A Brief Overview of the 33rd Annual STP Symposium on the Translational Pathology

Abstract

The 33rd Society of Toxicologic Pathology’s Annual Symposium focused on translational science and the relevance of toxicologic pathology to human health. Toxicologic pathologists work in diverse settings studying changes elicited by pharmacological, chemical, and environmental agents and factors that modify these responses. Regardless of the work setting, society members are dedicated to the integration of toxicologic pathology into hazard identification, risk assessment, and risk communication regarding human and animal exposure to potentially toxic substances. Toxicologic pathologists routinely face not only questions regarding pathological changes related to compound exposure but also questions concerning what translational relevance those lesions and exposures have to a human population or organ system. This symposium provided a basis for the membership to understand the variety of roles the toxicologic pathologist plays in translational science, where our gaps in translational science are, and how we can move forward to better address the challenges in the field translational science in order to continue to positively impact human health.

Toxicologic pathologists work in diverse settings studying changes elicited by pharmacological, chemical, and environmental agents and factors that modify these responses. Regardless of the work setting, society members are dedicated to the integration of toxicologic pathology into hazard identification, risk assessment, and risk communication regarding human and animal exposure to potentially toxic substances. Toxicologic pathologists routinely face not only questions regarding pathological changes related to compound exposure but also questions concerning what translational relevance those lesions and exposures have to a human population or organ system.

Primary topics of the 2014 Annual Symposium focused on the ability of nonclinical models to inform human end points as well as how human end points inform nonclinical models. Discussions included the progress in developing relevant nonclinical models as well as the utility of nonclinical models in terms of their prediction of relevant human end points, and where these models fall short in their predictivity. Furthermore, emerging technologies, which have the potential to continue to improve translational capabilities, were introduced and discussed as well as how these advancements enable us to drive decision making in the regulatory setting in a meaningful way. The field of epigenetics is rapidly advancing, and although most of our understanding of epigenetic mechanisms has been drawn from investigation of mechanisms of carcinogenesis, it is becoming apparent that epigenetic mechanisms play a significant role in other diseases and toxicity. Therefore, the importance of understanding the role and utility of epigenetic end points in toxicologic pathology and their relevance to human health was also a major topic of discussion. As human health is subject to a variety of environmental exposures, pathology outcomes informing human health assessment and regulatory decisions were also discussed. Finally, as the incidence of comorbidities in the human population increases, there is a pressing need for the development of animal models with concurrent disease that better inform on human populations with specific comorbidities. How relevant models are developed and used to inform on these complex human populations was discussed.

This symposium provided a basis for the membership to understand the variety of roles the toxicologic pathologist plays in translational science, where our gaps in translational science are, and how we can move forward to better address the challenges in the field translational science in order to continue to positively impact human health.

The General Scientific Symposium—Translational Pathology: Relevance of Toxicologic Pathology to Human Health. Monday—Thursday, June 23 to 26

The general meeting kicked off on Monday morning with an outstanding keynote address given by Dr. Bruce Car, Vice President of Pharmaceutical Candidate Optimization and Biocon Research Center at Bristol-Myers Squibb, titled “Translational Research and Development (TR&D) in the Context of Toxicologic Pathology.” In his presentation, Dr. Car discussed the philosophy of translational science as an important component of risk assessment of various compounds, including pharmaceuticals, to which humans are exposed. In other words, the effects of compound administration at certain doses in preclinical studies are ascertained and then further studied to determine how those effects are relevant to human exposures. This is inherently translational. He went on to discuss how translational research and development has often been synonymous with targeted medicine approaches and high-density systems biology technologies, including metabolomics, transcriptional profiling and next-generation sequencing, proteomics, virtual pathology, and in silico approaches, in order to extrapolate findings in preclinical studies to those in human disease states. However, he stated that to some, such paradigm shifts in the predictive ability of nonclinical sciences have been disappointing, since their use has had only incremental benefit in terms of definitive advances in the development of registered therapeutic drugs. He stressed that while these technologies have accelerated the understanding of disease in many cases, thoughtful hypothesis-driven research into the pathogenesis of toxicity and a detailed understanding for how these changes are relatable across species is what more commonly drives advances in translational science and drug development.

