuroradiology, June 21–27, 1996, Seattle, WA. Chicago: Old Smith Printers. Kim SS, Chang KH, Kim ST, Suh DC, Cheon JE, Jeong SW, Han MH, Lee SK. Focal lesion in the splenium of the corpus callosum in epileptic patients: antiepileptic drug toxicity? AJNR Am J Neuroradiol 1999;20(1):125–129. Notebaert A, Willems J, Coucke L, Van Coster R, Verhelst H. Expanding the spectrum of MERS type 2 lesions, a particular form of encephalitis. Pediatr Neurol 2013;48(2):135–138. Mirsattari SM, Lee DH, Jones MW, Blume WT. Transient lesion in the splenium of the corpus callosum in an epileptic patient. Neurology 2003;60(11):1838–1841. Hackett PH, Yarnell PR, Hill R, Reynard K, Heit J, McCormick J. Highaltitude cerebral edema evaluated with magnetic resonance imaging: clinical correlation and pathophysiology. JAMA 1998;280(22):1920–1925. Takanashi J, Tada H, Maeda M, Suzuki M, Terada H, Barkovich AJ. Encephalopathy with a reversible splenial lesion is associated with hyponatremia. Brain Dev 2009;31(3):217–220. Oster J, Doherty C, Grant PE, Simon M, Cole AJ. Diffusion-weighted imaging abnormalities in the splenium after seizures. Epilepsia 2003;44(6):852–854. Ramirez JA, Mendell JR, Warmolts JR, Griggs RC. Phenytoin neuropathy: structural changes in the sural nerve. Ann Neurol 1986;19(2):162–167. Dóczi T, Szerdahelyi P, Gulya K, Kiss J. Brain water accumulation after the central administration of vasopressin. Neurosurgery 1982;11(3):402–407. Tada H, Takanashi J, Barkovich AJ, Oba H, Maeda M, Tsukahara H, Suzuki M, Yamamoto T, Shimono T, Ichiyama T, Taoka T, Sohma O, Yoshikawa H, Kohno Y. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 2004;63(10):1854–1858. da Silva WV, de Andrade Gomes Silva MI, Tavares Toscano L, Dantas de Oliveira KH, de Lacerda LM, Sérgio Silva A. Supplementation prevalence and adverse effects in physical exercise practitioners. Nutr Hosp 2014;29(1):158–165. Leukoencephalopathic changes on magnetic resonance imaging associated with a thermogenic dietary supplement (Thermatrim) 391 Baylor news ■ Baylor Scott & White Health and Tenet to partner on five North Texas hospitals Baylor Scott & White Health and Tenet Healthcare Corporation announced a definitive agreement to partner on providing care through five North Texas hospitals. The partnership will focus on delivering integrated, value-based care to communities in Rockwall, Collin, and Dallas counties. Through this new partnership, the two organizations will jointly own Centennial Medical Center, Doctors Hospital at White Rock Lake, Lake Pointe Medical Center, and Texas Regional Medical Center at Sunnyvale—currently owned and operated by a subsidiary of Tenet—and Baylor Medical Center at Garland—currently owned and operated by Baylor Scott & White Health. Baylor Scott & White Health will hold a majority ownership interest in the five hospitals, and all five will operate under the Baylor Scott & White Health brand. The transaction is subject to regulatory review and customary closing conditions. “This is an exciting step as we partner with a like-minded organization to create a strong network that will improve the health of individuals, families, and communities across eastern and northeastern Dallas,” says Gary Brock, president and chief operating officer of Baylor Scott & White Health, North Texas. “This partnership demonstrates our commitment to advancing population health in North Texas.” The partnership will be governed by a jointly appointed board of managers. In addition, each hospital will have a governing board and independent medical staffs and medical staff leadership responsible for certain medical staff and clinical matters. Tenet will continue to manage the operations of Centennial Medical Center, Doctors Hospital at White Rock Lake, Lake Pointe Medical Center, and Texas Regional Medical Center at Sunnyvale on behalf of the partnership. Baylor Scott & White Health will continue to manage Baylor Medical Center at Garland. The leadership teams for each hospital will remain in place, and there should be little to no change for employees at the five hospitals. In addition, each hospital will maintain an independent medical staff, and physicians will retain their current hospital privileges. Separately, Tenet’s North Texas accountable care organization recently entered into 392 an affiliation agreement with the Baylor Scott & White Quality Alliance (BSWQA). For members of the BSWQA, a leading accountable care organization in Texas, this agreement increases convenient access to coordinated and integrated care by adding four hospitals, six outpatient centers, and more than 170 physicians to the network. Collaborating with health plan partners such as UnitedHealthcare enables BSWQA physicians to support a value-based health care model in which they receive payment incentives for achieving total cost savings by meeting certain evidence-based measures, such as disease management, primary care screenings, and patient safety. ■ Baylor Scott & White Quality Alliance ■ Baylor Health Care System telestroke and UnitedHealthcare collaborate to improve patient care in North Texas BSWQA and UnitedHealthcare are collaborating to improve care coordination and enhance health services for more than 52,000 North Texas residents enrolled in UnitedHealthcare’s employer-sponsored health plans. BSWQA is an accountable care organization established in 2011 as part of Baylor Scott & White Health’s strategy to improve health care delivery. BSWQA’s network of more than 3800 primary and specialty care physicians and 46 hospitals and post-acute care facilities will be available to people enrolled in UnitedHealthcare employer-sponsored health plans. BSWQA will leverage population health management, including care coordination, disease management, preventive health services, a health information exchange, and data analytics, to deliver a higher standard of quality care at lower costs. The two organizations will help shift Texas’ health care system to one that rewards quality and value instead of the volume of procedures performed. BSWQA is one of 250 new accountable care programs UnitedHealthcare has committed to in 2015 as it engages in deeper, more collaborative relationships with physicians and hospitals across the country. UnitedHealthcare will complement BSWQA’s established population health infrastructure with technology and actionable patient data, enabling physicians to take specific measures to improve quality and lower costs. Actionable data can include patient profiles, specific Healthcare Effectiveness Data and Information Set (HEDIS) gaps, and real-time information about emergency room and inpatient admissions. A team of care coordinators will support community-based care coordination, such as helping with transition plans after an individual is discharged from the hospital, scheduling follow-up appointments, and closing care gaps. program increases use of clotbusting drug Before Baylor Health Care System (BHCS) began its hub-and-spoke model of stroke care with telemedicine in 2013, Baylor Medical Center at Irving had treated only one stroke victim with tissue plasminogen activator (rtPA). In the program’s first 26 months, 56 of 58 eligible patients received the clot-busting drug that minimizes the damage caused by a stroke if it is administered within 3 to 4.5 hours after symptoms begin. Baylor University Medical Center at Dallas (BUMC) is the system’s hub, and Baylor Irving is one of the seven community hospital spokes, with more hospitals planning to come aboard in the near future. The system, often called telestroke, allows neurohospitalists on the medical staff at BUMC to evaluate patients remotely and make recommendations to emergency medicine doctors at community hospitals. The doctors use iPads and laptop computers to communicate. The physicians located at BUMC use a portable robot to view and evaluate stroke patients at the community hospitals. Typically, if an emergency medicine doctor suspects a patient has had a stroke, the BUMC telestroke team is notified. The team, which is always available, includes a program manager, clinical coordinator, vascular neurologists, neurosurgeons, and radiologists. The team recommends the most appropriate care after the evaluation. The telemedicine program has allowed Baylor Irving to be certified as a primary stroke center by The Joint Commission, a certification that acknowledges facilities “that make exceptional efforts to foster better outcomes for stroke care.” Four participating hospitals—Baylor Medical Center at Garland, Baylor Regional Medical Center at Plano, Baylor Regional Medical Center at Grapevine, Proc (Bayl Univ Med Cent) 2015;28(3):392–396 RECENT GRANTS • Development of microRNA biomarkers for noninvasive detection of colorectal cancer Principal investigator: Ajay Goel, PhD Sponsor: National Cancer Institute Funding: $360,402 Award period: 7/1/2015–6/30/2016 • Familial and early onset colorectal cancer Principal investigator: Ajay Goel, PhD, and C. Richard Boland, MD Sponsor: National Cancer Institute Funding: $372,400 Award period: 8/1/2015–7/31/2016 • Models for optimal liver transplant outcomes Principal investigator: Sumeet Asrani, MD Sponsor: Board of Trustees of Leland Stanford Jr. University/National Institute of Diabetes and Digestive and Kidney Diseases Funding: $67,141 Award period: 7/1/2014–6/30/2015 • Use of integrated personal omics profiling to identify biomarkers for autoimmune disease and Baylor All Saints Medical Center at Fort Worth—also have this certification. Other spoke hospitals include The Heart Hospital Baylor Denton and Baylor Medical Centers in Waxahachie and Carrollton. Nationally, about 15% to 40% of patients with symptoms of an acute stroke arrive at hospitals in time to receive rtPA; however, the treatment rate is low. Only about 6.7% of ischemic stroke patients receive the therapy at certified US primary stroke centers, and about 2% are treated at noncertified US hospitals. The treatment rate for hospitals participating in the BHCS hub-and-spoke system is more than 12%. Dion Graybeal, MD, architect of and medical director for BHCS’s hub-and-spoke stroke program, estimated that BUMC stroke teams will consult on about 800 cases in community hospitals this year. “We’ve seen an increase in consultations from all of our regional medical centers. Also, we don’t just log on and log off only where there are cases to be evaluated. We’re constantly monitoring quality processes and working toward performance improvement,” he said. July 2015 Principal investigator: Brandi Cantarel, PhD Sponsor: The Discovery Foundation Funding: $60,000 Award period: 11/24/2014–11/23/2015 • Spatial organization of the transcriptome in pustular psoriasis Principal investigator: Gerlinde Obermoser, MD Sponsor: National Psoriasis Foundation Funding: $75,000 Award period: 6/1/2015–5/31/2016 • Next-generation sequencing-based approaches for the development of epigenetic biomarkers for predicting therapeutic outcome in patients with colorectal cancer Principal investigator: Ajay Goel, PhD Sponsor: Cancer Prevention and Research Institute of Texas Funding: $886,982 Award period: 8/1/2014–8/30/2017 • Short-course therapy for multidrugresistant tuberculosis based on pharmacokinetic/pharmacodynamic answers for biological variability ■ Baylor University Medical Center performs first POEM procedures in Texas A surgeon on the medical staff at BUMC recently performed two peroral endoscopic myotomies (POEM) as part of a clinical trial, marking the first time that this minimally invasive technique has been done in Texas. The two procedures involved patients with achalasia, a rare disorder that prevents proper digestion. One of the patients underwent the procedure as an alternative to the Heller myotomy; the other patient had completed the Heller myotomy by a Principal investigator: Tawanda Gumbo, MD Sponsor: National Institute of Allergy and Infectious Diseases Funding: $736,025 Award period: 11/15/2014–7/31/2015 • DC-ASGPR as a novel target for controlling graft-versus-host disease and allograft rejection Principal investigator: Sangkon Oh, PhD Sponsor: National Institute of Allergy and Infectious Diseases Funding: $392,000 Award period: 1/1/2015–3/31/2016 • Glycemia reduction approaches in diabetes: a comparative effectiveness study Principal investigator: Priscilla Hollander, MD, PhD Sponsor: George Washington University/ National Institute of Diabetes and Digestive and Kidney Diseases Funding: $216,609 Award period: 8/1/2014–7/31/2015 chest approach in 2010 but later reexperienced swallowing difficulties. The POEM procedure has grown quickly in popularity worldwide over the past 6 years. As an incision-free alternative to surgery, the POEM technique represents a larger trend in endoscopic surgery. As Steven Leeds, MD, an esophageal surgeon on the medical staff of BUMC’s Department of Minimally Invasive Surgery, stated, “Surgical endoscopy is paving the way for many new procedures, and the POEM procedure is only the tip of the iceberg.” UPCOMING CME PROGRAMS The A. Webb Roberts Center for Continuing Education of Baylor Scott & White Health is offering the following programs: Chest Cancer Conference, July 18, 2015, at Baylor Sammons Cancer Center Hematologic Malignancies 2015, October 3, 2015, at Baylor Sammons Cancer Center 42nd Annual Williamsburg Conference on Heart Disease, December 6–8, 2015, at Williamsburg Conference Center, Williamsburg, Virginia For more information, call 214.820.2317 or visit www.cmebaylor.org. Baylor news 393 PHILANTHROPY NOTES ■ $2 million Rees-Jones Foundation grant to support Canine Companions for Independence The Rees-Jones Foundation has made a generous $2 million grant in support of the Canine Companions for Independence® at Baylor Scott & White Health–Kinkeade Campus. In honor of this gift, the building that houses functions in support of the dogs will be named the Jan Rees-Jones Canine Center. The center will house a veterinary clinic and radiology lab equipped for minor procedures and observation of each dog in residence. The center will also be equipped with a food prep kitchen, grooming spa, and laundry facility in addition to office space for the kennel staff. In 2014, Baylor Scott & White Health announced its partnership with Canine Companions for Independence, the nation’s premiere assistance dog training program, to provide a Canine Companions training site in the heart of North Texas. Slated to open in August 2015, it will be the first Canine Companions training center in Texas and the first to be connected with a major health care system. At the Kinkeade Campus, three types of assistance dogs will be trained to master more than 40 specialized commands. Service dogs assist adults with physical disabilities by performing everyday functions like turning on lights, picking up dropped keys, or opening a door; skilled companions enhance independence for children and adults with cognitive and developmental disabilities; and facility dogs work with a professional in a visitation, education, criminal justice, or health care setting. The average cost to breed and train each assistance dog is $50,000, and assistance dogs are provided free of charge to individuals. The POEM procedure takes a cameraequipped tube, called an endoscope, through the mouth into the esophagus. From there, a small hole is made in the lining of the esophagus and the endoscope travels along the muscle layer passing the lower sphincter. There, the layer of muscle causing the obstruction is cut to allow passage of food. The small hole in the esophageal 394 To provide this service to the community, the Foundation is seeking community support to cover capital and operating costs for the construction and maintenance of the Kinkeade Campus. To date, more than $3.5 million has been raised in support of this program. ■ Joan Lunden to speak at 16th annual Celebrating Women luncheon Joan Lunden, breast cancer survivor and former host of Good Morning America, will be the featured speaker at the 16th annual BHCS Foundation Celebrating Women luncheon on Thursday, October 15, at the Hilton Anatole Hotel in Dallas. Joan Lunden is an award-winning journalist, bestselling author, health and wellness advocate, motivational speaker, successful entrepreneur, and a mom of seven children. As the longest-running host ever on early morning TV, Joan greeted viewers every morning on Good Morning America for nearly 20 years. In June 2014, Joan was diagnosed with triple-negative breast cancer, which required chemotherapy, surgery, and radiation. Since then, she has shared her journey with the world, becoming a prominent voice in the breast cancer community. An eternal optimist, Joan decided to take her diagnosis and turn it into an opportunity to help demystify cancer treatment. Since the first Celebrating Women luncheon in 2000, more than $24 million has been raised to support BHCS’s fight against breast cancer. Every 4 hours, someone in Dallas–Fort Worth is diagnosed with breast cancer. Donations to Celebrating Women have supported advanced diagnostic equipment, innovative clinical research, and most importantly, safe, quality, compassionate care for Baylor’s patients and lining is then repaired and the endoscope is removed. “The procedure is shorter in duration and requires minimal instrumentation,” Dr. Leeds said. “And since the POEM procedure does not require access through the abdomen or chest, there is no risk for injuring intra-abdominal organs, especially in patients with previous surgeries.” The minimally invasive technique Baylor University Medical Center Proceedings families. Approximately 1200 passionate men and women attend the Celebrating Women luncheon each year in a show of support for Baylor’s efforts to fight the disease. ■ $100,000 grant to allow physicians to perform innovative surgeries in utero The leaders at the Fetal Care Center at BUMC have a clear vision: to become the first center in North Texas to provide perinatal correction of spina bifida and to develop new treatments for other complicated birth defects. Thanks to a recent $100,000 grant from the RGK Foundation, the Fetal Care Center is well on its way to realizing this vision. Currently, North Texas families must travel far from home to places such as Houston, San Francisco, or Philadelphia to receive this type of care for their unborn child. The first step to offer this care at BUMC is getting an advanced ultrasound system. The RGK Foundation grant will do just that, by funding the purchase of a Toshiba APLIO 300 V3 Ultrasound Imaging System. This will be located in the hospital’s Maternal Fetal Care Unit. The increase in capabilities will allow the Fetal Care Center to diagnose and treat a wider range of high-risk obstetric patients. In the near future, the center will be able to care for mothers whose unborn babies have spina bifida and other medically complicated birth defects. Generous donor support will allow the Fetal Care Center to provide more innovative diagnostic testing, new fetal interventional procedures, more fetal surgeries, and expanded pre- and postcare for moms and their babies in Dallas. For information on how you can support these or other initiatives at Baylor, please contact the Foundation at 214.820.3136. generally affords patients reduced pain, faster recovery, and equivalent ability to swallow compared with the traditional Heller myotomy. ■ Baylor Research Institute study reveals that uterine cooling can reduce C-section blood loss A never-before-seen childbirth technique could help a woman’s body heal itself through Volume 28, Number 3 ACCOLADES David J. Ballard, MD, PhD, chief quality officer at Baylor Scott & White and president of the STEEEP Global Institute, was named one of the 2015 “Experts Leading the Field of Patient Safety” by Becker’s Hospital Review. The American College of Physicians selected W. Mark Armstrong, MD, MACP, for the Ralph O. Claypoole Sr. Memorial Award for Devotion of a Career in Internal Medicine to the Care of Patients. This award is given to proven role models who have demonstrated excellence in and devotion to the clinical care of patients. Dr. Armstrong is chief of the general internal medicine division at BUMC. The American Society of Transplantation has awarded Jacqueline O’Leary, MD, its Clinical Science Investigator Award. Dr. O’Leary is medical director of the Liver and Transplant Unit at the Baylor Annette C. and Harold C. Simmons Transplant Institute. The annual award is given to only one US clinical investigator who has made a substantial contribution to the field of transplantation medicine. C. Richard Boland, MD, chief of gastroenterology at BUMC, received two awards for his achievements in gastroenterology research. In May 2015, the American Gastroenterology Association presented Dr. Boland the William Beaumont Prize in Gastroenterology. This award, given out every 3 years, recognizes those with an “outstanding contribution of major importance for the field of gastroenterology.” In October 2015, the Collaborative Group of the Americas on Inherited Colorectal Cancer will present Dr. Boland a Lifetime Achievement Award. Marvin J. Stone, MD, past chief of oncology at BUMC, received the Lifetime Achievement Award from the American Osler Society during its annual meeting in April 2015. temperature changes, according to a pilot study from Baylor Research Institute (BRI). Led by a team of physicians and nurses from BUMC, the study explored “uterine cooling,” an experimental method that showed significant results in early testing. The theory is based on biological fact: Cold temperatures make some smooth July 2015 muscles contract. The research suggests that the uterus is among that group. The study, cocreated by Jack Stecher, MD, an anesthesiologist on the medical staff at BUMC, and Jamie Crowson, CRNA, investigated the use of cold temperatures to fight uterine atony, a condition that prevents the uterus from self-contracting. It can often lead to postpartum hemorrhage, which is the leading cause of maternal death in the world, accounting for 38 instances every 100,000 births. The two researchers engaged Janice Mitchell, MD, a physician on the medical staff at BUMC, to serve as the study’s principal investigator. Organizers divided the study’s participants into two groups of 100 women, all of them receiving cesarean sections. While uterine hemorrhage is common in both natural and surgical childbirth, the researchers studied cesarean section patients because the uterus is exposed during the procedure, which allowed the team to test its cooling method more easily. Women in the control group had standard surgeries, which protect the exposed uterus with sponges soaked in a saline solution at 99°F. Women in the test group had their uteruses covered with sponges soaked in the same solution, but they were cooled to 30°F. The women who underwent the cooling technique bled an average of 32% less than women in the control group. Given those dramatic differences, the results could imply big changes in obstetric practice. “It’s unique because it’s a nonthreatening, nonpharmaceutical method that’s simple and that people can conceptualize,” Dr. Mitchell said. “We hope to apply it on a much larger scale to see whether it decreases the need for emergency hysterectomies, blood transfusions, and even more.” While this study was isolated to cesarean section patients, the findings suggest uses for uterine cooling beyond surgery, including during intrauterine balloon procedures after vaginal delivery. “Vaginal births comprise nearly two-thirds of all deliveries, and those patients are still at risk for uterine atony and bleeding,” said Crowson, a nurse anesthetist at BUMC. “In these cases, intrauterine balloon devices inflated with saline are sometimes placed to slow and stop bleeding.” Chilling those balloons could represent an opportunity to apply these findings to vaginal hemorrhage circumstances, he added. A future BRI study, now in enrollment, could determine if below-freezing temperatures also Baylor news work on women who require a cesarean section after spending hours in labor without success. This is the so-called “tired uterus” effect. “We want to analyze those patients who have had a dysfunctional labor experience to see if the cold is as effective on a uterus that has been working all day as opposed to one that hasn’t gone through an all-day labor,” Dr. Stecher said. If future investigations corroborate this pilot study’s findings, it could shift the way babies are delivered, potentially helping the 3% to 6% of women who suffer from postpartum hemorrhage. ■ Using big data to help the tiniest patients An increasing number of babies across the country are born addicted to opioids and require intensive care, according to a study analyzing MEDNAX Clinical Data Warehouse statistics from 299 neonatal intensive care units (NICUs) around the United States. The study results are reported in a paper authored by a Baylor researcher and published by the New England Journal of Medicine. The illness, called neonatal abstinence syndrome (NAS), is a drug withdrawal syndrome that most commonly occurs after in utero exposure to opioids. It can lead to seizures, difficulty feeding, respiratory complications, and low birthweight in affected infants. The study, titled “Increasing Incidence of the Neonatal Abstinence Syndrome in U.S. Neonatal ICUs,” directly addressed the NICU care of these infants and found that NAS is responsible for a substantial and growing portion of resources dedicated to critically ill neonates in NICUs nationwide. Dr. Veeral N. Tolia, a neonatologist on staff at BUMC, led a team of researchers from US hospitals that determined that between 2004 and 2013 the rate of NICU admissions nationwide for NAS increased almost fourfold, from 7 to 27 cases per 1000 infants. The research also found that the length of hospitalization increased by more than 40%, from 13 to 19 days. The total percentage of NICU days attributed to NAS increased by more than 500%, with eight centers reporting one in five of all NICU days devoted to care of these infants in 2013. The team also found that a substantial number of these infants presented after maternal exposure to prescription opioid pain relievers, a class of medication that the Food and Drug Administration (FDA) recently has chosen to regulate more tightly. The study found that among 395 these NICU patients, treatment with medication was common, occurring in 87% of the infants from 2012 to 2013. This is also problematic