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Journal: Veterinary and comparative oncology

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Cancer relapse following chemotherapy has been attributed in part to the presence of cancer stem cells (CSC), which drive tumor growth and metastasis and are highly resistant to the effects of cytotoxic chemotherapy. As a result, treatment with cytotoxic chemotherapy selects for drug-resistant CSC populations that eventually drive tumor recurrence. Little is known currently regarding the role of CSC in dogs with lymphoma, nor the impact of chemotherapy on CSC populations. Therefore, we prospectively quantitated CSC populations in dogs with B cell and T cell lymphoma, using tumor aspirates and flow cytometric analysis with a panel of CSC markers. In addition, in vitro studies were done to determine the impact of chemotherapy resistance on the stem cell phenotype and stem cell properties of lymphoma cells. We found that the percentages of tumor cells expressing CSC markers were significantly increased in dogs with B cell lymphoma, compared to B cells from normal lymph nodes. Similar findings were observed in dogs with T cell lymphoma. In vitro studies revealed that lymphoma cells selected for resistance to CHOP chemotherapy had significantly upregulated expression of CSC markers, formed spheroids in culture more readily, and expressed significantly greater aldehyde dehydrogenase activity compared to chemotherapy-sensitive tumor cells. Similar results were observed in tumor samples dogs with relapsed B cell lymphoma. These findings suggest that cytotoxic chemotherapy can lead to a relative enrichment of tumor cells with CSC properties, which may be associated with lymphoma recurrence. This article is protected by copyright. All rights reserved.

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In humans, advanced mast cell (MC) neoplasms are rare malignancies with a poor prognosis. Only a few preclinical models are available and current treatment options are limited. In dogs, MC neoplasms are the most frequent malignant skin tumors. Unlike low-grade MC neoplasms, high-grade MC disorders usually have a poor prognosis with short survival. In both species, neoplastic MCs display activating KIT mutations which are considered to contribute to disease evolution. Therefore, tyrosine kinase inhibitors against KIT have been developed. Unfortunately, clinical responses are unpredictable and often transient, which remains a clinical challenge in both species. Therefore, current efforts focus on the development of new improved treatment strategies. The field of comparative oncology may assist in these efforts and accelerate human and canine research regarding diagnosis, prognostication and novel therapies. In this article, we review the current status of comparative oncology approaches and perspectives in the field of mast cell neoplasms. This article is protected by copyright. All rights reserved.

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An increased serum alkaline phosphatase concentration is known to be associated with a negative prognosis in canine and human osteosarcoma. To expand upon previous studies regarding the biological relevance of increased serum alkaline phosphatase as a negative prognostic factor, xenogeneic heterotopic transplants were performed using six canine primary osteosarcoma cell lines generated from patients with differing serum alkaline phosphatase concentrations (three normal and three increased). Three of the six cell lines were capable of generating tumours and tumour formation was independent of the serum alkaline phosphatase status of the cell line. Microarray analysis identified 379 genes as being differentially expressed between the tumourigenic and non-tumourigenic cell lines. Frizzled-6 was upregulated to the greatest extent (7.78-fold) in tumourigenic cell lines compared with non-tumourigenic cell lines. Frizzled-6, a co-receptor for Wnt ligands has been associated with enhanced tumour-initiating cells and poor prognosis for other tumours. The increased expression of frizzled-6 was confirmed by quantitative reverse transcription polymerase chain reaction (QPCR) and Western blot analysis. Additionally, the tumourigenic cell lines also had an increase in the percentage of side population cells compared with non-tumourigenic cell lines (5.89% versus 1.58%, respectively). There were no differences in tumourigenicity, frizzled-6 or percentage of side population cells noted between osteosarcoma cell lines generated from patients of differing serum alkaline phosphatase concentration. However, to our knowledge this is the first study to identified frizzled-6 as a possible marker of osteosarcoma cell populations with enhanced tumourigenicity and side population cells. Future work will focus on defining the role of frizzled-6 in osteosarcoma tumourigenesis and tumour-initiating cells.

