Evaluating the feasibility of using whole blood gene expression profiles to identify novel targets in canine septic peritonitis.

Objective: To assess gene expression profiles in canine whole blood with and without septic peritonitis to assess workflow feasibility and identify potential blood biomarkers that could be further investigated in future studies.

Methods: This study enrolled 6 dogs with cytologically confirmed septic peritonitis of any cause and 6 healthy dogs. All dogs had a CBC and biochemistry performed.

Ultrasonographic liver nodules are more often benign lesions in dogs with hemoperitoneum secondary to splenic tumor rupture.

Objective: To evaluate the reliability of preoperative abdominal ultrasonography as a staging tool for dogs with hemoperitoneum due to presumed splenic tumor rupture, focusing on the detection of metastatic lesions in the liver.

Animals: 99 dogs from 20 emergency and specialty hospitals across the US.

Methods: Dogs with nontraumatic hemoperitoneum secondary to splenic tumor rupture were included.

Osteosarcoma Explorer: A Data Commons With Clinical, Genomic, Protein, and Tissue Imaging Data for Osteosarcoma Research.

Purpose: Osteosarcoma research advancement requires enhanced data integration across different modalities and sources. Current osteosarcoma research, encompassing clinical, genomic, protein, and tissue imaging data, is hindered by the siloed landscape of data generation and storage.

Materials And Methods: Clinical, molecular profiling, and tissue imaging data for 573 patients with pediatric osteosarcoma were collected from four public and institutional sources.

An early clinical phenotype of necrotizing meningoencephalitis in the Pug reveals similarities to multiple sclerosis in humans.

Necrotizing meningoencephalitis (NME) is a fatal neuroinflammatory disease that previously carried a uniformly grave prognosis. Our recent identification of a novel early form of NME in Pugs suggests that disease onset and progression are likely more insidious than previously recognized and provides new hope that early therapeutic intervention may halt disease progression and ultimately prevent or cure NME. This novel perspective also sheds new light on the clinical similarities to multiple sclerosis (MS) in humans and provides a rationale for cross-species translation.

Retrospective evaluation of the impact of hypoxemia during thoracic surgery in dogs on outcome: a multicenter analysis of 94 cases.

Objective: To investigate the statistical association of severe intraoperative hypoxemia in thoracic surgery with mortality, postoperative hospitalization times and cost of care.

Study Design: Retrospective study.

Animals: Dogs that underwent thoracic surgery in three veterinary hospitals between October 1, 2018 and October 1, 2020.

PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6.

encodes a tumor suppressor with lipid and protein phosphatase activities whose dysfunction has been implicated in melanomagenesis; less is known about how its phosphatases regulate melanoma metastasis. We demonstrate that PTEN expression negatively correlates with metastatic progression in human melanoma samples and a PTEN-deficient mouse melanoma model. Wildtype PTEN expression inhibited melanoma cell invasiveness and metastasis in a dose-dependent manner, behaviors that specifically required PTEN protein phosphatase activity.

Pharmacokinetic Exposures Associated With Oral Administration of Sorafenib in Dogs With Spontaneous Tumors.

Sorafenib is a multi-kinase small molecule inhibitor that targets serine/threonine and tyrosine kinases including the RAF kinase family, VEGFR-2, and PDGFR. The aim of this study was to evaluate the systemic pharmacokinetics of a previously defined tolerable oral dose of sorafenib in tumor-bearing dogs. Six client-owned dogs with a cytologic or histologic diagnosis of cancer were enrolled in this open-label, tolerability study.

A potential early clinical phenotype of necrotizing meningoencephalitis in genetically at-risk pug dogs.

Background: Necrotizing meningoencephalitis (NME) in the pug dogs is a fatal neuroinflammatory disease associated with rapid progression and poor response to conventional immunosuppressive therapy. Diagnosis is typically made after severe neurological abnormalities have manifested.

Hypothesis/objective: Pug dogs at genetic risk for NME might manifest neurological abnormalities before developing pathognomonic clinical signs of NME.

Prevalence and clinical features of thoracolumbar intervertebral disc-associated epidural hemorrhage in dogs.

Background: Intervertebral disc-associated epidural hemorrhage (EH) in dogs is a poorly understood neurological condition.

Objective: To compare the clinical presentation, magnetic resonance imaging (MRI) changes, and clinical outcome of dogs with acute thoracolumbar intervertebral disc herniation (TL-IVDH) with and without EH.