because of the scarce research about the best way to care for these infants. None of the commonly used medications are FDA approved for treating NAS, and there is substantial variability in how these infants are treated. ■ 30 years of innovation: organ transplant program celebrates three decades, thousands of lives saved What started as a heroic effort to save a 5-year-old girl has turned into one of the largest and most renowned transplant centers in the country. The Baylor Annette C. and Harold C. Simmons Transplant Institute, a leader in solid organ transplantation in the US, has successfully transplanted more than 7300 organs over the last 30 years and continues to push the boundaries of innovation. “We plan to maintain our status as a recognized world leader in both transplant science and patient care,” said Göran Klintmalm, MD, PhD, chairman of the transplant institute since its inception. “We will do this not only by focusing on innovations in transplantation surgery, but also by researching alternative treatments.” Dr. Klintmalm has literally coauthored the textbook on liver transplantation, the surgery that began the transplant institute 30 years ago. Through the urging of then-First Lady Nancy Reagan, the medical community took notice of a little girl from Indiana named Amie Garrison, who was in desperate need of a liver transplant. The only resource at that time for the surgery, in Pittsburgh, Pennsylvania, could not take the case. The surgeon known as the father of solid organ transplantation, Thomas Starzl, MD, PhD, asked a pioneering team of physicians at BUMC to take the case. Within hours of BUMC president and CEO Boone Powell Jr. agreeing to the operation, teams from Pennsylvania, Indiana, and Canada—where a pediatric donor liver was located—mobilized to perform the time-sensitive surgery. Baylor Annette C. and Harold C. Simmons Transplant Institute, which includes both BUMC and Baylor All Saints Medical Center at Fort Worth, is one of the largest multispecialty transplant centers in the country. Through the dedication of the transplant medical staff, Baylor has been “first” in a number of areas and is credited with milestones: • First and only adult living liver donor program in North Texas 396 • First islet cell transplant in North Texas • First certified ventricular assist device program in the US • First matched unrelated donor bone marrow transplant in Texas • First adult liver transplant in the Southwest • World’s first extracorporeal perfusion (bridge to transplant) using a genetically engineered pig liver, allowing the patient to survive and successfully undergo liver transplantation • First heart/lung/heart “domino” procedure in North Texas, in which a patient with terminal emphysema receives a single heart and two lungs, while another patient with cardiomyopathy receives the good heart from the patient with emphysema • First paired kidney donor transplant in North Texas ■ Baylor Scott & White Health–affiliated Hope Clinic moves into new facility, receives top national recognition Hope Clinic in Garland has a lot to celebrate these days. The 501(c)(3) nonprofit, faith-based organization has been providing medical care and resources for Garland’s medically indigent since 2002, operating out of small, overcrowded quarters. In 2011, Hope Clinic entered into an agreement to collaborate with HealthTexas Provider Network, a Baylor Scott & White Health affiliate, in connection with the operation of the clinic where services are provided to patients. The clinic was recently moved into a newly renovated location that more than doubles patient-care space. Adding to the excitement, the clinic received the National Committee for Quality Assurance Level 3 recognition as a patient-centered medical home—the organization’s top certification. From primary care to chronic disease management and prescription assistance programs, from behavioral health care to spiritual care, the clinic assists those most in need. Last year, prescription assistance totaled $500,000. Under a new arrangement with North Texas Food Bank, clinic patients with dietary restrictions are able to obtain food boxes designed for those with diabetes and heart disease. “Hope Clinic is all about giving back,” said Jenny Williams, executive director of Hope Clinic. “The patients served deserve this commitment to quality. Providing charitable medical care is not about enabling people. Poverty opens up a multitude of needs. We give patients the Baylor University Medical Center Proceedings necessary tools and resources, equipping them to move forward in life.” ■ Two Baylor Scott & White Health hospitals among top 100 for quality BUMC and Baylor All Saints Medical Center at Fort Worth were among the top 100 large US hospitals based on 40 measures of quality sought by the Affordable Care Act (ACA), according to a Kentucky-based organization that focuses on patient safety, quality, and efficiency of care. The SafeCare Group, a software company, conducted the analysis that used ACA’s metrics aimed at reducing hospital readmissions, curtailing hospital-acquired conditions, and achieving value-based care. The Baylor Scott & White Hospitals received the 100 SafeCare Hospitals distinction in the over400 beds category. The organization said that 400,000 deaths and 5.1 million preventable complications would be reduced annually if all US hospitals matched the performance of the top 100. ■ Baylor researcher’s hollow fiber system tuberculosis model approved by European FDA equivalent The European Medicines Agency (EMA), the equivalent of the FDA, has approved the use of the hollow fiber system for the development of drugs to treat and prevent tuberculosis. The hollow fiber system model of TB was developed about 12 years ago by Tawanda Gumbo, MD, investigator at BRI and the director of the Center for Infectious Diseases Research and Experimental Therapeutics at Baylor Institute for Immunology Research. This model, sometimes called the “glass mouse,” is used to select and evaluate possible drugs and treatment regimens before they are tested in clinical trials. The system aids researchers in determining which drugs to combine and at what doses to effectively fight multidrug-resistant Mycobacterium tuberculosis, the causative agent of TB. “This is a significant advance over many drug development models. The ‘glass mouse’ hollow fiber model has now been found to have a forecasting accuracy of within 94% of the clinical values that have been observed later in tuberculosis clinical trials,” Dr. Gumbo said. The approval allows for the hollow fiber system to be used in the development of TB drugs. Dr. Gumbo’s group is working to expand its uses to other clinical conditions. They are also collaborating with other BRI investigators in projects that will utilize the hollow fiber system. Volume 28, Number 3 Precision medicine: hype or hope? Robert G. Mennel, MD I recently attended the 10th Annual Harvard Personalized Medicine Conference. One presentation at this meeting was preceded by a video outlining the course of a patient who was diagnosed 4 years earlier with a stage IV non–small cell lung cancer—a diagnosis that normally would portend a 6-month survival. However, this woman who never smoked had an EGFR mutation, which predicted a longer response based on treatment with erlotinib, a drug that inhibits the pathway activated by the EGFR mutation and was not approved by the Food and Drug Administration until May 2013 (1, 2). She was treated on a clinical trial with erlotinib and had a remarkable response. However, a year later, her tumor developed resistance to this drug because of a second mutation. This is a common scenario that oncologists frequently experience. A few years ago this woman would have never made it to this point, since we had no drugs to effectively treat her at the outset. This case was especially poignant for me since my wife and I experienced the exact same scenario in 2008 and 2009. My wife had a cough, which was initially thought to be pneumonia. However, a computed tomography (CT) scan (Figure 1a) showed a mass, mediastinal adenopathy, and a pleural effusion. A bronchoscopic biopsy diagnosed an adenocarcinoma. My extreme depression was somewhat alleviated when I found out that she expressed a mutation in exon 19 (L747-A750 deletion) of the EGFR gene. I knew that we had a chance for a prolonged response, and I hoped that if our remission lasted long enough, the explosion of scientific discovery that was occurring in this field might actually produce a cure (a hope that most patients have). The first part of my dream came true. The first CT 7 weeks after starting erlotinib (Figure 1b) showed a near complete response, and her brain metastases had disappeared with just one erlotinib tablet per day. However, a year later she developed a T790 mutation, which caused the erlotinib to be ineffective (3). No new drug had been developed, and she died. It was bittersweet for me to watch the video shown at Harvard’s personalized medicine meeting. Thankfully, the woman in the video had her carcinoma a couple years later than my wife. In that interval, new drugs had been developed, which this woman was able to get through a clinical trial. A panoply of clinical trials exists with these new therapies that are being developed at an amazing pace. Unfortunately, Proc (Bayl Univ Med Cent) 2015;28(3):397–400 even though these trials offer the possibility of life-prolonging results, as was evidenced in this woman in the video, most physicians do not offer these trials to their patients. This woman in the video obtained another complete response, which she is still enjoying 4 years later. I doubt that she is cured, but she is getting closer, and another drug may come along before she has her next recurrence. Since this woman’s last drug was made available to her, the science has mushroomed at an even faster pace with the development of next-generation sequencing, RNA sequencing, metabolomics, and other building blocks of systems biology that identify for physician-scientists the mutations that are really important for the patient they are treating. If my wife’s illness had started 5 years later, my grandchildren would still be enjoying their loving and fun grandmother. What has allowed these amazing therapies to develop? The answer is discovery of disease mechanisms through an investment in research. Th e groundwork was laid in the 1980s with the development of the polymerase chain reaction, which allowed expanded research on DNA and brought genetics into the modern era (4). This led to a much better understanding of what drives the growth of tumors and gave oncologists targets to develop much more effective and directed therapies against. The science and therapies have not been limited to oncology. Examples include ivacaftor (5) to treat type 3 cystic fibrosis, L-dopa to treat Segawa’s dystonia (6), and the 12/14 translocation to define people at risk for sudden death because of the long QT interval (7), to name just three. Medicine, and especially oncology, has entered a new era. But what is the real promise of this new era in medicine? The stories enumerated above are amazing and could not have been told 10 years ago. However, we do not know the targets for most of the diseases that we see, and in oncology we have an especially difficult problem. After we discover an effective drug against a driver mutation, the tumor will usually discover a way around From the Charles A. Sammons Cancer Center and Baylor University Medical Center at Dallas, Dallas, Texas. Corresponding author: Robert G. Mennel, MD, Charles A. Sammons Cancer Center, 3410 Worth Street, Suite 580, Dallas, TX 75420 (e-mail: RobertMe@ baylorhealth.edu). 397 b a Figure 1. (a) The initial CT scan showing the left lung mass (1a), a pleural effusion (1b), and mediastinal adenopathy (1c). (b) The CT scan after 47 days of erlotinib showing near complete resolution of the pathologic findings. our therapy, as was demonstrated in my wife’s case. This leaves oncologists and their patients at the point that they started a number of months earlier. This scenario should not be a surprise, since there are many different metabolic pathways in the cell. Let me ask a simple question: If you had a specific route to work and one day the route that you normally took was blocked, would you be able to find your way to work? I think you would, since it is a rarity to have only one way to get to any destination. Figure 2 shows some of the pathways in a cell used by tumors for growth. Think of this as a roadmap. If our drug blocked one growth pathway, don’t you think that the tumor would find another pathway for growth, like you would find another route to work? Have we made progress? Yes, without a doubt we have made remarkable progress! Where do we need to go from here? Straight ahead! We need to stay the course or, better yet, chart a new course. As director of the Baylor Precision Medicine Institute, I have a very vested interest in precision or personalized medicine. I honestly think that the principles of precision medicine will change the practice of medicine to a much greater degree than it has already. However, there are a number of obstacles to the promise of precision medicine. These obstacles are the expectations of patients and physicians, the culture of physicians, and the ability to do the needed research. Precision medicine needs to simultaneously increase and decrease the expectations of patients and physicians. The examples that I have given above will excite patients and physicians alike. However, this excitement will lead to unrealistic expectations of what precision medicine can accomplish right now, at this point in history. If precision medicine cannot produce now what people are expecting it to produce, precision medicine’s development will be delayed. We cannot promise what we cannot deliver now. Therefore, we need to simultaneously curb the enthusiasm about what precision medicine can produce at this time, while increasing the enthusiasm over what precision medicine will eventually deliver in the future. The 398 potential accomplishments of precision medicine are without bounds. Five years ago, there was virtually no effective therapy for metastatic melanoma. Now we have ipilimumab, BRAF inhibitors, MEK inhibitors, and PD-1 and PD-L1 inhibitors. The four images in Figure 3 show remarkable responses that occurred during the vemurafenib trial. These results, which would have never been witnessed 2 years before, are so exciting that patients and physicians may interpret them as cures. They are not usually cures. However, they are probably the first steps on the journey to cure most disease. They are the first steps on the research journey. Research is the paramount event that will allow precision medicine to reach its full expectations. Research may also delay the development of precision medicine. These two statements frame a paradox. If we sequence a person’s genome, we will find thousands of mutations. However, we will know what to do with <1% of them. The remaining 99% comprise the basis for the basic and clinical research that is needed to advance precision medicine. This delineates the enormity of precision medicine’s task. This research is expensive, and research dollars are being cut back. How are we going to pay for this research? There are more questions than investigators and patients to answer these questions. Where are the investigators and patients going to come from? How are we going to frame the most important questions to be answered and convince investigators to cooperate in answering these questions? The gold standard for clinical research is the randomized controlled trial. If you have a drug against the driver mutation or its products causing the disease, is it ethical to do a randomized controlled trial in a group of patients with this driver mutation? The precision medicine community needs a coordinated plan to approach all of these questions. This organized approach is needed in a medical research community that prefers to work independently, is very protective of its data, is not likely to freely share data, generally lacks banked biologic data to answer questions, and for the most part does not have adequate informatics to solve their problems. This is Baylor University Medical Center Proceedings Volume 28, Number 3 Figure 2. A simplified representation of a cell’s proliferation pathway. Image courtesy of Abcam. an enormous but surmountable problem for precision medicine that needs to be solved. The culture that physicians practice in is another obstacle to the implementation of precision medicine. Most physicians are not fluent in the principles of precision medicine. Research in precision medicine will take more time than the standard care of patients. This will require a culture change for all of us. Medicine has made amazing progress in the 45 years that I have been a physician. But if we are honest with ourselves, we do not have the answer to most of the diseases that we treat. Therefore, research is necessary. We need to stay our course in very unfriendly waters, continuing the basic research and translating these findings into new diagnostics and new therapies. We need to do this in an era July 2015 where research funding is decreasing and where most patients are not enrolled in clinical trials but are treated with standard, often ineffective therapies. As physicians, we need to be honest with ourselves and recognize areas where our therapies are inadequate; if our patients still want therapy, we need to find trials that make sense and not continue to treat them with therapies that usually do not work. This is easy to say but difficult to do. Precision medicine can deliver amazing results now, but the promise for even greater results in the future is huge. In order to reach this prediction for precision medicine, we as physicians need to use the science that is available, encourage and participate in basic and clinical research, and ask ourselves whether the therapies that we are using are effective or ineffective and in need of a new treatment paradigm. Precision medicine: hype or hoax? 399 Figure 3. Positron emission tomography scans before and after vemurafenib therapy showing the dramatic response with the early use of this drug. 1. Nguyen KS, Neal JW. First-line treatment of EGFR-mutant non-smallcell lung cancer: the role of erlotinib and other tyrosine kinase inhibitors. Biologics 2012;6:337–345. 2. Yap TA, Popat S. Toward precision medicine with next-generation EGFR inhibitors in non-small-cell lung cancer. Pharmgenomics Pers Med 2014;7:285–295. 3. Ding D, Yu Y, Li Z, Niu X, Lu S. The predictive role of pretreatment epidermal growth factor receptor T790M mutation on the progressionfree survival of tyrosine-kinase inhibitor-treated non-small cell lung cancer patients: a meta-analysis. Onco Targets Ther 2014;7:387–393. 4. Nguyen KS, Neal JW, Wakelee H. Review of the current targeted therapies for non-small-cell lung cancer. World J Clin Oncol 2014;5(4):576–587. 5. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen 400 6. 7. 8. F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365(18):1663–1672. Yosunkaya E, Karaca E, Basaran S, Seven M, Yüksel A. Marked improvement in Segawa syndrome after L-dopa and selegiline treatment. Pediatr Neurol 2010;42(5):348–350. Mahida S, Hogarth AJ, Cowan C, Tayebjee MH, Graham LN, Pepper CB. Genetics of congenital and drug-induced long QT syndromes: current evidence and future research perspectives. J Interv Card Electrophysiol 2013;37(1):9–19. Arking DE, Pulit SL, Crotti L, van der Harst P, Munroe PB, Koopmann TT, Sotoodehnia N, Rossin EJ, Morley M, Wang X, et al. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet 2014;46(8):826–836. Baylor University Medical Center Proceedings Volume 28, Number 3 Update on the Baylor Scott & White Quality Alliance Carl E. Couch, MD, MMM T he US health care system has been widely characterized as having unsustainably rising cost, continuing quality issues, and uncoordinated or disintegrated delivery of care. Accountable care organizations (ACOs) focus on clinical integration in care delivery while improving quality and reducing costs. Clinical integration is considered essential to true systemic change and meaningful reform that expands coverage, improves quality and care coordination, rewards effective and efficient care, promotes innovation, and helps control cost (1). After 2 full years in operation, the Baylor Scott & White Quality Alliance (BSWQA) has made significant progress in achieving these elements of meaningful reform. BSWQA is a physician-led, patient-centered comprehensive network, with more than 3900 primary and specialty care physicians, 46 hospitals, a number of post–acute care facilities, and other members of the care continuum assuming joint responsibility for accessible and efficient care delivery. In the past year, BSWQA has collaboratively managed the health of patient populations, including more than 40,000 lives attributed to BSWQA through the Baylor Scott & White North Division employee health plan, Humana Medicare Advantage product, Aetna Medicare Advantage product, Scott & White’s Vital Traditions Medicare Product, and most recently the Aetna Whole Health–BSWQA ACO health plan. Preliminary data captured from these agreements point to BSWQA’s notable improvements in important quality, efficiency, cost, and outcome measures that have led to achieving the Triple Aim™—“Better Care, Better Health, and Better Value.” POSITIVE OUTCOMES IN POPULATION HEALTH MANAGEMENT Data over a 2-year period show that BSWQA population health strategies are working. Within the Baylor Scott & White North Division employee health plan population, readmission rates dropped 15% (Figure 1a), admissions per thousand were reduced by 9% (Figure 1b), and an internal projected analysis showed a $10 million savings in medical plan costs (actual vs. target) (Figure 1c). In addition, there was an increase in “innetwork” usage of BSWQA physicians, along with a growing number of high-acuity patients being assigned to nurse care managers. Throughout its 2 years in operation, BSWQA has met or exceeded all quality metrics set forth in all of its managed care contracts. Many of these accomplishments were driven by the Proc (Bayl Univ Med Cent) 2015;28(3):401–403 deployment of three key population health strategies centered on improving quality and coordinating care: • Patient-centered medical homes (PCMHs). BSWQA’s patient-centered medical home model is the primary driver for many BSWQA quality initiatives developed to improve care. As the first step in maintaining wellness and managing chronic disease for its patients, the patient-centered medical home serves as the stimulus for BSWQA quality improvements and efficiencies, such as developing physician-directed care teams, increasing the rate at which generic medications known to reduce costs are prescribed, and creating protocols to achieve standardized, quality care. Characterized by teambased physician-led primary care physicians, these PCMHs have been shown widely to improve outcomes and lower costs for patients served by them. • Care coordination. Appropriate care resources are assigned to patients in accordance with their health risk status. Registered nurse care managers are assigned to the 5% of patients who are sickest, who drive half the cost of health care and need special care coordination resources. These care managers augment physician services by facilitating posthospital transitions, coordinating specialty visits, helping to navigate the health system, and coaching patients in self-management and wellness. The next 15% of rising-risk patients are assigned to medical assistant health coordinators, who perform transitional care management and close gaps in care. The 80% of generally well patients are contacted through automated modes of communication, such as patient portals and Televox, reminding them of screenings and wellness visits that may be due. • Data analytics. Through risk stratification and predictive modeling, BSWQA is segmenting patients into specific health risk pools and tailoring their care appropriately. To prepare for future cost savings and align financial incentives with the work being done to improve efficiencies and quality, BSWQA has developed a shared savings distribution model. Supporting BSWQA’s belief in the equitable distriFrom Baylor Scott & White Quality Alliance, Dallas, Texas. Corresponding author: Carl E. Couch, MD, MMM, President, Baylor Scott & White Quality Alliance, 8080 N. Central Expressway, Suite 900, Dallas, TX 75246 (e-mail: carl.couch@baylorhealth.edu). 