Gastroenterology News

EMT and Dissemination Precede Pancreatic Tumor Formation

noreply@blogger.com (M Baker) — Mon, 20 May 2013 11:42:37 PDT

Currently, two major paradigms have been proposed to explain the metastatic process. The first, or classical model, sees metastasis as the final step in a progressive sequence in which tumors acquire mutations that promote invasive behavior and dissemination late in tumor evolution. The alternative model envisions metastasis as an inherent feature of a tumor very early in its natural history.

This model is consistent with recent investigations in the field of breast cancer that suggest that cellular dissemination leading to metastasis (or metastatic seeding) may occur prior to the formation of an identifiable primary tumor among cells that would not meet a standard definition of cancer.

Recently, this alternative model has evoked the concept that pancreatic cancer cells precede the formation of tumors. Among the mysteries of pancreatic adenocarcinoma is that while it is often discovered after the cancer has matured and metastasized, it is rarely found in its nascent stages.

To examine the early events leading to pancreatic tumor formation, a team of researchers at Penn Medicine led by Ben Z. Stanger, MD, and Andrew Rhim, MD, developed a sensitive lineage-labeling system to tag (detect and isolate) cells of pancreatic epithelial origin during stochastic tumor progression in a mouse model.

An advantage of the labeling system was that it allowed the team to determine the kinetics of the epithelial-to-mesenchymal transition (EMT) and hematogenous dissemination during the natural evolution of pancreatic ductal adenocarcinoma (PDAC). It has been proposed that carcinoma cells undergo EMT, losing epithelial characteristics and acquiring invasive properties and stem-like features in the process.

Results
The Penn team discovered that tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial to mesenchymal transition (EMT).

Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.

This study was published in Cell.

Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert
M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ. EMT and
dissemination precede pancreatic tumor formation. Cell. 2012 Jan 20;148(1-2):349-61.

Pancreatitis Research

noreply@blogger.com (M Baker) — Mon, 20 May 2013 10:24:23 PDT

The Rustgi lab is investigating the ways in which pancreatic development and regeneration and pancreatitis and cancer overlap. Funded by the NIH, the group pioneered the use of 3-dimensional cell culture model systems, and uses these with animal models and human tissues to identify key genes and pathways that drive these processes. A recent report from the group that explored the regulatory processes that overlap ductal development, acinarductal metaplasia and the progression of normal cells to pancreatic intraepithelial neoplasia appeared in Genes and Development.

Reichert M, Takano S, von Burstin J, Kim SB, Lee JS, hida-Stansbury K, Hahn C, Heeg S, Schneider
G, Rhim AD, Stanger BZ, Rustgi AK. The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis. Genes Dev. 2013; Jan 25.

Translational Research in Pancreatic Cancer

noreply@blogger.com (M Baker) — Mon, 20 May 2013 10:17:46 PDT

From the Spring 2013 Penn Medicine Gastroenterology Division Newsletter

This edition of the Gastroenterology Newsletter features a selection of the groundbreaking research examining the pathophysiology, genetics, diagnostics and treatment of pancreatic cancer and cystic disease. These studies represent a cooperative effort between the Divisions of Gastroenterology and Hematology-Oncology, the Abramson Cancer Center and the Departments of Medicine, Surgery, Pathology and Laboratory Medicine, and Oncology and Clinical Pharmacology at Penn Medicine.

Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer

The tumor microenvironment of pancreatic ductal adenocarcinoma (PDA) is defined by active suppression of the immune response concomitant to inflammatory cell-associated tumor development and progression. Recently, a team of researchers at Penn Medicine identified granulocyte-macrophage colony-stimulating factor (GM-CSF) as an important regulator of inﬂammation and immune suppression in PDA.

The team, comprised of specialists from the Abramson Cancer Center, the Divisions of Hematology-Oncology and Gastroenterology, and the Departments of Medicine and Pathology and Laboratory Medicine, was led by Robert H. Vonderheide, MD, DPhil, with contributions from Ben Z. Stanger MD PhD.

The GM-CSF finding was the result of a wider investigation into the role of the antigens Gr-1 and CD11b in PDA. Both antigens are expressed as markers on myeloid-derived suppressor cells (MDSCs), which contribute to immunosuppression in PDA. Numerous in vitro studies have reported the expansion of Gr-1+ CD11b+ cells in implantable tumor models. However, the in vivo relevance of the T cell suppressive qualities remains controversial.

The Penn researchers focused on the KPC mouse model of spontaneous PDA to evaluate a mechanism of tumor-induced immune modulation critical to maintaining the local immune suppressive network characteristic of the disease. KPC mice develop primary PDA lesions that faithfully recapitulate features of the human disease, including progression from preinvasive pancreatic intraepithelial neoplasia (PanIN) to invasive cancer to metastatic disease.

The Penn researchers found that the dense desmoplasia and leukocytic inﬁltration classically observed in the tumor stroma of patients with PDA is reproduced in tumors of KPC mice. In addition, Gr-1+ CD11b+ cells were shown to accumulate in the spleen as well as the tumor in this model, where these cells maintained a close proximity to tumor cells and were prominently associated with metastatic lesions.