Concepts: DNA, Gene, Gene expression, Polymerase chain reaction, Molecular biology, Enzyme, Cell biology, Real-time polymerase chain reaction

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Canine mammary carcinomas (CMC) represent a range of histolopathological subtypes with diverse biological behaviors. Several individual factors, including stage, grade, subtypes, and presence of invasion, predict outcome. Less is known how these factors interact and impact prognosis. The purpose of this work was to develop and test comprehensive bio-scoring systems in CMCs. Clinical and histopathological data from 127 dogs with MCs treated through two prospective studies were obtained. All dogs underwent standardized presurgical staging, treatments, and regular follow-up visits. All tumors were evaluated, classified, and graded according to published guidelines. Time to primary metastasis was the main endpoint in this study. Two bio-scoring systems were developed: The Multivariate Scoring; MVS was based on traditional statistical analysis where only factors significant in the multivariate analysis (tumor size and grade) were kept for the final model. The Refined Flexible Scoring; RFS system was based on results from subgroup analysis, which guided the development of a flexible system. Progressive worsening prognosis was observed with increasing bio-scores in both systems. MVS: Median primary metastasis free survival (TTM1 days) was not reached in dogs with bio-scores 0-5, 10, 15, and 648, 149, 317, in MVS groups 25, 30, 40, respectively. Similarly, TTM1 was not reached in dogs with RFS 0, 1, 2, and 374, 407, and 149, in dogs with bio-scores 3, 4, 5, respectively. However, a more distinct separation between dogs with high risk versus low risk for metastasis was observed with RFS, suggesting superior overall prognostication regarding the risk for metastasis. This article is protected by copyright. All rights reserved.

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Small cell intestinal lymphoma has not been well characterized in dogs. The objective of this study was to describe clinical characteristics and outcome in dogs with small cell intestinal lymphoma. We hypothesized that affected dogs would have prolonged survival compared with high-grade gastrointestinal (GI) lymphoma. Pathology records were searched for dogs with histologically confirmed small cell GI lymphoma. Seventeen dogs with confirmed small cell intestinal lymphoma were identified, and clinical and outcome data were retrospectively collected. Histopathology was reviewed by a board-certified pathologist, and tissue sections were subjected to immunophenotyping and molecular clonality assessment. All dogs had small cell, T-cell, lymphoma confirmed within various regions of small intestine, with 1 dog also having disease in abdominal lymph nodes. All dogs had clinical signs attributable to GI disease; diarrhoea (n = 13) was most common. Ultrasonographic abnormalities were present in 8 of 13 dogs with abnormal wall layering (n = 7) and hyperechoic mucosal striations (n = 7) representing the most common findings. In total, 14 dogs received some form of treatment. The median survival time (MST) for all dogs was 279 days and the MST for the 14 dogs that received any treatment was 628 days. Dogs with anaemia and weight loss at presentation had significantly shorter survival times and dogs that received a combination of steroids and an alkylating agent had significantly longer survival times. Small cell, T-cell, intestinal lymphoma is a distinct disease process in dogs, and those undergoing treatment may experience prolonged survival.

Concepts: DNA, Cancer, Pathology, Lymph node, Large intestine, Intestine, Small intestine, Lymph

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Oncolytic virotherapy is a novel treatment involving replication-competent virus in the elimination of cancer. We have previously reported the oncolytic effects of reovirus in various canine cancer cell lines. This study aims to establish the safety profile of reovirus in dogs with spontaneously occurring tumours and to determine a recommended dosing regimen. Nineteen dogs with various tumours, mostly of advanced stages, were treated with reovirus, ranging from 1.0 × 10(8) to 5.0 × 10(9) TCID50 given as intratumour injection (IT) or intravenous infusion (IV) daily for up to 5 consecutive days in 1 or multiple treatment cycles. Adverse events (AEs) were graded according to the Veterinary Cooperative Oncology Group- Common Terminology Criteria for Adverse Events (VCOG-CTCAE) v1.1 guidelines. Viral shedding, neutralizing anti-reovirus antibody (NARA) production and immunohistochemical (IHC) detection of reovirus protein in the tumours were also assessed. AE was not observed in most dogs and events were limited to Grade I or II fever, vomiting, diarrhoea and inflammation of the injected tumour. No infectious virus was shed and all dogs had elevated NARA levels post-treatment. Although IHC results were only available in 6 dogs, 4 were detected positive for reovirus protein. In conclusion, reovirus is well-tolerated and can be given safely to tumour-bearing dogs according to the dosing regimen used in this study without significant concerns of viral shedding. Reovirus is also potentially effective in various types of canine tumours.

Concepts: Cancer, Oncology, Microbiology, Virus, Brain tumor, Tumor, Neoplasm, Viruses

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Combination chemotherapy holds promise for improving outcomes in malignancy when compared with single-agent approaches. Care must be taken to avoid overlapping toxicity and to utilize agents with differing mechanisms of action. A phase I dose-finding trial was performed to determine the maximally tolerated dose (MTD) of a concurrent toceranib and doxorubicin (DOX) combination protocol where toceranib dose was maintained at or near 2.75 mg kg(-1) by mouth every other day (PO EOD) while escalating DOX dosage. The dose-limiting toxicity was found to be neutropenia and the MTD of the combination was determined to be 25 mg m(-2) of DOX q 21 days given concurrently with toceranib 2.75 mg kg(-1) PO EOD. This combination was well tolerated with no excessive gastrointestinal toxicity nor novel adverse events (AEs) noted. Anti-tumour activity was observed in the majority of cases. This combination warrants further investigation in the context of phase II/III clinical trials to characterize efficacy and long-term AE profiles.

