Doxorubicin and zoledronate treatment in a dog with hemophagocytic histiocytic sarcoma.

A 6-year-old castrated male greyhound dog was referred for hemophagocytic histiocytic sarcoma (HHS) diagnosed following splenectomy. Severe thrombocytopenia, mild hypoalbuminemia, mild hypocholesterolemia, and mild hyperbilirubinemia were present. Abdominal ultrasound findings were concerning for hepatic metastasis. Doxorubicin and zoledronate combination therapy was initiated. The dog improved clinically and its thrombocytopenia, hypoalbuminemia, and hyperbilirubinemia resolved. The dog appeared well for 147 d before tumor progression was noted. The dog was treated with lomustine as a final measure, with no response. The dog survived for 6 mo with chemotherapy. To the authors' knowledge, this is the first report of clinical benefit of chemotherapy for HHS. Key clinical message: Doxorubicin should be considered for treating canine HHS since this variant of the disease is historically refractory to lomustine. Further research regarding efficacy of doxorubicin and zoledronate should be pursued.

Traitement à la doxorubicine et au zolédronate chez un chien atteint de sarcome histiocytaire hémophagocytaire. Un lévrier mâle castré de 6 ans a été vu pour un sarcome histiocytaire hémophagocytaire (HHS) diagnostiqué à la suite d'une splénectomie. Une thrombopénie sévère, une hypoalbuminémie légère, une hypocholestérolémie légère et une hyperbilirubinémie légère étaient présentes. Les résultats de l'échographie abdominale étaient préoccupants quant aux métastases hépatiques. Un traitement associant doxorubicine et zolédronate a été instauré. Le chien s'est amélioré cliniquement et sa thrombocytopénie, son hypoalbuminémie et son hyperbilirubinémie ont disparu. Le chien semblait en bonne santé pendant 147 jours avant de constater une progression tumorale. Le chien a été traité avec de la lomustine comme mesure finale, sans réponse. Le chien a survécu 6 mois grâce à la chimiothérapie. À la connaissance des auteurs, il s'agit du premier rapport faisant état d'un bénéfice clinique de la chimiothérapie pour le HHS.Message clinique clé :La doxorubicine doit être envisagée pour traiter le HHS canin puisque cette variante de la maladie est historiquement réfractaire à la lomustine. Des recherches plus approfondies concernant l'efficacité de la doxorubicine et du zolédronate devraient être poursuivies.(Traduit par Dr Serge Messier).

Evaluation of zoledronate for the treatment of canine stage III osteosarcoma: A phase II study.

BACKGROUND: Greater than 90% of dogs with appendicular osteosarcoma will develop pulmonary metastasis despite the standard of care. Available treatments have limited efficacy for stage III disease. Zoledronate, a bisphosphonate, induces apoptosis of canine osteosarcoma cells and appears to modulate the tumour microenvironment. OBJECTIVES: This prospective, single institutional phase IIa trial investigated the use of single agent zoledronate in dogs with pulmonary metastases from osteosarcoma. METHODS: Zoledronate was administered once monthly, and thoracic radiographs were used to assess response. RESULTS: Eleven dogs were enrolled. Stable disease was achieved in two of eight dogs available for response assessment. The median progression-free survival was 28 days (range: 4-93 days). The median stage III-specific survival time was 92 days. Adverse events were reported in four dogs; two dogs developed grade III or higher toxicities. Notable adverse events included conjunctivitis, fever, hypocalcaemia, and hypophosphatemia. CONCLUSIONS: Zoledronate appears to have limited efficacy as a single agent for stage III osteosarcoma and may be associated with unexpected toxicity in this population. This clinical trial was registered on the AVMA Animal Health Studies Database (AAHSD004396).

Transcriptomic Analysis of Canine Osteosarcoma from a Precision Medicine Perspective Reveals Limitations of Differential Gene Expression Studies.

Despite significant advances in cancer diagnosis and treatment, osteosarcoma (OSA), an aggressive primary bone tumor, has eluded attempts at improving patient survival for many decades. The difficulty in managing OSA lies in its extreme genetic complexity, drug resistance, and heterogeneity, making it improbable that a single-target treatment would be beneficial for the majority of affected individuals. Precision medicine seeks to fill this gap by addressing the intra- and inter-tumoral heterogeneity to improve patient outcome and survival. The characterization of differentially expressed genes (DEGs) unique to the tumor provides insight into the phenotype and can be useful for informing appropriate therapies as well as the development of novel treatments. Traditional DEG analysis combines patient data to derive statistically inferred genes that are dysregulated in the group; however, the results from this approach are not necessarily consistent across individual patients, thus contradicting the basis of precision medicine. Spontaneously occurring OSA in the dog shares remarkably similar clinical, histological, and molecular characteristics to the human disease and therefore serves as an excellent model. In this study, we use transcriptomic sequencing of RNA isolated from primary OSA tumor and patient-matched normal bone from seven dogs prior to chemotherapy to identify DEGs in the group. We then evaluate the universality of these changes in transcript levels across patients to identify DEGs at the individual level. These results can be useful for reframing our perspective of transcriptomic analysis from a precision medicine perspective by identifying variations in DEGs among individuals.

Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

Pharmacological blockade of the EP3 prostaglandin E2 receptor in the setting of type 2 diabetes enhances ß-cell proliferation and identity and relieves oxidative damage.

OBJECTIVE: Type 2 diabetes is characterized by hyperglycemia and inflammation. Prostaglandin E2, which signals through four G protein-coupled receptors (EP1-4), is a mediator of inflammation and is upregulated in diabetes. We have shown previously that EP3 receptor blockade promotes ß-cell proliferation and survival in isolated mouse and human islets ex vivo. Here, we analyzed whether systemic EP3 blockade could enhance ß-cell mass and identity in the setting of type 2 diabetes using mice with a spontaneous mutation in the leptin receptor (Leprdb). METHODS: Four- or six-week-old, db/+, and db/db male mice were treated with an EP3 antagonist daily for two weeks. Pancreata were analyzed for α-cell and ß-cell proliferation and ß-cell mass. Islets were isolated for transcriptomic analysis. Selected gene expression changes were validated by immunolabeling of the pancreatic tissue sections. RESULTS: EP3 blockade increased ß-cell mass in db/db mice through enhanced ß-cell proliferation. Importantly, there were no effects on α-cell proliferation. EP3 blockade reversed the changes in islet gene expression associated with the db/db phenotype and restored the islet architecture. Expression of the GLP-1 receptor was slightly increased by EP3 antagonist treatment in db/db mice. In addition, the transcription factor nuclear factor E2-related factor 2 (Nrf2) and downstream targets were increased in islets from db/db mice in response to treatment with an EP3 antagonist. The markers of oxidative stress were decreased. CONCLUSIONS: The current study suggests that EP3 blockade promotes ß-cell mass expansion in db/db mice. The beneficial effects of EP3 blockade may be mediated through Nrf2, which has recently emerged as a key mediator in the protection against cellular oxidative damage.

Retrospective study of survival time and prognostic factors for dogs with small intestinal adenocarcinoma treated by tumor excision with or without adjuvant chemotherapy.

OBJECTIVE To estimate survival time for dogs with small intestinal adenocarcinoma (SIACA) following tumor excision with or without adjuvant chemotherapy and to identify factors associated with survival time. DESIGN Retrospective case series with a nested cohort study. ANIMALS 29 client-owned dogs with surgically resected, histologically diagnosed SIACA. PROCEDURES Medical records were reviewed and data collected regarding dog signalment; clinical signs; physical examination findings; PCV; serum total solids concentration; diagnostic imaging results; tumor size, location, and histologic characteristics (serosal extension, lymphatic invasion, surgical margins, and lymph node metastasis); type of adjuvant chemotherapy; NSAID administration; and survival time. Variables were assessed for associations with survival time and hazard rate via Kaplan-Meier and Cox proportional hazards analyses. RESULTS Overall median survival time for dogs with SIACA following tumor excision was 544 days (95% confidence interval, 369 to 719 days). Based on Kaplan-Meier estimates, the 1- and 2-year survival rates were 60% and 36%, respectively. On multivariate analysis, only age category was an independent predictor of survival over the follow-up period. Dogs < 8 years of age had a significantly longer median survival time (1,193 days) than dogs ≥ 8 years (488 days). Lymph node metastasis, adjuvant chemotherapy, NSAID administration, and other assessed variables were not associated with survival time. CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that SIACA in dogs carries a fair prognosis following excision, even when lymph node metastasis is present. Prospective studies are warranted to better characterize the effects of adjuvant chemotherapy or NSAID administration on survival time.

Clinical Response and Adverse Event Profile of Bleomycin Chemotherapy for Canine Multicentric Lymphoma.

Although canine multicentric lymphoma is initially responsive to multidrug chemotherapy, resistance and relapse create a need for novel chemotherapeutics. Bleomycin is an antitumor antibiotic with a minimal adverse event profile; though commonly used for human non-Hodgkin's lymphoma, its use is poorly characterized in dogs. The purpose of this retrospective case series was to describe the clinical response and adverse event profile of systemic bleomycin for canine multicentric lymphoma (n = 10). A partial response was noted in one dog that died 24 days later due to unrelated disease. Adverse events were infrequent and limited to grade 1 gastrointestinal and grade 1 constitutional toxicity. Although clinical response was minimal, systemic bleomycin was well tolerated when administered at 0.5 U/kg. Additional studies are warranted to determine the influence of administration schedule and dose on the efficacy of bleomycin for veterinary neoplasia.

The nature and timing of social deficits in child and adolescent offspring of parents with schizophrenia: preliminary evidence for precursors of negative symptoms?

Children with social dysfunction and a first-degree relative with schizophrenia are at elevated risk for schizophrenia; however, the nature of this dysfunction is unclear. It was hypothesized that familial high-risk (HR) children and adolescents (n=17) would have social skill deficits relative to healthy controls (HC; n=35). HR participants had a bimodal distribution of social skill scores (47% excellent; 53% poor). HR participants had worse social skills, assertion and empathy scores, suggesting possible developmental precursors to the social amotivation domain of negative symptoms. Characterizing HR children's social deficits could assist identification of those at risk for schizophrenia.