The authors noted that Gr-1+ CD11b+cells derived from tumor-bearing KPC mice suppressed the proliferation of splenic T cells from normal mice and that the cells exhibited high levels of arginase activity and nitrite, suggesting expression of inducible nitric oxide synthase (iNOS); both arginase and iNOS have been previously linked to immunosuppression by Gr-1+ CD11b+ cells in tumorbearing mice.

Splenic cells proved to be the link to the potential origin of Gr-1+ CD11b+ cells in PDA. In the KPC murine model, splenocytes from tumor-bearing KPC mice exhibited a c-kit+ population similar in percentage to that of c-kit+ precursors found in bone marrow and higher than that found in splenocytes from normal mice. C-kit is a cell surface marker used to identify some types of hematopoietic progenitors in bone marrow.

When the researchers isolated c-kit+ Gr-1+ CD11b+ lineage cells from the spleens of tumor-bearing KPC mice and incubated them with conditioned media obtained from previously isolated cultured PDA tumor cells, c-kit+ cells expressed high levels of Gr-1 and CD11b, exhibited arginase and iNOS activity, and potently suppressed T cell proliferation in the OT-1 T cell suppression assay.

The Penn researchers hypothesized that a tumor-derived factor might drive the generation of Gr-1+ CD11b+ cells from c-kit+ cells in the spleen. To identify this factor, a set of secreted proteins from a panel of PDA tumor cell lines was measured in conditioned media and the results compared to those for conditioned media from benign pancreatic ductal cells from normal control mice. Conditioned media from every PDA line supported proliferation of c-kit+ cells into Gr-1+ CD11b+ cells, whereas media from none of the normal pancreatic ductal cells supported c-kit+ cell proliferation.

Among 11 proteins examined, only granulocyte-macrophage colony-stimulating factor was expressed at high levels by every PDA line but by none of the normal pancreatic ductal lines, suggesting that tumor-derived GM-CSF might be linked to Gr-1+ CD11b+ cell generation.

When recombinant GM-CSF was tested in in vitro assays, the researchers found that GM-CSF drove proliferation and differentiation of c-kit+ Gr-1+ CD11b+ splenocytes isolated from tumor-bearing mice into functional myeloid-derived suppressor cells. Further investigation concluded that GMCSF
is both necessary and sufficient for in vitro generation of functional, immunosuppressive Gr-1+ CD11b+cells, and that in vivo GM-CSF secreted by transformed pancreatic epithelial cells is critically involved in the regulation of inflammation associated with PDA.

When tumor-derived GM-CSF was abrogated in vivo, tumors failed to grow, rejected by an T cell response. Importantly, the investigators showed that GM-CSF is expressed by more than 95% of pancreatic tumors from patients, providing further rationale for novel strategies to inhibit GM-CSF in clinical trials.

This study was published in Cancer Cell.

Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, Vonderheide
RH. Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor
Regulates Myeloid Inﬂammation and T Cell Immunity in Pancreatic Cancer.
Cancer Cell. 2012 Jun 12;21(6):822-35.

Defining the Toxic Etiology of Biliary Atresia

noreply@blogger.com (M Baker) — Fri, 25 May 2012 08:00:37 PDT

From the Spring 2012 GI News

Biliary atresia (BA) is the leading indication for liver transplantation in children. The condition is characterized by a progressive fibroinflammatory process that leads to the obliteration of all or part of the extrahepatic biliary tree, and manifests in the neonatal period.

Surgery (i.e., Kasai portoenterostomy) in infancy is required in virtually all cases to permit bile drainage. Approximately two-thirds of children with the disease ultimately require a liver transplant due to overwhelming fibrosis (deposition of scar tissue).

Biliary atresia is uncommon (~ 1/15,000 live births) and has no known cause. Most researchers suspect it occurs in genetically susceptible patients who receive an environmental exposure (potentially a virus or toxin) late in gestation; however, no specific exposure has ever been identified, and the nature of the bile duct damage that leads to biliary atresia is not known.

This may soon change as a result of the combined efforts of Rebecca Wells, MD, and Michael Pack, MD, at the Perelman School of Medicine and their collaborator John Porter at the University of the Sciences. Dr. Wells’ laboratory studies mechanisms of liver fibrosis, while Dr. Pack’s laboratory uses zebrafish models to study the development of the biliary system.

Dr. Wells’ interest in biliary atresia began in 2004 when Elizabeth Rand, MD, medical director of the liver transplant program at Children’s Hospital of Philadelphia (CHOP), urged her to investigate the mechanism of fibrosis in this disease.

Several years later, while gathering background material on the disease, Dr. Wells discovered that there had been a recent epidemic of biliary atresia in lambs in rural Australia. Similar to two previous epidemics decades before, this epidemic seemed to be associated with the ingestion of Australian pigweed (Dysphania glomulifera) by pregnant ewes grazed in unusual pastures during drought years.

It appeared that the plants contained a toxin that affected the lambs’ biliary system late in development, causing them to be born with biliary atresia. Dr. Wells contacted the Australian veterinarians who had diagnosed biliary atresia in the lambs, and arranged for them (in collaboration with botanists, rangers and veterinary pathologists) to collect samples of the plant.