Therefore, in order to ensure that the discipline of toxicologic pathology remains relevant in the translational science sphere, it is essential to continue to develop and better understand methods to more fully analyze data involving dysregulation of pathogenetic biochemical and metabolic pathways in terms of systems biology between nonclinical and clinical studies. In addition, toxicology and pathology databases and historical knowledge of drug-related alterations and risk-assessment approaches used to deal with those changes need to be further strengthened. With this framework, the discipline of toxicologic pathology can continue to lead in the translational sciences and in the development of effective therapeutic drugs. The keynote address was recorded and is available for free at the Society of Toxicologic Pathology (STP) Web site (www.toxpath.org/).

One of the most central and challenging aspects of translational science in toxicologic pathology is the predictivity of target organ toxicity in animal models to human exposures, and the relevance of these models to outcomes in human populations. To this end, the first scientific session, “Toxicity Concordance from Animals to Humans: How Predictive Are Traditional Preclinical Studies of Adverse Effects or Toxicities in Clinical Studies?” was chaired by Drs. Sabine Francke (U.S. Food and Drug Administration [FDA]/Center for Food Safety and Applied Nutrition [CFSAN]), Daniela Ennulat (GlaxoSmithKline), and Jeff Engelhardt (Isis Pharmaceuticals, Inc.). Dr. Francke provided an overview of the challenges of predictivity in our current testing paradigm and how the discipline is attempting to meet these challenges. For example, since the advent of FDA-mandated testing of xenobiotics in animals in 1939, traditional safety testing has been critical in developing various compounds such as new pharmaceuticals, food additives, and occupational and environmental chemicals. A main question, as new and more complex compounds are developed, is how well animal models predict target organ toxicity and responses in humans and therefore, the robustness of concordance between morphologic or biochemical changes in animal models compared with humans. The overview of these important issues led into presentations discussing the limitations and advantages of current and traditional animal models and biomarkers and how they translate from preclinical findings to clinical use. The first presentation by Dr. Thomas Jones (Eli Lilly, Inc.) focused on strengths and limitations of the current preclinical safety testing paradigm and offered a framework for assessing preclinical safety model performance, discussing the implications for the applications of new models and technologies including in silico or in vitro models to complement the current paradigm. The second presentation by Dr. Kirk Ways (Janssen Research and Development LLC) focused on how nonclinical and clinical data can be successfully integrated in a mechanism-based manner to fully understand the relevance of a tumor response in safety assessment pharmaceutical trials in rodent models to clinical cancer risk in humans. The third presentation provided by Dr. Thomsa Monticello (Amgen, Inc.) was an informative overview of the development and implementation of an industry-wide shared database by the International Consortium for Innovation and Quality in Pharmaceutical Development Preclinical Safety Leadership Group (IQ-PSLG) to better interrogate toxicity data in terms of reliability and prediction in preclinical models for human safety in phase 1 clinical trials. The final two presentations by Dr. Daniela Ennulat (GlasxoSmithKline) and Dr. Scott Adler (AstraZeneca) stimulated useful discussions on the development, qualification, and concordance of early translational biomarkers in preclinical studies and the translation of those biomarkers both to tissue changes in preclinical models and their translational utility to human end points in the clinic. Dr. Ennulat discussed considerations in the selection, characterization, and preclinical use of novel urinary biomarkers. She emphasized that selection of new biomarkers should focus on biological considerations as well as translatability across species to optimize their chance of success in the preclinical environment. Dr. Adler’s presentation focused on the use of several urinary biomarkers in the clinical setting as well as a thoughtful overview of the qualification process of urinary biomarkers in humans.