A novel approach to the discovery of survival biomarkers in glioblastoma using a joint analysis of DNA methylation and gene expression.

Glioblastoma multiforme (GBM) is the most aggressive of all brain tumors, with a median survival of less than 1.5 years. Recently, epigenetic alterations were found to play key roles in both glioma genesis and clinical outcome, demonstrating the need to integrate genetic and epigenetic data in predictive models. To enhance current models through discovery of novel predictive biomarkers, we employed a genome-wide, agnostic strategy to specifically capture both methylation-directed changes in gene expression and alternative associations of DNA methylation with disease survival in glioma. Human GBM-associated DNA methylation, gene expression, IDH1 mutation status, and survival data were obtained from The Cancer Genome Atlas. DNA methylation loci and expression probes were paired by gene, and their subsequent association with survival was determined by applying an accelerated failure time model to previously published alternative and expression-based association equations. Significant associations were seen in 27 unique methylation/expression pairs with expression-based, alternative, and combinatorial associations observed (10, 13, and 4 pairs, respectively). The majority of the predictive DNA methylation loci were located within CpG islands, and all but three of the locus pairs were negatively correlated with survival. This finding suggests that for most loci, methylation/expression pairs are inversely related, consistent with methylation-associated gene regulatory action. Our results indicate that changes in DNA methylation are associated with altered survival outcome through both coordinated changes in gene expression and alternative mechanisms. Furthermore, our approach offers an alternative method of biomarker discovery using a priori gene pairing and precise targeting to identify novel sites for locus-specific therapeutic intervention.

Complications after 90Y microsphere radioembolization for unresectable hepatic tumors: An evaluation of 112 patients.

PURPOSE: The aim of this study was to estimate the incidence of complications after (90)Y microsphere radioembolization for unresectable hepatic tumors and evaluate risk factors for late complications. METHODS AND MATERIALS: A cohort of 112 consecutive patients from two institutions underwent (90)Y microsphere radioembolization for unresectable hepatic tumors. Complications were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Symptoms secondary to postradioembolization syndrome occurring within 30 days were recorded as early complications, and all other complications were considered late complications. RESULTS: Seventy-eight patients (70%) experienced postradioembolization syndrome, including fatigue, abdominal pain, nausea, vomiting, anorexia, or fever. Three patients (3%) experienced a Grade 3 early complication; no Grade 4 or 5 early toxicity occurred. Two patients (2%) experienced clinically significant liver dysfunction; 13 patients (12%), 27 patients (24%), and 9 patients (8%) had an elevation of bilirubin, aspartate aminotransferase, and alanine aminotransferase, respectively. Eleven patients (10%) experienced gastrointestinal ulceration, including two Grade 3 complications and one Grade 4 complication. Cholecystitis occurred in 7 patients (6%), including two Grade 3 complications. Grade 2 pancreatitis occurred in 1 patient (1%). No radiation pneumonitis was observed. The cumulative incidence of late Grade 3 or 4 complications at 12 months after radioembolization was 8%. No Grade 5 toxicity occurred. CONCLUSIONS: (90)Y microsphere radioembolization is a well-tolerated treatment for unresectable hepatic tumors with a low risk of Grade 3 or higher early or late toxicity.

DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma.

BACKGROUND: Although much is known about molecular and chromosomal characteristics that distinguish glioma histological subtypes, DNA methylation patterns of gliomas and their association with other tumor features such as mutation of isocitrate dehydrogenase (IDH) genes have only recently begun to be investigated. METHODS: DNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at the University of California San Francisco, as well as nontumor brain tissues (n = 7), was assessed with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Differential DNA methylation between tumor and nontumor was also assessed. The association between methylation class and IDH mutation (IDH1 and IDH2) was tested using univariate and multivariable analysis for tumors (n = 95) with available substrate for sequencing. Survival of glioma patients carrying mutant IDH (n = 57) was compared with patients carrying wild-type IDH (n = 38) using a multivariable Cox proportional hazards model and Kaplan-Meier analysis. All statistical tests were two-sided. RESULTS: We observed a statistically significant association between RPMM methylation class and glioma histological subtype (P < 2.2 × 10(-16)). Compared with nontumor brain tissues, across glioma tumor histological subtypes, the differential methylation ratios of CpG loci were statistically significantly different (permutation P < .0001). Methylation class was strongly associated with IDH mutation in gliomas (P = 3.0 × 10(-16)). Compared with glioma patients whose tumors harbored wild-type IDH, patients whose tumors harbored mutant IDH showed statistically significantly improved survival (hazard ratio of death = 0.27, 95% confidence interval = 0.10 to 0.72). CONCLUSION: The homogeneity of methylation classes for gliomas with IDH mutation, despite their histological diversity, suggests that IDH mutation is associated with a distinct DNA methylation phenotype and an altered metabolic profile in glioma.