Concepts: DNA, Clinical trial, Cancer, Oncology, Chemotherapy, Adverse event, Doxorubicin, Anthracycline

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Understanding the relationship between drug dose and exposure (pharmacokinetics, PK) and the relationship between exposure and effect (pharmacodynamics) is an important component of pharmacology when attempting to predict clinical effects of anticancer drugs. PK studies can provide a better understanding of these relationships; however, they often involve intensive sampling over an extended period of time, resulting in increased cost and decreased compliance. Doxorubicin (DOX), one of the most widely used antineoplastic agents in veterinary cancer therapy, is characterized by large interpatient variability in overall drug exposure and the development and degree of myelosuppression following equivalent dosages. We have developed and validated a limited-sampling strategy for DOX, in which three blood samples are obtained over 1 h post-treatment, that accurately predicts patient exposure. This strategy could allow for refining of dosing variables and utilization of therapeutic drug monitoring to ensure optimized dosing.

Concepts: Pharmacology, Breast cancer, Oncology, Chemotherapy, Pharmacokinetics, Pharmacy, Doxorubicin, Anthracycline

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Thirty dogs with macroscopic plasma cell tumours (PCTs) were treated with radiation therapy (RT). Twelve patients were treated with palliative-intent prescriptions (range, 4-10 Gy/fraction (median, 7 Gy/fraction) for a total dose of 20 to 35 Gy (median total dose 30 Gy). Eighteen patients received definitive-intent prescriptions (range, 3.0-4.2 Gy/fraction (median, 3 Gy/fraction) for a total dose of 42 to 54 Gy (median total dose 48 Gy). Involved sites included the oral cavity, skin, multiple myeloma (MM)-associated lytic bone lesions, bone (solitary osseous plasmacytoma; SOP), nasal cavity, larynx, retrobulbar space, lymph node and rectum. Ninety-five percent of evaluable dogs had a complete (CR; 16/22) or partial response (PR; 5/22). Patients with MM experienced significant analgesia. The median progression-free survival (PFS) was 611 days (range: 36-2001 days). Events in the non-MM cases included in-field progression (5/26, 19%) and disseminated disease (5/26, 19%). The median survival time (MST) for all dogs was 697 days (range: 71-2075 days), and when only non-MM cases were considered, MST was 771 days (range: 71-2075 days). Fourteen patients were alive without disease progression or had died of unrelated causes. Achievement of a PR was associated with an inferior PFS and MST as compared with CR. Palliative-intent RT was associated with inferior MST as compared with definitive-intent RT. RT is a useful therapeutic modality for PCTs and tumour responses are often complete and durable, with protracted survivals. The optimal radiation dose and schedule are yet to be defined.

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Low tetrahydrocannabinol Cannabis sativa products, also known as hemp products, have become widely available and their use in veterinary patients has become increasingly popular. Despite prevalence of use, the veterinary literature is lacking and evidence-based resource for cannabinoid efficacy. The most prevailing cannabinoid found in hemp is cannabidiolic acid (CBDA) and becomes cannabidiol (CBD) during heat extraction; CBD has been studied for its direct anti-neoplastic properties alone and in combination with standard cancer therapies, yielding encouraging results. The objectives of our study were to explore the anti-proliferative and cell death response associated with in vitro treatment of canine cancer cell lines with CBD alone and combination with common chemotherapeutics, as well as investigation into major proliferative pathways (e.g. p38, JNK, AKT, mTOR) potentially involved in the response to treatment with CBD. CBD significantly reduced canine cancer cell proliferation far better than cannabidiolic acid (CBDA) across five canine neoplastic cell lines when treated with concentrations ranging from 2.5-10 μg/mL. Combinatory treatment with CBD and vincristine reduced cell proliferation in a synergistic or additive manner at anti-proliferative concentrations with less clear results using doxorubicin in combination with CBD. The cellular signaling effects of CBD treatment, showed that autophagy supervened induction of apoptosis and may be related to prompt induction of ERK and JNK phosphorylation prior to autophagy. In conclusion, CBD is effective at hindering cell proliferation and induction of autophagy and apoptosis rapidly across neoplastic cell lines and further clinical trials are needed to understand its efficacy and interactions with traditional chemotherapy. This article is protected by copyright. All rights reserved.