The second scientific session, “Progress in Preclinical Testing for Translational Science” cochaired by Drs. Glenn Cantor (Bristol-Myers Squibb), Jerry Ward (Global Vet Pathology), and Cory Brayton (Johns Hopkins University), continued the theme of the first session and the keynote address in terms of relevance of animal models in translational science and introduced new models for use in translational science in terms of pharmaceutical discovery, safety assessment of pharmaceuticals, and cancer therapeutics, in order to better optimize preclinical translational research. This session continued to tackle the fact that, while translational research has led to important advances in science and medical research, much scrutiny has been given to many of our animal models in terms of relevance to human conditions when used as surrogates in preclinical testing and hypothesis-driven research. The first presentation by Dr. Jeffrey Everitt (GlaxoSmithKline) provided an illuminating overview of how preclinical models should be evaluated to better understand responses in animals for extrapolation to humans. While animal models have provided an important tool for decision making in preclinical studies, they have recently come under scrutiny because of a lack of concordance with human disease. Dr. Everitt stressed that this discrepancy often is due to deficiencies in planning, conduct, and reporting of in vivo studies, rather than robustness of the animal model and focused on best practice methods to ensure rigor in methods and reporting of animal studies. The next presentation, by Dr. Allison Harrill (University of Arkansas for Medical Sciences), focused on the use of genetically diverse mouse populations in safety testing of pharmaceuticals. Dr. Harrill provided data showing that the use of a genetically diverse mouse model, such as the Diversity Outbred (DO) model, is more relevant and a better model of the genetic diversity of the human population and therefore provides a better model by which to accurately predict and understand adverse drug reactions in a diverse human population. The third presentation by Dr. Markus Grompe (Oregon Health and Science University) introduced a thought-provoking discussion on the use of humanized mice for hematologic and hepatic studies. Chimeric animals that bear human tissues (humanized) provide better models for tissue- and species-specific responses to chemicals. Mice chimeric for human lymphoid populations may be used for immune function studies, and those humanized with human hepatocytes are useful for evaluation of human-specific drug metabolism and hepatotoxicity. Dr. Grompke’s group has developed double-chimeric mice useful for studying conditions involving both the liver and lymphoid systems, such as immune-mediated liver disease. The last presentation by Dr. Emmanuel Schenck (MedImmune) provided an overview of current issues in the development of biopharmaceuticals. Dr. Schenck’s overview emphasized the importance of safety science and pathology as a core component of translational research in drug development. As prediction of efficacy improves, scientists will be challenged to provide better mechanistic data using relevant animal models.

The third scientific session, “Emerging Technologies,” cochaired by Drs. Eric Blomme (AbbVie, Inc.) and Gary Boorman (Covance Laboratories), provided an interesting look at new strategies and tools currently used or under development to address translational end points including human conditions refractory to traditional therapies and human risk assessment. This session focused on the role that pathologists involved in drug development and safety assessment play in development and evaluation of new and emerging technologies to better translate preclinical findings to humans. New emerging technologies are potentially useful tools for discovery pathologists who need to become sufficiently knowledgeable in their utility, interpretation, and design, in order to provide useful advice on their use and applicability in the translational space. The increasing number of new and unique therapeutics under development challenge preclinical safety assessment pathologists who must then interpret a multitude of complex alterations with frequently unknown mechanisms and poorly understood relevance to human health. The first presentation of the session was by Dr. Yvonne Will (Pfizer), which focused on the potential and utility of these new technologies for early compound characterization. Attrition in drug development, particularly due to hepatotoxicity and cardiotoxicity, remains high. Dr. Will focused on the challenges of predicting early toxic effects using in vitro and in silico methods, and even in vivo, due to the multifactorial nature of toxic events. She emphasized that a combination of validated technologies is crucial in moving those drug candidates that are most promising to proof of concept testing in humans. Dr. Eric Blomme next gave an overview on how discovery technologies have impacted toxicology-related attrition and have influenced regulatory preclinical assessment. He echoed Dr. Will’s sentiment that early prediction of toxicity of drug candidates is a challenging but important component for optimizing a candiate’s success in the drug development process. His talk proposed integration of new technologies into the current drug discovery paradigm and discussed the strengths and weaknesses of some of the various technologies currently used at AbbVie, Inc. and some of the key challenges faced by pathologists in the pharmaceutical industry. The fourth presentation, by Dr. Kendall Frazier (GlaxoSmithKline), focused on the development and safety assessment of antisense oligonucleotide agents. Despite decades of research, until recently a few antisense oligonucleotides have been successfully marketed. Recent research and successful screening methods have renewed interest in this class of compounds, including the development of new molecules with improved efficacy. However, some toxicity issues remain, including vasculitis, nephrotoxicity, hepatotoxicity, and thrombocytopenia, associated with their use in preclinical models. Dr. Frazier outlined these issues and discussed recent investigative work that uncovered the underlying mechanisms of toxicity, allowing for a better understanding of the relevance of these toxicities in humans. The last presentation of the session focused on recent advances in prediction and characterization of adverse effects on the immune system, by Dr. Ellen Evans (Pfizer). Many therapies target components of the immune system to dampen immune function, or to stimulate it, for various therapeutic implications including autoimmune disease, chronic inflammatory conditions, or cancer. Unwanted immune responses may occur with various therapies including oligonucleotide and nanoparticle products, and Dr. Evans discussed approaches for identifying such potential adverse reactions and stressed the importance of preventing, mitigating, and understanding the mechanisms of such responses in humans.