401 b a 95 100 20% 86 20% 18% 80 9% drop 15% drop 60 10% 40 20 0% 2012 0 2014 2012 c 530 $521.47 520 2014 $516.22 510 500 $494.00 490 $480.63 480 470 460 2013 2014 Target Actual Figure 1. Outcomes of the Quality Alliance population health strategies for the Baylor Scott & White North Texas Division employee health plan population, including (a) all-cause readmission rates, (b) admissions per thousand, and (c) medical plan costs (actual vs. target). bution of shared savings, this model allows all physicians to earn a percentage of savings based on attribution as well as on a pro rata basis within the respective primary care and specialty care pools of the distribution method. The only caveat to participating in shared savings is the requirement for physicians to achieve clinical integration measures such as local pod meeting attendance and website usage and to remain a member in good standing for 1 full year. over time. In addition, the BSWQA ACO is now an important differentiator among competing health plan options. BSWQA activity centered on contract agreements with payers and employers is quickly ramping up our covered lives, which are expected to grow to just over 400,000 by January 2017. This is astronomical growth considering our humble beginnings of managing the health of the 34,000 lives through the Baylor Scott & White North Texas Division employee health plan. SIGNIFICANT GROWTH IN COVERED LIVES The word is out: BSWQA is doing great work as demonstrated by the improved outcomes mentioned above, which were realized in just 2 short years in operation. These improvements and savings have prompted the development of BSWQA’s compelling story for accountable care driving positive outcomes and true health care transformation through population health management. As its story continues to unfold, payers and employers are taking notice of BSWQA achievements and seeking collaborative agreements to use the organization and its providers as a preferred network for their patients. These agreements are becoming a vital element for creating the value-driven care delivery model of the future. New collaborations between payers have been emerging, and the Aetna Whole Health–BSWQA ACO health plan continues to be actively marketed throughout the Dallas–Fort Worth area. These types of value-based network contracts are viewed by payers and employers as a way to control costs and ensure quality BUILDING THE POPULATION INFRASTRUCTURE BSWQA can credit achievements in improving care not only to the incredible collaborative and accountable efforts of its physicians, administrators, and staff, but also to invaluable resources provided by a solid population health infrastructure. BSWQA’s population health infrastructure was built following the playbook for population health set forth by industry experts and reported by the Advisory Board Company (2) (Table 1). In an industry inundated with overwhelming change and what seems like endless reform requirements, it is often difficult to see the light at the end of the tunnel. There have been ACO skeptics everywhere. However, the impressive early results emerging from BSWQA’s population health efforts are inspiring. To see BSWQA’s hard work associated with true care transformations among our patient populations is testament to the organization’s competence in forming a network of willing physicians and hospitals. It also confirms 402 Baylor University Medical Center Proceedings Volume 28, Number 3 Table 1. The population health strategies of Baylor Scott & White Health Quality Alliance Playbook for population health* Prioritize a list of key initiatives with stakeholder buy-in BSWQA’s response BSWQA focuses on delivering value by eliminating unnecessary services, better managing chronic disease, and improving coordination of care. Invest in information exchange, analytics, Substantial investments have been made in Humedica, Crimson Real-Time, Explorys, and Crimson Care Manager. and patient-facing technology All systems are up and running and offering a longitudinal patient view, as well as automated patient identification, risk stratification, predictive modeling, and workflow analysis functionality. A patient portal called FollowMy Health (an AllScripts solution) has been made available by Baylor Health Care System. The BSWQA information technology committee is hopeful to announce that the patient’s medical data can be viewed at the point of care utilizing the system’s health information exchange browser. Stay tuned. Develop a preferred partner network with BSWQA is a broad network of primary and specialty care physicians, hospitals, post–acute care facilities, and shared culture and accountability other members of the care continuum willing to assume joint responsibility for patient access and care delivery. It participates in managed care contracts with the North Texas Division employee health plan and Medicare Advantage programs through Humana, Aetna, and Scott & White Vital Traditions. As a result of its success in managing more than 40,000 lives, prominent payers and employers in the market are seeking direct contracting opportunities with BSWQA. Train and redeploy existing staff to match BSWQA’s broad network of primary and specialty care physicians—with their proficiency in disease management new demand for patient services and adult preventive health services, their solid reputation for high-quality care and patient satisfaction, along with their existing capacity for superior practice management—is central to BSWQA development. *The playbook is from the Advisory Board Company (2). BSWQA indicates Baylor Scott & White Health Quality Alliance. BSWQA’s capacity to generate positive outcomes as it begins the transition from volume-based to value-based care delivery. Even more inspiring is the health transformation being achieved throughout the nation that is already causing a shift in the health care cost curve. A new report from the Council of Economic Advisors stated that according to recent data, health care spending and prices are growing at their slowest rates in decades (3). Specifically, the Centers for Medicare and Medicaid Services had a 6% annual increase in spending from 2002 through 2011, but for the past 2 years only a 1% increase. While this marked slowdown likely has many causes that are not fully understood, the available evidence suggests that, as a nation, contributions to meaningful reform such as ACOs are already having an impact and improving the quality of care for patients. Adding to BSWQA accomplishments is the honor of being named by Becker’s Hospital Review as one of the “100 Accountable Care Organizations to Know,” being recognized among the Top 30 ACOs in the country by SK&A Consulting, and earning ACO accreditation from the National Committee for Quality Assurance. As we round out 2015, BSWQA care July 2015 strategies will continue to focus on value and accountability. BSWQA will concentrate on becoming more proficient in managing patient populations and will continue to explore opportunities to participate in direct contracting with employers and payers. BSWQA’s performance initiatives will be selected to target best cost-reduction opportunities for each contracted population. In addition, BSWQA is beginning to serve as the population health integrator for Baylor Scott & White Health, now the largest not-for profit health system in Texas. 1. American Hospital Association. Clinical integration: the key to real reform. TrendWatch 2010(February), 1-12. Available at http://www. aha.org/research/reports/tw/10feb-clinicinteg.pdf; accessed May 12, 2015. 2. The Advisory Board Company. Playbook for Accountable Care: Lessons for the Transition to Total Cost Accountability. Washington, DC: Advisory Board. 3. Council of Economic Advisors. Trends in Health Care Cost Growth and the Role of the Affordable Care Act. Washington, DC: Executive Office of the President of the United States, November 2013. Available at https:// www.whitehouse.gov/sites/default/files/docs/healthcostreport_final_noembargo_v2.pdf; accessed May 12, 2015. Update on the Baylor Scott & White Quality Alliance 403 Nobel laureates and their medical schools: who selected whom? Allen B. Weisse, MD B y the beginning of 2015, the United States had largely recovered from the economic crisis of 2008. The Dow had topped 18,000; unemployment was down; productivity was up. Despite this, much of the American public is uneasy about the future. Dating even before the Great Recession, poll after poll registered the belief that the outlook was bleak. When asked, “Do you think your children will grow up to be as well off or better off than you are?” the reply was usually in the negative. This was not only the case for those in the shrinking middle class and those lower on the economic ladder. The affluent, those in the top 1% or 5% of the income spectrum, were equally unenthusiastic about the future. This angst about the prospects awaiting their children has spurred efforts to obtain the best education possible to evade the glum fate threatening them. In cities such as New York, young parents, when they can afford it, seek out preschool or kindergarten programs that will give their kids a better edge in the future. Private grammar and high schools are often engaged. And then, before one knows it, high school graduation is upon them and the frantic search for the “right” college begins. For those contemplating a career in medicine, where the openings for medical school are limited, the emphasis is on obtaining a place in one of the elite colleges in the hope that this will ease the pathway into medical school. And with this, a future success in life will be achieved. Is such a belief justified? No emblem of success in medicine is greater than that of a Nobel Prize in Medicine or Physiology. For those reaching this pinnacle, is it in any way related to the colleges or graduate schools attended along the way? Between 1901 and 2014, 207 individuals received the Nobel Prize in Physiology or Medicine. Of these individuals, 95 were Americans. Among these, 17 received their formal educations abroad before settling in the United States, where the bulk of their research was performed. This leaves 78 who, in the course of their education, were confronted by college selection and later medical school selection in the United States. Details of their education and biographical facts are available online from the Nobel Foundation (1). Identification of the 10 most selective colleges was obtained from a common source, U.S. News and World Report (2). The 10 most selective of our 141 medical schools was also obtained from this source (3). 404 Table 1. Ranked undergraduate colleges attended by 78 Nobel laureates Rank Institution Number 1 Princeton University 0 2 Harvard University 2 3 Yale University 5 4 Columbia University 6 4 Stanford University 0 4 University of Chicago 1 7 Massachusetts Institute of Technology 1 8 Duke University 0 8 University of Pennsylvania 2 California Institute of Technology 1 10 Other undergraduate schools 60 Table 1 indicates the undergraduate colleges attended by the 78 Nobel laureates included in our sample. Since the total number of undergraduate institutions in the United States is over 3000, the 10 schools constitute only a fraction. Nevertheless, 18 of the 78, or 23%, attended one of these highly rated schools, attesting to their drawing power for the intellectually gifted. Still, three quarters of the group attended one of the lower-ranked colleges. Table 2 lists the top 10 medical schools and the numbers of Nobel laureates who attended them in the course of their education. The total tallied is 77, since one of the Nobel laureates, Gertrude B. Elion, a biochemist and pharmacologist, never obtained a doctorate degree. Here, the denominator of our calculation (“Others”), the number of medical schools in the United States, is much lower than the number of undergraduate schools applying to Table 1. However, this number has grown over the years. In 1930, there were 76 US medical schools; in 1950, 79; in 1984, 127. Currently there are 141 US medical From the Department of Medicine (retired), Rutgers–New Jersey Medical School, Newark, New Jersey. Corresponding author: Allen B. Weisse, MD, 164 Hillside Avenue, Springfield, NJ 07081 (e-mail: allenweisse@gmail.com). Proc (Bayl Univ Med Cent) 2015;28(3):404–405 Table 2. Top-rated research schools of medicine attended by 77 Nobel laureates Rank Institution MD PhD MD/PhD Total 1 Harvard University* 12 6 – 18 2 Stanford University* – – – – 3 Johns Hopkins University* 8 2 – 10 4 University of California, San Francisco* – – – – 5 University of Pennsylvania 1 – – 1 6 Washington University in St. Louis 3 – – 3 7 Yale University* – 2 – 2 8 Columbia University* 3 2 – 5 9 Duke University – – – – 10 University of Washington – 1 – 1 Other medical schools 17 18 2 37 77 *Also among the top 10 rated for graduate schools in science. schools in existence. Using these figures one can estimate that over the last 50 years or so, the highly ranked schools have constituted roughly between 8% (10/127) and 13% (10/76) of the total. Among the 77 individuals counted, 40 (52%) obtained their MD or PhD degrees from one of the top 10 schools. As in Table 1, this disproportionate figure reflects the desirability of these highly rated institutions. What is not shown in the table is that, among these 40, only 11 (28%) had attended a top 10 college prior to entering medical school. In other words, the bulk of these did not require a degree from an elite top 10 college before being accepted into that institution’s graduate program. During the period studied, none of the laureates attending a top 10 school obtained both MD and PhD certification, although two attending lower-ranked schools did. This will probably change in the future, given the highly specialized work currently in progress. In the gathering of these data some interesting demographic findings regarding the Nobel laureates’ birthplaces emerged. Many of them were born in the Northeast, the most densely populated section of the country. New England produced 11 laureates, but only one was from Boston. New York City claimed 17 as their birthplace. Women were underrepresented. Rosalyn Yalow, a developer of radioimmunoassays (Nobel in 1977), was the first native-born American woman to be so honored. However, over the next 27 years, only 4 more American women joined her in receiving this award. Such a disappointing finding is tempered by the fact that today the number of women in American medical schools is often equal to and, at times, greater than the number of men. Although no attempt has been made to quantify this, a reading of the 78 biographies revealed that a number of future Nobel Prize winners were often disengaged during their early school years and had only lackluster records during that time. Others began their intellectual pursuits in the humanities or other nonscientific pursuits before being directed into the field of bioscience. July 2015 An associated concern about selective colleges has been addressed at some length by the provocative author Malcolm Gladwell (4). He notes that more than half of all American students who start out in science, technology, or mathematics programs drop out after the first or second year. It appears that many very bright students, when accepted into one of the top-ranked schools, become intimidated by the prodigies around them. This results in a diminishing of self-esteem and abandonment of this course of study. Gladwell argues that, had they matriculated in a second- or third-tier college, they would have succeeded in their initial goals and emerged with the credentials enabling them to function in these fields to the benefit of society, which needs more of such professionals. Although this phenomenon does not appear to apply to medical schools, given their high graduation rates, it poses an intriguing pedagogical question: When is the “best” school not the best choice? Finally, how valid is this “retrospectroscopic” approach to addressing the questions posed? Are the findings concerning this small and highly selective group applicable to the hundreds of thousands of students applying to college or medical school? Are our numbers just too small? How reliable is U.S. News and World Report? Is the awarding of a Nobel Prize the best gauge for universal success when errors of omission have been so common in the past history of the Nobel Foundation (5)? Such doubts may be justified, but the results reflected from even this small facet of investigation are compelling. We Americans like to think of ourselves as egalitarian in contrast to our British cousins. Although their educational system is organized differently from ours, it was enticing to determine the relationship of their two major universities to the awarding of the Nobel Prize. During the time period covered, 25 Nobel Prizes in Medicine or Physiology were awarded to citizens of the United Kingdom. Of those so honored, 15, or 60%, had attended either Oxford or Cambridge. This does not seem terribly different from the 52% of American Nobel laureates who attended top-tier medical schools in the United States. Perhaps we are more class conscious than we would like to think. On the other hand, tucked into Harlem, of all places, is a small cluster of incongruously designed Gothic buildings that represent the City College of New York. This once tuition-free public institution, catering mainly to the children and grandchildren of impoverished immigrants, served as an intellectual incubator for 13 Nobel Prize winners, 6 of them in Medicine or Physiology. Not a bad record for a college with no great financial endowment, no hoary traditions, and no long historical record of scholarly achievements. 1. 2. 3. 4. 5. Nobel Foundation and Nobel Media. All Nobel laureates in physiology or medicine. Available at http://nobelprize.org/nobel_prizes/medicine/ laureates; accessed April 7, 2015. U.S. News and World Report. Best Colleges, 2015 Edition. Washington, DC: U.S. News and World Report, 2014:72. U.S. News and World Report. Best Graduate Schools, 2015 Edition. Washington, DC: U.S. News and World Report, 2014:64. Gladwell M. David and Goliath. New York: Little, Brown & Co., 2013:63–95. Weisse AB. Notes of a Medical Maverick. New York: iUniverse, 2010:101– 128. Nobel laureates and their medical schools: who selected whom? 405 On Camel Rides and Moses Maimonides John Davis Cantwell, MD W hile in Morocco, mainly to celebrate a 75th birthday by riding camels in the Sahara desert with my wife and several good friends, I also had another objective. I wanted to visit the old city (medina) of Fes and to find the home of the legendary Middle Ages physician, Jewish theologian, and philosopher, Moses Maimonides, said to be a direct descendent of King David. The sand dunes in the Sahara were formidable, as I’d heard (Figure 1). The 1-hour camel ride was enjoyable (sort of ), although the downhills were a bit hard on my postoperative low back. I could only imagine what it must have been like to make the 52-day journey to Timbuktu in years past. The medina of Fes is a maze of narrow, twisting alleyways, lined with souks (shops) selling a wide variety of goods, mainly food, clothing, and various crafts. Unlike the medina of Marrakech, this one is free of motorized vehicles, although traversed by heavily laden donkeys and horses (Figure 2), their owners shouting a harsh balak, which roughly translates into “get out of my way.” Our guide, Jalil, had grown up in the medina and took us to the house where Maimonides lived during his 5 years in the city. Now a restaurant (Figure 3), the interior revealed the mosaics and various beautiful mismatched Berber carpets, so typical of the country. Nearby was a sign (Figure 4) noting the former site of a hospital dating back to the time of Maimonides, where he most likely trained in medicine. MOSES MAIMONIDES Maimonides (Figure 5) was born in Cordoba, southern Spain, in 1135. The Almohad Berber dynasty conquered Cordoba when he was a teenager, forcing his family to try different areas in Spain more tolerant of Jews before coming to Fes. He trained in medicine both in Cordoba and in Fes. The fanatic Islamic sect of Almohad eventually took over Fes in 1145, after a 9-month siege. Maimonides had departed for Egypt years before and eventually settled in Old Cairo, where he died at age 69. A prolific writer and thinker, Maimonides produced a 14-volume work on codification of Jewish law among his many works. He became the chief rabbi of all the lands controlled by Saladin, the sultan of Egypt and Syria, and was also the personal physician to Saladin (who had defeated the crusaders in Jerusalem) and to Saladin’s son, Al-Afdal. The latter was said 406 a b Figure 1. The author and his wife, Marilyn, riding in the Sahara desert. to have had “unhealthful habits” and was “burdened by black thoughts and physical symptoms,” which no doubt kept his physician busy. THE APHORISMS I was mainly interested in perusing some of the 10 medical books of aphorisms Maimonides wrote. As Nuland noted, he was “a commentator on the art of medicine as it had been From Piedmont Heart Institute, Atlanta, Georgia. Corresponding author: John Davis Cantwell, MD, Piedmont Heart Institute, 275 Collier Road, NW, Suite 500, Atlanta, GA 30309 (e-mail: john.cantwell@piedmont.org). Proc (Bayl Univ Med Cent) 2015;28(3):406–408 Figure 4. A sign indicating the hospital location where Maimonides probably worked. Figure 2. The medina of Fes. handed down to him by Hippocrates and especially Galen, basing the commentary on his world view and the experiences he had had when caring for his many thousands of patients” (1). He described a number of common conditions, from pneumonia and asthma to diabetes and hepatitis. He had the chutzpah to criticize Galen for contradictions “in that which he previously stated,” saying that “this requires explanation.” He also challenged Galen’s belief that the testicles were more a b Figure 3. The former home of Maimonides, now a restaurant. July 2015 important than the heart, pointing out that one could live without testicles (i.e., eunuchs) but not without the heart. It would take another 500 years before William Harvey disproved Galen’s theory of the circulation. Some of Maimonides’ aphorisms (1, 2) are still pertinent today, such as the following: • “The more perfect a person becomes in one of the sciences, the more cautious he grows, developing doubts, questions, and problems that are only partially solved” (whereas one defi cient in science will fi nd it “easier to understand every difficulty”). • “Immobility is as great a deterrent to the maintenance of health as activity is of benefit.” • “One should not neglect physical exercise for the body as do people of learning who diligently study the entire day and night without any gymnastics.” • “Moderate physical exercise . . . is good both for the body and soul.” • “It is not good for a person to drink more than a reasonable amount of wine.” • “Thus, rejoicing and happiness alone will make many people’s illness milder. For On Camel Rides and Moses Maimonides 407 • “Excessive ingestion of walnuts causes hindrance of speech.” • “Excrement of goats, mixed with barley flour and kneaded with vinegar, dissolves hand inflammation.” • “The consumption of rabbit heads, as much as one is able to eat, helps against tremors.” (Sorry, I can’t eat many rabbit heads.) • “The wearing of rabbit skins strengthens the bodies of the elderly and the young.” • “Mustard oil trickled into the ear of a deaf person restores hearing.” (Maybe I’ll try that on a friend who is going deaf.) • “Ivory, if pulverized and the teeth brushed therewith, whitens them.” • “If his right testicle is larger he will give rise to male offsprings; if it is the left, he will give rise to females.” (I’ll test this in a patient whose wife is pregnant.) • “A cattle hoof, if burned and drunk with oxamel, shrinks an enlarged spleen and stimulates the desire for coitus.” (Worth a try, even if one’s spleen isn’t enlarged.) Figure 5. 18th-century portrait of Maimonides. others, both the illness on the one hand as well as the emotional upset that led to it disappear.” • “Colchicine . . . dissolves inflammation of gout.” SUMMARY A birthday celebration trip to Morocco featured a camel riding adventure in the Sahara desert and a visit to the home of the noted physician, Jewish theologian, and philosopher Maimonides. After a prolific life, Maimonides died in Egypt and was buried in Tiberias in the Holy Land, a site that some still debate. His medical aphorisms were referred to for centuries after his death. Many hospitals and schools throughout the world today bear his name, such was his influence. His gravestone says simply, “From Moses to Moses, none arose as Moses.” Of less value are off-the-wall statements: • “Radishes and beets and the like are quite often altered and converted to blood, but only a small amount.” 408 1. 2. Nuland SB. Maimonides. New York: Schokem Books, 2005. Rosner F, Muntner S, eds. The Medical Aphorisms of Moses Maimonides. New York: Yeshiva University Press, 1971. Baylor University Medical Center Proceedings Volume 28, Number 3 DAVID BRUCE HELLMANN, MD: a conversation with the editor David Bruce Hellmann, MD, and William Clifford Roberts, MD D r. David Hellmann (Figure 1) gave medical grand rounds at Baylor University Medical Center at Dallas on November 18, 2014, and between his wonderful grand rounds and his noon presentation to the medical houseofficers, the following interview was done. Dr. Hellmann is one of the modern greats in internal medicine. Since 1996, he has been professor of medicine at The Johns Hopkins School of Medicine and, since 2000, chairman of the Department of Medicine at Johns Hopkins Bayview Medical Center, where 40% of the Hopkins Department of Medicine faculty works. He also is vice dean and vice president for research at Bayview Medical Center and the Aliki Perroti Endowed Professor at Johns Hopkins University School of Medicine. Dr. Hellmann was born on March 2, 1951, in Louisville, Kentucky, and that is where he grew up. He graduated magna cum laude from Yale College, New Haven, in 1973, and from the Johns Hopkins University School of Medicine (faculty selection to Alpha Omega Alpha) in Baltimore in 1977. His 3-year training in internal medicine was on the Osler Medical Service at The Johns Hopkins Hospital. In July 1980, he moved to San Francisco, California, to do a 2-year fellowship in rheumatology/clinical immunology and upon completion was appointed assistant clinical professor of medicine at the University of California, San Francisco (UCSF). By 1985, he was acting chief of the Division of Rheumatology/Clinical Immunology at their Moffitt Hospital. In 1986, he returned to Johns Hopkins as assistant professor, deputy director of the Department of Medicine, and associate physician-in-chief of The Johns Hopkins Hospital. By 1987, he was clinical director of the Division of Molecular and Clinical Rheumatology and by 1989, associate professor in the Department of Medicine and the Mary Betty Stevens Endowed Chair in Rheumatology. For 1 year spanning 1994 to 1995, he was acting director of the Department of Medicine and the acting physician-in-chief of The Johns Hopkins Hospital. In 2000, Dr. Hellmann became chairman of the Department of Medicine at the Johns Hopkins Bayview Medical Center and director and cofounder of The Johns Hopkins Center for Innovative Medicine. His contributions to the Johns Hopkins institutions have been enormous. He has served on numerous important committees and has received teaching awards from the Johns Hopkins Osler medical housestaff. Despite these numerous Proc (Bayl Univ Med Cent) 2015;28(3):409–419 time-consuming activities, Dr. Hellmann has continued his investigative activities and has published nearly 100 articles in peer-reviewed medical journals, edited 13 books, including three editions of Current Rheumatology: Diagnosis & Treatment, and written nearly 100 chapters in various textbooks. Along the way he has been associate editor and editor in chief of Medicine, a journal that has published Figure 1. David Hellmann, MD. numerous classic articles through the years. He and his wife, Linda, are the proud parents of two successful offspring. Dr. Hellmann is one of the kindest and most informed physicians I have been privileged to meet, and it was an honor to have him at Baylor University Medical Center. William Clifford Roberts, MD (hereafter, Roberts): Dr. Hellmann, it’s really a pleasure to speak with you. To start, could you talk about your early years, your parents, and your siblings? David Bruce Hellmann, MD (hereafter, Hellmann): I grew up in Louisville, Kentucky, and had the most wonderful of childhoods. My father was a solo family practitioner (Figure 2). No one in his family had been a physician or had gone to college. The searing experiences in his life were the Great Depression, in which his family lost their house and his father, an From the Department of Medicine, Johns Hopkins University School of Medicine and Johns Hopkins Bayview Medical Center, Baltimore, Maryland (Hellmann) and the Baylor Heart and Vascular Institute, Baylor University Medical Center at Dallas (Roberts). Corresponding author: David B. Hellmann, MD, MACP, Chairman, Department of Medicine, Johns Hopkins Bayview Medical Center, 5200 Eastern Avenue, Mason F. Lord Building, Center Tower, Room 322, Baltimore, MD 21224 (e-mail: hellmann@jhmi.edu). 