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Toxicologic Pathology

Nicolette Jackson, Michel Assad, Derick Vollmer, James Stanley, Madeleine Chagnon
Orthopedic medical devices are continuously evolving for the latest clinical indications in craniomaxillofacial, spine, trauma, joint arthroplasty, sports medicine, and soft tissue regeneration fields, with a variety of materials from new metallic alloys and ceramics to composite polymers, bioresorbables, or surface-treated implants. There is great need for qualified medical device pathologists to evaluate these next generation biomaterials, with improved biocompatibility and bioactivity for orthopedic applications, and a broad range of knowledge is required to stay abreast of this ever-changing field...
January 17, 2019: Toxicologic Pathology
Sunish Mohanan, Sean Maguire, Jan Klapwijk, Rick Adler, Richard Haworth, Peter Clements
GlaxoSmithKline has recently made significant organizational changes to its nonclinical safety, drug metabolism and pharmacokinetic, and laboratory animal science/veterinary functions, with the goal to increase our focus on scientific partnership with the discovery part of the organization. One specific change was bringing together pathologists and comparative medicine veterinarians and scientists into a single functional unit. We describe our early activities (assessing our capabilities and gaps, external benchmarking, listening to our discovery partners, redesigning some of our working practices) aimed at implementing these changes...
January 16, 2019: Toxicologic Pathology
Masayuki Tomohiro, Takeshi Okabe, Yasushi Kimura, Kiyoshi Kinoshita, Mitsunori Maeda, Yuko Mitobe, Keiko Motoyama, Riichiro Yonezawa, Shoji Sasaki, Michio Fujiwara, Kazuto Watanabe
In nonclinical safety studies for new drug development, healthy animals have been commonly used. However, in some cases, the use of animal models of human disease is considered to be more favorable in evaluating risks in patients. To elucidate the current status of the use of animal models for nonclinical safety assessment, an internal questionnaire from the Japan Pharmaceutical Manufacturers Association and surveys (questionnaire period: August 27 to September 30, 2015) of both common technical documents and review reports of approved drugs (approval period: May 1999 to May 2017) disclosed by the Pharmaceutical and Medical Devices Agency were conducted...
January 13, 2019: Toxicologic Pathology
Alys Bradley, Matt Jacobsen
Whole slide imaging (WSI) technology has advanced to a point where it has replaced the glass slide as the primary means of pathology evaluation within many areas of medical pathology. The deployment of WSI in the field of toxicologic pathology has been delayed by a lack of clarity around the degree of validation required for its use on Good Laboratory Practice (GLP) studies. The current opinion piece attempts to provide a high-level overview of WSI technology to include basic methodology, advantages and disadvantages over a conventional microscope, validation status of WSI scanners, and perceived concerns over regulatory acceptance for the use of WSI for (GLP) peer review in the field of toxicologic pathology...
January 13, 2019: Toxicologic Pathology
Stuart W Naylor, Melissa Czajkowski, Warren Harvey, Matt Smith, Alys E Bradley, Maurice Cary
Biotherapeutics are pharmaceutical products derived from or synthesized by biological systems. Such molecules carry the potential for immunogenicity which may lead to adverse immune responses. The cynomolgus macaque ( Macaca fascicularis) is the species of choice in nonclinical safety assessment of biotherapeutics. The main aim of this study was to confirm whether mononuclear cell infiltrates at specific locations represent a generic effect of biotherapeutics, and therefore the result of their immunogenicity...
January 13, 2019: Toxicologic Pathology
Sarah D Cramer, Juliana S Lee, Mark T Butt, Jaime Paulin, William C Stoffregen
Thorough morphologic evaluations of medical devices placed in or near the nervous system depend on many factors. Pathologists interpreting a neurologic device study must be familiar with the regulatory framework affecting device development, biocompatibility and safety determinants impacting nervous tissue responses, and appropriate study design, including the use of appropriate animal models, group design, device localization, euthanasia time points, tissue examination, sampling and processing, histochemistry and immunohistochemistry, and reporting...
January 1, 2019: Toxicologic Pathology
Marian A Esvelt, Zachary T Freeman, Alexander T Pearson, Jack R Harkema, Gregory T Clines, Katrina L Clines, Melissa C Dyson, Mark J Hoenerhoff
Zibotentan, an endothelin-A receptor antagonist, has been used in the treatment of various cardiovascular disorders and neoplasia. Castrated athymic nude mice receiving zibotentan for a preclinical xenograft efficacy study experienced weight loss, gastrointestinal bloat, and the presence of an audible respiratory click. Human side effects have been reported in the nasal cavity, so we hypothesized that the nasal cavity is a target for toxicity in mice receiving zibotentan. Lesions in the nasal cavity predominantly targeted olfactory epithelium in treated mice and were more pronounced in castrated animals...