The fourth and “free for government employees” scientific session on “The Role of the Toxicologic Pathologist in Informing Regulatory Decisions and Guiding the Interpretation and Application of Data from New Technologies and Tools” was developed by colleagues in the regulatory arena to evoke active dialogue among regulatory and industry scientists. The session was cochaired by Drs. Shashi Amur (U.S. FDA/Center for Drug Evaluation and Research [CDER]) and Douglas Wolf (Syngenta). This session echoed the topic of the third session, in introducing how data derived from the use of new technologies is used by regulators in the decision-making process of human risk assessment. The application of this data holds great promise in safety assessment of new drugs, food constituents, and environmental and occupational compounds. The integration of these methods into risk assessment requires analytic validation to enable accurate and appropriate application in regulatory decision making. The first presentation by Dr. Anthony Bahinski (Wyss Institute, Harvard University) introduced a technique to model the general functions of a tissue known as “organs-on-chips” and discussed how safety assessments performed using this technology simulates organ-level physiology in vitro, including multicellular architectures, tissue–tissue interfaces, and physiologic microenvironments. Dr. Bahinski discussed that this technology could potentially fill a need for improved model systems in drug development, and he further discussed the issues which need to be addressed for the integration of this technology in safety assessment. The second presentation by Dr. Weida Tong (U.S. FDA/National Center for Toxicologic Research [NCTR]) focused on the application of genomics in safety assessment and discussion of its applicability and validation for prediction in the regulatory space. Toxicogenomics has been recognized by the FDA as a useful tool in advancing drug development. However, its utility has been hampered by the lack of adequate data mining and analysis technologies. Dr. Tong discussed new methodologies to analyze large microarray data sets, and the application of this data for safety assessment, as well as compared the utility and performance of RNA-Seq with microarray technology. The third talk, by Dr. Nancy Everds (Amgen, Inc.), addressed methods of interpretation of clinical pathology end points in toxicity studies, and their translation relative to tissue changes assessed by histopathology, in order to better translate these findings to human risk assessment. Clinical pathology end points are quantitative, easily obtained, and translatable to human health. Dr. Everds discussed the importance in correlating in-life and histopathology data with clinical pathology data to provide a better understanding of mechanisms of toxicity and provided relevant case examples focused on agrochemical and pharmaceutical toxicity studies to illustrate this. Finally, in the last two talks, Dr. Shashi Amur (U.S. FDA/CDER) focused on the development, qualification, and use of biomarkers as tools in drug development, from the perspective of FDA, and Dr. Jon Sobus (U.S. Environmental Protection Agency [U.S. EPA]) discussed the use of biomarkers in prediction of risk and regulatory management decisions from the perspective of U.S. EPA. Dr. Amur outlined the FDA’s biomarker qualification process and the use of biomarkers as drug development tools. The CDER has four types of biomarkers currently in the qualification process, including preclinical safety, clinical safety, patient selection, and efficacy response biomarkers, a majority of which involve submissions from consortia which otherwise would be unable to develop these biomarkers because of the significant resources needed. Dr. Sobus focused on the EPA’s development of biomarkers as indicators of exposure to environmental chemicals (biomonitors) and biologic responses that may indicate an adverse human health outcome. He highlighted novel methodologies used by the EPA in a series of computational case studies to determine a best practices process to evaluate biomonitoring data. The session rounded out with an informative and interactive panel discussion between the audience and all session speakers on issues surrounding the identification and establishment of biomarkers and bioindicators.

