FALL 2019 | GASTROENTEROLOGY |

DIGEST DIVISION OF GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION

Inside This Edition 1 Message from the Chief Message From the Chief 2 Research Center It was a cold December day in St. Petersburg when a blindfolded Fyodor Obtains Digestive Diseases Research Dostoevsky was about to be executed. The men were taken into the square, Core Center (DDRCC) Designation tied to pillars, and blindfolded. As the rifles were loaded, raised and aimed, a messenger arrived on horseback waving a white flag and telling the armed 3 UPMC Center for Liver Diseases men to stop the execution, on direct orders from the Tsar. This was not a at The Liver Meeting 2019 show of mercy. It had all been planned. Every last detail — from the blindfolds 4 When to Refer Your Patient for a to the firing squad, to the extraordinarily convenient last-minute messenger Liver Transplant and the Benefits of — had been pre-arranged in a twisted form of psychological torture. Living Donation A friend of mine experienced a similar event, though in a modern medical context. The initial diagnosis based 6 Next Generation Sequencing (NGS) on CT was stage IV kidney cancer with bone metastases. After seven different scans and various organ of Biliary Specimens Improves Pre- biopsies, including a drilled biopsy from the os pubis, all tissue samples were negative for malignancy. The Operative Detection and Management PET-CT scan was also negative. Finally, after a radiologist eradicated all the colors from the PET-CT, a of Malignant Bile Duct Strictures reprieve: Paget’s Disease, a benign sclerotic bone disease. Like Dostoyevsky, at the last minute, while 8 Division Updates and CME Courses contemplating mortality with profound fear — saved. 9 The 2019 Annual Update in Medical Being a physician is both spiritually and financially rewarding. Instances where you have made a difference by Hepatology correctly assessing a problem and providing a solution are recognizable. It’s easy to take those moments for granted. Prescribing a PPI, detecting a cancer in the setting of iron deficiency, or even diagnosing a less 10 Malignant Vascular Tumor of the Liver: common condition, such as achalasia, can be obvious to the initiated. Of course, for a patient who has no A Cause of Liver Failure insight other than the problem they are experiencing, our analysis, investigation, and rendering of a solution can be perceived as miraculous, meriting substantial gratitude and admiration. While administering the right test and right treatment may often be routine, there is no escaping the humbling feeling of how little we know and how complex a machine the body is. A recent study estimated that about five percent of CME Credit outpatient U.S. adults experience diagnostic errors, defined as missed opportunities to make a correct or Disclosures: Dr. Monga, Dr. Ganesh, Dr. Singhi, timely diagnosis. Over half of these included the possibility of harm. A Johns Hopkins study in 2013, based on Dr. Slivka, and Dr. Cheng reported no relevant relationships with entities producing goods 35 million hospitalizations, estimated that 250,000 deaths stemmed from medical error, making medical or services. error the third leading cause of death.

Instructions: To take the CME evaluation and receive For Dostoyevsky or for my friend, how does one react to the trauma? A near death experience is a form of credit, please visit UPMCPhysicianResources.com/GI, psychological torture that can induce depression, anxiety and PTSD. Alternatively, one can rebound from a and click on Gastroenterology Digest, Fall 2019. death sentence with a renewed lease on life, maximizing every moment, living life with gusto and joy, and Accreditation Statement: In support of improving loving every minute of what you thought you’d never have. patient care, the is jointly accredited by the Accreditation Council for Continuing Dostoyevsky boils down these two approaches in the novel The Brothers Karamazov, published shortly Medical Education (ACCME), the Accreditation Council before his death, into the conflict between faith and doubt. Faith for him involved belief in God, which led to a for Pharmacy Education (ACPE), and the American love of mankind, kindness, forgiveness, and a devotion to goodness. Doubt referred to skepticism, which lent Nurses Credentialing Center (ANCC), to provide itself to the rejection of morality and an inner coldness and despair. continuing education for the healthcare team.

The University of Pittsburgh designates enduring As physicians, a medical mistake, complication, or misadventure mirror all setbacks in life. All we can do after material activity for a maximum of 0.5 AMA PRA falling off the horse is get back on and try to do better. But getting back on must include rigorous attempts to Category 1 Credit[s]™. Physicians should claim only understand and avoid making the same mistake. That is the essence of research! the credit commensurate with the extent of their participation in the activity. It is my great pleasure to present another edition of Digest, where we share our research, and our attempts to

Other health care professionals will receive a certificate learn and do better. Thanks for joining us. of attendance confirming the number of contact hours commensurate with the extent of participation in In good health, this activity.

