Creation of an NCI comparative brain tumor consortium: informing the translation of new knowledge from canine to human brain tumor patients

On September 14–15, 2015, a meeting of clinicians and investigators in the fields of veterinary and human neuro-oncology, clinical trials, neuropathology, and drug development was convened at the National Institutes of Health campus in Bethesda, Maryland. This meeting served as the inaugural event launching a new consortium focused on improving the knowledge, development of, and access to naturally occurring canine brain cancer, specifically glioma, as a model for human disease. Within the meeting, a SWOT (strengths, weaknesses, opportunities, and threats) assessment was undertaken to critically evaluate the role that naturally occurring canine brain tumors could have in advancing this aspect of comparative oncology aimed at improving outcomes for dogs and human beings. A summary of this meeting and subsequent discussion are provided to inform the scientific and clinical community of the potential for this initiative. Canine and human comparisons represent an unprecedented opportunity to complement conventional brain tumor research paradigms, addressing a devastating disease for which innovative diagnostic and treatment strategies are clearly needed

Characterization and modulation of the pro‐inflammatory effects of immune cells in the canine intervertebral disk

Abstract Background Intervertebral disk (IVD) degeneration affects both humans and canines and is a major cause of low back pain (LBP). Mast cell (MC) and macrophage (MØ) infiltration has been identified in the pathogenesis of IVD degeneration (IVDD) in the human and rodent model but remains understudied in the canine. MC degranulation in the IVD leads to a pro‐inflammatory cascade and activates protease activated receptor 2 (PAR2) on IVD cells. The objectives of the present study are to: (1) highlight the pathophysiological changes observed in the degenerate canine IVD, (2) further characterize the inflammatory effect of MCs co‐cultured with canine nucleus pulposus (NP) cells, (3) evaluate the effect of construct stiffness on NP and MCs, and (4) identify potential therapeutics to mitigate pathologic changes in the IVD microenvironment. Methods Canine IVD tissue was isolated from healthy autopsy research dogs (beagle) and pet dogs undergoing laminectomy for IVD herniation. Morphology, protein content, and inflammatory markers were assessed. NP cells isolated from healthy autopsy (Mongrel hounds) tissue were co‐cultured with canine MCs within agarose constructs and treated with cromolyn sodium (CS) and PAR2 antagonist (PAR2A). Gene expression, sulfated glycosaminoglycan content, and stiffness of constructs were assessed. Results CD 31+ blood vessels, mast cell tryptase, and macrophage CD 163+ were increased in the degenerate surgical canine tissue compared to healthy autopsy. Pro‐inflammatory genes were upregulated when canine NP cells were co‐cultured with MCs and the stiffer microenvironment enhanced these effects. Treatment with CS and PAR2 inhibitors mediated key pro‐inflammatory markers in canine NP cells. Conclusion There is increased MC, MØs, and vascular ingrowth in the degenerate canine IVD tissue, similar to observations in the clinical population with IVDD and LBP. MCs co‐cultured with canine NP cells drive inflammation, and CS and PAR2A are potential therapeutics that may mitigate the pathophysiology of IVDD in vitro

Investigation into diagnostic agreement using automated computer-assisted histopathology pattern recognition image analysis

The extent to which histopathology pattern recognition image analysis (PRIA) agrees with microscopic assessment has not been established. Thus, a commercial PRIA platform was evaluated in two applications using whole-slide images. Substantial agreement, lacking significant constant or proportional errors, between PRIA and manual morphometric image segmentation was obtained for pulmonary metastatic cancer areas (Passing/Bablok regression). Bland-Altman analysis indicated heteroscedastic measurements and tendency toward increasing variance with increasing tumor burden, but no significant trend in mean bias. The average between-methods percent tumor content difference was -0.64. Analysis of between-methods measurement differences relative to the percent tumor magnitude revealed that method disagreement had an impact primarily in the smallest measurements (tumor burden <3%). Regression-based 95% limits of agreement indicated substantial agreement for method interchangeability. Repeated measures revealed concordance correlation of >0.988, indicating high reproducibility for both methods, yet PRIA reproducibility was superior (C.V.: PRIA = 7.4, manual = 17.1). Evaluation of PRIA on morphologically complex teratomas led to diagnostic agreement with pathologist assessments of pluripotency on subsets of teratomas. Accommodation of the diversity of teratoma histologic features frequently resulted in detrimental trade-offs, increasing PRIA error elsewhere in images. PRIA error was nonrandom and influenced by variations in histomorphology. File-size limitations encountered while training algorithms and consequences of spectral image processing dominance contributed to diagnostic inaccuracies experienced for some teratomas. PRIA appeared better suited for tissues with limited phenotypic diversity. Technical improvements may enhance diagnostic agreement, and consistent pathologist input will benefit further development and application of PRIA