December 30, 2018: Toxicologic Pathology
Björn Jacobsen, Christian Freichel, Anne Eichinger-Chapelon, Andreas Brink, Jean-Christophe Hoflack, Mudher Albassam, Barbara Lenz
The chemically induced accumulation of α2u-globulin protein in male rats causes specific renal lesions and subsequent nephropathy. Herein, we report additional parallel findings in the kidney of male rats consistent with obstructive and retrograde nephropathy. Kidney and urinary bladder samples were evaluated from Wistar rats treated with RG7129 for 2 week and 8 week and from an 8-week mechanistic study using females, intact and castrated males. Histopathological findings were present in intact males in all studies, including hyaline droplet accumulation and granular casts consistent with α2u-globulin nephropathy...
December 26, 2018: Toxicologic Pathology
Tae-Won Kim, Chris N Papagiannis, Laura S Zwick, Jeffery A Engelhardt, Christine M Hoffmaster, Noah M Post, John E Matson, Jill A Hsiao, Sebastien A Burel, Scott P Henry
The 6-month Tg.rasH2 mouse carcinogenicity model provides an acceptable alternative to the 2-year carcinogenicity study in CD-1 mice. However, key questions related to the use of this model for testing antisense oligonucleotides (ASOs) include the similarity in the biologic response between mouse strains and the feasibility of using data from the CD-1 mouse to set doses and dose schedules for a Tg.rasH2 carcinogenicity study. To evaluate the potential strain differences, four distinct 2'- O-(2-methoxyethyl) ASOs were administered to CByB6F1 (wild type), Tg...
December 25, 2018: Toxicologic Pathology
Laura E Leigh Perkins, Marian K Rippy
Atherosclerosis places a significant burden on humankind; it is the leading cause of mortality globally, and for those living with atherosclerosis, it can significantly impact quality of life. Fortunately, treatment advances have effectively reduced the morbidity and mortality related to atherosclerosis, with one such modality being percutaneous intervention (PCI) to open occluded arteries. Over the 40-year history of PCI, preclinical models have played a critical role in demonstrating proof of concept, characterizing the in vivo behavior (pharmacokinetics, degradation) and providing a reasonable assurance of biologic safety of interventional devices before entering into clinical trials...
December 25, 2018: Toxicologic Pathology
Atsushi Isobe, Kouichi Iwatani, Junko Souba, Hisako Terao, Hitomi Hagiwara, Fumiaki Kumagai, Yoshiaki Saito, Kasuke Nagano, Masako Tasaki
We have developed a new method for obtaining information on whole tissues by light microscopy (LM) and ultrastructural features by transmission electron microscopy (TEM). This method uses serial sections of a stented artery embedded in resin. Stents were implanted in porcine coronary arteries in this study. The heart was perfusion fixed in a 2% paraformaldehyde and 1.25% glutaraldehyde mixed solution. The stented artery was then removed, fixed in 1% osmium, embedded in Quetol 651 resin, and sectioned serially...
December 25, 2018: Toxicologic Pathology
Elodie Drevon-Gaillot
Ocular medical devices (MDs) represent a very wide and promising field of human ophthalmology. In preclinical studies evaluating the safety and/or performance of these ocular MDs, the choice of histologic technique and the focus of the histopathologic evaluation method should take into consideration the following aspects: the specific guidelines possibly associated with the MD or combination product, the ocular compartment in contact with the MD and its specificities, and last the nature of the biomaterial used in the MD...
December 25, 2018: Toxicologic Pathology
Jaime Paulin, Serge D Rousselle, Stacey Fossey
Medical devices comprise a wide variety of therapeutic tools aimed at modulating or restoring organ function. Devices may be implanted or activated temporally or permanently, and are used to deliver a wide range of therapies such as drugs, electrical stimulation, laser, thermal energy, offer mechanical support, and restore sensory functions. Technological advancements allow improvement and development of devices at a rapid pace. This special issue of Toxicologic Pathology addresses a need for more publications focused on pathology evaluation of medical devices in preclinical studies and highlights fundamental approaches through practical examples bringing into perspective the essential role of pathologists in this field...