Robert E. Schoen, MD, MPH Professor of Medicine and Epidemiology Chief, Division of Gastroenterology, Hepatology and Nutrition

Affiliated with the University of Pittsburgh School of Medicine, UPMC Presbyterian Shadyside is ranked among America’s Best by U.S. News & World Report. Research Areas and Scientific 4. The Clinical Component is an essential The Future of the PLRC FALL 2019 Pittsburgh Liver Research Center (PLRC) Obtains Service Cores element of the PLRC that serves as its For the continued health of any research conduit for translation and To foster translational science, dynamic community, some percentage of resources Digestive Diseases Research Core Center Designation commercialization of research. The Clinical dialogue, and enhanced collaboration, the must be dedicated to the pursuit of Component is led by Ramon Bataller, MD, PLRC hosts monthly group round tables preliminary data in novel studies and to the PhD. Dr. Bataller and colleagues have The Pittsburgh Liver Research Center (PLRC) has operated with support from UPMC and the covering three topics: chronic liver injury, development of new research talent within assembled a team of clinicians from various University of Pittsburgh since 2016. Its mission is to bring Pittsburgh liver researchers together for liver tumorigenesis, and regenerative the community’s networks. Under the disciplines to offer a direct clinical medicine, which form the research base of direction of Gavin Arteel, PhD, and Paul meaningful collaborations and to build infrastructure to support their research with cutting-edge perspective to researchers at any stage in the PLRC. During these roundtables, a Monga, MD, the PLRC funds novel technology. The Digestive Diseases Research Core Center (DDRCC) designation from the National their project. This helps investigators to researcher and a clinician are paired initiatives and new investigators who are select clinically meaningful end-points, Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) serves as validation for the high- together by topics and are allowed to pursuing liver-related research through the design a clinically consequential quality work being done at the PLRC, and this honor will help to further the legacy of liver research present and discuss the topics from their Pilot and Feasibility grant funding program. methodology, and to select appropriate perspective. Additional education occurs The PLRC has supported many early and care in the Pittsburgh area. human biospecimens. through invited seminars from visiting University of Pittsburgh investigators from professors with expertise in specific areas Each core group has contributed to the a variety of disciplines through annual, of liver health and disease. These success of the PLRC, and its directors are longitudinal mentoring. The PLRC’s designation as a Core Research especially those interested in immunology educational activities are coordinated by pivotal to this DDRCC designation and the The PLRC offers exciting new insights for Center is an honor that only 20 research and liver transplantation, as well as PLRC’s Enrichment Program under the success of this endeavor. investigators and clinicians, and our centers in the United States can claim. This researchers interested in regenerative leadership of Kari Nejak-Bowen, MBA, PhD. “I’d like to offer a special thanks to Dr. patients are provided with consequent new designation and the associated five-year medicine, stem cells, artificial liver devices, Members also have free or low-cost access Bataller and to each of the core directors hope to overcome their diseases. The PLRC grant allow the PLRC to be sustainable and and the reparative qualities of the liver. | NUTRITION AND HEPATOLOGY GASTROENTEROLOGY, OF | 3 DIVISION for their leadership and support to obtain underscores that young researchers can ensure that this research will continue to to a variety of scientific resources, an Other strengths of Pittsburgh research this grant,” said Dr. Monga. advance their careers in Pittsburgh through benefit patients with liver disease. infrastructure that the PLRC has developed include the pathological diversity and sheer through four unique cores: program support for preliminary “This application required a herculean volume of liver patients in the area. The investigations. Critical PLRC mission Advanced Cell Tissue and Imaging Satdarshan (Paul) Singh Monga, MD, effort from PLRC leadership, and the greater metro area has a high incidence of 1. The components include the ability to establish is the founding director of the Pittsburgh Liver Center, directed by Donna Stolz, PhD, proactive liver research leaders and