If the toxin could be purified and tested in animal studies, Dr. Wells reasoned, similar compounds of relevance to humans might be identified.

Both Dr. Wells and Dr. Pack are members of the Fred and Suzanne Biesecker Pediatric Liver Center at CHOP, which is dedicated to studying biliary atresia and liver development. Dr. Pack had developed an interest in biliary atresia through his membership in the Biesecker Center and his laboratory had previously developed assays to identify biliary damage in zebrafish.

To identify the molecular structure of the plant toxin, Dr. Wells and Dr. Pack contacted John Porter, PhD, an experienced natural products biologist at the University of the Sciences in Philadelphia. Dr. Porter agreed to fractionate the plant in an attempt to isolate a toxic fraction. The team was able to import the plant samples in 2008.

For the next 16 months, Dr. Porter fractionated the plant and Dr. Pack tested the fractions to determine whether they caused biliary damage in zebrafish. Throughout this process, they received support from the Biesecker Center and the University of Pennsylvania NIDDK Center for Molecular Studies in Digestive and Liver Diseases.

In July 2009, Dr. Pack found that exposure to a highly purified fraction of the plant caused damage to the gallbladders and extrahepatic bile ducts of zebrafish, mimicking biliary atresia – a new animal model of the disease. In February 2012, Dr. Porter’s team identified the structure of one of the toxins, a compound never before described.

The laboratories of Dr. Wells and Dr. Pack are now seeking to determine the mechanism of action of the toxin, to find chemical mimetics to which humans might be exposed, and to use this information to develop potential therapies for biliary atresia. The collaborators have recently been awarded four years of funding from the NIH to further this line of research.

Diet, Genetic Factors, and the Gut Microbiome in Crohn’s Disease

noreply@blogger.com (M Baker) — Fri, 25 May 2012 07:59:47 PDT

From the Spring 2012 GI News

With Frederic Bushman, PhD, of the Department of Microbiology at the Perelman School of Medicine, Gary Wu, MD, and James Lewis, MD, MSCE, of Penn Gastroenterology have initiated a series of studies to investigate the relationship between alterations in the human gut microbiome and the pathogenesis of Crohn’s disease and colitis.

The large intestine is home to one of the most densely populated microbial communities on earth, with the number of bacteria exceeding host cells by more than ten-fold. The aggregate of all human gut bacteria, or microbiome, holds 100 fold more genes than those of its host.

These microbiota provide a metabolic diversity that, among other benefits, aids in the digestion of foods and the development of the immune system. Alterations in the gut microbiome are associated with numerous diseases, however, including opportunistic infections such as C. difficile colitis and inflammatory conditions such as Crohn’s disease.

Drs. Wu, Bushman and Lewis of Penn have previously examined the role of diet in modulating the gut microbiome composition.1-2 More recently, they have initiated a series of studies, as part of the NIH Human Microbiome Project, to investigate the hypothesis that dietary therapy leads to consistent changes in the human gut microbiome that are associated with clinical response in Crohn’s disease.

The investigators are using deep sequencing to characterize the composition of the gut microbiome. Described below are two completed studies, FSM and COMBO, and a third study (known as PLEASE) that is ongoing.

Fecal Storage Methods (FSM)

This initial study was designed to systematically evaluate methods for surveying bacterial communities in human feces using 454/Roche pyrosequencing of 16S rRNA gene sequences, generating a total of 797,276 tags.

Fecal samples from 10 individuals were analyzed and comparisons made of methods for fecal storage, DNA purification and sequence acquisition compared. These data were used to optimize protocols to collect, process and sequence bacterial 16S rDNA from fecal samples in subsequent studies.

Cross-sectional Study of Diet and Stool Microbiome Composition (COMBO)

Objectives: To evaluate the association between dietary intake, as determined by dietary questionnaire, and the composition of the gut microbiome in healthy subjects in the outpatient setting.

Methods: Diet inventories and 16S rDNA sequencing were used to characterize fecal samples from 98 individuals. Specific nutrients associated with variation in the gut microbiome for the 98 subjects were extracted, along with demographic factors. A controlled-feeding study of 10 subjects sequestered in a hospital environment was performed to compare high-fat/low-fiber and low-fat/high fiber diets. For these subjects, stool samples were collected and DNA samples analyzed by 454/Roche pyrosequencing of 16S rDNA gene segments and, for selected samples, shotgun metagenomics.

Results: Fecal communities clustered into enterotypes distinguished primarily by levels of Bacteroides and Prevotella. Enterotypes were strongly associated with longterm diets, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella).

Results of the controlled feeding study showed that microbiome composition changed detectably within 24 hours of initiating a high-fat/low-fiber or low-fat/high-fiber diet, but that enterotype identity remained stable during the 10 days of sequestration. Thus, alternative enterotype states are associated with long-term diet.

Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition (PLEASE)

Currently under way, this study examines the effects of an elemental diet treatment on pediatric patients diagnosed with inflammatory bowel disease (IBD), particularly Crohn’s disease. Elemental diet therapy is often effective in treating pediatric Crohn’s disease. This study permits investigators
to examine the microbiome changes associated with successful therapy, failed therapy and relapse. Longitudinal studies allow the investigators to specify microbial changes associated with successful or failed elemental diet therapy.