December 25, 2018: Toxicologic Pathology
Catherine Thirion-Delalande, Frédéric Gervais, Bernard Palate, Roy Forster, André Almeida Schenka
We describe here an angiomyomatous hamartoma in the right axillary lymph node of a three-year-old male cynomolgus monkey ( Macaca fascicularis), used as a control subject in a short-term toxicity study. This is a very rare lesion that has been reported almost exclusively in inguinal lymph nodes, and to date only in human beings. In the present case, light microscopy revealed partial replacement of the lymph node parenchyma by a disorganized, irregular vascular network, sparsely distributed smooth muscle cells, and a fibro-adipocytic stroma...
December 25, 2018: Toxicologic Pathology
Shinji Takasu, Yuh Yokoo, Yuji Ishii, Aki Kijima, Kumiko Ogawa, Takashi Umemura
Long-term exposure to piperonyl butoxide (PBO) induces multiple nodular masses along with hepatocellular tumors in the liver of mice. The histopathological features of the nodules led to our diagnosis of nodular regenerative hepatocellular hyperplasia (NRH). However, because of the lack of data on the biological characteristics of NRH, whether this lesion is truly nonneoplastic remains unknown. In this study, the molecular characteristics of NRH were compared with those of hepatocellular adenoma (HCA) by global gene expression analysis...
December 20, 2018: Toxicologic Pathology
Nancy E Everds, James Reindel, Jonathan Werner, W A Craven
We assessed the variability of spleen and mesenteric lymph node (MLN) microscopic observations and the correlations of these observations with other study data from 478 control cynomolgus monkeys from 53 routine nonclinical safety studies. Spleen weight parameters (absolute and relative to body or brain weights) were highly variable both within a control group on an individual study (up to 5.11-fold) and among animals with the same light microscopic observation. Grades for microscopic observations were also highly variable...
December 18, 2018: Toxicologic Pathology
John H Keating, Raffaele Melidone, Fernando Garcia-Polite
Surgical and laparoscopic implantation of mesh devices is on the rise for a variety of applications. The complexity and range of evolving mesh designs calls for consistent and detailed pathologic evaluation in determining host responses and assessing overall safety. This review addresses the components of evaluation of mesh implants in animal models, with emphasis on histologic parameters, semiquantitative scoring matrices, and morphometric analyses that have been specifically adapted to this class of implants...
November 20, 2018: Toxicologic Pathology
Chihiro Noguchi, Kenta Matsue, Yutaka Nakanishi, Fumiko Asanuma, Hiroto Miyata, Minoru Sasaki
We evaluated the growth plates (GPs) of rats after a 14-day reduction in food consumption caused by either daily oral dosing with 5-fluorouracil (5-FU: a positive control reducing food consumption and affecting the GPs) or a direct reduction in food consumption to determine whether the observed changes were attributable to a direct effect of drug toxicity. Histomorphometric analyses of the femoral GP were performed for a nontreated (NT) control group, three groups treated with 5-FU (12, 15, and 18 mg/kg/day) and three groups with food intake restricted to levels corresponding to those consumed by the rats in the three 5-FU-treated groups...
November 20, 2018: Toxicologic Pathology
Lyn M Wancket
Lymph nodes and associated lymphatics filter extracellular fluid and lymph to maintain tissue-fluid balance and detect distant tissue injury. Examination of regional draining lymph nodes (RDLs; lymph nodes that drain the route of article dosing) is an important step in detecting immunotoxicity and other associated changes during general toxicology studies. Similarly, evaluation of RDLs is often a key component of evaluating medical devices. Nonclinical medical device studies can present challenges for RDL evaluation, due to the wide variety of tissues and organs that are implanted with devices, the potential for wear debris/degradation products, and the likely disruption of normal lymphatic drainage by surgical procedures...
November 9, 2018: Toxicologic Pathology
Madhav G Paranjpe, Jessica L Belich, Peter C Mann, Marie E McKeon, Reem H Elbekai, Caren M Brown, Daniel J Patrick
This article presents the historical control data of spontaneous tumors in Tg.rasH2 published in 2013 (2004-2012) and compares and contrasts it to more recent data collected from 2013 to 2018, reporting differences in the average percentage incidences or incidence ranges as well as the incidence of new tumors. In 2013, we published a comprehensive review of spontaneous tumors in Tg.rasH2 mice used in 26-week carcinogenicity studies, which included data from control dose groups from 26 studies and a total of 710 mice per sex...
November 8, 2018: Toxicologic Pathology
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