The fifth session, “Epigenetic Endpoints in Toxicologic Pathology and Relevance to Human Health,” cochaired by Drs. Mark Hoenerhoff (University of Michigan) and James Hartke (Celgene), focused on the application of epigenetic end points to drug development and discovery, risk assessment, and hazard identification. While epigenetic mechanisms involved in cancer development have been well studied for several years, these alterations have largely been left unaddressed in routine toxicology studies. This session focused on applicability of epigenetic end points in toxicity testing and the utility and prediction of these end points in preclinical studies. In the first presentation, Dr. Jay Goodman (Michigan State University) gave a very informative overview of epigenetics in toxicology, the effects of nutrition, inflammation, DNA damage, and metabolism and epigenetic changes. A good understanding of these relationships is important when considering epigenetic end points with regard to the mechanism of action and safety assessment, as well as considerations for dose–response, normal biologic variability, beneficial versus nonadverse versus adverse effects, and rodent to human extrapolation. The second presentation, by Dr. Reza Rasoulpour (The Dow Chemical Company), continued on the theme of epigenetic end points in safety assessment and focused on the relationship of the exposome, epigenome, and transcriptome with regard to chemical exposure and compared molecular, epigenetic, and apical end points across multiple species to understand how epigenetics plays a role in product safety assessment. Dr. Rasoulpour discussed the difficulty in anchoring epigenetic responses to changes in transcription or apical end points such as histopathology or clinical pathology. Using case examples involving estrogenic and nongenotoxic molecules, he showed that epigenetic alterations do correlate with points of departure based on a no-observed-adverse-effect level (NOAEL) but stressed that since the epigenome is in a constant state of flux depending on factors such as development, aging, and nutrition, without a concurrent phenotypic anchor a single epigenetic alteration cannot be deemed adverse, making it difficult to determine if these changes are related to toxicity. In the third presentation of the session, Dr. Stephen Baylin (Johns Hopkins University) focused on the study of epigenetic mechanisms in cancer development, methodologies to detect epigenetic alterations, and methods to target molecules involved in epigenetic mechanisms of toxicity and carcinogenesis for potential therapies. As a major epigenetic mechanism involved in the development of cancer and other diseases in humans, chromatin remodeling was discussed in the fourth presentation of the session, by Dr. Michael Boyle (Amgen, Inc.). This presentation focused on how alterations in chromatin remodeling impact cellular signaling involved in embryonic development, organogenesis, and carcinogenesis, and the identification of potential targets for therapy. For example, Brg1, a chromatin remodeling factor responsible for transcriptional control, is protective in animals exposed to the cardiotoxin doxorubicin. Animals with induced deletion of Brg1 had more severe heart lesions than wild-type animals, showing that Brg1 confers some degree of resistance to doxorubicin-induced cardiotoxicity. The final presentation of the session, by Dr. Theresa Alenghat (University of Pennsylvania) provided interesting data on how the microbiome influences the epigenome and how human health is impacted through the complex interplay between mammalian histone deacetylases and the trillions of commensal microorganisms that normally reside in the gastrointestinal tract. For example, mice lacking intestinal expression of HDAC3 have alterations in gut microflora and increased susceptibility to intestinal disease.