| 2 | GASTROENTEROLOGY DIGEST | DIGEST | 2 GASTROENTEROLOGY PLRC is honored to have received this many advanced liver conditions, including Research Center and is an endowed research designation after only its first application,” chronic liver injury due to alcoholic and supports liver research through the Center resources and to invest in the future of liver chair as well as the vice chair for the Division of said Dr. Monga. nonalcoholic liver diseases in adults and a for Biologic Imaging, one of the largest care in Pittsburgh and around the world. Experimental Pathology at the University of high occurrence of liver tumors. Many adult optical imaging centers in the country. This The PLRC also recognizes the incredible For more information about Pittsburgh. He serves in leadership roles in the and pediatric patients also present with the center provides our members access to history of advanced liver research and the PLRC and its innovative work, American Society for Investigative Pathology black boxes of liver diseases, such as cutting-edge optical imaging equipment, clinical care within the broader Pittsburgh visit LiverCenter.pitt.edu. (ASIP) and American Association for the Study primary biliary cholangitis and primary with priority given to funded collaborations community, a community that the PLRC of Liver Diseases (AASLD). Dr. Monga is the sclerosing cholangitis, and even rarer and joint outputs. brings together and provides with important editor-in-chief of Gene Expression and is an diseases, such as progressive familial Biospecimen Repository and resources. To achieve the NIDDK 2. The associate editor for the American Journal of intrahepatic cholestasis (a disease more Processing Core designation, a center must have a history provides a centralized Pathology, Annual Review of Pathology, and common in Old Order Amish communities), of integrating, coordinating, and fostering location for investigators to request tissues, UPMC Center for Liver Diseases Seminars in Liver Disease. He is also the alpha-1 antitrypsin deficiency, and other interdisciplinary cooperation among cells, and tissue microarrays. A tissue assistant dean and co-director of the Medical monogenetic disorders. Researchers are at The Liver Meeting® 2019 established investigators, who themselves utilization committee considers each Scientist Training Program of the University of attracted to the ability to study the deeper must conduct high-quality research request for tissues and determines Pittsburgh and Carnegie Mellon University. mechanisms of these complex liver on digestive and liver diseases. The specimen distribution based on project Friday, Nov. 8 to Tuesday, Nov. 12 diseases, as well as liver functionality and His research interests include personalized PLRC’s members are recognized for their relevance and feasibility. This committee is regenerative capacities. medicine in hepatocellular carcinomas excellent research, which is enhanced by led by David Geller, MD, co-director of the The UPMC Center for Liver Diseases was well represented at The Liver UPMC Liver Cancer Center, Richard L. (HCC), liver cell and tissue therapies, Pittsburgh’s patient population and Until now, researchers from the University of Meeting® 2019. Our physicians discussed a wide variety of clinical and regenerative medicine, cellular and molecular innovative research history. Pittsburgh and UPMC have worked in Simmons Professor of Surgery, and Aatur signaling in liver development, liver relative isolation in many departments (e.g., Singhi, MD, PhD, a leading collaborator basic science topics on every day of the conference. regeneration, and liver cancer. from the Department of Pathology. Liver Research and Care pediatrics, surgery, medicine, and in Pittsburgh pathology), in addition to specialized 3. The Genomics and Systems Biology Saturday, Nov. 9, we hosted a reception in collaboration with the Thomas institutes including UPMC Hillman Cancer Core For some time, Pittsburgh has been at the provides primary genome and data Center and McGowan Institute for E. Starzl Transplantation Institute and the Pittsburgh Liver Research forefront of liver research. The country’s first analysis services to researchers seeking Regenerative Medicine. The primary goal of Center. Thank you to all who attended and all who participated in our liver transplant program and first insight at the levels of RNA and DNA. the PLRC is to bring these incredible immunosuppressant therapies were Directed by Jianhua Luo, MD, PhD, and presentations. Please join us again next year. researchers together in collaboration and to developed in Pittsburgh through the work of Takis Benos, PhD, this core provides offer them cutting-edge research tools. integral technological resources for Dr. Thomas E. Starzl, namesake for the For more information about our presence at the AASLD annual meeting, Thomas E. Starzl Transplantation Institute. research and works to build a precision- His innovative work created a platform that medicine, biomarker-centered approach to visit the Featured News section at UPMCPhysicianResources.com/GI. helped to draw researchers to the city, liver disease treatments. When to Refer Living-Donor Liver Partnering With FALL 2019 When to Refer Your Patient for a Liver Transplant for a Liver Transplant Transplant for Patients Referring Physicians Referral for a liver transplant should be With Low MELD Scores Our understanding of the field of liver and the Benefits of Living Donation initiated early, before the patient is too sick Certain diagnoses or conditions carry a transplantation has allowed us to gain to be considered an appropriate candidate higher risk of death than the patient’s MELD invaluable insight and experience in In a short period of time, transplantation has progressed from an experimental procedure to the for transplantation. Early referral allows our score may indicate. Some aspects working with referring physicians. standard of care for patients with end-stage organ failure. With the establishment of the country’s team to address and resolve any concerning medical urgency for liver Throughout the transplant process, first liver transplant program in 1981, to performing our first adult living-donor liver transplant in 1999, pretransplant complications while the transplants are not accurately represented the referring physician remains an integral patient’s liver disease is relatively controlled. by a patient’s MELD score, and the current part of the patient’s care by: to becoming one of the top and most experienced programs in the country for living donor MELD allocation system greatly General indications for when to refer • Identifying patients with end-stage liver transplants, physicians and researchers at UPMC have refined new therapies, giving hope to patients underestimates the risk of waiting list include continued progress of the patient’s disease who will benefit from mortality. Ongoing symptoms of liver across the country and around the world. disease despite maximized medical transplantation. decomposition such as loss of weight and therapies, development of a life-threatening • Timely referral of those patients to the muscle mass and ascites in the chest and complication such as hepatocellular transplantation center. limbs can reduce a patient’s quality of life carcinoma (HCC), or an increasingly • Assisting in the coordination of specialists and, in some cases, may be life-threatening. CURRENT STATUS OF LIVER TRANSPLANT IN THE U.S. unsatisfactory quality of life. in pretransplant evaluation. While patients with a MELD score less than The MELD score determines how urgently a • Continuing to medically manage the 18,000 Deceased donor tx Living donor tx Waiting List 15 are often not listed for a liver transplant patient requires a liver transplant based on patient’s care while he or she awaits 16,000 because their chance of receiving a liver the likelihood of death within a three-month transplantation. 14,000 through traditional allocation is so low, a • Collaborating with the transplant team in period. A MELD score of 10 or higher is a | NUTRITION AND HEPATOLOGY GASTROENTEROLOGY, OF | 5 DIVISION living-donor liver transplant offers a 12,000 clinical indication of liver dysfunction. the long-term care and posttransplant life-saving option and the opportunity to care of the patient. 10,000 Patients with higher MELD scores have receive a transplant sooner. By exploring a Swaytha Ganesh, MD, is the medical worse short-term prognoses and are given 8,000 As an integral member of the patient care director of the Living Donor Program at living donor transplant, patients with a low higher priority for the next available team, the referring physician will be 6,000 MELD score who should still be considered UPMC. She is renowned for her clinical deceased-donor liver. for a living-donor liver transplant include continually updated about the patient’s | 4 | GASTROENTEROLOGY DIGEST | DIGEST | 4 GASTROENTEROLOGY expertise in treating a wide range of patients 4,000 progress by a member of the transplant with liver disease with a specific interest in A patient’s MELD score is based on: those with: 2,000 team. Continuous interaction with the living-donor liver transplantation. Her areas 0 • Serum creatinine • Hepatocellular carcinoma transplant team can range from in-person of research include evaluating recipients and 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 • Bilirubin • Ascites requiring periodic and telephone interactions to email donors and assessing their ability for living • International normalized ratio (INR) large-volume paracentesis communications or teleconference sessions donor surgery and developing disease • Hepatic hydrothorax for physicians located remotely. management protocols in post-liver transplant A miracle of modern medicine, liver A candidate for liver transplant may • Cholangiocarcinoma patients with metabolic syndrome, transplantation is the only definitive suffer from: • Significant life-altering HSE hyperlipidemia, and systemic hypertension. treatment for patients with end-stage liver TRANSPLANT About UPMC’s Liver • Hepatitis C • Multiple admissions for HSE, disease. The one-year survival rate following REFERRAL PROCESS Transplant Program • Hepatitis B ascites, or GI bleeding a liver transplant ranges from 87 to 93 One of the oldest and largest liver • Alcoholic liver disease percent with the five-year survival rate being • Patients with decompensated transplant programs in the country, UPMC • Nonalcoholic steatohepatitis Referred for cirrhosis whose overall health is more than 75 percent. Unfortunately, due to Transplant has performed more than 6,000 adult liver or fatty liver disease the growing transplant waiting list (Figure 1) continuing to decline transplants and more than 400 adult and hesitations among referring physicians • Primary liver cancers Preliminary Clinical Review Early access to a liver transplant allows living-donor liver transplants. We believe • Primary biliary cirrhosis to refer patients for a living donor transplant, patients to avoid the considerable burden of that liver transplantation should be an • Autoimmune hepatitis many patients have a 15 to 20 percent Financial chronic liver disease, which, over time, can option for any patient with end-stage liver Authorization chance of succumbing to their disease • Primary sclerosing cholangitis lead to deteriorating health, multiple disease who no longer experiences results before making it to transplant. • Acute liver disease from toxins Evaluation/Meld medical interventions, and hospitalizations. with medical therapy. including acetaminophen/Tylenol Score Ranking Additionally, UPMC works with hospitals Indications for • Alpha-1 Antitrypsin deficiency Further Studies Completed/ that have an existing liver transplant a Liver Transplant • A failed prior liver transplant Medical Condition Not Suitable for Approved for program and want to provide patients the • Polycystic disease Deteriorating Transplantation Transplantation A patient with liver disease and a high risk option of a living-donor liver transplant. Ongoing Medical Wait List • Hemochromatosis or Surgical of decomposition is a candidate for a liver Management When partnering with another , Management transplant. At UPMC, we are committed • Veno-occlusive disease UPMC provides pre- and postsurgery • Wilson’s disease to providing liver transplant services to all Transplantation consultation and training for clinicians, patients who will benefit—even those with while the surgery itself occurs at UPMC. a low Model for End-Stage Liver Disease Post-Op Medical Management/ For more information about our program (MELD) score or complex cases who Partner with PCP and how to begin the referral process, visit have been deemed high-risk and have UPMC.com/LiverTransplantReferral. been turned down for a transplant at another center. FALL 2019 Next Generation Sequencing (NGS) of Biliary Specimens Improves Preoperative Detection and Management of Malignant Bile Duct Strictures

