A Brief Overview of the 32nd Annual STP Symposium on the Toxicologic Pathology of the Digestive Tract and Pancreas

The digestive tract and pancreas are rapidly growing areas of toxicologic inquiry and regulatory concern, and this symposium provided a great opportunity to review and expand one’s knowledge base in this important field. In a series of plenary and poster sessions, the symposium focused on correlating advances in morphologic evaluation interpretation and integration of findings in the digestive tract and pancreas with functional, cellular, and molecular end points. It also provided a venue for interactive discussion of the current methods in both conventional and specialized nonclinical safety studies involving the digestive tract and pancreas. The six core scientific sessions included Normal Digestive Tract Functional Anatomy and Physiology, Inflammatory Bowel Disease, Digestive Tract Toxicity and Risk Assessment, Digestive Tract Carcinogenesis, Biomarkers of Digestive Tract and Pancreatic Injury and Disease, and Pancreatic Toxicity and Carcinogenesis. The symposium keynote address focused on the gut microbiome and its critical interactions with the digestive tract epithelium and the mucosal immune system during health and disease.

Individual presentations focused on a mix of traditional and contemporary strategies for the pathophysiologic and toxicologic evaluation of the digestive tract and pancreas. The symposium also provided a unique forum for reviewing recent progress in developing and optimizing best practices for routine and specialized toxicologic pathology evaluation of digestive tract and pancreas across academia and the pharmaceutical and chemical industries. The symposium also featured practical case study presentations as part of the scientific sessions on Digestive Tract Toxicity and Risk Assessment and Pancreatic Toxicity and Carcinogenesis.

The General Scientific Symposium Toxicologic Pathology of the Digestive Tract and Pancreas: Monday–Thursday, June 17–20

The general meeting had a terrific start on Monday morning with the keynote address, “Gut Microbiota, Low-grade Inflammation, and the Metabolic Syndrome,” given by Andrew Gewirtz, University Center Professor at the Center for Inflammation, Infection, and Immunity at Georgia State University in Atlanta, Georgia. In his keynote presentation, Dr. Gewirtz, a leading authority in this field with over 100 peer-reviewed publications, addressed the link between intestinal bacteria, chronic intestinal inflammation, and metabolic disease, focusing on the interaction of the intestinal epithelial barrier with the intestinal microbiota. Dr. Gewirtz described how the overarching mechanism by which an aberrant gut microbiota negatively impacts health is by driving chronic inflammation. More specifically, how the gut inflammation that defines inflammatory bowel disease (IBD) is a severe but relatively rare outcome of an altered host–microbiota relationship. A much more common consequence of such disturbances is “low-grade” chronic inflammation, characterized by elevated proinflammatory gene expression that associates with, and may promote, the metabolic syndrome. He then elaborated how a variety of chronic inflammatory diseases may stem from an inability of the mucosal immune system to properly manage a stable healthy relationship with the gut microbiota, dictated in part by genetics, but also markedly influenced by the composition of the microbiota one inherits from their early environment. He concluded by providing specific examples of how the host–microbiota relationship can be perturbed by instigator bacteria or dietary components, and how these perturbations may play a role in promoting chronic inflammatory disease states leading to metabolic disturbances.

Meaningful interpretation and translation of results from animal models of digestive disease must be rooted in an understanding of the similarities and differences of normal structure and function of the gastrointestinal (GI) tract in different species. Toward this goal, the first scientific session, Normal Digestive Tract Functional Anatomy and Physiology, cochaired by Arlin Rogers and Piper Treuting, provided a great overview of the comparative morphology and physiology of each segment of the digestive tract in small and large animals in order to set the stage for the remaining scientific sessions as well as to provide meaningful context for the translation of experimental outcomes into human health. An overview of regenerative medicine, an emerging industry requiring understanding by toxicologic pathologists, was also presented with particular emphasis on the intestinal tract.

The second scientific session, Inflammatory Bowel Disease, cochaired by Lauri Diehl and Brad Bolon (Dimitry Danilenko sat in for Brad), continued on the theme from the keynote address and first scientific session. Key points that were addressed included the different aspects of IBD, including the complex interaction between immune cells, the mucosal epithelium, and the intestinal microbiome in IBD. The first session discussed the pathogenesis, current treatments, and unmet medical needs for IBD. The next two presentations examined the innate immune system and its role in GI health, particularly its relationship with gut commensal organisms. The final presentation explored animal models of IBD, emphasizing their biology and pathology as they apply to the discovery and development of new anti-IBD therapies. A key take home message in this session was that animal models only represent a subset of human diseases, and the use of specific models to ask specific questions is more likely to provide value than is using one animal system to model the entire spectrum of human disease.