The sixth session, “Environmental Toxicologic Pathology and Prediction of Human Health Risks” was cochaired by Drs. Charles Wood (U.S. EPA), Wanda Haschek-Hock (University of Illinois), and David Malarkey (U.S. National Toxicology Program [NTP]). This session focused on the use of different model systems in the study of environmental hazards, the application of data derived from these systems in hazard identification and risk assessment, and the impact that environmental factors have on human populations as an important aspect of translational science. The first presentation on current and emerging regulatory issues in chemical safety was given by Dr. Jeffrey Morris (U.S. EPA) and included activities currently being developed at the U.S. EPA to enhance the safety evaluation of chemicals and advance environmental sustainability. Dr. Morris focused on the EPA’s Office of Pollution Prevention and Toxics role in enhancing chemical safety and environmental health through accurate and timely chemical safety decisions and integration of pollution prevention considerations and green chemistry approaches into chemical-related decisions. This was followed by a presentation by Dr. Jack Harkema (Michigan State University) on translational studies of health effects related to air pollution, including diabetes and metabolic syndrome, which showed that inhalation exposure of rodent models of type 2 diabetes to particulate matter and ozone causes insulin resistance, lending additional support that airborne pollutants play a role in enhanced susceptibility to the disease in diabetic humans. The third presentation was a very interesting (and entertaining) debate on the similarities, differences, and general relevance of rodent models of lung cancer. In this presentation, Drs. Arun Pandiri (EPL, Inc./U.S. NTP) and Samuel Cohen (University of Nebraska Medical Center) presented differing viewpoints in terms of the benefits and limitations of using rodent models in the study of human lung cancer. The presentation highlighted some of the molecular similarities between rodent and human lung cancers, including mutation spectra of major cancer genes and global gene expression as well as morphologic similarities of certain subtypes of human lung cancer to rodent lung tumors; conversely, data opposing their use included a bronchial origin of tumor in humans, greater variety of transformed cell types, increased metastatic disease, more prominent stromal response, aggressive clinical course, and lack of continuum of proliferative lesions through the course of disease. The next presentation by Dr. Matthew Martin (U.S. EPA) outlined the development of a computational toxicology model to study points of departure and performance baselines for predictive modeling through the use of the U.S. EPA Toxicity Reference Database (ToxRefDB). This database contains toxicity data from over 6,000 animal studies on 1,071 chemicals, including pesticides and pharmaceuticals, and environmental and occupational hazards. The last presentation of the session, by Dr. Olga Pulido (University of Ottawa), overviewed the health effects of harmful algal blooms, which are responsible for widespread toxicity due to elaboration of toxins from certain species. These phycotoxins contaminate freshwater and seawater and accumulate in aquatic animals that enter the human food system, such as mollusks and fish. Algal blooms occur as a result of water pollution and climate change, including the presence of new toxins and algal species. This talk included the pathophysiology of disease and target organ lesions in humans and animals exposed to these toxins and the important role toxicologic pathologists play in risk management programs to combat exposures or minimize intoxication.

The last session of the symposium, titled “The Challenges of Safety Evaluation in Populations with Concurrent Disease,” chaired by Drs. LuAnn McKinney (U.S. FDA/CDER/Office of New Drugs [OND]/Division of Neurology Products [DNP]) and John Sagartz (Seventh Wave Laboratories), focused on the prediction of drug-related adverse effects in human populations with comorbidities, such as cardiovascular disease, obesity, or diabetes, in preclinical studies before human patients are adversely affected. This session focused on the current methodologies used to detect adverse effects in these individuals, identify safety issues and minimize adverse safety events, and translate findings from preclinical animal studies to comorbid patients. The first presentation, by Dr. Ellis Unger (U.S. FDA/CDER), provided an overview of how nonclinical studies inform the safety decisions in translation to patient populations with concurrent disease. The totality of the data include observations in animal studies, mechanisms of action and drug classes, background incidences in the patient population, as well as dose levels and time course relative to treatment. The next presentation was an overview of pharmacovigilance methods used to detect adverse clinical events in comorbidities by Dr. Ajay Singh (GlaxoSmithKline). In the past several years, there has been an increase in the recognition of patients with severe comorbidities and risk factors due to increasing emphasis on targeted therapies, immunotherapy, and individuals with resistant disease. This has led to a shift in pharmacovigilance and risk mitigation strategies in pharmaceutical companies and regulators in terms of implementation of proactive and flexible methods to assess the safety of new compounds. Challenges in the identification and mitigation of risk of adverse events due to drug therapy that may also be influenced by underlying disease or comorbidity, as well as strategies to address such issues, were discussed. This presentation was followed by a discussion by Dr. John Sagartz (Seventh Wave Laboratories) on how early preclinical safety assessment can play a critical role in the identification of safety issues relevant to patient populations with comorbidities and prevent or minimize adverse safety events. The fourth presentation of the session was given by Dr. Sherry Morgan (AbbVie, Inc.) and provided information on the benefits and risks of using animal models of human disease in the safety assessment of novel therapeutics, rather than conventional (healthy) animals. The use of such models is highly dependent on the understanding of the disease model, as selection of an inappropriate disease model may result in substantial risks to development, whereas selection of the appropriate model and a hypothesis-driven study plan can aid in a more complete understanding of the risks to the comorbid human population. The session ended with an informative panel discussion focusing on current challenges in safety evaluation in comorbid populations and methods of pharmacovigliance, and how preclinical studies can meet those challenges.