The poor performance of current preoperative methods for differentiating between malignant and This previous literature has shown that A preliminary observation from this study References NGS testing of bile duct strictures may is the striking improvement in sensitivity • Singhi AD, Nikiforova MN, Chennat J, benign biliary strictures results in some patients undergoing surgical resection despite having benign have promise, but a more comprehensive that BiliSeq allowed for patients with PSC. Papachristou GI, Khalid A, Rabinovitz M, Das R, strictures. Alternatively, this can result in a delay in the diagnosis of biliary cancer. Seeking a solution, study was required for definitive evaluation These patients’ strictures are typically Sarkaria S, Ayasso MS, Wald AI, Monaco SE, of the impact on patient management caused by inflammation, so it is often Nalesnik M, Ohori NP, Geller D, Tsung A, Zureikat Aatur Singhi, MD, PhD, and Adam Slivka, MD, PhD, developed a targeted NGS assay called BiliSeq. AH, Zeh H, Marsh JW, Hogg M, Lee K, Bartlett DL, Testing endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens against when genomic alterations are detected in challenging to procure a sample, and Pingpank JF, Humar A, Bahary N, Dasyam AK, bile duct specimens. pathologic evaluation usually produces Brand R, Fasanella KE, McGrath K, Slivka A. this assay offers clinicians a more reliable diagnosis compared to standard methods. unreliable diagnoses. Routine cytologic Integrating Next Generation Sequencing to Endoscopic Retrograde Cholangiopancreatography Methodological Improvements evaluation tested at an eight percent sensitivity for PSC patients, but BiliSeq (ERCP)-Obtained Biliary Specimens Improved the Benign biliary strictures are typically due NGS and Its Use in Previous and Results Detection and Management of Patients With achieved a sensitivity of 83 percent for at to conditions such as sclerosing Studies of Biliary Strictures In our study, we developed a highly Malignant Bile Duct Strictures. Gut. 2019. Epub cholangiopathies, iatrogenic injury, and least high-grade biliary dysplasia. This is ahead of print. Sequencing of the human genome was once sensitive, targeted NGS assay called BiliSeq infection, while malignant strictures are compelling evidence to further explore the in a laboratory with Clinical Laboratory 1. Korc P, Sherman S. ERCP Tissue Sampling. an expensive, time-consuming process, but potential of BiliSeq to improve clinical