References
1. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA,
Bewtra M, Knights D, Walters WA, Knight R, Sinha R, Gilroy E, Gupta
K, Baldassano R, Nessel L, Li H, Bushman FD, Lewis JD. Science.
2011;334:105-108.

2. Wu, GD,* Lewis, JD,* Hoffmann C, Chen YY, Knight R, Bittinger K, Hwang
J, Chen J, Berkowsky R, Nessel L, Li H, Bushman FD.* BMC Microbiol.
2010;10:206. *Joint corresponding authors.

Advances in Enteral Feeding at Penn Medicine

noreply@blogger.com (M Baker) — Mon, 07 Nov 2011 07:37:23 PST

Gastroenterologists at Penn Medicine are partnering with a variety of specialists throughout the health system to introduce new enteral feeding tube (ETF) techniques and devices for patients with conditions that prevent normal swallowing and feeding. The indications for ETF include impaired swallowing as a result of brain injury or trauma, gastrointestinal obstruction, pancreatitis, motility disorders and cystic fibrosis and other hypercatabolic states, including burn injuries and Crohn’s disease.

In these critically ill patients, enteral feeding has been shown to complement nutrition by modulating the metabolic reaction to stress and enhancing the immunological function of the bowel. Moreover, ETF is superior to total parenteral nutrition (TPN) in cost and adverse events (catheter and blood infections and venous thromboses).

“Enteral nutrition is an important facet of health care in patients with digestive and related disorders at Penn,” explains Gregory Ginsberg, MD, director of endoscopy at Penn and current president of the American Society for Gastrointestinal Endoscopy. “Enteral feeding employs the functional gut and as such preserves aspects of gut flora and function. This facilitates retention of the immunological function of the gut and is associated with decreased risk for bacterial translocation and lowered infection risk.”

Endoscopic means of enteral access to facilitate nutritional support can assume many forms. Short-term nutritional support is typically accomplished via nasoenteric feeding tubes (NETs). Longer-term feeding arrangements generally involve percutaneous endoscopic gastrostomy (PEG) tubes or direct-percutaneous endoscopic jejunal (DPEJ) tubes, a specialty of gastroenterologists at Penn Medicine.

Used when the proximal-most portion of the digestive tract must be bypassed and feeding must be delivered beyond the ligament of Treitz, the DPEJ technique is technically challenging, Dr. Ginsberg says.

“We’ve worked to develop tools and techniques to best ensure success in selected patients. In preclinical work, for example, we incorporate magnetic attraction forces to help localize and transiently fix the small intestine to the anterior abdominal wall to facilitate the placement of DPEJ tubes.”

Appropriate indications for the DPEJ procedure include post-operative anatomy, pancreatitis and entero-respiratory reflux.

Low-profile PEG Button Tubes Improve Enteral Feedings for Young Patients
Penn gastroenterologists have recently introduced low-profile percutaneous endoscopic gastrostomy (PEG) button tubes designed for single-step application in young patients and those with pre-existing tubes.
“The concern with conventional PEG tubes is that they can come loose as a result of forces placed on the exterior tubing,” says Octavia Pickett-Blakely, MD, MHS. “The button design places the bolster at the abdominal wall, which decreases the risk of pull-out and irritation at the wound site in young, active patients.”
In studies of pediatric patients, those with low-profile PEG tubes were likely to have fewer tube dislodgments and briefer hospital stays than patients with standard PEG tubes.

Hepatocellular Cancer Management at Penn

noreply@blogger.com (M Baker) — Mon, 27 Jun 2011 08:34:52 PDT

Penn GI News Spring 2011

The Penn Liver Cancer team consists of hepatologists, surgeons, medical oncologists, interventional radiologists, radiologists and radiation oncologists whose primary focus is the care of patients with liver cancer and those at risk for the disease.

Diagnostic and Treatment Options

A variety of liver diseases, including Hepatitis C, can cause inflammation and progressive scar formation in the liver resulting in cirrhosis. Over time, patients with cirrhosis are at risk of developing primary liver cancer (hepatocellular carcinoma or HCC). Consequently, HCC is often the result of a process that started years before the onset of cancer.

Because HCC is present years before its manifestations appear, it is often possible to identify patients at risk of developing HCC at a stage where it is curable. Early diagnosis may be achieved, for example, with screening tests that are used to detect incipient cancer.

The primary challenge in the treatment of liver cancer emanates from the fact that HCC typically occurs in the background of a liver diseased by cirrhosis. Therefore, one has to consider that patients with HCC have two serious health problems: a cancer and a chronic liver disease.

This is important because the severity of liver disease often has a major impact on the choice of treatment options in hepatocellular carcinoma. In all cases, early detection is key, because only early cancer can be cured.

Surgical resection of the tumor can achieve cure of hepatocellular carcinoma, particularly when the tumor is small, but can only be safe and effective if liver function is nearly intact. Liver transplantation, where the entire liver – including the tumor – is removed and replaced with a normal liver from a donor, is a very effective treatment for HCC, as long as the tumor is within specific size limits.