The third scientific session, Digestive Tract Toxicity and Risk Assessment, cochaired by Zaher Radi and Mehrdad Ameri, included presentations on the relevance of preclinical findings to the clinical setting for digestive tract toxicity, derisking small molecule receptor targets and digestive tract risk assessment, and sympathetic regulation of digestive tract pathophysiology and neuroimmune interactions in the digestive tract. The session concluded with three practical case studies including pertinent examples of drug-induced GI tract toxicities encountered in the drug development of novel therapeutics.

The fourth scientific session, Digestive Tract Carcinogenesis, cochaired by Jerry Ward and Kishore Guda, covered comprehensive aspects of digestive tract carcinogenesis in humans and laboratory animals. The overall intent of this session was to provide a perspective on the current state as well as the potential future arsenal of therapies against these deadly GI cancers. The session started with a thorough review of the various therapeutic options available to treat colon cancer. This presentation was followed by a review of the pathology and molecular aspects of carcinogenesis in esophagus, stomach, and colon, with the aim of targeting key molecular pathways for cancer chemoprevention. The burgeoning field of novel molecular biomarkers for the early detection of cancer was also discussed. Preclinical animal models for studying the etiology, pathogenesis, methods of prevention, and therapy with goals of applications to humans were presented. Finally, since both genetics and environment play an equally important role in GI cancer predisposition, the effect of diet in modulating cancer risk was discussed.

The fifth scientific session, Biomarkers of Digestive Tract and Pancreatic Injury and Disease, cochaired by Allison Vitsky and Florence Poitout, commenced with a review of commonly utilized digestive biomarkers in clinical veterinary settings, and progressed to discussions of the ways that these and other novel biomarkers are being utilized to successfully detect and evaluate compound-associated GI and pancreatic lesions in exploratory toxicity studies. This session presented recent advances in technology, including genomic and proteomic approaches, that have improved the throughput and sensitivity of existing biomarker assays for the digestive tract and pancreas, and have also helped expand the biomarker toolkit.

The sixth and final scientific session, Pancreatic Toxicity and Carcinogenesis, cochaired by Arun Pandiri and Eric Schultz, provided an update on pancreatic toxicologic pathology, including novel information on responses of the pancreas to xenobiotics, and provided a current understanding on pancreatic tumorigenesis. The session began with an overview of anatomy and physiology of the pancreas as well as pancreatic responses to xenobiotics. The session then highlighted various rodent models used to study nonneoplastic pancreatic diseases and the molecular pathogenesis of pancreatic tumorigenesis. The session concluded with two specific case studies, pancreatic toxicity at the endocrine–exocrine interface and pancreatic toxicity of a novel cholecystokinin-1 receptor agonist, examples that illustrated the practical aspects of pancreatic toxicity and specific derisking activities.

Additional Symposium Educational Opportunities: Saturday–Monday, June 15–17

Premeeting activities kicked off on Saturday with the now very well-entrenched traditional start to the meeting: the National Toxicology Program Satellite Symposium: Pathology Potpourri chaired by Susan Elmore. This interactive symposium provided continuing education (CE) on interpreting pathology slides by generating lively and productive conversation, and provided participants and the audience an opportunity to have a good time while learning. Each speaker projected a series of images of lesions on one screen with a choice of diagnoses/answers on a separate screen. The audience members were provided with wireless keypads for selecting their choices the results were displayed on the screen in real time, and the results were then discussed after each presentation and session. And a good time was indeed had by all!

On Saturday afternoon, the Coalition for Veterinary Pathology Fellows, a joint educational effort between the American College of Veterinary Pathologists and the Society of Toxicologic Pathology (STP) to establish new training positions for veterinary pathologists at North American universities held its 5th Scientific Conference. This half-day Conference focused on the progress of Coalition Fellows and included platform presentations by six currently enrolled Fellows, featuring case reports, diagnostic investigations, and results of PhD dissertation research. In addition, representatives of academia and industry gave a joint presentation entitled “Current and Future Trends in Jobs for Veterinary Pathologists,” a topic of great interest to trainees as well as to other individuals considering a job change.

Several half-day CE courses followed on Sunday morning and Sunday afternoon. CE course 1, the Role of the Pathologist in Good Laboratory Practice (GLP) Studies, cochaired by Kathleen Funk and Klaus Weber, provided a summary of the many different tasks performed by pathologists throughout differing stages of evaluations, described expectations of each phase of pathology review, and explored the relationship of the pathologist with the Study Director, Sponsor, and other pathologists. Also discussed was the issue of what constitutes study raw data and what is to be included in the toxicology report. The roles of the Study Pathologist, Peer Review Pathologists, Pathology Working Group (PWG) Chairperson, and participants of PWGs or Scientific Advisory Panels were detailed along with the applicable GLP regulations and best practices for pathology evaluations.