A Revised Diagnostic Classification of Canine Glioma: Towards Validation of the Canine Glioma Patient as a Naturally Occurring Preclinical Model for Human Glioma.

The National Cancer Institute-led multidisciplinary Comparative Brain Tumor Consortium (CBTC) convened a glioma pathology board, comprising both veterinarian and physician neuropathologists, and conducted a comprehensive review of 193 cases of canine glioma. The immediate goal was to improve existing glioma classification methods through creation of a histologic atlas of features, thus yielding greater harmonization of phenotypic characterization. The long-term goal was to support future incorporation of clinical outcomes and genomic data into proposed simplified diagnostic schema, so as to further bridge the worlds of veterinary and physician neuropathology and strengthen validity of the dog as a naturally occurring, translationally relevant animal model of human glioma. All cases were morphologically reclassified according to a new schema devised by the entire board, yielding a majority opinion diagnosis of astrocytoma (43, 22.3%), 19 of which were low-grade and 24 high-grade, and oligodendroglioma (134, 69.4%), 35 of which were low-grade and 99 were high-grade. Sixteen cases (8.3%) could not be classified as oligodendroglioma or astrocytoma based on morphology alone and were designated as undefined gliomas. The simplified classification scheme proposed herein provides a tractable means for future addition of molecular data, and also serves to highlight histologic similarities and differences between human and canine glioma

Creation of an NCI comparative brain tumor consortium: informing the translation of new knowledge from canine to human brain tumor patients

On September 14–15, 2015, a meeting of clinicians and investigators in the fields of veterinary and human neuro-oncology, clinical trials, neuropathology, and drug development was convened at the National Institutes of Health campus in Bethesda, Maryland. This meeting served as the inaugural event launching a new consortium focused on improving the knowledge, development of, and access to naturally occurring canine brain cancer, specifically glioma, as a model for human disease. Within the meeting, a SWOT (strengths, weaknesses, opportunities, and threats) assessment was undertaken to critically evaluate the role that naturally occurring canine brain tumors could have in advancing this aspect of comparative oncology aimed at improving outcomes for dogs and human beings. A summary of this meeting and subsequent discussion are provided to inform the scientific and clinical community of the potential for this initiative. Canine and human comparisons represent an unprecedented opportunity to complement conventional brain tumor research paradigms, addressing a devastating disease for which innovative diagnostic and treatment strategies are clearly needed

Numerical treatment of a discontinuous top surface in 2D shallow water mixed flow modeling

This paper presents a numerical strategy based on shallow water equations (SWE) coupled with the 2D Preissmann slot model to handle a ceiling step discontinuity in finite volume schemes for mixed flow modeling. In practice, a typical situation would be a closed structure, such as a bridge or culvert, which induces a sudden vertical flow constriction and may even run partly or totally full in high flow conditions. In such case, both the inlet and outlet of the structure involve a discontinuity in the top elevation. This special singularity is topologically represented by inserting a fictitious cell between 2 adjacent computational cells characterized by sharply different ceiling elevation. The 2D SWE are solved by means of a well-balanced quasi-conservative Godunov-type numerical scheme based on the Slope Limiter Centered (SLIC) scheme. The flow variables at each boundary of the fictitious cell are reconstructed by adopting the cross-sectional shape of the adjoining cell. Accordingly, the dynamic effect of the structure deck on the flow is suitably modeled, and the C-property for a stationary solution is rigorously satisfied, even when the closed structure is partially full. The capability of the numerical scheme is verified by comparison with both novel analytical solutions of 1D Riemann problems with a ceiling step discontinuity and experimental data of steady and unsteady mixed flows available in literature. Finally, a real-scale application to a multiple arch bridge is presented. The results show that the method is robust and effective in predicting the 2D features induced by a crossing structure on the flow dynamics