Two trainees were awarded Society of Toxicologic Pathology Travel Awards and were given the opportunity to present their data to the membership. The inclusion of student speakers in the program provides a unique experience for individuals in terms of exposure to the membership and experience in presenting scientific data. The first student presentation was given during the third scientific session (Emerging Technologies) by Dr. Artem Shkumatov (University of Illinois), which discussed the enhancement of perfusion recovery in a mouse model of hind limb ischemia through the use of mesenchymal stem cells. The second student speaker, Dr. Jessica Simmons (The Ohio State University), gave her presentation during the fifth scientific session (Epigenetics) which focused on wingless-type MMTV integration site family (Wnt) signaling in bone metastasis in prostate cancer.

Additional Symposium Educational Opportunities

The continuing education (CE) offerings of the 33rd Annual STP Symposium started off with a long-time meeting favorite of the STP meeting audience, the NTP Satellite Symposium: Pathology Potpourri, organized and chaired by Dr. Susan Elmore (U.S. NTP/National Institute for Environmental Health Sciences [NIEHS]). This symposium is designed to provide an interactive forum to discuss challenging cases among the membership and to provide CE on interpretation of pathology specimens. During each presentation, images of lesions are projected by the speaker, with a list of differential diagnoses provided on a separate screen. The audience is provided wireless keypads on which to vote for their choice, after which the voting results are provided on the screen. Following voting, discussion of the lesions proceeds and lively and productive conversation over each case generally ensues.

The formal CE courses spanned a variety of topics which included Biomarkers of Endocrine Effects and Reproductive Toxicity chaired by Drs. Adam Aulbach (MPI Research) and David Honor (AbbVie, Inc.; CE1), Scientific and Regulatory Considerations in the Safety Evaluation of Stem Cell–Derived Therapies in Preclinical Studies chaired by Drs. Basal Assaf (Oregon National Primate Research Center) and Timothy Bertram (Tengion, Inc.; CE2), Fundamentals of Translational Neuroscience in Toxicologic Pathology: Optimizing the Value of Animal Data for Human Risk Assessment chaired by Drs. Alok Sharma (Covance Laboratories, Inc.) and James Morrison (Charles River Pathology Associates; CE3), and The Art of Study Monitoring and Pathology Peer Review: How to Maintain a Relationship of Mutual Respect with Contract Research Organizations (CROs) chaired by Drs. Daniel Kemp (GlaxoSmithKline) and John Wilson (GlaxoSmithKline; CE4).

The CE sessions 1, 2, and 4 have been recorded and a Web link to these recordings is available for free at the STP Web site to serve future continued educational needs of the STP membership (www.toxpath.org/).

The Career Development Workshop of the 33rd STP Symposium titled Effective Communication of Pathology Results in Regulatory Studies was cochaired by Drs. Sabine Francke (US FDA/CFSAN), Emily Meseck (Covance Laboratories, Inc.), Steven Mog (U.S. FDA/CFSAN), Annette Romeike (Covance Laboratories, Inc.), and Charles Wood (U.S. EPA). The course presented a regulatory and international CRO perspective on useful tools and strategies to communicate pathology information for regulatory purposes more effectively.