related to carcinomas arising from the | NUTRITION AND HEPATOLOGY GASTROENTEROLOGY, OF | 7 DIVISION Improvement Amendments certification Gastrointest Endosc. 2016; 84(4): 557–71. Review. pancreatobiliary duct cell, ampulla of Vater, the advent of NGS and the introduction of outcomes for this high-risk patient and accreditation by the College of 2. Dudley JC, Zheng Z, McDonald T, et al. and liver cancers. The preferred methods for novel molecular diagnostics have created population. American Pathologists. Investigation Next-Generation Sequencing and Fluorescence In pathologic confirmation during endoscopic unparalleled opportunities for low-cost use centered on 28 genes that are commonly Situ Hybridization Have Comparable Performance retrograde cholangiopancreatography of DNA sequencing in clinical and research mutated, amplified, and/or deleted in Clinical Implications of Results Characteristics in the Analysis of Pancreaticobiliary Aatur Singhi, MD, PhD, is an associate (ERCP) are bile duct brushings and forceps environments. Consequently, our Brushings for Malignancy. J Mol Diagn. 2016; 18(1): understanding of the genomic landscape of malignant neoplasms involving the bile These results highlight the diagnostic 124–30. | 6 | GASTROENTEROLOGY DIGEST | DIGEST | 6 GASTROENTEROLOGY professor in the Department of Pathology and is biopsies, but the sensitivity of these duct system. applicability of NGS-based assays to a member of both the Gastrointestinal approaches to detect malignancy can vary neoplasms arising in, or secondarily ERCP-obtained biliary specimens in the 3. Foutch PG, Kerr DM, Harlan JR, Kummet TD. A Pathology Center of Excellence and the Division from eight to 67 percent. Several ancillary involving, the bile duct system has improved During an initial training cohort followed Prospective, Controlled Analysis of Endoscopic early detection and management of of Molecular and Genomic Pathology. His detection techniques have been developed, at an incredible pace in recent years. by a validation cohort, a total of 163 biliary Cytotechniques for Diagnosis of Malignant Biliary research has a translational focus in the areas of patients with indeterminate bile duct Strictures. Am J Gastroenterol. 1991;86(5): 577–80. including digital image analysis, KRAS These innovations have played a pivotal role brushings and 172 biliary biopsies were gastrointestinal, pancreatic, hepatobiliary, and strictures. For clinicians, this testing can mutation testing, and multicolor in recent research studying the efficacy to collected for pathological evaluation. For a full list of references, visit peritoneal pathology. grant the ability to avoid unnecessary UPMCPhysicianResources.com/GI and click on fluorescence in situ hybridization (FISH), distinguish between malignant and benign Rather than relying on DNA-extraction but these methods also fail to produce resections and to make evidence-based Gastroenterology Digest, Fall 2019. strictures. Bankov et al. published the results methods from processed pathology reliable diagnoses due to the wide variance clinical decisions before the disease of an NGS assay that was used to test a specimens that might have reduced the in sensitivity and, in the case of the latter progresses. retrospective cohort of patients and found yield and quality of the genome, we method, a propensity for subjective a sensitivity of 81 percent. However, this performed a dedicated bile duct brushing Our results also have implications for the interpretation errors, which can only be study tested only 16 patients, did not and/or biopsy for each patient and growing body of literature around precision avoided by an experienced pathologist evaluate biliary brushing specimens, and submitted the resultant 160 brushings medicine. BiliSeq testing identified two performing labor intensive work. used DNA extracted from Formalin-Fixed and 135 biopsies for BiliSeq testing. patients with ERBB2 amplifications, a genomic alteration known to respond well Distinguishing between the two is difficult, Paraffin-Embedded (FFPE) tissue blocks for NGS was performed prospectively as part to trastuzumab in conjunction with especially because certain conditions, sequencing, resulting in such a low-quality of clinical care with a 10-day turnaround in like primary sclerosing cholangitis (PSC), of DNA that it had to be enriched before standard first-line chemotherapy. Both Adam Slivka, MD, PhD, is the medical the UPMC Molecular & Genomic are associated with benign strictures but analysis. A more comprehensive patients exhibited measurable radiographic director of the UPMC Digestive Disorders Pathology (MGP) Laboratory. We then are also associated with an increased risk assessment of NGS testing on bile duct responses and normalization of serum Center and is the associate chief of Clinical compared the results of NGS testing with of bile duct cancer and may harbor pre- specimens was reported by Dudley et al, CA19-9, and both are currently alive and Affairs for the Division of Gastroenterology, the results of diagnostic pathology of 145 cancerous changes. which studied a cohort of 73 bile duct and well thanks to the ability of NGS to provide Hepatology and Nutrition, where he also serves surgically resected specimens or biopsy eight main pancreatic duct brushing a personalized, targeted treatment option. as a professor of medicine. His research The failure of current diagnostic methods specimens and with the results of further specimens, finding a sensitivity of 68 To learn more about these patients, visit interests include noninvasive diagnosis of for malignant biliary strictures often leads clinical evaluations on 75 of the patients. percent and a specificity of 97 percent. inside.upmc.com/deadly-diagnosis- pancreaticobiliary cancer, the development and to repeated ERCP procedures and delayed BiliSeq was found to have a sensitivity of But even this larger study did not collect precision-medicine. testing of new drugs and devices used during clinical decisions that risk disease 73 percent and a specificity of 100 percent, dedicated brushings for DNA isolation and ERCP, and the development of new strategies to progression, and even more alarmingly, an improvement over pathological extracted DNA from CytoLyt-preserved treat pancreatitis and pancreatic cancer. can lead to a high percentage of patients evaluation alone for detecting at least undergoing an unnecessary surgical specimens. Unsurprisingly, 11 percent of high-grade biliary dysplasia involving resection. A more reliable method is their specimens had degraded to the point the bile duct. The combination of both required for preoperative diagnosis of of failing NGS testing. pathological and BiliSeq testing brought malignant biliary duct strictures, and this sensitivity up to an incredible 83 percent serves as the motivation for this study of a while maintaining a specificity of promising new methodology involving NGS. 99 percent. FALL 2019 Division of Gastroenterology, Hepatology and New Online CME Courses Nutrition News & Updates UPMC Physician Resources offers video CME courses in gastroenterology. New additions for 2019 include:

Advances and Controversies in Gastroenterology Year in Review Colorectal Cancer Screening Kenneth E. Fasanella, MD Robert E. Schoen, MD, MPH Hepatology Year in Review System Modeling and Naudia L. Jonassaint, MD, MHS Precision Medicine To view these courses, visit David C. Whitcomb, MD, PhD UPMCPhysicianResources.com/GI. Incorporating Genetic Testing David Levinthal, MD, PhD, received a Experts from the UPMC Liver Transplant Paul Monga, MD is pleased to announce into the Care of a PDAC Patient national research award from the Program, led by Abhinav Humar, MD, that the Pittsburgh Liver Research Center Randall E. Brand, MD International Foundation for chief of The Division of Transplantation (PLRC) has been funded by the NIDDK Gastrointestinal Disorders (IFFGD) at the at UPMC, authored a report in Annals of through a P30 grant, a grant that is only 2019 Digestive Disease Week (DDW) for Surgery that highlights advantages of received by 20 Digestive Diseases Research his work as a basic/translational living-liver donation. In a retrospective Core Centers in the country. This prestigious investigator. Dr. Levinthal’s research focuses analysis of surgical outcomes, they find five-year grant will allow the PLRC to

on treating patients with cyclic vomiting numerous advantages of living-donor liver continue to provide scientific resources and | NUTRITION AND HEPATOLOGY GASTROENTEROLOGY, OF | 9 DIVISION syndrome (CVS). transplant compared to deceased-donor translational consultations to the research liver transplant, including better three-year community in Pittsburgh. For a full survival rates and lower costs. explanation of the PLRC’s activities, read the article on page 2. 2019 Annual Update in Medical Hepatology | 8 | GASTROENTEROLOGY DIGEST | DIGEST | 8 GASTROENTEROLOGY

Saturday, Dec. 7 • 7:30 a.m. to 2:30 p.m.

James Squires, MD, received the 2019 Autoimmune Liver Disease Pilot Research Award from the AASLD Foundation for his Randall Brand, MD, received the National Thank you to all who attended the 2019 Annual Update in project “A Learning Health System for Pancreas Foundation’s keynote “Courage Marc Schwartz, MD, was recognized by Medical Hepatology. This CME program was intended for Pediatric Autoimmune Liver Disease Award” in Sept. 2019 in recognition of his the Crohn’s & Colitis Foundation at its experts in hepatology, gastroenterology, and abdominal and Through Partnership with advanced patient care and his valuable 2019 “Night of Steel” event at Pittsburgh’s general surgery, referring primary care physicians, and other ImproveCareNow.” Dr. Squires will utilize contributions to pancreatic cancer on Saturday, Nov. 2. Dr. health care professionals with an interest in the treatment the tested model of a Learning Healthcare research. Our pathology colleague, Aatur Schwartz was recognized for his University Club and latest research for liver disease. System (LHS) to decrease variability and Singhi, MD, PhD (see page 6), received outstanding patient care and his leadership 123 University Place, improve care for children with autoimmune NPF’s “Nobility in Science Award” as well. in Pittsburgh’s IBD community. Pittsburgh, PA 15260 liver disease. Additional awards for “Compassionate At the event, our experts presented recent advancements Care” were presented to Beth Dudley, MS, Presented by: The and new innovations in highly active research areas. MPH, CGC, Helen Carleton, RN, and Gail UPMC Center for Topics included: Smoulder, RN, CGRN, and staff member Joy Jenko Merusi, MA received NPF’s Liver Diseases in “Professional Excellence Award”. collaboration with · An Integral Approach to Treat Alcohol-Induced Liver Disease the Community Liver · Recent Advances in the Management of NAFLD Alliance · Management of Complications of Cirrhosis · Living-Donor Liver Transplant: the UPMC Experience · Current Trends in Liver Transplantation