Animals: One hundred sixty client-owned dogs that underwent MRI and hemilaminectomy for acute TL-IVDH at a private practice in Colorado, including 63 dogs with EH and 97 dogs without EH.

Feasibility of circulating tumor DNA analysis in dogs with naturally occurring malignant and benign splenic lesions.

Comparative studies of naturally occurring canine cancers have provided new insight into many areas of cancer research. Development and validation of circulating tumor DNA (ctDNA) analysis in pet dogs can help address diagnostic needs in veterinary as well as human oncology. Dogs have high incidence of naturally occurring spontaneous cancers, demonstrate molecular heterogeneity and clonal evolution during therapy, allow serial sampling of blood from the same individuals during the course of disease progression, and have relatively compressed intervals for disease progression amenable to longitudinal studies.

Leukocyte and cytokine variables in asymptomatic Pugs at genetic risk of necrotizing meningoencephalitis.

Background: Necrotizing meningoencephalitis (NME, aka Pug dog encephalitis) is an inflammatory brain condition associated with advanced disease at initial presentation, rapid progression, and poor response to conventional immunomodulatory therapy.

Hypothesis/objectives: That genetic risk for NME, defined by a common germline DNA haplotype located on chromosome 12, is associated with altered blood cytokine concentrations and leukocyte subsets in asymptomatic Pugs.

Animals: Forty Pug dogs asymptomatic for NME from a hospital sample.

Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis.

Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed and optimized a phenotypic screen for drugs that may target OS disseminated tumor cells (DTCs) and inhibit their metastatic outbreak rather than merely screening for cytotoxic activity against proliferating cells, as is commonly conducted in conventional drug discovery approaches.

Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard-of-Care Therapy for Appendicular Osteosarcoma: A Prospective, Randomized Trial of 324 Dogs.

Purpose: The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression.

Identification of potential modulators of osteosarcoma metastasis by high-throughput cellular screening of natural products.

A high-throughput screening assay was developed and applied to a large library of natural product extract samples, in order to identify compounds which preferentially inhibited the in vitro 2D growth of a highly metastatic osteosarcoma cell line (MG63.3) compared to a cognate parental cell line (MG63) with low metastatic potential. Evaluation of differentially active natural product extracts with bioassay-guided fractionation led to the identification of lovastatin (IC  = 11 µm) and the limonoid toosendanin (IC  = 26 nm).

Prospective observational study of dogs with splenic mass rupture suggests potentially lower risk of malignancy and more favourable perioperative outcomes.

Haemoperitoneum secondary to ruptured splenic tumours can be either benign or malignant in origin. The majority of previous studies of canine haemoperitoneum have been retrospective, which are associated with well-recognized biases, such as the potential to underappreciate the diversity of outcomes in a complex presentation such as haemoperitoneum. This study seeks to prospectively define perioperative morbidity and mortality of haemoperitoneum in dogs secondary to ruptured splenic masses.

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group.

Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care.

Towards the Delivery of Precision Veterinary Cancer Medicine.

We introduce a next phase in the evolution of medicine affecting human and veterinary patients. This evolution, genomic cancer medicine (Pmed), involves expansion of genomic and molecular biology into clinical medicine. The implementation of these new technologies has already begun and is a commercial reality.

Polymerase chain reaction for antigen receptor rearrangement: Benchmarking performance of a lymphoid clonality assay in diverse canine sample types.

Background: Polymerase chain reaction for antigen receptor rearrangement (PARR) is a molecular diagnostic tool used for discrimination of lymphoid malignancies in dogs from benign processes. Assay variations have been described and are commercially available, but performance metrics are not uniformly reported.

Objectives: To describe performance (accuracy, sensitivity, specificity) and rigorous benchmarking of a PARR protocol (ePARR) in clinically relevant samples.

Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis.

Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases.

NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma.

Purpose: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use.

Tolerability of oral sorafenib in pet dogs with a diagnosis of cancer.

Sorafenib is a multi-target small molecule inhibitor of the RAF kinase family and VEGFR-2/PDGFR. The US Food and Drug Administration approved sorafenib in human patients with liver, thyroid, or renal carcinoma. The aim of this study was to help guide future pharmacokinetic (PK) studies of sorafenib in dogs with a cancer diagnosis.

Corrigendum: Positively selected enhancer elements endow osteosarcoma cells with metastatic competence.

This corrects the article DOI: 10.1038/nm.4475.

Positively selected enhancer elements endow osteosarcoma cells with metastatic competence.

Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic human tumors and between near isogenic pairs of highly lung metastatic and nonmetastatic osteosarcoma cell lines.