Dr. Charles Wood (U.S. EPA) presented an overview on Communicating More Effectively in Pathology Reports followed by Common Pathology Report Issues from a Nonpathologist Regulatory Reviewer’s Perspective. In this talk, Drs. Christopher Toscano (U.S. FDA/CDER/OND/DNP) and Lois Freed (FDA/CDER) provided the audience with real-life examples from their daily review work at U.S. FDA/CDER to illustrate points of “mis”communication. Dr. Erio Barale (Janssen Pharmaceuticals Research and Development) presented on behalf of Dr. Romeike on Communicating With Regulators: Organization for Economic Cooperation and Development (OECD) Peer Review Guidelines as a case example providing a global perspective on how communication with regulatory agencies could have gone wrong. A thorough collection of “mostly available for free” Current Web-Based Pathology Resources for Regulatory Study Reports was presented by Dr. Stephen Mog (U.S. FDA/CFSAN) followed by Dr. Emily Meseck’s (Covance Laboratories, Inc.) presentation on The Role of Historical Control Data in the Interpretation of Nonneoplastic Pathology Findings in Preclinical Toxicology Studies, which spurred an interesting discussion with the audience on issues pertaining to nonrodent databases. Updates and Issues Related to International Harmonization of Nomenclature and Diagnostic Criteria (INHAND for Lesions in Rats and Mice) and Standard for Exchange of Nonclinical Data (SEND) Terminology Harmonization Efforts were presented by Dr. Charlotte Keenan (CM Keenan ToxPath Consulting) who informed the audience of the interrelationship of the two initiatives and the need of toxicologic pathologists and their institutions to become aware of them, as SEND submissions to U.S. FDA/CDER will be mandatory in 2016. The Career Development session concluded with a lively discussion of all cochairs and speakers responding to questions by the audience; the entire session can be viewed on the STP Web site (www.toxpath.org) as this session was recorded for free future viewing by the larger STP membership.

The Career Development and Outreach Committee lunchtime series, chaired by Dr. Bevin Zimmerman (Janssen Pharmaceuticals Research and Development), presented the Draft OECD Guidance on the Requirements for Peer Review of Histopathology: A Panel Discussion during which the panelists Drs. Erio Barale (Janssen Research and Development), Greg Furrow (WIL Research), David Jacobson-Kram (ToxRox Consultancy), Peter Mann (EPL, Inc.), and James Reindel (Amgen, Inc.) discussed the draft OECD guidance document and its potential impact on the peer review process with the audience.

The International Academy of Toxicologic Pathology (IATP) and the STP cosponsored the lunchtime seminar Excel Tips and Tricks: Easy Ways to Quickly Visualize Your Pathology Data presented by Dr. Nancy Everds (Amgen, Inc.). The session spanned a variety of techniques, from getting data into Excel from Word/PDF documents to graphing methods and customizing data tables and charts for export to PowerPoint or Word, and provided the audience with exciting new tools for data interpretation and presentation.

The Town Hall meeting focused on the topic of Adversity and the NOAEL in Nonclinical Regulatory Reports—Definition, Application, and Communication. Most members of the STP/Scientific Regulatory and Policy Committee (SRPC) Adversity Working Group, consisting of Drs. Roy Kerlin (Pfizer; Chair), John Burkhardt (AbbVie, Inc.), Brad Bolon (The Ohio State University), Sabine Francke (U.S. FDA/CFSAN), James Popp (Stratoxon LLC), and Vince Meador (Covance Laboratories, Inc.; absent), served on the Town Hall panel. Dr. Kerlin’s opening remarks set the stage surrounding the difficulties of defining the word “adversity” in an all-encompassing context. He then provided a PowerPoint overview of the 9 Draft Proposed STP Best Practice Recommendations for the use of adversity/NOAEL in nonclinical study reports to which audience participants responded. Over 40 questions and comments were addressed by the panel, including a request to include “study duration” as a metric for determining adversity. In addition, it was commented that the recommendations need to “be more specific” in terms of “what changes deemed adverse need to be clearly documented in the report.” Finally, it was commented by the membership that “it might be difficult to convince management on some of these points” included in the Best Practices Recommendations document. The panel, on behalf of the working group, thanked the audience for very helpful feedback that will be considered during revisions of the draft document that was available for membership comment prior to the Town Hall Meeting.