Because the entire liver is replaced, liver transplant circumvents the strict need for a good liver function that surgical resection requires. The other major advantage of transplantation is that it results in removal of the tumor as well as removal of the rest of the liver which, if left behind, will remain at risk of developing additional cancer.

A select group of patients with small favorably located tumors can be cured with minimally invasive treatments such as radiofrequency ablation.

Effective treatment for HCC is also possible in patients with more advanced disease. Transarterial chemoembolization (TACE), in which a chemotherapy mixture is injected directly into the tumor to interrupt its blood supply, results in tumor death and is effective at controlling even larger tumors confined to the liver.

TACE is also useful to prevent tumors from growing while patients with smaller tumors are on the transplant waiting list.

Another effective modality, radioembolization kills tumor cells by injection of radiation-emitting beads into the tumor and is also an effective treatment for larger tumors. Chemotherapy in the form of the oral drug Sorafenib, or clinical trials with new drugs are also a possible effective treatment options.

Navigating the various treatment options in HCC can be complex and requires the expertise of physicians with different areas of specialization.

The Penn Liver Cancer team includes: Rajender Reddy, MD, Director of Hepatology; Thomas W. Faust, MD; Kimberly A. Forde, MD , MHS; Maarouf A. Hoteit, MD;David E. Kaplan, MD, MSc; Karen Krok, MD; and George A. Makar, MD, MSCE.

At Penn, all cases are discussed every week by a multidisciplinary team of specialists in the context of the Penn Liver Tumor Conference. Patients are then evaluated by multiple experts in a single visit to the Penn Liver Tumor Clinic where treatment options are discussed. The Liver Cancer team at Penn has the unique capability of an efficient and expert evaluation of patients, and is committed to offering convenient access to skilled medical care of a complex disease.

Download a pdf of the Spring 2011 Penn GI News.

Penn Division of Gastroenterology - Announcements & Awards

noreply@blogger.com (M Baker) — Fri, 26 Aug 2011 07:36:47 PDT

Penn GI News Spring 2011

Chief's Corner

Anil K. Rustgi, MD
T. Grier Miller Professor of
Medicine and Genetics
Chief, Division of Gastroenterology

The gastroenterology team at the University of Pennsylvania School of Medicine and Penn Medicine is nationally recognized for clinical research and superlative care of its patients.

I am pleased to announce the following honors and awards accorded our faculty, as well as recent additions to our team:

GARY D. WU, MD, has been elected to the American Academy of Physicians, a national honor society.

The following new appointments see patients at the Perelman Center for Advanced Medicine.

Rotonya Carr , MD, completed an internship and residency in internal medicine at Massachusetts General Hospital and a fellowship in gastroenterology and hepatology at the University of Pennsylvania School of Medicine.

Vinay Chandrasekhara , MD, is a graduate of the University of Virginia School of Medicine. He completed an internship and residency at the University of Texas Southwestern Medical Center, Dallas, TX, and a post-doctoral clinical fellowship in gastroenterology and hepatology at Johns Hopkins University School of Medicine, Baltimore, MD. He subsequently completed a fellowship in advanced endoscopy at the University of Pennsylvania School of Medicine.

Brintha Enestvedt , MD, completed her residency in internal medicine at Oregon Health & Science University. She completed a fellowship in gastroenterology and hepatology at Oregon Health & Science University.

David Goldberg , MD, completed an internship and residency in internal medicine at New York Presbyterian – Columbia University Medical Center and a fellowship in gastroenterology and hepatology at the University of Pennsylvania School of Medicine.

Caroline Kerner , MD, completed an internship and residency in internal medicine at the University of California, San Francisco and a fellowship in gastroenterology and hepatology at the University of Pennsylvania School of Medicine.

Pari Shah , MD, completed an internship and residency in internal medicine at Barnes Jewish Hospital, Washington University School of Medicine, St. Louis. She completed a fellowship in gastroenterology and hepatology at the University of Pennsylvania School of Medicine.

Download a pdf of the Penn GI News for Spring 2011.

Management of Viral Hepatitis at Penn

noreply@blogger.com (M Baker) — Mon, 27 Jun 2011 08:35:22 PDT

Penn GI News Spring 2011

The Penn Center for Viral Hepatitis comprises leading authorities in the diagnosis and management of viral hepatitis C and B dedicated to serving the needs of patients and their family members, physicians and allied health personnel.

Located in the Perelman Center for Advanced Medicine with direct access to radiology, pathology, surgery and other disciplines, the center’s model also benefits from pharmacy, social worker and psychiatry evaluation. Care is provided in one visit. Subsequent care is streamlined so that the patients have the best chance of obtaining success from their treatment.

While patients are evaluated for standard of care treatment, the center structure offers an opportunity to be engaged in a discussion on cutting edge and upcoming therapies that the center will be able to provide.

Further, the center provides an opportunity to seek evaluation for comprehensive primary liver cancer care if that were to be diagnosed. The Penn Medicine liver transplant program is recognized nationally and internationally and patients have direct access from the Viral Hepatitis Center to the transplant program, if needed.

For patient referrals and appointments to Penn Center for Viral Hepatitis in the Perelman Center for Advanced Medicine, please call 877.937.PENN (7366).

Download a pdf of the Penn GI News for Spring 2011.