For more information, visit the Featured Events section at UPMCPhysicianResources.com/GI. Please join us again next year. FALL 2019 Malignant Vascular Tumor of the Liver: A Cause of Liver Failure

Two years ago, while on his honeymoon, a 36-year-old male presented with spontaneous splenic rupture and liver lesions concerning for angiosarcoma. He did not respond to doxorubicin. He was later diagnosed with hepatosplenic T-cell lymphoma (HSTCL) on repeat liver biopsy and responded to chemotherapy including hyper-CVAD. He underwent stem-cell transplant (SCT) that was complicated by graft-versus-host disease and CMV viremia, although he eventually achieved remission.

The patient presented with two months of increasing Malignant Vascular Tumors Surgical resection may be performed for HAS, but References: abdominal pain and distension. A CT scan was of the Liver even with complete resection, patient survival is notable for hepatomegaly and numerous lesions less than one year. Because of a high recurrence 1. Groeschl RT, Miura JT, Oshima K, Gamblin TC, Turaga KK. Does Histology Predict Outcome Malignant vascular tumors of the liver include involving the liver, ribs, vertebra, and sacrum (see rate and poor survival posttransplant, liver for Malignant Vascular Tumors or the Liver? J Surg Oncol. 2014; 109: 483-86. hepatic angiosarcomas (HAS), epithelioid Figure 1). Bone marrow biopsies were unrevealing for transplantation is not recommended. Various hemangioendotheliomas (HE), and malignancy. His liver function declined, and he was chemotherapy regimens have been tested 2. Bioulac-Sage P, Laumonier H, Laurent C, Blanc JF, Balabaud C. Benign and Malignant Vascular hemangiopericytomas. HAS is a high-grade tumor referred for liver transplant evaluation. (including doxorubicin, ifosfamide, and paclitaxel), Tumors of the Liver in Adults. Semin Liver Dis. 2008; 28(3): 302-14. that can progress rapidly with metastases to areas but there has been no proven effectiveness with

On exam, the patient was jaundiced and including the spleen, lymph nodes, lungs, bone, and | NUTRITION AND HEPATOLOGY GASTROENTEROLOGY, OF | DIVISION | 11 these therapies. 3. Mehrabi A, Kashfi A, Fonouni H, Schemmer P, Schmied BM, Hallscheidt P, Schirmacher P, demonstrated massive hepatomegaly and anasarca. adrenals. It typically presents in patients 50 to 70 Weitz J, Friess H, Buchler MW, Schmidt J. Primary Malignant Hepatic Epithelioid Labs revealed renal insufficiency, anemia, years of age and is more common in men. HAS is Epithelioid hemangioendotheliomas (EH) are less Debbie Cheng, MD, is a gastroenterology thrombocytopenia and coagulopathy, total bilirubin characterized by poorly defined hemorrhagic and common (incidence of less than 0.1 per 100,000) Hemangioendothelioma: A Comprehensive Review of the Literature With Emphasis on the fellow, Year II, in the Division of 33 mg/dL, AST 1336, ALT 378, and alkaline necrotic nodules that are hypodense and do not than HAS and are low-grade, although they Surgical Therapy. Cancer. 2006; 107(9): 2108-21. Review. Gastroenterology, Hepatology and Nutrition. phosphatase 134 (IU/L). His course was enhance with contrast on imaging. These tumors frequently metastasize to the lungs, lymph nodes, complicated by rapid deterioration due to a large may be associated with certain exposures, such as peritoneum, bone, and spleen. Most commonly, EH 4. Putra J, Gupta A. Kaposiform Hemangioendothelioma: A Review With Emphasis on