CE course 2, Inflammatory Biomarkers—Sponsored by the STP Clinical Pathology Special Interest Group and cochaired by Lila Ramaiah and William Reagan, explored the current use of inflammatory biomarkers in preclinical safety assessment. Topics encompassed the evaluation of acute phase proteins, cytokines, and complement in rodent and large animal models of inflammation. Inflammatory biomarker relevance, utility, application, and use, as well as their translatability and predictivity from in vitro to in vivo models and from nonclinical to clinical settings, were emphasized. Factors that influence study design and biomarker selection, including preanalytical and analytical considerations, technologies and platforms, and species differences were discussed. The session also had several short case studies that included open discussions that involved audience members.

CE course 3, Juvenile Animal Studies in Pediatric Drug Development—Sponsored by the American College of Toxicology and cochaired by Kok Wah Hew and LaRonda Morford, provided guidance on the current U.S. and European Union (EU) nonclinical regulatory requirements and toxicity study considerations when preparing for pediatric clinical trials, as well as the timing of juvenile toxicity studies. Regulatory presentations included current pediatric regulations in the United States and EU as well as Pediatric Investigation Plan evaluation procedures by the Nonclinical Working Group of the Pediatric Committee in European Medicines Agency. Speakers from industry shared their experiences in designing and conducting juvenile animal studies, and scientific considerations when designing a nonclinical program to support pediatric drug development. Both small molecule and large molecule (biologics) pharmaceuticals were discussed. The speakers also discussed the results of surveys for juvenile animal studies that were conducted across the pharmaceutical industry with both new chemical entities and new biological entities. The course concluded with a panel discussion where speakers addressed questions and comments from attendees.

CE course 4, Immunogenicity/Hypersensitivity of Biologics chaired by Michael Leach, reviewed the different types of hypersensitivity reactions associated with biologics, methods of assessing immunogenicity and hypersensitivity reactions, and covered the changes that pathologists might observe in studies where these types of reactions are occurring. The challenges and importance of differentiating the on-target, pharmacologically mediated effects of biologics from hypersensitivity reactions were discussed, including specific case studies.

Additional opportunities for CE included two sessions provided by the Career Development and Outreach Committee (CDOC). The first, Career Development Workshops on Environmental Toxicologic Pathology on Sunday morning, featured speakers on a wide range of topics in environmental toxicologic pathology. The first presentation was on alternative animal species in environmental toxicologic pathology, the second was on secondary poisoning in wildlife with a forensic approach, and the final presentation was on a regulatory perspective on environmental toxicologic pathology. The workshop concluded with a round table discussion involving all of the speakers. The second CDOC-sponsored event was the Career Development Lunchtime Series on Transitioning to Management on Monday noontime. This session included four panelists from the pharmaceutical industry and featured an informal discussion among panelists and audience members on transitioning from “Bench Pathology” to a career with expanded roles in management. This session allowed attendees to become more familiar with some tools that have helped pathologists make a successful transition to management as well as discussing some of the challenges involved in making this transition.

A final educational session that followed the second scientific session on Monday evening was a Town Hall Meeting on Thresholds in Toxicologic Pathology. Inconsistent application of thresholds can lead to confusion, incomplete and inaccurate reporting of study findings, and incomplete and inaccurate historical control data. Thresholding impacts how we report our often complex data sets and can strongly affect the ability of nonpathologists to understand our reports. The objective of this Town Hall Meeting was to openly discuss and debate the topic of thresholding but not to come to a “best practice” conclusion on how and when thresholds should be applied. The meeting commenced with an expert panel of toxicologic pathologists from various aspects of our society presenting their definition of thresholding, and differing perspectives on how, when, and why thresholding is used in toxicologic pathology. The audience then actively participated in these discussions and presented their perspectives and concerns with the use, or lack of use, of thresholds, and recommendations for how the best consistency in thresholding can be achieved.

The digestive tract and pancreas are rapidly growing areas of toxicologic inquiry and regulatory concern, and this symposium provided a great opportunity to review and expand one’s knowledge in this important field. The articles compiled within this issue reflect the outstanding efforts of the scientific session and CE course cochairs and their speakers and tell the full tale of the 2013 STP scientific symposium. We anticipate that the high quality of this symposium issue will enable readers to appreciate the complexities of the toxicologic pathology of the digestive tract and pancreas and will serve as a go-to reference for years to come.