Research at the Penn Center for Viral Hepatitis

noreply@blogger.com (M Baker) — Mon, 27 Jun 2011 08:35:12 PDT

Penn GI News Spring 2011

A Phase 2a/2b Study of BMS-650032 in Combination With Peginterferon Alfa-2a (Pegasys) and Ribavirin (Copegus) in Treatment-Naive Subjects With Genotypes 1 and 4 Chronic Hepatitis C Infection
Principal Investigator at Penn: Rajender Reddy, MD
Contact: 215.898.3981

The purpose of this randomized, double blinded, safety/ efficacy study is to identify one or more doses of investigational agent BMS-650032 that, when used with pegylated-interferon alpha and ribavirin, are safe and demonstrate sufficient activity against HCV (Genotypes 1 and 4).

HBRN: Immune Regulation and Costimulation in Natural History of Chronic Hepatitis B
Principal Investigator: Kyong-Mi Chang, MD
Contact: Mary Valiga, RN 215.823.5800
mevaliga@mail.med.upenn.edu

The Hepatitis B Research Network (www.hepbnet.org) is a clinical research network supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). It brings together 13 clinical centers, one data coordinating center and one immunology center within North America to conduct research on chronic hepatitis B in order to better understand the physiological effects of the disease and develop effective treatment strategies with the currently available therapies.

Immunological determinants of clinical and virological course as well as therapeutic response in HBV-infected patients enrolled through the clinical centers will be examined by the HBRN Immunology Center at Penn Medicine. However, there is no direct patient recruitment into HBRN at the Immunology Center.

Phase 3, Multi-Center Randomized, Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucassin® (Terlipressin)
(REVERSE Trial)
Principal Investigator: K. Rajender Reddy, MD
Contact 215.898.3981

This study is designed to evaluate the efficacy and safety of intravenous Lucassin® (terlipressin) versus placebo for the treatment of type 1 hepatorenal syndrome (HRS) in subjects receiving standard of care albumin therapy.

Download a pdf of the Penn GI News for Spring 2011.

Penn Center for Viral Hepatitis - Managing Viral Hepatitis and its Clinical Effects at Penn Medicine

noreply@blogger.com (M Baker) — Mon, 27 Jun 2011 08:35:02 PDT

Penn GI News Spring 2011

The Penn Center for Viral Hepatitis was established in 2010 as a regional nucleus for viral hepatitis care, research and education, combining expertise in hepatology and infectious disease disciplines. The Center operates under the direction of K. Rajender Reddy, MD, with the support of Drs. Kyong-Mi Chang, Vincent Lo-Re III, Jay Kostman and Pablo Tebas. Patients are seen in the Division of Gastroenterology at the Ruth and Raymond Perelman Center for Advanced Medicine.

The center acts as a nexus for the research and development of new antiviral agents, advanced approaches to treat viral hepatitis (and HIV-coinfection, when present) and education for patients and providers.

Patients living with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) and those co-infected with human immunodeficiency virus (HIV) have access to an interdisciplinary team of clinicians and advances in care resulting from clinical, translational, and basic research.

Education—of medical students, residents, fellows, pharmacy students, and physician extenders—occurs throughout the center’s programs. Training involves the virology, immunology, epidemiology, and clinical management of viral hepatitis and HIV/viral hepatitis co-infection.

The center also seeks to enhance public awareness, patient education and patient advocacy of viral hepatitis infections and HIV/viral hepatitis co-infection.

About HBV and HCV

Of the five types of hepatitis virus, HBV and HCV present particular risks in the United States due to their ability to establish chronic infection. Recent reports suggest that up to 4 million people in the US are infected with HCV, with 300,000 also co-infected with HIV.

In addition, there are more than 800,000 HBV infected persons in the U.S. Both viruses contribute to significant morbidity and mortality in the US population.

HBV and HCV are genetically distinct but share similar immune-mediated disease pathogenesis. HBV is a double stranded DNA virus whereas HCV is a single-strand RNA virus. Both viruses are transmitted by blood and body fluid, although risk factors for their transmission can’t always be clearly defined.

HBV infection is typically identified by the serological detection of the viral surface or envelope protein (HBsAg) in blood followed by the viral DNA. HCV infection is generally detected by antibody test for HCV proteins followed by viral RNA in blood.

Both HBV and HCV can cause acute hepatitis that isn’t clinically apparent in many cases. Acute HCV infection becomes chronic in 50 to 75 percent of infected adults. While HBV is cleared in most acutely infected adults, it becomes chronic in most babies exposed to HBV at birth if they are not immunized in a timely manner.

Over many years, patients with chronic HBV or HCV infection can develop chronic necroinflammatory liver disease, often without symptoms. The liver inflammation is mediated by an ongoing immune attack that fails to clear the infection but promotes liver injury, ultimately leading to cirrhosis and liver cancer.

HCV-associated cirrhosis is both the most common cause for primary liver cancer and the leading indication for liver transplantation in the U.S. Similarly, HBV infection is a leading cause for liver cancer in the world.

While an effective vaccine is available to prevent HBV infection, no vaccine is available against HCV. Importantly, the ability to treat both HBV and HCV infection has been improving with better understanding of the viruses and host responses, as well as the development of new antiviral therapeutics. In particular, treatment options for HCV infection are changing rapidly with exciting new direct antiviral agents in development to be used with existing agents.