409 Figure 2. At age 7, with his father, Jack K. Hellmann, MD, 1958. engineer, lost his job, and war. Before finishing high school, he joined the Army Air Force and was a navigator during World War II. During the war he dropped napalm in parts of Asia. Although he didn’t speak much of his experiences, like many of that generation, he told me one time that the planes did not fly very high or very fast so he saw the devastation that was brought. Given these experiences, he decided that he would be guided by 1) spending his whole life promoting health and 2) working only for himself. Those two principles at that time (late 1940s to 1950s) meant he would become a physician. Through the G.I. Bill, he attended an abbreviated college and full medical school. Four of his five children attended his graduation. My mother was a chemistry major and later in life became a talented math teacher. Another experience influenced my career choice. When I was 5, I developed Legg-Calve-Perthes disease, the softening of the hipbone. (It’s an idiopathic avascular necrosis of the hip that occurs chiefly in young boys [90%] between the ages of 5 and 6.) Initially, I was thought to have tuberculosis of the hip because my parents during my first year lived in public housing where tuberculosis was common. Additionally, I had a positive PPD at age 5. Quickly, however, it became clear that it wasn’t tuberculosis. For about a year I did not walk normally. For about 4 to 6 months I was in a full-body cast that kept my right leg from moving. The cast was from my belly button to my knees. Later I was in a brace and then crutches. I remember well the kindness of the nurses and physicians while I was in a cast. We moved to St. Matthews, Kentucky, when I was 3 or 4 and lived there when I developed Legg-Calve-Perthes disease. On one side of our house was a huge cornfield and on the other, a neighbor with nine children. That family ran the local bakery and the father (Mr. Bernie Bowling), who also was the mayor, noticed I couldn’t walk. He invented an “Irish mailer,” a tricyclelike device with two wheels in the back and one in the front. It 410 was guided by the feet and propelled by hand bars connected to a drive chain. He altered the “mailer” by removing the bars and replacing the guide wheel with a wheel with pedals so that I could lie on the plywood and propel myself using handles on the wheels. As a result, I had no impediment or drawback to going wherever I wanted. Now that I have two children, I marvel at my parents and my neighbor for not making me feel limited in any way. My illness introduced me to medicine and also perhaps instilled in me the sense that you cannot count on everything working out well and that you need to put your own effort into an endeavor to get where you want to go. I have experienced people’s generosity throughout my life. I’m not a particularly religious person but I was raised with the concept that grace is a gift from God and that these gifts are received not because you deserve them but because someone has to receive them and you are the lucky recipient. As I look back on my life, I have been showered with gifts of grace, including from Mr. Bowling, our neighbor. Roberts: How long were you in the cast? Hellmann: In total, 1 year. I was in the cast for 4 to 6 months, then in a big heavy metal brace. A few classmates in kindergarten called me Chester, a character in Gunsmoke who walked with a limp. That’s about as harsh as it got. From the brace I went to crutches, and by the year’s end the hip hardened with a good ball and socket. There were no residual consequences. People who don’t get the care that I received often need an early hip replacement. The only consequence I remember was having a bigger foot than before so I had to get two pairs of shoes for about a year after. I am the second oldest of five children, the oldest male. By the time I was ready to try and walk again, I could have won the Olympics in hopping. I was a phenomenal hopper on my left leg and a very rapid crawler, the two ways I was allowed to get around. I asked my younger brother, Don, how to walk. He took about a nanosecond and said, “Well, put one foot in front of the other.” I tried that and immediately fell. I started to crawl. My sister, a born leader, grabbed me by my shirt and said, “You’re a Hellmann and no Hellmann is going to crawl. Walk!” So with my sister’s words of “encouragement,” I kept at it and soon walked again. Roberts: Does anyone know what causes that disease? Hellmann: No. Roberts: What is your father’s name? Hellmann: Jack King Hellmann. He was not named John because his father was Frederick Heinrich Hellmann, the first of 12 children to be born in the USA. My great-grandfather was a pacifist and didn’t want to be in Bismarck’s army in the 1870s. He came to this country as a dairy farmer in St. Louis and then was transferred with his company to Louisville, Kentucky, where my dad was born. My grandfather didn’t believe in formality because everyone referred to him as Henry or Heine, so he wanted his son (my dad) to be Jack. My uncle’s name was Bruce, which is my middle name. He did not give my uncle a middle name because he said people don’t use middle names. Roberts: When did your father live? Baylor University Medical Center Proceedings Volume 28, Number 3 Hellmann: March 21, 1925, until May 14, 1999. He developed multiple sclerosis when I was in college/medical school and spent the last 16 years of his life in a nursing home. There he dressed every day in a coat and tie and even after 16 years had patients streaming in to visit him. He probably made many diagnoses sitting there unable to move his arms or legs but just by listening and knowing the patients very well. He may have received some graces but he was also cursed with health challenges. His experience was a great educator for me. In medical school I wrestled with the question of what my father’s illness meant, and I always exhorted to give people hope. Did it mean sugarcoating when people had metastatic cancer or did it mean misrepresenting the seriousness of an illness like systemic lupus erythematosus? It struck me that in almost everyone I’d met from any culture, part of hope means having a sense of control over your life. I saw in my father’s case that multiple sclerosis robbed him of the sense of control that he had had. For many years my father functioned fine, but I saw that he woke up each day with doubt, something absent unless one has an illness or has suffered some unexpected tragedy. Most of us who are able to take our health for granted believe we have control over our lives. I came to understand that the art of medicine was to help each person restore a sense of control, and since each person does this differently—through religion, love, exercise, diet, literature, and combinations—one of the really attractive aspects of being a physician is that you are asked to have a Shakespearean range. You are given the chance to try to understand people and help them restore a sense of control in a way that works for them. Sometimes this means that the physician just stays out of the way. I remember once treating a woman who had terrible rheumatoid arthritis and she rapidly and dramatically improved. One slow day in clinic, I asked her what she thought made her better. I expected her to laud my talents and stroke my ego and instead she looked at me quizzically, doubtfully, and said, “Okay, I’ll tell you.” She then explained to me that she had been going to a Polish healer who had been chanting up and down over 9 inches of her body with his hands (the 9 inches apparently was an important part of this), and she believed that his chanting made her better and that her improvement had nothing to do with the treatment I had prescribed. As a man of science and a man whose ego had been wounded, I was about to try and debunk her notion but caught myself and said, “Who am I to understand fully what is the faith that heals?” Had she lauded my white coat, I would have smiled and been happy with her answer. Instead, I realized she had figured out a way that was harmless that had helped her reestablish control. So, I swallowed hard and thanked her for the bravery she was showing in explaining to me what she had discovered. I told her I would try to figure out how to apply her method to other people. What she was reteaching me was the principle that illness robs one of the sense of control and that becoming healthy again requires reestablishing control. Roberts: What was your mother’s name? Hellmann: Mary Jane Hellmann. Roberts: When did she live? July 2015 Hellmann: August 26, 1925, to May 31, 2008. Roberts: What was your home life like with your mother and father gone so much? Hellmann: I had an ideal childhood. Our first house was next to a cornfield. The school was only one-third of a mile from home. I walked every day to school with neighbor kids and often with our dog that had learned the route. In kindergarten, I was taught a few things, but mostly played in a sandbox with others. There were hordes of children, and we all played on the weekends and after school. My mother would ring a cowbell when dinner was ready. My brother made the mistake of telling her when he was late that he hadn’t heard the bell the first time. We were called to lunch on the weekends by the volunteer fire department, which had a siren that rang out to tell the kids it was noontime. Mr. Bowling and his family raised chickens. I have vivid memories of their preparing some chickens for cooking by wringing their necks. We were free to explore. There was no sense of threat to us from outside. I have nothing but wonderful memories. My father, who was very interested in education, always said that he wasn’t leaving us an inheritance but would do everything possible to support us and get us into the best schools possible. Being in the Armed Service and meeting people from around the country opened his eyes to the rest of the world. He had a rule that none of his children would go to college in Kentucky. He believed that it was good to explore the world. Of course, these are rules that ambitious parents make and that children don’t necessarily follow. Roberts: What was the size of St. Matthews when you were there? Hellmann: St. Matthews was located just outside of Louisville. Its population was about 10,000. Louisville was about 300,000. Roberts: Your father’s practice was in St. Matthews? Hellmann: No. His was in Louisville, maybe 5 or 6 miles from our house. My dad was always partial to cars, and as soon as he could afford it he had an Oldsmobile, a fancy car in those days. The five of us often would go on rounds with him, both at the hospital and on home visits. Sometimes we were left to fight in the car, and other times we went inside with him. Even as a 5-year-old, I could see that our father was playing a special role in the lives of the people we were visiting. I was struck that he had the privilege of seeing and witnessing how health or ill health was influencing the lives of the ones he was caring for. I came to appreciate that he was doing something special. Roberts: Where did your father go to college? Hellmann: He went to the University of Louisville for college and medical school. They had an accelerated program where after 2 years in college one could be selected to go to medical school. Lots of veterans from World War II were in a hurry to complete their schooling. When he received his MD degree, he also received his undergraduate degree. He did a 1-year rotating internship at St. Joseph’s Hospital (no longer there) and then went into family practice. He was an internist at heart. When he graduated from medical school his goal was to go into internal medicine and be a consultant. Because neither his parents nor David Bruce Hellmann, MD: a conversation with the editor 411 my mother’s parents were wealthy and he had four offspring already, further training was not possible. Roberts: Your father was the first in his family to go to college? Hellmann: Yes. And my mother, one of fi ve, won a scholarship to college and also was the first and only one in her family to attend college. She graduated with a BS in chemistry. Roberts: What did her parents do? Hellmann: Her father finished only sixth grade, but being quite good at arithmetic he became treasurer of a wholesale grocery store. I went with him to the grocery warehouse on occasion, took the elevator to the second or third floors, and was mesmerized by all the food and by the gigantic safe in his office. Roberts: Did most of your mother’s and father’s siblings live in the Louisville area? Hellmann: Yes. We moved to a new house when I was 6, and my maternal grandfather’s house was between our house and our parish school. He worked until he was 82, when he fell, broke his hip, and soon died. Like a lot of families at the time, he had a key under his front doormat, and we were welcome to stop by his house on the way home from school. My favorite dessert in life is oatmeal cookies from Plehn’s Bakery in Louisville, Kentucky, which is the German bakery that Mr. Bowling, our next-door neighbor, ran. To this day, my kids, when they want to please me, will FedEx to me some of these oatmeal cookies that my grandfather introduced to me. I went to a parochial school named Holy Spirit that focused more on building character than it did on teaching academics. Roberts: Was this junior high or high school? Hellmann: This was grade school. I never was in a class smaller than 45 students. In the third grade I was in a split class: half was third grade and the other half was fourth grade. The desks were made for two students, and I sat next to a fourth grader. When the nun was trying to teach the third graders, the fourth grader was always sticking a pencil in my leg and when she taught the fourth grade I was sticking him in his leg. I don’t think anyone would have suggested that this was going to be the route to an academic career, but they did try to teach me when to speak and when not to. Roberts: Were you able to skip a grade with that setup? Hellmann: No. I attended St. Xavier High School. My mother was very interested in a religious education; father not so much, but he was very interested in their good reputation for academic preparation. I grew up hearing only about Harvard, Yale, and Princeton. My father repeated those school names at least 5000 times. I applied to all three, and got into only one, namely Yale. The first time I saw Yale was when I showed up for the first day of classes. At that time it was unusual not to visit each campus before enrolling. Roberts: You entered Yale in what year? Hellmann: I entered in 1969 and graduated in 1973. Roberts: What was your home life like growing up? You indicated that to see your father you almost had to go on rounds with him. Obviously he was quite busy. Did you eat dinner together as a family? I gather that home life was pleasant, not a lot of arguing? 412 Hellmann: My father, I believed, was seared by his early experiences: his father losing their house and moving a number of times during the Depression; having lived through World War II, he understood that one couldn’t necessarily count on anything and that chaos could occur at any time. These experiences plus his love for the profession of medicine meant that he worked many hours daily. Vacations were rare. I remember my family going on only two vacations in the first 12 or 13 years of my life, both times to Daytona Beach, Florida—once by car and once by airplane. These experiences combined to create an incredible work ethic for our family. My mother, after she raised five children, spent 20 to 25 years as a math teacher. At her funeral one of her former students came up and explained that my mother had great enthusiasm for chess and had the school adopt an annual chess tournament where the children were the chess pieces. This person also told me that during a math test my mother discovered that one of the children was trying to open a book when he wasn’t supposed to. My mother suggested that the students get their books out and sit on them and that would inspire them. As a physician I was familiar with various medicines being administered rectally but that was the first time I had heard of mathematics being administered rectally! Roberts: Did school always come easy for you? Hellmann: Yes, but I did not take it seriously until around seventh or eighth grade. Before that I was more interested in playing football. Then I started trying in school and appreciated that I was doing well. From that time on and particularly in high school, I really exerted myself. My high school prided itself on the fact that most students went to college. I was shielded from the pressures many kids are under today. The high bar at my high school was simply going to college. About 85% of the graduating students went to college. Roberts: Were you an athlete in high school? Did you play sports? Hellmann: I was small in high school, going from 128 pounds my junior year to 168 pounds my senior year. In 18 months I gained about 40 pounds and multiple inches. If that growth spurt had occurred earlier, I probably would have played football. I was on the track team my third and fourth years. Roberts: What’s your height? Hellmann: 5′10″. Roberts: What have your siblings done? Hellmann: My older sister, Jean, became a high school English teacher and then a guidance counselor. She retired in 2012. My younger brother, Don, became a banker, and my next brother, John, initially worked with the Baptist Health System in Tennessee and then joined a group that staffs emergency medicine physicians. My other sister, Sue, has focused entirely on being a mother for her two children and does a great job. She was also the main caregiver to my mother in the last few years of her life because my mother had developed Lewy body dementia, a variant of Parkinson’s disease. It’s Parkinson’s with hallucinations and sometimes psychosis. My mother had been a talented athlete and had won the tennis championships in Baylor University Medical Center Proceedings Volume 28, Number 3 Louisville as a teenager. This mathematician and tennis player played into her late 70s. Roberts: Did your father participate in that at all? Hellmann: He did a little bit. He realized that he had multiple sclerosis when playing tennis because he stopped being able to hit the ball well due to the double vision. Roberts: Did you get a full scholarship to Yale? Hellmann: At that time and even now, Yale provides money to any student who needs it. Since my father didn’t need it I wasn’t provided a scholarship. Scholarship was directly related to financial need. The tuition at Yale at that time was $3,003, and that was a lot of money. The cost of education already had exceeded the rate of inflation. Roberts: How did Yale and New Haven hit you? It sounds like you hardly ever went out of the city of Louisville. Now you are in New England surrounded by very smart people. Hellmann: I loved it. I feel that each school I have attended starting with high school has been an enormous gift to me. The major value of Yale for me was that it opened my eyes to so many intellectual subjects and most importantly gave me a group of friends who are still among the closest friends I have. Every year I get together with about five or six buddies from Yale. We’ve watched each other’s children grow up and get married. That closeness is still a great support for me. In Louisville, I knew students who were interested only in football and beer, and I knew students who were interested only in poetry and mathematics. At Yale, I met students who were interested in both. In a sense I felt alone as a high school student in Louisville, but at Yale I found others like me. That was incredibly validating to me. I found a family and a community and my eyes were opened to a whole new world. I took history courses from John Morton Blum, a great Theodore Roosevelt scholar, and heard Shakespearean lectures from Alvin Kernan. Kernan’s lectures on Shakespeare were so enchanting that the lecture hall was filled—some students were “hanging from the rafters” to hear him speak. My favorite course was the 19th and 20th century French novel taught by Victor Brombert. Although my high school French was pretty good, at Yale we were reading 400- to 600-page French novels every week and I struggled. In those days, the Yale French group was generally generous in their grading, but after I bombed the midterm exam, the teaching assistant suggested that I drop the course before my poor performance was indelibly recorded in my final grade. I told them that I harbored no illusions about my skills but that I really liked the course and wanted to hang in there. After the final the professor said to me, “Magnifique!” He explained that while I hadn’t done all that well, I had greatly exceeded the expectations suggested by my midterm exam. Providing the broader exposure to so many different subjects was one of the greatest gifts from Yale. I felt like I went to an intellectual Disneyland where my admission ticket never expired. Roberts: What did you major in? Hellmann: Chemistry. Roberts: When you entered Yale, did you know you wanted to be a physician? July 2015 Hellmann: I think I did, but like many teenagers I did not want to please my parents. My father always said, “Do whatever you want but do it well.” His subliminal message, however, was that he couldn’t imagine how anyone could have as much fun or have a better professional life than being a physician. I knew that my becoming a physician would please him, but being a little rebellious I wasn’t eager to fit into the mold he thought I should be in. Roberts: Were there many books in your home? Hellmann: My parents collected a lot of books, especially my dad: the classics and also the Time-Life series. I was introduced to Vladimir Nabokov, a Russian-American writer who famously or infamously wrote Lolita, Bend Sinister, and Speak, Memory, as well as Graham Greene novels and various books on Rousseau. We had a 2-volume version of the Oxford English Dictionary, and that played a minor role in my life because during high school I won a motorcycle. There was a singing group “The Monkeys” that followed the Beatles, and they made a movie Monkeys Go Home. To try to drum up publicity for this movie, the radio station announced a contest. The object of the contest was to come up with as many words as possible from the letters in the title of the movie. I heard about this contest the same night that a rare snowstorm hit Louisville. (It doesn’t take much snow to cancel school so I knew that there wouldn’t be school the next day.) I was particularly interested in arithmetic and took the letters from the title and made every combination of the letters, as a code, and checked out every one of the combinations to find out which was an actual word using the Oxford Dictionary. I finished this project at 4:00 am and knew that I had won. There simply could not be anybody who had a more exhaustive list. Then I was somewhat discouraged as a month or two passed and I hadn’t heard anything. I was out playing basketball and listening to the radio station, and as I was going up for a shot I heard my name called out as the winner of the “Monkeys Go Home” contest! I was 15 years old and I owned a motorcycle. I thought that that was perhaps one of the first lessons where academics could actually pay dividends. Roberts: What happened to the motorcycle? Did your father let you keep it? Hellmann: He did. I was able to ride it when I had a driver’s license. I kept it for maybe 2 years. I just drove it around the neighborhood. Roberts: No accidents? Hellmann: I survived. Roberts: Were there any teachers in grade school, junior high, or high school who had a particular influence on you? Hellmann: Yes, my high school biology teacher my freshman year taught the subject in such an engaging way that it really fueled my interest in science. My fabulous senior year English teacher opened my eyes to literature. I also remember my fourth-grade den mother in Cub Scouts. I ended up writing a play for our troop and we presented it at some activity. I’m sure it was terrible, but I remember her because she gave me safe harbor for thinking differently about projects and for communicating that it was okay to think differently. There were a few teachers that encouraged me to be “different.” David Bruce Hellmann, MD: a conversation with the editor 413 Roberts: Do you read fast now? Hellmann: I don’t think I read particularly fast now. I am tenacious. I remember around the age of 7 or 8 playing football with the older kids in the neighborhood. I wasn’t particularly large, but it was known that when I tackled I did not let go. The older kids would drag me but I would not let go. There was talk that “Elmer’s Glue” should be replaced with “Hellmann’s glue.” Roberts: What happened when you brought your report cards home? Hellmann: My father was very encouraging. He kept describing a broader world that was out there and to keep up my efforts because he believed that if I sustained these efforts I could go other places and do other things. He was very laudatory and encouraging. I had an eighth-grade teacher who