| 10 | GASTROENTEROLOGY DIGEST | DIGEST | GASTROENTEROLOGY | 10 perihepatic hematoma with hemoperitoneum vinyl chloride, arsenic, and thorium. Clinical affects individuals 40 to 50 years of age and is Histological Differential Diagnosis. Pathology. 2017; 49(4): 356-62. (requiring hepatic artery embolization), toxic presentation may vary, and possible symptoms characterized by cellular infiltration of tumor cells in epidermal necrolysis, disseminated intravascular include abdominal pain, jaundice, ascites, and, rarely, sinusoids and intrahepatic veins. Presentation can coagulation, and, ultimately, multiorgan failure with Budd-Chiari syndrome. Fifteen percent of HAS range from absence of symptoms to portal septic shock. Given concerns for an aggressive patients present initially with acute spontaneous hypertension or hepatic failure with slow or rapidly malignancy, he was not deemed to be a candidate hemoperitoneum due to nodule rupture. Causes of progressive disease, however, a multifocal tumor for transplant. death include liver failure and intra-abdominal with varying sized nodules is typical. In contrast to bleeding. Microangiopathic hemolytic anemia and HAS, the tumor periphery may enhance with Postmortem analysis revealed a liver measuring thrombocytopenia may result from damage when contrast and may retract the liver capsule with 30 x 25 x 20 cm, weighing 7.0 kilograms with blood cells pass through tumor vasculature. On calcifications in 20 percent of cases. Pathology is 90 percent of hepatic parenchyma composed of pathology, characteristic findings include variably characterized by neoplastic cellular infiltration with blood-filled vascular masses and confluent dark red differentiated tumor endothelial cells with severe epithelioid-type cells of sinusoids and intrahepatic hemorrhagic tumor nodules. Review of previously nuclear atypia and frequent mitoses along dilated veins. Kaposiform hemangioendothelioma (KHE) is obtained biopsies by multiple pathology specialists sinusoids. HAS and HE can have positive a rare, locally aggressive tumor more frequently diagnosed a malignant vascular tumor of the liver, immunostaining for vascular markers, including seen in children. KHE may be associated with representing either a hepatic angiosarcoma or ERG transcription factor, CD31, CD34, and Factor Kasabach-Merritt phenomenon, or consumptive hemangioendothelioma. VIII antigen. coagulopathy with intravascular fibrin deposition with thrombocytopenia and purpura. The Division of Gastroenterology, Hepatology and Nutrition is honored and proud to welcome the following June 2019 gastroenterology & hepatology fellow graduates as GI colleagues: Jeffrey Dueker, MD: Assistant Professor of Medicine, Division of Gastroenterology, Hepatology and Nutrition, UPMC Digestive Disorders Center, and the VA Pittsburgh Healthcare System – Pittsburgh, PA Diana Jaiyeola, MD: Gastroenterologist, St. Luke’s Gastroenterology Specialists and St. Luke’s University Health Network – Philadelphia, PA Matthew Klinge, MD: Hepatologist and Gastroenterologist, Bayfront Digestive Diseases at UPMC Hamot – Erie, PA Bassem Matta, MD: Advanced Therapeutic Endoscopy Fellow, New York University Langone Health – New York, NY

Figure 1. Hepatomegaly (measuring 36.5 cm craniocaudally, seen on left) R. Warren Sands, MD, PhD: Continuing studies as an Advanced ABIM Research with numerous confluent hypodense lesions. Pathway Fellow – Division of Gastroenterology, Hepatology and Nutrition – Pittsburgh, PA 200 Lothrop St. Pittsburgh, PA 15213-2582

ABOUT THE UPMC DIVISION OF GASTROENTEROLOGY, UPMC Division of Gastroenterology, HEPATOLOGY AND NUTRITION Hepatology and Nutrition

EDITORS Julia B. Greer, MD, MPH The Division of Gastroenterology, Hepatology and Nutrition is one of the leading centers for Janet R. Harrison, MD Joy Jenko Merusi, MA gastrointestinal clinical care and research in the country. ADDRESS CORRESPONDENCE TO: The UPMC Digestive Disorders Center is a comprehensive care program for patients that covers Joy Jenko Merusi the full range of digestive health conditions, including: [email protected] — Inflammatory Bowel Diseases — Hepatic Disorders and Diseases For consults and referrals, please call UPMC’s 24-hour — Cancer Prevention and Treatment — Pancreatic and Biliary Diseases physician OnDemand service at 1-866-884-8579. — Functional Bowel Disorders — Nutrition Support About UPMC The Division also includes eight Centers of Excellence that provide specialized care for complex A $20 billion health care provider and insurer, cases and conduct research on numerous fronts to better understand, and develop treatments for, Pittsburgh-based UPMC is inventing new models of patient-centered, cost-effective, accountable care. The disorders and diseases of the gastrointestinal and related systems. largest nongovernmental employer in , UPMC integrates 87,000 employees, 40 hospitals, 700 doctors’ offices and outpatient sites, and a more than Centers of Excellence 3.5 million-member Insurance Services Division, the largest medical insurer in . In the — Pancreas and Biliary Center — IBD Center and UPMC Total Care-IBD most recent fiscal year, UPMC contributed $1.2 billion in benefits to its communities, including more care to the — Center for Liver Diseases — GI Cancer Prevention and Treatment Center region’s most vulnerable citizens than any other health — Center for Intestinal Health and — Neurogastroenterology and Motility Center care institution, and paid $587 million in federal, state, and local taxes. Working in close collaboration with the Nutrition Support University of Pittsburgh Schools of the Health Sciences, — Center for Women’s Digestive Health UPMC shares its clinical, managerial, and technological skills worldwide through its innovation and commercialization arm, UPMC Enterprises, and through UPMC International. UPMC Presbyterian Shadyside is ranked #1 in Pennsylvania and #15 in the nation, and is one of only nine hospitals ranked in the nation’s top 20 of America’s Best Hospitals for 10 years in a row by U.S. To learn more about the UPMC Division of News & World Report. UPMC Children’s Hospital of Gastroenterology, Hepatology and Nutrition, Pittsburgh is ranked in the nation’s top 10 of America’s Best Children’s Hospitals by U.S. News & World Report. please visit UPMCPhysicianResources.com/GI. For more information, go to UPMC.com.

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