Download a pdf of the Penn GI News for Spring 2011.

Penn GI News Winter 2011

noreply@blogger.com (Penn Medicine) — Tue, 14 Jun 2011 12:19:51 PDT

Penn Neuroendocrine Tumor Treatment Program

A collaboration between Penn Gastroenterology and the Penn Renal, Electrolyte and Hypertension results in an interdisciplinary program to diagnose, stage and treat neuroendocrine tumors.

The Penn Neuroendocrine Tumor Treatment Program provides a comprehensive, inter–disciplinary approach to the diagnosis, staging, and medical and surgical treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and pheochromocytomas.

GEP-NETs are a rare (~2 percent of all GI tumors), heterogeneous group of malignancies occurring in the digestive tract. Pheochromo-cytomas are tumors of neuroendocrine chromaffin cells, and are found in both the adrenal glands and in extra-adrenal locations. They are rarer (~2/100,000 persons) than GEP-NETs. With early diagnosis and treatment, tumors in both neuroendocrine classes are potentially curable and manageable for the long term.

Originating in cells having both nervous and endocrine properties, GEP-NETs are classified by histology as either alimentary tract carcinoid lesions (NETs) or pancreatic endocrine tumors (PETs) and subcategorized by whether or not they secrete neuroamines, hormones or peptides at levels sufficient to cause a syndromic response.

A recent standard WHO classification has proposed that GEP-NETs be assigned to one of three categories (well-differentiated tumor, well-differentiated carcinoma, and poorly differentiated carcinoma) based on histology, size and proliferative indices.

A Foundation in Experience: The Penn NET Treatment Program

As a result of the rarity and indolent character of GEP-NETs and pheochromo-cytomas, their early diagnosis depends largely on the experience and expertise of treating clinicians and access to advanced imaging and laboratory facilities––a combination of advantages unique to Penn in the Philadelphia region.

Both Dr. Metz and Dr. Cohen have researched and published on NETs and both have wide experience in the long-term management of NET patients within their respective specialties. In addition, the Penn NET Treatment Program incorporates the full armamentarium of services, procedures and technologies at Penn into the management of NETs, engaging the diagnostic services of the Divisions of Gastroenterology, Hematology-Oncology (Weijing Sun, MD, Director of GI medical oncology), Renal Electrolyte and Hypertension, Interventional Radiology and Medical Genetics, as well as the capabilities of the Abramson Cancer Center.

Thus, Dr. Cohen explains, at Penn patients with NETs have the advantage of a clinical environment capable not only of familiarity with these rare and idiosyncratic tumors, but also of heightened diagnostic scrutiny.

The diverse goals of the Penn NET Treatment Program include accurate diagnosis and staging, effective symptom control, curative surgery (when possible), prevention of tumor progression (using medical, radiological and surgical approaches), genetic counseling (when indicated), and individualized long-term patient management depending on disease progression.

Patients enter the program by being referred to a gastroenterologist, nephrologist, oncologist, surgeon or endocrinologist at Penn. This specialist then refers the patient for further diagnostics, which may involve biochemical measurements and imaging studies, or treatment via surgery, medical or radiation oncology and nuclear medicine.

“Each patient has a central physician,” Dr Metz says. “This specialist, who might be a gastroenterologist, an oncologist or a nephrologist, is the primary contact for both the patient and the treatment team.”

Clinical Diagnosis and Management of GEP-NETs at Penn

Secreting (functional) alimentary tract NET lesions represent only a small portion of carcinoids and are associated with a variable and nonspecific array of symptoms collectively termed the carcinoid syndrome. These symptoms include intense flushing, diarrhea, abdominal pain, heart rate variability and blood pressure lability and are typically caused by the vasoactive neurotransmitter serotonin among others.

Functional pancreatic NETs (PETs) produce a variety of clinical syndromes in association with the substances they secrete (e.g., Zollinger-Ellison syndrome [gastrin], insulinoma syndrome [insulin], glucagonoma syndrome [glucagon], VIPoma syndrome [vasoactive intestinal polypeptide], etc).

Several inherited conditions are associated with PETs. These include multiple endocrine neoplasia-type 1 [MEN1] and von Hippel-Lindau syndrome. Nonfunctional GEP-NETs are clinically silent and indolent. Most are identified late in their course when tumor bulk or metastases to the liver cause abdominal pain and other symptoms.

Surgery can be curative, and is typically the first-line treatment for resectable patients with GEP-NETs. At Penn, surgery is offered through the divisions of Gastrointestinal Surgery and Endocrine and Oncologic Surgery.

In patients with unresectable lesions, hormonal therapy with octreotide, a somatostatin analogue, is used to inhibit tumor growth (MIBG therapy is particularly suited to patients with malignant, unresectable pheochromocytomas). Patients with resectable PETS are candidates for surgery. Patients with unresectable lesions may benefit from debulking surgery.

Surgery in patients with MEN-1 is used in some, but not all, situations. Biotherapy is usually the first modality employed for patients with metastatic PETs because it is generally well tolerated. Typically, systemic or regional therapies are reserved until symptoms occur or tumor growth accelerates.