had 48 hormonally surging guys in her class and she was giving up hope of teaching us. She took me aside and told me I was good at math and gave me the teacher’s version of the math books and told me to teach myself. Roberts: Your mother must have very proud of that effort? Hellmann: Yes. It was my mother who taught me multiplication because she was good at it. I have fond memories of being in the kitchen with her learning multiplication. I won the school competition in multiplication in the fourth grade. One of my father’s former teachers had found out about this competition and gave me a beautiful German clock as a reward. Roberts: Did the family eat together at night? Hellmann: We did. My father came home around 6:30 pm. We would all eat together, and at 7:30 pm he was gone, back to the hospital, and then he would be home by 10:00 pm. He worked all day on Saturdays at the hospital and half a day on Sundays. Roberts: How did you go back and forth to New Haven from Louisville? Hellmann: I would usually fly to LaGuardia and then take a car service to New Haven. In my junior year I had my own car and would drive the trip. It was 850 miles and I would drive straight through. Roberts: When it came time to pick medical school, how did you do it? Hellmann: My father, who had never laid eyes on Johns Hopkins, played a large role. While growing up, I frequently heard my dad talk about Johns Hopkins. I knew as a high school student, for instance, that A. McGehee Harvey was the chairman of the Department of Medicine at Hopkins. In addition, my next-door neighbor in Louisville, David Waller, was 10 years older and had gone to Harvard College and then to Johns Hopkins Medical School. David Waller became a psychiatrist on the faculty at the University of Texas Southwestern. His wife, Barbara Waller, also a physician, was a noted dean of students for many years there. I applied to Johns Hopkins early and was accepted. I withdrew from most other schools where I had been accepted. Although I was offered a very generous scholarship at the University of Kentucky Medical School—with all tuition and books 414 paid and even being paid to attend—my father, well along with multiple sclerosis, never blinked about my choosing Hopkins, even though a scholarship was unavailable. (That institution offered scholarships only on the basis of need.) Now that I’m a father with grown children, I perceive how great an act of generosity that was back then. He firmly believed that if I went to Johns Hopkins, my life would be different. It’s a life that he wanted me to have. He would have loved having the opportunities that I got. Roberts: What struck you about Hopkins? There are a lot of bright people at Yale but yet you raised yourself a notch because it’s quite a select group that goes to Johns Hopkins for medical school. Hellmann: Hopkins is a wonderful institution. At every institution I have been very privileged. (I have this disease called metaphorosis in which I can’t talk for very long without appealing to a metaphor.) The best medical schools allow one the opportunity to climb the Mt. Everest of the profession. There are some medical schools that are not very big hills, not even mountains. But there are some that really give you the opportunity to go to the peak of the profession. Johns Hopkins is one of those places. Hopkins has become a better place over time because while it has always provided a lot of inspiration, it did not always cherish its students. It said, “Here’s Mt. Everest, and the view from the top is unparalleled, but we are not going to give you Sherpas or provide you with any oxygen tanks, so you are pretty much on your own. It’s a very high and dangerous climb. Don’t expect that everyone is going to make it, and there might be some bodies along the way.” Today, it still offers inspiration but it also cherishes its students and provides essential supplies. The school does not tell anyone that they will be carried; you have to march and climb. But it gives you clothing and hooks you with us; there are times when you are going to be pulled and times when you will be pulling other people, but we are all going to make it together. It is possible to both inspire and take good care of people. I’m very grateful that Johns Hopkins introduced me to extraordinary people and values and a love of the profession of medicine. Roberts: Were there any surprises after you had been at Hopkins for a while? Hellmann: I was surprised how hard we worked. I thought I had worked hard in college, but in medical school classes were 9:00 am to 5:00 pm every day, and during the first 6 months we had Saturday classes in histology. I tell people this now and they shudder and think it would have been easier to be waterboarded than have these experiences. I also had extraordinary roommates. We worked all the time. We loved it. I came to understand that no matter how hard I had worked in college, it was nothing compared to medical school. I remember when a roommate had opted to take clinical rotations earlier than I did, and the other roommates sat around listening to him telling us what it was like. The only other time I remember being astounded was when I was first learning the facts of life from some of my friends in grade school and could not quite fathom what they were telling me. To hear my roommate talk about staying up all night and then working the entire next day seemed unfathomable. I had thought if you stayed up all Baylor University Medical Center Proceedings Volume 28, Number 3 night you got a week off. And yet at the same time while I was shaking in my boots at the horror of this description, I couldn’t help but perceive that my roommate felt this was a fascinating and wonderful experience. Roberts: Were there any professors and/or teachers who had a particular influence on you in medical school? Hellmann: There were many. Dr. Mary Betty Stevens was one of the few female faculty members. She was head of rheumatology, and she ran a 40-bed rheumatology unit. It was an extraordinary clinical experience, and many opted for it. The faculty at that time had lunch together, so as students we got to have lunch with Dr. Stevens. We were struck that few patients remembered the name of their doctors. The exception was Mary Betty Stevens; they all remembered her name. She made a dramatic impression on everyone. I remember having lunch with her one day and she leaned over, put her arm around me, and said, “Dave, I know what you are going to be. And when you figure it out, come see me.” She was right. I ultimately decided to be a rheumatologist. Roberts: What were some of her characteristics that made Dr. Stevens such an impressive personality? Hellmann: She was a meticulous physical examiner. She was able to find clues in fingernails, in the skin; she could look at the back of patients’ eyes and come up with clinical clues as to what the patient had, and she was often right. She was also a gifted interviewer. She could make patients come alive. She could make both their illness and their lives and personalities come forward: the drama of the science of clinical medicine and the natural drama of people’s lives. Dr. Philip Tumulty was the Osler incarnate at Johns Hopkins at that time, and he deeply impressed patients. He was an extraordinary physician because of his knowledge, his history, and his interpersonal interactions. I particularly remember the clinicopathologic conferences that Dr. Tumulty conducted. Up until that time I had seen maybe three or four. They were titanic intellectual battles of the internists and pathologists. It was physiology or anatomy or pathophysiology. Then I saw Dr. Tumulty do a clinicopathologic conference, and I remember his beginning. Instead of summarizing the clinical information, it turned out that he had known the patient and he talked about the patient as a person. He did something that had not been done since Christ: he made this dead person come alive. We all understood that this exercise was not a pathophysiologic experiment; it was the intricate story and puzzle of a person who had walked this Earth, who had loved and been loved, and who had cared about their work. I was mesmerized that he could bring a person back to life. And then he solved their puzzle. Like many others who witnessed Dr. Tumulty, I wanted to be like him. Dr. Victor McKusick (Figure 3), chair of medicine at that time, instilled a love of medical history and an interest in human genetics. Dr. McKusick would make rounds with the students 3 days a week, and every student would present to him and everyone was terrified to do so because he was totally unpredictable. We later realized that he was an extraordinarily kind human being but his curiosity was so broad and his interest so wide that one couldn’t anticipate any question. You could anticipate July 2015 Figure 3. McGehee Harvey, Victor A. McKusick, John D. Stobo, David Hellmann, and Edward Benz in Dr. McKusick’s home, about 1995. that he would always ask the history of something. If you were, for example, treating a patient with Wilson’s disease, he would ask, “Who was Wilson?” But he was just as likely to ask, if the patient was wearing glasses, how you could tell if the patient was nearsighted or farsighted by looking at their glasses. Or he might ask you about your tie and whether the stitching revealed that it was American-made or British-made. His interests were broad and we later realized that his questions were never meant to shame anyone but to exhibit that you should always approach every person you meet with wonder that could take you anywhere. I was deeply impressed by him. Roberts: Do you think he enjoyed being chairman? Hellmann: I think he loved being chairman. I don’t think he loved some of the aspects of being chair, but his sense of medical history was such that he felt that by being the “Osler professor” he had connected himself in almost familial fashion with William Osler. Being the descendent of William Osler was the apogee of his aspiration. Roberts: You started to speak of A. McGehee Harvey. Hellmann: Dr. Harvey was the chair when I first began medical school. In my third year (1975), Dr. McKusick became chairman. As senior students we asked Dr. Harvey (who had retired) if we could join him in a seminar series. He agreed. Hopkins was the kind of place where you could approach the most towering figures and they would embrace you. Later, when I joined the faculty, I came to know him more intimately and had the privilege of being his physician the last 5 or 6 years of his life. Getting to know him better was one of the extraordinary gifts that I received from a patient. Roberts: What was his age when he died? Hellmann: I think he died in his mid-80s. He lived a long time after being chairman. He threw himself into the history of medicine and wrote a number of books about medical history, particularly the history of Johns Hopkins. Roberts: What did you do during the summer months while in medical school? Hellmann: I became enamored of cardiac physiology in my first year because of Bill Milnor, who taught it. I went to Richard Ross, then chief of cardiology (later dean), and told him that I David Bruce Hellmann, MD: a conversation with the editor 415 wanted to do research in cardiology. He gave me three names, including Bertram Pitt, who was glad to have me. I spent that summer and another year during medical school working in a dog lab in cardiology. Dr. Pitt was working on a drug, made by Abbott, at that time trying to dilate coronary arteries. It was a magical time at Hopkins. Bernadine Healy was a fellow while I was there as a medical student. To imagine that I worked with someone who ultimately became head of the National Institutes of Health was inspiring. Dr. Pitt later headed cardiology at the University of Michigan Medical School, where he has been responsible for major trials in cardiology. I also met a number of the technicians in cardiology that were African American, so I learned the two sides of Johns Hopkins. Vivien Thomas was the famous surgical technician who had helped Dr. Alfred Blalock and Dr. Helen Taussig come up with the “blue baby” operation. Thomas had been head of the dog lab when I was a surgical student and attempted to teach me dog surgery. I think he recognized that I had the hands of a rheumatologist. I had a wonderful time doing cardiologic research and spent many summers there. I wrote two papers that were published and had the opportunity to make several presentations at Hopkins. Thanks to Dr. Pitts’ generosity, I ended up winning an award in research given at medical school graduation. Roberts: When it came time to pick your specialty, was it difficult or easy to focus solely on medicine? Hellmann: It was a little difficult because to my surprise I loved everything. The only specialty I excluded pretty quickly was pediatrics. I met my wife when I was taking pediatrics. She was a pediatric social worker. At that time Hopkins thought that in pediatrics it was important to know your patient as a person—a theme of my grand rounds—so each medical student was assigned a patient to visit in the community. They realized that students were probably incompetent to go on these home visits alone, and therefore each was assigned a social worker. I was randomly assigned to my future wife. My patient was a 15-year-old girl who was pregnant. She lived a half-block from the hospital. At that time Baltimore was the capital of lead poisoning in the United States. I, as a self-proclaimed hotshot medical student, went on the home visit with a mission to save this girl’s child from lead poisoning. I asked her family all sorts of invasive questions and rightly angered them. A Baltimore jury would have acquitted them of understandable or justifiable homicide. Fortunately, my future wife had much greater diplomacy and she came to my rescue, soothing the feelings that I had riled. I thought since she had saved my life it was only appropriate that I invite her to lunch, and she’s been saving my life for the last 38 years. As a result I tell students that if you can find your true love while doing a basic clerkship, go for it, but don’t expect to remember much of that specialty. I don’t remember pediatrics very much and was totally incompetent in taking care of our children. I enjoy conversation, and pediatrics didn’t allow me to talk to the patients. I found surgery and the immediacy of the results very attractive, but ultimately I realized that for me the two things that gave me meaning were getting to know people over time and solving complicated medical puzzles. Those two requirements came together in internal medicine. 416 Figure 4. With Linda Hellmann. By the end of my third year, it was clear to me that I wanted to go into internal medicine. Roberts: What is your wife’s name? Hellmann: Linda Smith Hellmann (Figure 4). Roberts: What is her birthday? Hellmann: June 27, 1949. Roberts: What were the features of Linda that attracted you to her? Hellmann: Well, she’s beautiful. She is an extraordinarily generous person who is also extremely strong. She, perhaps by professional training or perhaps by instinct, never allows a gap in understanding between two people to stand. She always insists on exploring the gap and understanding it. I had the sense that I had a quiet but strong personality. Although I had thought that most good ideas were ones I had thought of, I’ve learned that other people can have very good ideas, too! I realized that I was going to need a partner who was not shy about being able to challenge my views and could challenge them, as she showed that first day, diplomatically. Roberts: When did you get married? Hellmann: May 28, 1977, 24 hours after I graduated from medical school. She is from outside of Philadelphia and I was from Kentucky, and we thought we would have a wedding coincide with medical school graduation because all the family was already in town. Roberts: Was your father able to come? Hellmann: Yes. He was still walking at that time. He and my mother adored my wife. The first time my mother met Linda, she put her arm around her and turned to me and said, “David, I want you to know that I’m on Linda’s side.” Baylor University Medical Center Proceedings Volume 28, Number 3 Roberts: Was picking Hopkins to do your internship difficult, or did you look around at a number of places first? Hellmann: I did look around. Other than Hopkins, the place that really attracted me was the University of Rochester (New York). I was very impressed that their medical residents were very happy. I didn’t know much about Dr. George Engel, but apparently even then he had a profound effect on that place raising awareness of the importance of knowing patients as people. As chairman of medicine, he was one of the first in the country to emphasize the importance of the personal and social aspects of providing medical care. Although potentially attracted to Rochester, my future wife and I drove there together in January and my car heater did not work. When we got to the hotel we spent the first 45 minutes sitting on the radiator trying to thaw our rear ends. My wife turned to me and said, “If you come here, you are coming by yourself!” That experience plus the fact that I really enjoyed Hopkins, she had a good job there, and I was accepted, made the decision to intern at Hopkins easy. Roberts: Did you live in the compound? Hellmann: Yes. It had been built very quickly right after World War II, and it now was 40 years later and still there. Sometimes it was nicknamed “the hatchery” because so many houseofficers had so many children while there. East Baltimore then was a pretty gritty place, but this was an oasis with a swimming pool, and everyone was working the same long hours. A substantial percentage of residents lived there. We only needed one car since work was not much more than 100 yards away and it was also easier to have meals together. Roberts: Your residency at Hopkins was 3 years? Were there any major events during that time that stayed with you? Hellmann: Yes. As an intern, I was assigned to care for an 11-year-old boy who had failed chemotherapy for acute leukemia. Johns Hopkins was one of the few places at that time doing bone marrow transplants. Unfortunately, the transplant didn’t work and he died. As the intern, I was also the phlebotomist and felt completely out of my depth. I didn’t really know how to take care of a child. I went in to explain to him the reasons for switching physicians on him and how he had been dealt bad cards in life that he never asked for and shouldn’t have to endure all the pain and suffering that he had been through. He listened without saying a word. He had built cars and painted them. He reached over for his favorite one—a Mustang—and without a word handed it to me. In that instant I was converted from a cynic to an optimist. I didn’t realize it at the time, but ultimately I came to conclude that human beings are not always attractive, that they are capable of great cruelty, but I realized if humans were capable of creating a child who while dying could take in the worth of an awkward intern and reach out at a time of suffering to give a gift of something that mattered most to him, that we had to be made out of good stuff. That experience has stayed with me more than the shortcomings of people. I became an optimist having lived 27 years as a pessimist and cynic. Life as an optimist has been a whole lot more fun than I remember as a pessimist. I also thought that it embodied aspects of medicine that I love. Living a long life is possible because of July 2015 modern medicine and great teamwork providing care, but as wonderful as medicine is it could still be more wonderful. The other aspect is I have been astounded in my career by the generosity of patients, in what they have taught me about medicine and the opportunities they have given me. I feel I’ve been given unspeakable gifts throughout my life. I realize medicine is a partnership and the physician is the junior partner. Roberts: How did you pick rheumatology? Hellmann: During my surgical clerkship I was assigned to urology. Late one night the chief resident tried to extol the virtues of urology to me, hoping to attract me to urology. The ultimate sales pitch from his side was that in urology there are only three problems and urologists could fix each of them. I thought that could be attractive to someone but it wasn’t to me. I liked ambiguity and challenging puzzles, so the breadth of rheumatology was very attractive. I wouldn’t say I was a fast learner but I ultimately enjoyed learning. I love looking in the back of eyes and looking for the early signs of central nervous system lupus. I was looking for a field that would frequently call on me to integrate all of these skills and experiences. And rheumatology did that. Immunology was a negative for some but it was a great challenge for me. I was impressed that many of the clues in rheumatology were attainable at the bedside. The laboratory was an important tool for confirming suspicions rather than in shaping impressions on what was going on. At Johns Hopkins at the time, the best doctors I knew were rheumatologists: Mary Betty Stevens and Lawrence Shulman. Some people thought that Osler himself had been a rheumatologist and was greatly interested in lupus. There is a picture of Dr. Tumulty at the chalk board, and he wrote the initials of four diseases and three of them were rheumatic diseases. I was surrounded by physicians who were interested in rheumatology even before the field had been defined. Roberts: How did you decide to go to San Francisco for your rheumatology fellowship? Hellmann: My wife wanted to go to California because her sister lived there. Since I generally don’t want to do things that most people want to do, I did not want to go there. Somewhat reluctantly I did interview at UC-SF at the urging of several professors at Hopkins who said that I needed to meet Jack Stobo. He had been an Osler houseofficer and chief resident, and everyone talked about him with awe. He was head of the rheumatology program at UC-SF. I went and was smitten by the program from the beginning. People were on fire and excited about what they were doing. They had both a broad and a basic science experience. I felt this was the place for me and fortunately I was accepted. Roberts: That was a 2-year program? Hellmann: Yes. I had anticipated that it would be a longer program because at that time I thought I was going to be a basic scientist and spend an extra 3 years in laboratory training. The training at John Hopkins I loved, but I also felt that it could be made better. I was physically and spiritually exhausted when leaving Hopkins—so much so that I thought that I never wanted to see another patient. It was in the more relaxed circumstances of UC-SF that I realized the most enjoyable David Bruce Hellmann, MD: a conversation with the editor 417 Figure 5. At home with children, Jessica and Matt, and the family dog, about 1990. part was seeing patients and feeling confident about it. They lost their program director at that time and asked me, only a fellow, if I would do morning report and other jobs. Jack Stobo was very definitive —he kiddingly used to advise me, “You can be wrong, but be definite,” especially in treatment recommendations. I tried to incorporate my wife’s diplomacy and would diplomatically but firmly challenge him. We had some heated arguments (always civil) during conferences, and I told my wife that we needed to start looking for a place to go because I sure wasn’t going to last in San Francisco. I was stunned when at the later part of my first year, Dr. Stobo asked me to join the faculty and become the clinical director for rheumatology in his division. Linda was pregnant at the time with our first child, Matt (Figure 5). His birth and that offer came about the same time. Things were coming together in my own view of what I wanted to do with my career so I accepted. Working with Jack Stobo was such a fabulous experience that when he was recruited back to Hopkins in 1985 as the Osler Professor and Chairman of the Department of Medicine, I eagerly accepted his offer to join him in 1986 as executive vice chairman and then later as director of the Osler housestaff training program. My time at Hopkins has had symmetry: I spent the first 14 years on the Broadway (Johns Hopkins Hospital) campus and the last 14 years on the Johns Hopkins Bayview Campus (what used to be The Baltimore City Hospitals) (Figure 6). During that time I have served three exceptional Osler Professors of Medicine: first Jack Stobo (1986–1994), then Ed Benz (1995–2000) (Ed is now the president and CEO of the Dana Farber Cancer Institute), and now Mike Weisfeldt (2001–2014). Although 418 Figure 6. At Johns Hopkins. they have different personalities, each was a magnificent leader and mentor. Roberts: Could you summarize your grand rounds presentation earlier today? Hellmann: My grand rounds was a description of our creation of an educational initiative entitled the Aliki initiative, named for a Greek philanthropist, Mrs. Aliki Perroti. It attempts to make sure that the training of every medical student and resident incorporates the Oslerian notion that the foundation to being a great physician is knowing your patient well and knowing him or her as a person. Osler said, “It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.” For the last 7 years we have tried to create an experience that imbues that principle in every medical student and resident. We’ve found to do so requires two things: first, people have to be given the gift of time. It’s not possible to get to know patients well, either medically or personally, without adequate time. And second, you have to have a curriculum and faculty that teach you what to do with that time. Just sitting in the conference room is not adequate. One must get a very good history and physical exam, talk to the primary care physician, the patient, and family, and visit with the patients after they leave the hospital to understand what challenges they have. It is only by having both the gift of time and a curriculum of what to do with that time that you can get to know patients as people and derive the satisfaction that comes from doing so. Roberts: You started this program in 2007? Hellmann: Correct. Baylor University Medical Center Proceedings Volume 28, Number 3 Roberts: Have you made many changes in the program during the subsequent 7 years? Hellmann: We’ve made a number of changes. In the beginning we realized that the gift of time wasn’t enough, that we needed faculty who knew what to do with that time. We had to create a faculty development program. Over time we have extended the Aliki initiative not only to one floor but to all the general medical floors and more recently extended it to the intensive care units and to the outpatient areas. During this time we have also been able to do a number of research projects to assess the impact of the Aliki initiative on our patients, their families, and our students, residents, and faculty. One outcome we’ve found, somewhat to our surprise, is that patients who are on the Aliki initiative are much less likely to require readmission within 30 days if they have heart failure. On the non-Aliki service, the latest rehospitalization within 30 days for heart failure was 14%, whereas on the Aliki initiative for heart failure the readmission was only 4% within 30 days. We also found that patient satisfaction with the physician is much higher on the Aliki service than on the general medicine services. The Aliki initiative now involves 20 staff faculty and they meet every week to discuss how they can make the experience better. A byproduct of these discussions was the creation of a laboratory for education, something that does not exist in many places. From this laboratory, we’ve learned a few things about teaching, something that has led to many of the faculty receiving academic awards for their teaching. Dr. Roy Ziegelstein, the co-director of the Aliki initiative, was selected 2 years ago to become the vice dean of education of the entire school of medicine. Roberts: Do you have any hobbies? July 2015 Hellmann: My two individual passions are history and literature. My favorite authors are Tolstoy and Shakespeare. I don’t know much about music, but I am absolutely enraptured with Beethoven’s 9th symphony. With my penchant for metaphors, I fancy that when Beethoven composed this symphony in 1824 he did so while trying to envision the potential good that “the promise of medicine” could deliver to our patients and to society. I firmly believe that medicine is a public trust and that it is our joyful opportunity and obligation to get up each day and ask how we in health care can pay back society a higher dividend for the extraordinary investment society has made in us. In the fourth movement of the symphony, Beethoven suggests the heights to which medicine could ascend. He begins by playing a beautiful melody six times with just cello (which in my mind symbolizes research), then six times with just viola (symbolizing education), and then six times with just violin (representing patient care). Then Beethoven does what no medical center, in my opinion, has accomplished: he puts it all together by having the entire orchestra play the melody. Since you have heard the melody 18 times, it of course sounds familiar. Yet the ineffable beauty of the sound created by the whole orchestra is also shockingly new. Not only does Beethoven cherish the music created by each musician, his orchestration ensures that musicians achieve a greatness in playing together that cannot be attained by playing separately. I suspect that medical centers could learn something from listening to Beethoven. I believe we will deliver the promise of medicine only when we learn how to orchestrate so that clinicians, educators, and scientists play together in the same harmonious way that the musicians do in Beethoven’s 9th. Roberts: Dr. Hellmann, thank you. I wish that we had more time. David Bruce Hellmann, MD: a conversation with the editor 419 Reader comments LOW-VOLTAGE ELECTROCARDIOGRAM IN A PATIENT WITH TAKOTSUBO SYNDROME ASSOCIATED WITH HYPERTHYROIDISM The article by Omar et al (1), published in the April 2015 issue of Proceedings, about a 61-year-old woman with hyperthyroidism admitted with takotsubo syndrome includes an electrocardiogram (ECG) revealing atrial fibrillation with rapid ventricular response and nonspecific ST-T wave changes, while echocardiography and contrast ventriculography showed marked extensive left ventricular hypocontractility with a left ventricular ejection fraction of 35% to 39%. Figure 1 depicts the ECG in an elongated horizontal layout, and even if one assumes standard calibration (1.0 mV = 10 mm), some of the ECG leads reveal low QRS voltage. Recently, low QRS voltage has been reported in association with TTS (2). Would the authors oblige by providing information as to the changes in voltage, from a possibly available ECG of their patient prior to the index admission and subsequent ECGs recorded during hospitalization and at follow-up? —John E. Madias, MD Icahn School of Medicine at Mount Sinai, New York, NY Elmhurst Hospital Center, Elmhurst, NY E-mail: madiasj@nychhc.org 1. 2. Omar S, Ali E, Mazek H, Mahmood T, Soontrapa S, Suarez J. Takotsubo cardiomyopathy associated with hyperthyroidism treated with thyroidectomy. Proc (Bayl Univ Med Cent) 2015;28(2):194–195. Madias JE. Transient attenuation of the amplitude of the QRS complexes in the diagnosis of takotsubo syndrome. Eur Heart J Acute Cardiovasc Care 2014;3(1):28–36. The Authors Reply: I would like to thank Dr. Madias for his interesting letter. As he mentioned, it has been reported that low QRS voltage and attenuation of the amplitude of the QRS complexes are a highly prevalent sign in patients with takotsubo syndrome. Serial electrocardiograms in our patient prior to the index admission and during hospitalization showed both low QRS voltage and attenuation of the amplitude of the QRS complexes (Figure). —Sabry Omar, MD Texas Tech University Health Science Center, Lubbock, Texas 420 Figure. Serial electrocardiograms in the patient with takotsubo syndrome prior to the index admission and during hospitalization showed both low QRS voltage and attenuation of the amplitude of the QRS complexes. Proc (Bayl Univ Med Cent) 2015;28(3):420 From the Editor Facts and ideas from anywhere “THE PILL” AND ITS FOUR MAJOR DEVELOPERS In 2012, Jonathan Eig published The Birth of The Pill: How Four Crusaders Reinvented Sex and Launched a Revolution (1). In 36 chapters the fascinating story is told. She was already 71 years of age, had loved sex, and had spent William C. Roberts, MD. 40 years seeking a way to make it better. She wanted a scientific method of birth control that would allow women to have sex as often as they liked without becoming pregnant. She was Margaret Sanger (1879–1966) (Figure 1), one of the legendary crusaders of the 20th century. She was meeting with Gregory Goodwin Pincus (1903–1967), a scientist with a genius IQ but a dubious reputation. He was 47 and had been rejected as a radical by Harvard, humiliated in the press, and left with no choice but to conduct his oftentimes controversial experiments in a converted garage. He was a biologist and perhaps the world’s leading expert in mammalian reproduction in the 1930s. Pincus knew about Margaret Sanger; almost everyone in the US did. It was Sanger who had popularized the term “birth control” and almost singlehandedly launched the movement for contraceptive rights in the US. Women would never gain equality, she reasoned, until they were freed from sexual servitude. Sanger had opened the nation’s first birth control clinic in 1916 and helped launch dozens more around the world. But all she had to work with were condoms and cervical caps, usually ineffective, impractical, and difficult to obtain. Sanger explained to Pincus that she was looking for an inexpensive, easy-to-use, and completely foolproof method of contraception, preferably a pill. It should be something biological, she said, something a woman would swallow every morning, with or without the consent of the man with whom she was sleeping; something that would make sexual intercourse spontaneous, with no forethought or fumbling, no sacrifice of pleasure; something that would not affect a women’s fertility if she wished to have children later in life; something that would work everywhere from the slums of New York to the jungles of Southeast Asia; something 100% Proc (Bayl Univ Med Cent) 2015;28(3):421–432 Figure 1. Margaret Sanger. Photo: Public domain. effective. She asked Pincus, “Could it be done?” She had approached other scientists earlier and they said it could not be done. They had argued that it was dirty, disreputable work. And, even if somehow it could be done, they argued there would be no point. Thirty states and the federal government still had laws prohibiting birth control. Why go to the trouble of making a pill no drug company would dare to manufacture and no doctor would dare prescribe? But Sanger held out hope that Gregory Pincus was different, that he might be bold enough or desperate enough to try. Also, times were changing. In 1948, only 2 years earlier, a college professor in Indiana named Alfred Charles Kinsey published a study called “Sexual Behavior in the Human Male” to be followed 5 years later by “Sexual Behavior in the Human Female,” studies which disclosed that people were much freer with sex than previously admitted. Sex for the pleasure of women was an idea that was unthinkable in 1950. Worse, it was dangerous. What would happen to the institutions of marriage and family? What would happen to love? If women had the power to control their own bodies, if they had the ability to choose when and whether they got pregnant, what would they want next? Science, argued Sanger, would give women the chance to become equal partners with men. Once Sanger asked Pincus to start working on a pill, he drove directly to his office at the Worcester Foundation for 421 Experimental Biology, an institution he had founded with one of his colleagues, Hudson Hoagland, to speak with one of his researchers, M. C. Chang. While the foundation started out in a renovated barn in Worcester, by 1950, it had moved to an ivy-covered brick home in a residential section of nearby Shrewsbury. Pincus had known of Chang and enticed him to join the foundation for a salary of $2000 a year ($26,000 by today’s standards). Chang, who knew Pincus by reputation, thought he would be working in one of America’s prestigious institutions and that his fellowship would include free lodging. He did get free lodging, but his room was at the YMCA. He and Pincus would travel to and from work by bus. Later, Chang would move to the foundation, sleeping on a small bed in a corner of a converted laboratory using Bunsen burners to heat his meager meals. As a strict Confucian, Chang apparently did not mind. Pincus told Chang that he had spoken to Margaret Sanger about her desire for a pill to prevent pregnancy. It had to be a pill, not an injection, jelly, liquid, or foam, and not a mechanical device used in the vagina. When Pincus talked in this way with a sense of purpose, his colleagues paid attention. Pincus knew from the beginning that it would be one thing to build a birth control pill and another to persuade the world to accept it. Pincus and Chang already knew that injections of the hormone progesterone prevented ovulation in rabbits. Nevertheless, for many reasons, scientists had not tried to explore the implications for humans. There were too many risks. Also at the time, progesterone was very expensive. Pincus and Chang knew how progesterone functioned. When an egg is fertilized, progesterone prepares the uterus for implantation and shuts down the ovaries so no more eggs are released. In effect, Pincus recognized, nature already had an effective contraceptive. Now the task was to see if they could produce it, modify it, and put it to use. Fortunately, new technology was making progesterone less expensive to obtain. If Sanger would pay for it, Pincus thought he had a good idea of how to proceed. He and Chang began by repeating their experiments done in Pennsylvania 13 years earlier, adjusting the dosages and means of delivery to get a feel for progesterone and how it worked. They started with rabbits. Pincus sent a request for funding to the Planned Parenthood Federation of America, the women’s health and advocacy group that Sanger had helped form. He asked for $3100: a $1000 stipend for Chang, $1200 for the purchase of rabbits, $600 for animal food, and $300 for miscellaneous supplies. Sanger wrote to Pincus that they had $2000 but Pincus and Chang got to work. The first results were what they had expected: the animals receiving progesterone did not appear to ovulate! They next moved to rats, and once again the experiment worked: there were no pregnant rats and once again larger doses had a longerlasting effect. Within a relatively brief period, the Worcester Foundation had about 20 scientists and operated on an annual budget of $300,000, about $63,000 of which was contributed by local residents. 422 Fortunately, it was a time of enormous growth in the pharmaceutical industry. By the late 1940s and early 1950s, drug makers like G.D. Searle & Company were competing fiercely to discover and market new ones. In the 1940s, Searle, a small pharmaceutical company based in Skokie, Illinois, and other drug companies were looking for ways to synthesize cortisone, which had recently been demonstrated to relieve arthritic pain. Pincus persuaded the drug company that he could synthesize cortisone by pumping serum through the adrenal gland of sows and spent $500,000 of Searle’s money trying to prove it. But before Searle could make use of Pincus’ new technology, researchers at the Upjohn Company found a simpler and less expensive way to do the job. In the fall of 1951, hoping to repair the relation with Searle and secure their help on Margaret Sanger’s progesterone project, Pincus went to Skokie to meet with Albert L. Raymond, the drug company’s director of research. Pincus failed in his initial attempt to acquire money from Searle. Sanger. Who was Margaret Sanger? She was from a family of 11 children. She was number 6, born in 1879, in Corning, New York. Her mother was frail and submissive and died of tuberculosis at age 50. Her father was a charming stonecutter. Maggie, as she was known, left home at an early age and enrolled at Claverack College, a boarding school in New York’s Hudson Valley. She earned her way through and began speaking out on suffrage and women’s emancipation. She enrolled in nursing school at White Plains Hospital in Westchester County, New York. Though she considered marriage “akin to suicide,” at the age of 22 she met a handsome young painter and architect named William Sanger. They fell in love, married, and built a home in Hastings-on-Hudson, Westchester County, New York. Soon came three children, two boys and a girl. Not happy with either suburbia or marriage, in 1912, Margaret and her family moved to New York City and she began spending time in Greenwich Village. There she discussed sexual freedom, voluntary motherhood, and the need for women to have more autonomy in the bedroom and in society. During this time, Sanger worked for William Wald’s visiting nurse service, a group of nurses sent out by the Henry Street Settlement House to care for poverty-stricken women, and often helped the women through childbirth. Sanger was astonished by the poverty and misery: children sick, dirty, and underfed; tuberculosis rampant; and women seemingly unaware of how their bodies worked and the risk of repeated pregnancies and venereal disease. In the 1920s, the state health department distributed circulars warning women that pregnancies occurring too close together were dangerous, predisposing mothers to tuberculosis. But the same department barred women from receiving information about how to prevent pregnancy. Doctors estimated that one-third of all pregnancies in the US at the time ended in abortion. Sanger became convinced that women should have the right to contraception. In 1913, she wrote a 12-part series of articles about sex and Baylor University Medical Center Proceedings Volume 28, Number 3 reproduction for The Call, a radical newspaper. Sanger rejected the idea of full-time motherhood. She became involved in the right to vote for women and the drive to prohibit the sale of alcohol, with the idea that if men stopped drinking, they would be less abusive and less likely to force their wives to have sex. In 1914, soon after the publication of Sanger’s newspaper, The Woman Rebel, the US Post Office Inspector issued a warrant for her arrest, charging her with four counts of violating US obscenity laws. Sanger, now 34 years old, chose not to appear in court. Instead, she jumped bail, left her family, and moved to Europe, where she fell in love with 55-year-old Henry Havelock Ellis, one of the world’s preeminent sexual psychologists. Ellis had made it his mission to solve the mysteries of sex, collecting histories from men and women in an effort to prove that physical intimacy was natural and varied. Ellis introduced Sanger to more intellectuals, including the science fiction writer H. G. Wells, George Bernard Shaw, Bertrand Russell, and Lorenzo Portet. Ellis mentored Sanger. Now for the first time she had a plan. At first she had seen contraception primarily as a way to help women control the size of families. Now she was beginning to believe that if sex were disconnected from childbirth, women might be liberated in ways they had never imagined: there would be changes in marriage, in the meaning of family, and in career and educational opportunities for women. While Sanger was in Europe, her husband was arrested by Anthony Comstock, a special agent for the Postal Service, for distributing pamphlets about birth control. Comstock made it his mission to fight smut in America, almost singlehandedly creating a strict set of antiobscenity laws. Comstock was appointed special agent for the YMCA Committee for the Suppression of Vice. While leading raids and smashing up sex devices, pornographic pictures, and contraceptives, Comstock became famous for guarding America from pornography and disease. In 1873, he had persuaded Congress to pass a bill banning the use of the mail for transporting “any obscene, lewd, lascivious, or filthy book, pamphlet, picture, paper, letter, writing, print or other publication of an indecent character.” After that, every state had its own antiobscenity laws, many of which made it illegal to sell or disseminate information on contraceptives. To enforce the federal law, Comstock was appointed a special obscenity agent of the US Post Office. Soon after, he was authorized to carry a gun. The Comstock Law defined immorality so broadly that it could have included nearly anything. Thus, it was not surprising that it was deemed to ban not only the sale of contraceptive devices but also the transmission of information regarding contraception. The law influenced policy and kept women from getting birth control for decades! Soon after her arrival in England, Sanger wrote to her husband that she considered their 12-year marriage over. She asked for a divorce, but he did not feel the same way. In 1915, however, Sanger’s husband was convicted on obscenity charges with a judge saying he had violated not only the laws of man, July 2015 but the law of God in his scheme to prevent motherhood. He served 30 days in prison. Only then did Margaret agree to return home. Soon afterwards, her 5-year-old daughter Peggy developed pneumonia and died. For the rest of her life she was tormented by dreams of babies. This tragedy, however, did not compel her to pay more attention to the care of her two surviving children. Instead, Sanger went back to work. She began by posing for publicity photos, wearing a wide Quaker collar with her young son by her side, looking like a respectable young mother. It was about this time that she began using the phrase “birth control” instead of contraception. The key word in the phrase was “control.” If women truly got to control when and how often they gave birth, they would hold a kind of power never before imagined. Without control, women were destined to be wives and mothers and nothing more. In 1916, Sanger opened her first birth control clinic in Brooklyn, where a team of nurses distributed condoms and pessaries (flexible rubber caps that were commonly sold in drug stores as a “womb support” but in reality functioned similarly to a diaphragm or cervical cap). The clinic, of course, operated in direct violation of New York state law, so no one was surprised when police raided the place 10 days after it opened, confiscating contraceptive devices and arresting Sanger. She served 30 days in the penitentiary charged with illegal distribution of birth control products. Sanger gradually became more sophisticated in her radicalism. Instead of challenging society’s conservative views on sex and challenging obscenity laws, she tried to recruit physicians, scientists, and corporate leaders to join her crusade, emphasizing the benefits to public health. She encouraged women to see their doctors to get fitted for diaphragms, hoping that doctors would be valuable allies in her fight. One of her allies at the time was a wealthy widower named James Noah Slee, who met Sanger and quickly fell in love with her. Slee was 20 years older than Sanger and had been president of the 3-in-1 Oil Company, makers of the product that almost every American at the time kept on hand to grease typewriters, bicycle chains, and sewing machines. Sanger had been separated from her first husband 7 years when she met Slee. In 1922, she finally divorced William Sanger and married the crusty aristocratic Slee. Slee gave Sanger all the money she wanted for her cause. She and her husband now owned their own company to design and market birth control devices. By 1925, more than 1000 doctors from around the world sought admission to Sanger’s annual birth control conference held in New York City. British economist John Maynard Keynes, as well as Norman Thomas, W. E. B. Du Bois, Upton Sinclair, and Bertrand Russell attended. The birth control movement was clearly gaining visibility in the US and spreading quickly around the world. Overall, the birth rate in the US fell 30% between 1895 and 1925, even though women had begun to marry at younger ages. By 1930, the Birth Control League, the organization Sanger founded, was overseeing 55 clinics in 23 cities. Facts and ideas from anywhere 423 In 1932, US Custom officials, citing obscenity laws, seized a box of experimental diaphragms sent to Sanger by a Japanese physician and father of 12 who believed his new design would make contraceptives more effective. Sanger and her allies challenged the seizure, arguing that the law was blocking scientific progress and hindering the advancement of medicine. In a landmark decision, a New York State Board of Appeals judge agreed. After that, as long as physicians were involved, it would be legal to use the mail to spread information about contraception or to ship contraceptive devices. The decision opened the door for the American Medical Association to recognize contraception as preventive medicine. Pincus. In January 1952, Pincus filed a report to Planned Parenthood stating that 10 mg doses of progesterone administered orally had suppressed ovulation in 90% of the rabbits tested. The results were good enough to justify tests on women, and he was ready to begin. When her second husband died in 1942 at the age of 83, Sanger inherited $5 million. She gave some of the money to the birth control movement, some to friends, and spent much of it on lavish vacations. Planned Parenthood had grown rapidly in the 1940s, adding branches across the country. It was led mostly by businessmen and male physicians. Prescott S. Bush, a Connecticut businessman whose son and grandson would both become US presidents, served as treasurer for Planned Parenthood’s first national fundraising campaign in 1947. The organization unfortunately was frightened by the idea of doing something that had never been tried before: giving medicine to healthy women simply to improve their lifestyles. A scandal or a lawsuit could sink the entire organization. Planned Parenthood was not ready to go out on a limb and certainly not for Pincus. Gregory Goodwin Pincus (Figure 2) fancied himself a poet, philosopher, tiller of the soil, and lover of women. His passion Figure 2. Dr. Gregory Pincus. Photo from Images from the History of Medicine, Library of Congress, ID 186672. 424 for life and ideas was great. As a teenager he wrote in his diary, “Our one duty is self-development; man’s job is to get the most out of his talents and to help others do the same.” It was not sex, money, or fame that guided Pincus. It was his quest for greatness, a desire that never ebbed as long as he lived. The Pincus family arrived in New York City in 1891 from Odessa, a cosmopolitan Russian city. The anti-Jewish pogroms were sweeping Russia at the time and the Pincuses fled. They moved to a New York City slum and from there to Colchester, Connecticut, and then to a kibbutz. In 1902, Lizzie Lipman and Joseph Pincus married, and six offspring followed. Gregory (“Goody”) was the first, arriving in 1903. He worked his way through Cornell University washing dishes and waiting tables. One day during his senior year, Pincus returned home to find a visitor with his family. Her name was Elizabeth Notkin, 4 years older than he. The five Pincus boys had never seen anyone like Lizzie. She cursed, drank, and chain-smoked cigarettes. In 1923, she and Goody married before a judge while she visited him at Harvard where he was doing a PhD in biology. It wasn’t long before she was pregnant with her first child. At age 27, Goody Pincus was appointed an instructor in the department of general physiology at Harvard. A year later he was promoted to assistant professor of biology. At Harvard he experimented mostly with rats, studying how they responded to heat and light. When he graduated, he had a postdoctoral fellowship, studying for 2 years at Harvard and 1 year in Europe. In Europe for the first time, Pincus began researching the eggs of mammals, the subject that would become his life’s work. He returned to Harvard as a professor in 1930. Pincus’ interest was how animals passed along genetic traits, and that led him to the study of mammalian eggs, specifically how they were fertilized and how they developed in vitro. He tried hormone injections to see how they affected rabbits and at one point noted that estrogen injections prevented pregnancy. In 1934, Pincus announced to the National Academy of Sciences that he had fertilized rabbit eggs in a test tube, transplanted them into the body of a host mother, and brought the baby rabbits to term. This was radical research at the time. He also wrote in a grant application that his goal was to apply his in vitro technique to humans. His work began to attract an unusual amount of attention beyond the academic community. The New York Times cited his work for the first time in a 1934 article. The newspaper unfortunately went on to portray Pincus as a sinister scientist trying to grow babies in bottles. After fertilizing rabbit eggs and restoring them to their mother, Pincus took another step: letting the eggs become embryos while remaining in the glass. In 1936, Pincus achieved parthenogenetic development of a rabbit ovum; they had begun the reproductive process without any fertilization, simply by manipulating the environment surrounding the egg. Not long after that, Pincus transplanted the egg successfully into surrogate female rabbits. The press called this “immaculate conception.” In the same year Harvard marked its 300th anniversary with a pamphlet listing the greatest scientific discoveries made Baylor University Medical Center Proceedings Volume 28, Number 3 by its faculty in three centuries of study. Pincus’ work made the list. The same year he published his groundbreaking book, The Eggs of Mammals. With each new discovery, each audacious claim, and each speech before a scientific body, Pincus attracted more attention in the mainstream press. Newspapers all over the country carried reports of his research. In 1937, Collier’s Magazine published a feature story on Pincus’ work. A critic was quoted as saying, “If babies were made in test tubes, it would be the ruin of women.” Pregnancy not only improved a woman’s looks, the critic noted, but also improved her nervous system. Suddenly, Pincus was being portrayed as a revolutionary or, worse, a deviant. Soon after the Collier’s article, Harvard gave Pincus the news: He would receive a grant to study for one more year at the University of Cambridge in England and then he would be finished. Thus, at age 34, Pincus had already published a groundbreaking book and a number of attention-grabbing scientific studies and was on the cusp of what appeared to be a brilliant career, teaching and conducting research at one of the wealthiest and most prestigious universities in the world. But, suddenly, he was gone. Pincus probably was the victim of small-mindedness and anti-Semitism, but he was also undone by his own outsized ego. He couldn’t find another college willing to hire him. His classmate, Hudson Hoagland, who had left Harvard and gone to work in Clarke University in Worcester, rescued him. The Pincuses arrived in Worcester in the fall of 1938, and Pincus went back to work on hormones. In 1944, he and several other scientists organized a major conference on hormones. They called it the Laurentian Hormone Conference. Pincus became the chairman of the conference, a position he maintained for the rest of his life. In 1944, he and Hoagland made a move almost entirely unheard of in the American scientific community. They founded their own laboratory, calling it the Worcester Foundation for Experimental Biology. Hoagland and Pincus proved to be excellent salesmen, and the people of Worcester responded generously. Hoagland in particular had a gift for raising money. He had come from an affluent family and projected an image of sophistication. He was no slouch as a scientist, but it was clear from the start that Pincus was the real genius and Hoagland the organization man. At first the two scientists operated out of a room at the Worcester State Hospital, but they soon had enough money to hire a dozen workers and purchase a 12-acre estate in nearby Shrewsbury. By 1951, the foundation employed 57 men and women, making it by some accounts the largest privately owned independent scientific research institution in the country. The family had little money and lived in several crowded apartments and finally found a place at the Worcester Lunatic Asylum, a frightening and dangerous place, but it saved money on rent and enabled Pincus to concentrate more completely on his work. He did not own a car or drive one until in his 40s. He would take a bus or hitch a ride with another scientist to get to work each day. Pincus was an accomplished Scrabble July 2015 and chess player and devoured mystery novels. At the beach he would swim more than a mile out to sea. In the early 1950s, with the Worcester Foundation being more stable, the Pincus family bought a house. It looked more like an old hotel than a house, and Pincus paid $30,000 for it (about $260,000 today). The red brick structure had a dozen bedrooms, 10 fireplaces, and a furnished basement where Pincus sometimes offered free lodging to visiting scholars. They had parties lasting late into the night and leaving nearly everyone drunk. Inebriated or sober, Lizzie was razor sharp, every bit her husband’s intellectual equal when conversations were not so scientific. She spoke French and Russian fluently. Despite his exile from Harvard, Pincus was beginning to establish a reputation for leadership among his peers. He was not only a brilliant scientist but he had a gift for organizational work. The Laurentin Hormone Conference became the biggest and most important hormone conference in the world and, as a result, Pincus, with no university or corporate affiliation and no landmark discovery to call his own, became an influential player in the scientific community. He helped decide which scientists would be invited to the conference each year, who would be permitted to present papers, and whose papers would be cited in the yearly conference report. McCormick. In the fall of 1950, shortly before Gregory Pincus first met Margaret Sanger, Sanger received a letter from a 75-year-old woman named Katharine Dexter McCormick (1875–1967) (Figure 3). It read, “I want to know a) where you Figure 3. Suffragists Katharine McCormick and Mrs. Charles Parker, April 22, 1913. Photo: Library of Congress (LC-USZ62-93552). Facts and ideas from anywhere 425 think the greatest need of financial support is today for the National Birth Control Movement; and b) what the present prospects are for further birth control research, and by research, I mean contraceptive research.” For Pincus and Sanger, the timing of the letter could not have been more fortuitous. McCormick was one of the world’s wealthiest women, and after years of personal struggle and tragedy (her husband was schizophrenic) she was at last free to spend that wealth. McCormick was the recently widowed wife of Stanley McCormick, the youngest son of Cyrus McCormick, inventor and manufacturer of the mechanized reaper and one of the wealthiest men in the world. Katharine was 29 years old at the time of her wedding, fierce and lovely, a leader in the women’s movement and one of the first women to graduate with a degree in science from the Massachusetts Institute of Technology. She had intended to go to medical school, but marriage changed that. With her husband ill, she sensed that hormones, a word coined in 1905, may have been responsible for her husband’s condition and she became a student of these chemical messengers. In 1909, she began volunteering with the Women’s Suffrage Movement and by 1921 began collaborating with Sanger, who was busy planning the first American birth control conference in New York. When her husband died in 1947, Mrs. McCormick inherited more than $35 million, including almost 32,000 shares in the McCormick-owned company International Harvester. Sanger too was now a widow, her husband having died in 1943. McCormick knew exactly what she wanted to do with her money. In January 1952, Sanger stopped to visit Katharine McCormick in her mansion in Santa Barbara, California. Just before the visit, Sanger had received a report from Pincus indicating the results of the experiments he and Chang had performed on rabbits and rats, explaining the effects of hormone injections versus administration by mouth. He confirmed that the oral doses were 90% effective and said he hoped to experiment with different progesterone compounds that might work better. Pincus concluded that the experiments “demonstrate unequivocally that it is possible to inhibit ovulation in the rabbit and successful breeding in the rabbit with progesterone. . . . It has been demonstrated furthermore that following the sterile period, normal reproduction may ensue.” In June 1952, McCormick made plans to visit the Worcester Foundation to see firsthand what was happening there. She met with Hoagland and Chang and learned about the progesterone work underway, but she did not see Pincus who was out of town. After that visit, McCormick became Sanger’s leading expert on the Pincus plan for contraceptive research. Rock. Pincus recognized that what the pill project needed now was not necessarily a biologist but a product champion— someone who could build a team to do the scientific work, forge alliances with manufacturers needed to supply chemicals, and if all went well, spread the news of the coming invention so it might have a chance of acceptance. He knew what to do next: test progesterone in women. To do that he would have to 426 Figure 4. Dr. John Rock. Photo: Library of Congress (LC-USZ62-128825). add a player to his team—a physician, preferably a gynecologist, someone who could reassure the patients involved in the experiments that they were safe and would convey to the drug companies supplying the progesterone that no one would be harmed by the experiments. He considered several but came down to a physician named John Rock (1890–1984) (Figure 4), who like Pincus was a Harvard man. Rock was respected by his peers and adored by his patients. He was tall, slender, and silver-haired with a gentle smile and a calm, deliberate manner. Even the name connoted strength, solidity, and reliability, and he was a Catholic. Born in 1890 in Marlborough, Massachusetts, Rock was a son of an Irish saloonkeeper, and although he was big, strong, and athletic, he preferred playing with his sisters, and his brothers sometimes called him “sissy.” He gained admission to Harvard and attended not only college there but also medical school. In 1926, he became director of the sterility clinic at the Free Hospital for Women in Boston. While the Catholic Church opposed abortion, Rock believed a woman’s health was more important than the health of her fetus and that pregnancies should be terminated when they imperiled patients’ lives. “Religion,” he used to tell his daughter, “is a very poor scientist.” Over time Rock underwent a fundamental change as compassion for his patients overwhelmed his compulsion to tow the church’s line. He sympathized with women who came to his office who said they were afraid of becoming pregnant again, whether it was because their bodies were worn out or because they couldn’t imagine caring for more children. Rock began seeing that many couples wanted contraception because they wanted to delay, not avoid, becoming parents. In 1931, he was one of 15 Boston doctors (and the only Catholic) to sign a petition calling for the repeal of the state’s ban on contraception. In 1925, Rock married Anna Thorndyke, a Boston woman who shared his sense of adventure, having served as an ambulance driver in France during World War I. He was 35 and she 29 at marriage. They had five children together. He adored his Baylor University Medical Center Proceedings Volume 28, Number 3 wife and had no fear of showing his affection publicly. In his practice, he counseled pregnant women and delivered babies but he also worked with women who could not conceive and came to believe that sexual intercourse offered an important bond for husbands and wives as they struggled unsuccessfully to have children. Although Sanger did not want Pincus to include Rock on his team investigating progesterone because of her mistrust of the Catholic Church, Pincus saw in Rock not only a talented scientist but also an important promoter of his new, as yet unrealized, birth control pill. Rock had already gained a small measure of fame as the Catholic doctor who dared defy his own church. In 1944, he made headlines when he achieved the first successful in vitro fertilization of human ova. In 1948, Rock had published a book called Voluntary Parenthood stating: “Nothing in a life of a man and woman is going to be as important to themselves or society as their parenthood.” Gregory Pincus and John Rock had met in the 1930s when Pincus was still at Harvard. In the 1940s when Rock began experimenting with in vitro fertilization of human ova, one of his first steps was to send his research assistant to Pincus for guidance. Rock was unusual among fertility specialists at the time because he also asked husbands to have their semen tested. He suspected (and his suspicions were confirmed in later years) that men were responsible for a large percentage of infertility problems. He was also unusual in that he operated a rhythm clinic down the hall from the fertility clinic. Rock’s rhythm clinic was the first free clinic in Massachusetts to offer birth control advice. The women visiting his rhythm clinic were asked to chart their menstrual cycles and sex lives for 3 months. After that, Rock tried to instruct the women who had regular cycles when they could safely have sex with little risk of fertilization. He knew that many of the women were using diaphragms, douches, and condoms, but the law would not allow him to prescribe or even discuss those items unless the woman’s health was in serious jeopardy! Rock had long believed that the church and the state of Massachusetts were wrong for rejecting birth control. In 1952, Pincus and Rock attended the same scientific conference and chatted between sessions about their work. When Rock described his work with the pregnant women, Pincus suggested to him that he try progesterone without estrogen. Rock experimented with different combinations of hormones in different methods of delivery, trying to find the medicine that worked best and caused the fewest side effects. He did not ask his patients to sign consent forms but he did explain to the women that the medicine they were about to take would not directly help their infertility. This was how experiments were done at the time. He started the women on 50 mg of progesterone and 5 mg of estrogen and escalated gradually to 300 mg of progesterone and to 30 mg of estrogen. When the first round of treatments ended, no one had died and no one had become seriously ill. Thirteen of the 80 women in Rock’s care became pregnant. Rock told col- July 2015 leagues about this promising result which came to be known as “The Rock Rebound.” The women taking the hormones were often convinced they were pregnant because the hormones produced many of the same symptoms as pregnancy. The women were desperate to have children since most had been trying for years. When he learned of Rock’s work, Pincus was pleased but not surprised that the progesterone was having a contraceptive effect. The important thing to Pincus was the fact that Rock’s patients were not dying. Here was proof, it seemed to him, that it was safe to give progesterone to women. Rock told Pincus that he was encouraged by his work with progesterone, but that he had a big problem: patients receiving the hormone believed that they were pregnant, no matter how much he assured them they were not. And they were crushed when the truth finally became clear to them. Pincus proposed an elegant solution and one that would have enormous consequences for his own work and for the future of women around the world. To keep the women from ovulating while permitting monthly menstruation, the simplest solution was to have the women stop taking the progesterone pills for 5 days each month. It made sense to both men. Early clinical trials. One company supplying hormones for his progesterone experiments was G.D. Searle. Although the drug maker had had no success with Pincus a year earlier, company officials had never given up on the brilliant but unpredictable scientist. Searle officials continued to believe that Pincus might come up with something useful, and it was a lot less expensive for the drug company to write grants for the Worcester Foundation than it would have been to hire its own researchers. For these reasons, despite Pincus’ failures, Searle agreed to pay the foundation $62,400 for a 12-month period beginning in June 1953. In addition, Pincus would receive shares of Searle’s stock starting with 19 shares valued at $921.50. Officials at Searle had not committed to a new contraceptive, and they asked Pincus not to publicize their involvement in his project. They told Pincus that they would not have anything to do with a birth control pill that interfered with the menstrual cycle. Because Massachusetts law banned all forms of contraception, Pincus devised a method to test a birth control formula by calling it a “fertility treatment.” If he had still been on the faculty of Harvard or even if he had still been operating in affiliation with Clarke University, he never would have gotten away with it. Pincus saw himself as more than a research scientist now. He was an activist, a crusader, and a businessman. He was also a builder of coalitions. In the 1950s, there was still no law requiring physicians to inform patients that they were being included in an experiment. Rock told his patients that the progesterone they were receiving would shut down their ovaries and make it impossible to get pregnant, that the treatment would simulate pregnancy and might cause nausea, and that they would have a better chance of becoming pregnant when the experiment was complete. Facts and ideas from anywhere 427 Beginning in 1953, Pincus and Rock enlisted 27 of Rock’s patients at the Free Hospital for a 3-month trial. Because Pincus wanted to be certain that the hormone was effective in halting ovulation, women who failed to ovulate regularly were not included. The women enlisted were still infertile, but Rock did not know what was causing their infertility. Instead of the progesterone-estrogen mix that Rock had used in the past, the women in this experiment received only progesterone and they received the tablets daily for 3 weeks of each month, stopping for a week to allow them to menstruate. The tests were demanding and the testing was referred to as “the Pincus progesterone project” or PPP because so many urine specimens were tested. Pincus tested the urine specimens in Shrewsbury. Pincus also included a gynecologist in Worcester, Dr. Henry Kirkendall, and asked him to recruit 30 women for a study similar to Rock’s. The women would need to take their own temperature every day and record their findings. They also were expected to take daily vagina smears and collect their own urine for hormone analyses. The progesterone dosage would be high, between 250 and 300 mg a day. The women were not paid for their participation, nor were they informed that the results might lead to the invention of a new form of birth control. Most of them were doing it simply because a trusted doctor had asked them to. In the first year of the trials, Pincus, Rock, and Kirkendall enrolled 60 women. Unfortunately, half of the women enrolled dropped out either because the test procedure was too demanding or because the side effects were too disturbing. Unfortunately, in that experiment 15% of the women showed signs of ovulation while taking progesterone, significantly worse results than Pincus had seen with rabbits and rats. In the meantime, Russell Marker, George Rosenkranz, and Frank Colton had developed synthetic progesterone (progestin), which was 4 to 8 times more potent than the natural progesterone, and the new compound was able to survive absorption in the digestive tract, which meant it could be taken orally. This was the compound that Pincus was searching for. In May 1953, as Pincus and Rock were launching their first round of tests on humans, Sanger and McCormick met with Pincus and see if he was someone McCormick might wish to support. The women were not put off by the cheaply furnished offices, the poor ventilation in the animal rooms, or the jerry-rigged appearance of the laboratories. If anything, they seemed captivated by the place’s strappy charm and were especially enthusiastic about Pincus’ plan for testing John Rock’s patients. As the tour concluded, McCormick asked Pincus how much money he needed. Pincus had already negotiated a grant of $17,500 from Planned Parenthood to cover the first year of clinical trials. McCormick had agreed to pay half that amount. McCormick now asked how much it would take to fund the entire research project. How much to get the pill? Pincus answered $125,000. The next day McCormick phoned Pincus to say she would write a check for $10,000 with more to come. By this time, Searle was funding 428 the Worcester Foundation at a rate of about $5600 a month, making it the foundation’s biggest private backer by far and accounting for about 8% of the foundation’s total income. Also Searle at this time was paying about one-third of Pincus’ $15,000 annual salary, when the median family income in the US was $5,000. By the fall of 1953, the Worcester Foundation had 46 grants providing a total of $622,000 in income. All but 11% was spent on research. Fortunately, Pincus received $50,000 from McCormick to build an animal testing center which was needed desperately. Meanwhile, he continued to try different progesterone compounds to see which one worked best and continued to look for ways to test on women. More than ever, McCormick was taking charge. Sanger was in poor health, low on energy and increasingly cantankerous. While Sanger at times was distracted or incapacitated by illness, it was McCormick who urged the work forward. She was beholden to no one and was free to speak her mind. McCormick alone among the team of developers had the courage and independence to declare that all women, married or not, should have access to the pill. About half of the women in Rock’s and Kirkendall’s study dropped out. Testing a birth control pill was more difficult than testing other drugs. It was one thing to try a new medication in sick people who wanted to get better, but these were healthy young women volunteering for experiments. Pincus told McCormick that he would need to test hundreds if not thousands more women and have more staff—doctors, nurses, and clerks—as well as more examining rooms. After a year of work and a dropout rate of about 50% in their first round of testing, Pincus and Rock had completed research on only about 30 women. In March 1954, Pincus and his wife went on a trip to Puerto Rico where he lectured at medical schools and before groups of doctors. He was impressed by the quality of work done on the island and encouraged to learn that dozens of birth control clinics were in operation. He concluded that experiments could be done in Puerto Rico on a relatively large scale. Best of all, birth control had been legal in Puerto Rico since 1937! In Puerto Rico, overpopulation and poverty had long been serious issues. The island was poor and crowded and family sizes were large. By age 55, the average mother in Puerto Rico had given birth to 6.8 children. Just over 8% of married Puerto Rican women under the age of 50 had volunteered for sterilization. Although abortion was illegal in Puerto Rico, it became so commonplace in the 1950s that Puerto Rico developed an international reputation as a place where the procedure could be obtained, no questions asked. Finally, McCormick and Rock agreed with Pincus that Puerto Rico was the place to go to study the women they needed. As Pincus began planning Puerto Rican trials for the birth control pill in 1954, another scientist, Jonas Salk, was launching the first trials of his polio vaccine. Salk would spend tens of millions of dollars on his vaccine trial, while Pincus would operate on a first-year budget of less than $20,000. Salk would Baylor University Medical Center Proceedings Volume 28, Number 3 go on to test his drug on 600,000 children during field trials while Pincus was hopeful that he could round up 300 subjects. Neither Salk nor Pincus were concerned with profiteering from their inventions. In 1954, as Pincus negotiated with Planned Parenthood for support and funding and arranged with Searle and Syntex for supplies of the necessary progesterone compounds, he, like Salk, focused on the scientific work, not on the money. While the public clamor for birth control hardly equaled the clamor for a polio vaccine, the growing concern was about population growth. When Pincus first visited the island in February 1954, he met Dr. Edris Rice-Wray, medical director of Puerto Rico’s Family Planning Association. She was not from Puerto Rica but from Detroit. She had earned a bachelor’s degree at Vassar College and her medical degree at Northwestern University. In 1949, she had moved to San Juan with her two children after divorcing her husband in Chicago. Dr. Rice-Wray became the point person for Pincus’ study in Puerto Rico. In the meantime, Pincus had found another site to acquire women for his study, namely, Worcester State Hospital, an asylum more than a century old. It was not difficult for Pincus to obtain permission to experiment on patients at the asylum. No permission slips needed to be signed. The directing physician, Dr. Bardwell Flower, a Harvard graduate, was pleased to have a few more physicians on hand in his enormous hospital. It helped too that McCormick offered money to paint and refurbish some of the asylum’s wards in exchange for cooperation in the progesterone study. They administered progesterone and estrogen in varying doses to women diagnosed with paranoia, schizophrenia, melancholia, manic depression, chronic alcoholism, Alzheimer’s disease, Pick’s disease, and others. Pincus managed to enroll 16 women—all of them classified as psychotics—for the first round of progesterone testing. He also gave the hormone to 16 men to see how it would affect their sterility. (Sanger and McCormick, however, had made it clear that they did not trust men to take responsibility for contraception, and they wanted women to possess control of their own bodies and their own fertility.) The pill in the men had varying results, and that side of the study was soon discontinued. In February 1955, Pincus visited McCormick in Boston to bring her up to date. In late 1954, Pincus began