Patients with advanced disease may have access to newer agents and receptor-directed radiotherapy, as well as interventional radiologic procedures. As in GEP-NETs, CgA appears to be the most useful serum marker for diagnosis, staging and monitoring.

Clinical Diagnosis and Surgical Treatment of Pheochromocytomas at Penn

The Penn NET Treatment Program is a major regional source of referrals for patients with pheochromocytomas. The elevated catecholamines induced by these tumors can cause a variety of diverse (and often confusing) symptoms, including (but not limited to) the classic triad of headache, palpitations and sweating. Many patients will have hypertension, which can be labile.

Patients with pheochromocytoma entering the Penn NET Treatment Program are diagnosed and treated by an interdisciplinary team of clinicians within the Renal-Electrolyte and Hypertension Division and the Division of Endocrine and Oncologic Surgery. Typically, initial therapy focuses upon relief of the symptoms caused by hormone over-secretion.

Coordinating Treatment for GEP-NETs and PETs

A nurse coordinator at the Abramson Cancer Center provides an important element of both patient care and confidence, overseeing diagnostics and treatment plans, coordinating visits and follow-up and administering central scheduling for all patients. The nurse coordinator also serves as the liaison for research should appropriate clinical trials become available to patients. According to Dr. Metz, the dedicated nurse coordinator is at the core of the process, ensuring cohesion in the treatment plan, involving the patient at every step and providing updates to the treatment team about important developments. Octreotide, MIBG and other necessary medications are administered through the divisions of Gastroenterology, Hematology-Oncology, Renal Electrolyte and Hypertension, Interventional Radiology and Nuclear Medicine and Medical Genetics.

Case Study 1: A 49-year-old female with metastatic carcinoid tumors of the liver

Mrs. G, a 49-year-old female, was referred to the Penn Neuroendocrine Tumor Treatment Program for carcinoid tumor surgery. Several months before presenting at Penn, she had developed lower leg edema, flushing and diarrhea.

These symptoms led her to visit her ob/gyn, who ordered an abdominal CT scan that found widely dispersed tumors in her liver. At Penn, a 24-hour urine test for 5-hydroxyindolacetic acid (5-HIAA), the main urinary metabolite of serotonin,measured >150 mg/day (normal=<6 mg/day); an assessment of chromogranin A (CgA), a NET marker, found levels >100 u/L (normal range = 2-18 u/L). An octreoscan identified a primary tumor in the terminal ileum and an extensive tumor burden in the right lobes of her liver but no metastases beyond the liver.

Mrs. G was diagnosed with widely metastatic carcinoid tumors in her liver and carcinoid syndrome and began octreotide LAR, 20 mg/month, which improved, but did not resolve her symptoms. Her dose was increased to 30mg/month and following an interdisciplinary review of her tests and scans, it was recommended that Mrs. G have chemoembolization of the tumors in her right liver followed by debulking surgery.

Following two visits to interventional radiology for chemoembolization, she had liver resection surgery in the division of gastroenterological surgery. She recovered from these procedures without incident. At this time, her 5-HIAA and CgA levels were within normal levels. Six months post-surgery, a CT scan revealed no new hepatic lesions and no new metastases. At one year, Mrs. G’s status remains stable on octreotide maintenance therapy.

Case study 2: Bilateral adrenal pheochromocytoma

Mr. R presented at age 12 with headaches and diarrhea; he was diagnosed with a right adrenal pheochromocytoma and underwent right adrenalectomy.

At age 37, Mr. R was seen at the Penn Center for Complex Hypertension with recurrence of diarrhea and headaches. His BP was 132/80 mm Hg and he was not on any antihypertensive medications. He was found to have a left adrenal mass consistent with pheochromocytoma and was scheduled for a second adrenalectomy.

He was treated with dibenzylene for preoperative alpha blockade and alpha methyl-tyrosine. A left-sided adrenalectomy was performed; now unable to produce endogenous steroids, Mr. R began a regimen of hydrocortisone and fludrocortisone. Because certain genetic mutations are associated with bilateral adrenal pheochromocytoma, Mr. R was referred for genetic testing.

Genotyping studies were positive for Von Hippel Lindau V84L mutation, an autosomal dominant trait with a 50 percent risk of inheritance. Mr. R’s 18-year-old son, JW, was also found to be carrying the vHL mutation. JW had no symptoms; supine and sitting BP were 120/78 mm Hg and 118/82 mm Hg. Standing blood pressure was 96/74 mm Hg with a heart rate of 120 beats/minute.

Urine studies show elevated normetanephrine levels. MRI of the abdomen showed a left adrenal mass and laparoscopic adrenocortical sparing surgery was performed. While his BP remained normal with home BP monitoring, JW’s plasma and urine metanephrines never “normalized.”

A repeat MRI performed a year later revealed a new tumor in the right adrenal gland and a second adrenal cortex sparing surgery for his second pheochromocytoma was performed. Both Mr. R and JW remain disease-free several years later with yearly surveillance with blood tests and imaging for recurrent pheochromocytoma.

Download a pdf of the Winter 2011 Penn GI News.