experimenting on animals with a new group of progestins that were many times more powerful than natural progesterone. Two of the compounds seemed especially promising. One, called norethindrone, had been developed by Syntex, and the other, named norethynodrel, had been developed by Searle. Pincus and Chang preferred the Searle product because the female animals with it did not develop slightly masculine characteristics. Pincus informed Searle that he wanted to use the compound norethynodrel and intended to try it as an oral contraceptive for women. Searle agreed to send the experimental drug under the condition that the bottles were unlabeled and Searle was not mentioned as the supplier. July 2015 Pincus brought McCormick up to date on the advantages of doing clinical trials in Puerto Rico. This time he would begin a new experiment with nurses and medical students on that island. He would drop the endometrial biopsies, which were extremely uncomfortable and scared off participants. In addition, the students would be required by the faculty to participate as part of their studies. If the young women were worried about the stigma of being birth control subjects, Pincus had a solution: he would label the project a “study of the physiology of progesterone in women.” And once the nurses and students enrolled, word would spread that the substances were safe and effective. From there it would get easier. Pincus told McCormick the new drugs would cost about 50¢ a gram, which would mean expenses of about $5000 for the treatment of 100 women during the first year of testing. In addition, he would need money for physicians, nurses, secretaries, travel, and printed materials. For the first year the total operating expenses would probably be about $10,000. McCormick assured him that money would not be a problem. In late 1955, John Rock reported to Searle preliminary results of his tests with the new progestin compound norethynodrel. Rock’s test showed that progestins stopped the pituitary gland from producing the hormones that signaled the ovaries to release eggs. But the pill had other effects that were not yet clearly understood. It appeared to change the consistency of the cervical mucus, making it more hostile to sperm. Rock indicated that he was relatively confident that the Searle progestin was safe and that it would not affect the woman’s ability to get pregnant. He was optimistic enough to encourage Searle to promote the drug more widely, but he was nowhere near as optimistic as Pincus. Additional results by Rock showed that both norethynodrel and norethindrone appeared effective. Best of all, they worked at doses of only 10 mg per day, which was one-thirtieth of the progesterone dose Pincus and Rock had been giving earlier. In October 1955, Pincus and Sanger went to Japan to attend a meeting where he initially had planned to announce that an oral contraceptive for humans was nearly ready when, in fact, he had not yet decided which form of the contraceptive worked best and at which dose. Sanger was greeted as a hero in Tokyo. The number of reported abortions in Japan had increased from 246,000 in 1949 to just over 800,000 in 1952, and the number of sterilization operations jumped from 6000 in 1949 to more than 44,000 in 1956. Sanger opposed abortion as a method of birth control and believed that Japan needed an oral contraceptive more desperately than most nations. She also believed that the country was well positioned to take advantage of innovations in contraception. Literacy rates, for example, were high. Midwives were active even in remote villages. If it worked in Japan, Sanger strongly hoped it would work all over Asia and the world. In February 1956, Pincus flew to Puerto Rico to see if he could salvage the trials. The university students and nurses had all quit. He needed a new approach. He met with Dr. Rice-Wray who was both the medical director of the Family Facts and ideas from anywhere 429 Planning Association and director of the training center for nurses at the Department of Health’s Public Health Unit, in a poverty-stricken district of San Juan. These dual roles made her an ideal guide to Puerto Rico for Pincus and Rock. She knew her way around the communities where the field trials would be taking place, and she was a rebel who had given up a comfortable medical practice in Chicago because she believed that women should have access to contraception. Rice-Wray began by visiting the superintendent of the housing development, a man who saw first hand the effects of overpopulation and the burdens it placed on young mothers. He turned over a detailed list of all the community’s residents and promised that his staff would help Rice-Wray recruit subjects. She enlisted a strong, smart, ebullient nurse whom everyone in the area knew. Puerto Rican government officials approved the study. By the end of March 1956, Rice-Wray and her nurse associate had selected a group of 100 women as well as a control group of another 125. Though almost all were Catholic, Rice-Wray encountered only one woman who said her religion prohibited her from enrolling in the study. The subjects receiving the birth control pill were told that they were taking an experimental new contraceptive. The women in the control group were told they were part of a survey on family size. They used Searle’s compound, norethynodrel. The subjects were supposed to take one pill a day for 20 days before stopping. Dr. Rice-Wray began distributing birth control pills in April 1956. She gave each woman a full bottle, enough to last 20 days. She told her patients to wait 5 days after completing one bottle before starting another. Even though she tried to keep the instructions simple, mistakes occurred. One patient went home and took all the pills at once. Others shared them with friends. Doctors, nurses, and social workers tried handing out calendars. They tried giving women beads on a string to help them count. Nothing worked. A newspaper got wind of the study and reported it. Afterwards, 30 women dropped out of the trial, some because their husbands objected, others because they were worried about what their priest would say, and still others because they were experiencing unpleasant side effects. After 6 months, an additional 48 patients had quit, leaving only about 20 of the original 100. After a slow start, the study was never again at a loss for volunteers. By the end of 1956, 221 women had participated. Seventeen of those women had gotten pregnant—a fact that might have been troubling to some scientists but not to Pincus. The pregnancies had nothing to do with the pill, he told Katherine McCormick. Women were getting pregnant because they weren’t following instructions. They either forgot to take the pill every day or chose not to take it because the side effects were becoming too much to bear. Among the first 221 women in the study, 38 (17%) reported negative reactions to the drug and at least 25 women withdrew from the study specifically because of the side effects. In December 1956, Dr. Rice-Wray and Pincus traveled to Skokie, Illinois, to present their findings to the officials at G.D. Searle, which had already 430 patented norethynodrel and had recently trademarked a new name for the drug, calling it Enovid. By 1957, Pincus and Rock both felt confident that the pill worked and that it worked safely. Their biggest challenge was to get more women to try it and at the same time see if they could do something about the side effects. Pincus believed that most of the side effects were psychosomatic. To test that theory, he designed a simple experiment. One group of women was given Enovid with the usual warnings about possible reactions. Another group was told they were getting Enovid but was given a placebo instead along with the same warnings on side effects given to the first group. The third group received the real Enovid and no warnings about the side effects. The side effects were 23% in the first group, 17% in the second group, and 6% in the third group. Pincus’ experiment violated two basic rules of modern medical research: his patients were not informed of the purpose of the study, nor were they warned of the risks. The results nevertheless convinced him that he was right. Many of the side effects were imaginary. Pincus sought more patients. He contacted Clarence Gamble of Proctor & Gamble fame who had been sponsoring research in Puerto Rico for years, and Gamble offered to fund a second trial. He connected the Pincus team with the medical director at Ryder Memorial Hospital in a city 35 miles from San Juan. The women came to the hospital for two reasons: to have babies and, immediately afterward, to get sterilized. If it were not for the latter procedure, they would have delivered at home by midwives. The area chosen by Gamble was a slum region with no toilets or sewers and housing so crowded there was scarcely room for a squeezed pedestrian. Gamble hired a woman to take a census of La Vega, going door to door asking mothers how many children they had, whether they were sterilized, and what type of birth control they were using, if any. Enovid was offered to the women who had been denied sterilization at the hospital. There was no trouble finding willing patients, but once again side effects complicated the work. Women complained of breakthrough bleeding, nausea, and headaches. Nevertheless, women desperate to avoid pregnancy continued to enroll in the studies. With trials now underway in two Puerto Rican communities, Pincus and his team began to work on a third location in Port au Prince, Haiti. Increasing numbers of patients gave Pincus and Searle hope that they might have enough information to prove Enovid’s safety. At one point, Pincus and Chang discovered that Searle’s compound had accidentally been contaminated with a tiny amount of synthetic estrogen, also known as mestranol. Pincus had always tried to avoid the estrogen, and when he learned of this accidental contamination he ordered the drug company to get rid of estrogen—not only because he felt it might be unsafe but also because he thought the estrogen might have been responsible for some of the side effects. To his surprise, however, not only did the nausea persist, but women began experiencing even more breakthrough bleeding. As a consequence, it dawned on Pincus that the accidental Baylor University Medical Center Proceedings Volume 28, Number 3 contamination might have been a good thing. With more experimentation, he found that breakthrough bleeding increased when the estrogen dose fell, and nausea and breast pain increased when it rose. He also discovered that when the estrogen levels were too low, the pill was less effective in preventing pregnancy. Now, instead of purifying the pill, he suggested that Searle intentionally make it 10 mg tablets with 1.5% mestranol. The side effects did not disappear completely but the bleeding almost stopped. Still in the first months of 1957, the dropout rates remained high and the number of women enrolled in this study was low—too low, Pincus believed, to win approval from the Food and Drug Administration (FDA). In an effort to remove emphasis on the number of patients enrolled in the trial, Pincus stopped talking about women altogether. Instead he talked about the number of menstrual cycles observed: in the 1279 cycles when the regime of treatment was meticulously followed, there was not a single pregnancy. Simply put, 1279 menstrual cycles sounded a lot more impressive than 130 women. Searle faced difficult questions: What were the rules for testing the pill in healthy people? How far did a company have to go to prove such a product? Was 1 year of testing enough to measure long-term effects? Pincus urged Jack Searle not to get bogged down. In the end, there was no way to answer such questions because no one had ever done anything like this. There were risks with any drug, but the rewards for this drug in particular were like no other. This was a drug that had a chance to make money, change lives, change the culture, and combat massive world problems, such as hunger, poverty, and overcrowding. Childbirth also was dangerous, especially for women who were sick or weak or starving. There was no way to measure how many lives might be saved by a reliable contraceptive. In the end, Jack Searle concluded that the potential rewards outweighed the risks. FDA submission. Searle did hedge its bet in one important way: Instead of seeking approval from the FDA for a birth control pill, the company applied for the approval of Enovid as a treatment for menstrual disorders. Searle’s application to the FDA in 1957 made no mention of contraception. Amenorrhea, dysmenorrhea, and menorrhagia were the menstrual problems Enovid was said to combat. The company also claimed that the new drug would be used to treat infertility, because even though the number of cases was small, tests showed that women resting the ovaries for several months were more likely to become pregnant when they stopped taking the drug. The FDA inspectors could not reject the drug as a contraceptive because Searle was not asking for approval as a contraceptive. The only question was whether it worked safely and effectively in treating menstrual disorders. On June 10, 1957, after taking 2 months to review the application filed by G.D. Searle and company, the FDA approved the sale of Enovid for infertility and menstrual irregularities. About the same time, the drug was approved for the same uses in England under the brand name Enavid. It turned out that July 2015 Searle did not have to market the pill as birth control because men and women were learning for themselves what it could do. It did not hurt that the FDA had required the drug company to include a warning on each bottle that said that “Enovid prevented ovulation”; in other words, the real purpose of the drug was listed as if it were a side effect. That statement was like a free ad. In 1958, 17 states still had laws banning the sale, distribution, or advertisement of contraception. Gradually, one state at a time, the laws were being overturned. Those in place were largely unenforced. It was clearer than ever that most Americans favored some type of birth control. In 1959, drugs came with labels and nothing more. There were no informational inserts to tell patients how the drug should be used or to warn them of possible side effects. If patients needed instructions beyond those printed on the bottle, they asked their physicians. For good reason, Searle was more worried than usual about how this drug would be received if they had received permission to sell it as birth control. For one thing, women would be taking it by choice rather than by necessity. They would be trying it for replacement of other forms of birth control, not to ease pain or cure an illness. Searle wanted to set the right tone, striking a balance between the pill’s medical uses and its social benefits. Searle invited John Rock who believed strongly in Enovid to help them with their pitch. He suggested the company use phrases such as “child spacing,” “postponement of pregnancy,” and “suppression of ovulation” in its writings rather than contraception or birth control. Searle would settle eventually on “family planning” as its euphemism of choice. In a brochure prepared for physicians, Rock spent 1.5 pages describing the menstrual cycle for general practitioners who were perhaps not as familiar with it as gynecologists. Enovid, he wrote, “completely mimics” the natural action of progesterone in suppressing ovulation. In a separate brochure for patients, he wrote: “Enovid is an artificially made hormone that is chemically quite similar to the two hormones, estrogen and progesterone, naturally produced in the human ovary.” On July 23, 1959, G.D. Searle asked the FDA to approve Enovid for birth control. (Though it was not yet officially recognized as birth control, more than 500,000 women were taking the pill.) Though the number of women enrolled in clinical trials for the pill remained small, Searle submitted the biggest new drug application in American history at that time, with 20 volumes of data. In 1959, the FDA had only four full-time and four part-time physicians assigned to investigate the 369 new drug applications submitted that year. Those seven investigators were under extreme pressure to keep up with applications, but they had little time to conduct their own research or maintain their professional education. The Enovid application wound up on the desk of one of the part-timers, Pasquale DeFelice, a 34-year-old obstetrician-gynecologist, who was still completing his residency at Georgetown Medical Center in Washington, DC. He was Catholic, and he was on his way to becoming the father of 10 children. Facts and ideas from anywhere 431 DeFelice seriously questioned the validity of the use of a progesterone and the small number (n ≈ 130) of patients studied and asked Searle for more data. Searle went back to work to collect more data. In the meantime, DeFelice sent a questionnaire to 61 US physicians who had considerable experience with the drug. The response barely favored release of Enovid as a birth control agent. Despite considerable FDA hesitancy, DeFelice phoned Searle on April 7, 1959, indicating the agency’s approval. The official announcement was May 9, 1960. The world has not quite been the same since. Soon after the pill was accepted, Pincus began working on a pill with lower hormone levels, and by 1964 Searle began selling Enovid-E, with a hormone dose of only 2.5 mg, reducing the cost for consumers to only $2.25 a month and reducing or eliminating the side effects for many. Looking back more than a half century, it seems unbelievable that a group of brave, rebellious misfits—Sanger, Pincus, McCormick, and Rock—made such a radical breakthrough and did it with no government funds and comparatively little corporate money. Pincus made relatively little money on his invention—only his wages from Searle and the company stock he purchased. He never patented the drug, but he had no regrets. He was a pure scientist. If there was one problem with Pincus’ invention, it was that even educated women sometimes had difficulty using it. Healthy young women were not accustomed to taking medicine every day. Sometimes they forgot or they lost track of how many tablets they had taken since the start of the menstrual cycle. Nervous men found themselves reminding their wives and girlfriends, which led to friction. The men wondered if the women might secretly be trying to get pregnant, and the women suspected that the men cared more about the women’s sexual availability than their health. After one such marital spout, David T. Wagner of Geneva, Illinois, decided not to leave the matter entirely in his wife’s hands. Wagner took a piece of paper and put it on the dresser in their bedroom. On the paper he wrote the days of the week; he then placed one pill atop each day. When Doris swallowed a pill, the day of the week would be revealed and husband and wife both would have confirmation that she had taken it. Wagner said that this did wonders for their relationship. Wagner, a product engineer for 432 Illinois’ Toolworks, began sketching a pill box that would also function as a calendar. In 1962, he applied for a patent on a circular pill dispenser. Searle declined interest in his invention, but Ortho’s contraceptive pill hit the market in February 1963, and it arrived not in a bottle but in a beautiful “Dialpack.” Eventually, all the pill producers used the distinctive package that Wagner had devised. In 1967, Time magazine put the pill on its cover, reporting that “in a mere 6 years it has changed and liberated the sex and family life of a large and still growing segment of the US population: eventually, it promises to do the same for much of the world.” In 2010, British scientists released the results of a 40-year study, “Mortality among contraceptive pill users,” that showed that women taking the birth control pill were less likely than other women to die of heart disease, cancer, and other ailments (2). The study, which tracked 46,000 women, helped ease concerns about elevated risks of cancer or stroke. The women who took the pill were 12% less likely to die of any cause during the study. In 2011, Laura Pincus Bernard, Goody’s daughter, walked through the empty halls of the ivy-covered building where her father once worked, where Chang once slept, and where animals once mated or attempted to mate before giving their lives to science. The place was deserted except for a lone woman tapping a computer keyboard at her desk. That something so big and world-changing had come from so humble a place seemed a little short of a miracle. William Clifford Roberts, MD May 20, 2015 1. 2. Eig J. The Birth of the Pill: How Four Crusaders Reinvented Sex and Launched a Revolution. New York: W. W. Norton & Company, 2014 (388 pp.). Hannaford PC, Iversen L, Macfarlane TV, Elliott AM, Angus V, Lee AJ. Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners’ Oral Contraception Study. BMJ 2010;340:c927. Baylor University Medical Center Proceedings Volume 28, Number 3 Volume 28 Number 3 July 2015 The peer-reviewed journal of Baylor Scott & White Health Scott & White Hospital -Brenham McLane Children’s Scott & White Hospital - Temple Baylor Medical Center at McKinney Metroplex Health System - Killeen Baylor All Saints Medical Center at Fort Worth Baylor Scott & White Hospital - Hillcrest Baylor Regional Medical Center at Grapevine Baylor University Medical Center Proceedings Baylor University Medical Center at Dallas Volume 28, Number 3 • July 2015 Pages 289–432 www.BaylorScottandWhite.com The largest not-for-profit health care system in Texas, and one of the largest in the United States, Baylor Scott & White Health was born from the 2013 combination of Baylor Health Care System and Scott & White Healthcare. For more information on our 43 hospitals and more than 500 patient care sites, please visit www.BaylorHealth.com and www.sw.org. Original Research 291 West Nile virus and the 2012 outbreak: the Baylor University Medical Center experience by A. Mora Jr. et al 296 Comparison of long-term follow up of laparoscopic versus open colectomy for transverse colon cancer by S. Agarwal et al 300 Mortality by treatment in patients ≥80 years of age with gastroesophageal cancer seen in a 20-year period at a single medical center by T. Barnett et al 304 Trends in the neonatal mortality rate in the last decade with respect to demographic factors and health care resources by V. Govande et al 307 Effect of adding tetracaine to bupivacaine on duration of analgesia in supraclavicular brachial plexus nerve blocks for ambulatory shoulder surgery by L. T. Pearson et al 312 Comparison of documentation and evidence-based medicine use for non–ST-segment elevation myocardial infarction among cardiology, teaching, and nonteaching teams by A. Metting et al 317 Assessment of leadership training needs of internal medicine residents at the Massachusetts General Hospital by T. N. Fraser et al 321 Abstracts from the First Annual Scholarly Day Review Article 325 Uses, limitations, and complications of endobronchial ultrasound by B. A Jalil et al Case Studies 331 Recurrent hospitalization for self-injuries and suicide attempts: case study of a super-utilizer by J. W. Roden-Foreman et al 334 Radiographic findings in the nail-patella syndrome by J. A. West and T. H. Louis 337 Solitary supratentorial Listeria monocytogenes brain abscess in an immunocompromised patient by J. A. West et al 340 Asplenia and fever by M. L. Huebner and K. A. Milota 342 Myroides odoratimimus bacteremia in a diabetic patient by T. R. Endicott-Yazdani et al 344 Right-sided hydropneumothorax as a presenting symptom of Boerhaave’s syndrome (spontaneous esophageal rupture) by S. Rassameehiran et al 347 Pneumomediastinum in inflammatory bowel disease by N. Mihatov and A. Z. Fenves 350 Pulmonary veno-occlusive disease as a cause of pulmonary arterial hypertension by M. Porres-Aguilar et al 353 Pulmonary artery catheter–induced perforation treated with coil embolization by D. S. Kumar et al 355 A hybrid repair of a superior mesenteric artery pseudoaneurysm using open mesenteric bypass and endovascular exclusion by T. A. Cumbie et al 358 Allergic acute coronary syndrome (Kounis syndrome) by S. Memon et al 363 Blood cyst of the anterior mitral leaflet causing severe mitral regurgitation by S. Madhavan et al 365 Right-sided superior vena cava draining into the left atrium in a patient with persistent left-sided superior vena cava emptying into the right atrium diagnosed by echocardiography by C. Clark and L. MacDonald 367 Spontaneous coronary artery dissection in a 22-year-old man on lisdexamfetamine by A. M. Afzal et al 369 Worsening dyspnea in a 38-year-old woman by D. L. Glancy et al 371 Chronic pulmonary embolism in a young athletic woman by T. R. Larsen and T. C. Ball 375 Nonhepatic hyperammonemic encephalopathy due to undiagnosed urea cycle disorder by T. Mahmood and K. Nugent 378 Anaplastic large-cell lymphoma in AIDS by M. Krol et al 381 Primary follicular lymphoma of the duodenum by R. Graham et al 384 Tubulocystic carcinoma of the kidney by V. Podduturi et al 386 Unusual presentation of metastatic ovarian carcinoma as an enlarged intramammary lymph node by C. Mason et al 389 Leukoencephalopathic changes on magnetic resonance imaging associated with a thermogenic dietary supplement (Thermatrim) by C. I. Olivas-Chacon et al Editorials and Interview 397 Precision medicine: hype or hoax? by R. G. Mennel 401 Update on the Baylor Scott & White Quality Alliance by C. E. Couch 404 Nobel laureates and their medical schools: who selected whom? by A. B. Weisse 406 On camel rides and Moses Maimonides by J. D. Cantwell 409 David Bruce Hellmann, MD: a conversation with the editor by D. B. Hellmann and W. C. Roberts From the Editor 421 Facts and ideas from anywhere by W. C. Roberts Miscellany 290 295 303 320 370 380 383 392 420 Clinical research studies enrolling patients Acknowledgment of contributors Proceedings’ annual editorial board meeting Avocations: Photograph by Dr. Solis Avocations: Photograph by Dr. Rosenthal Avocations: Poem by Dr. Khan In memoriam Baylor news Reader comments: Low-voltage electrocardiogram in a patient with takotsubo syndrome associated with hyperthyroidism (J. E. Madias, with response by S. Omar) www.BaylorHealth.edu/Proceedings Indexed in PubMed, with full text available through PubMed Central