Purpose Hyperthermia enhances cytotoxic effects of chemotherapeutic agents such as cisplatin. However, the underlying molecular mechanisms remain unclear. We hypothesised that hyperthermia increases cisplatin accumulation and efficacy by modulating function of copper transport protein 1 (Ctr1), a major regulator of cellular cisplatin uptake. We examined the significance of Ctr1 in the synergistic interaction between hyperthermia and cisplatin. We assessed the importance of cisplatin- and hyperthermia-induced Ctr1 multimerisation in sensitising cells to cisplatin cytotoxicity. Materials and methods Ctr1 protein levels and cisplatin sensitivities were assessed in bladder cancer cell lines with immunoblotting and clonogenic survival assays. Using Myc-tagged-Ctr1 HEK293 cells, we assessed the effect of hyperthermia on Ctr1 multimerisation with immunoblotting. The effect of hyperthermia on cisplatin sensitivity and accumulation was assessed in wild-type (WT) and Ctr1 knockout (Ctr1−/−) mouse embryonic fibroblasts (MEFs) with clonogenic assays and inductively coupled plasma-mass spectrometry (ICP-MS). Results Increased Ctr1 protein expression was observed for the most cisplatin-sensitive bladder cancer cell lines and MEFs. Heat-induced increase in Ctr1 multimerisation with cisplatin was observed in Myc-tagged Ctr1 cells. Hyperthermia enhanced cisplatin-mediated cytotoxicity in WT more than Ctr1−/− cells (dose modifying factors 1.75 versus 1.4, respectively). WT cells accumulated more platinum versus Ctr1−/− cells; this was further increased by hyperthermia in WT cells. Conclusions Hyperthermia enhanced cisplatin uptake and cytotoxicity in WT cells. Heat increased Ctr1 activity by increasing multimerisation, enhancing drug cytotoxicity. Furthermore, Ctr1 protein profiles of bladder tumours, as well as other tumour types, may predict their response to cisplatin and overall efficacy of treatment.

Despite high initial response rates, a subset of dogs with B‐cell lymphoma responds less robustly to CHOP‐based chemotherapy and experiences shorter survival. One hundred and four dogs with nodal B‐cell lymphoma were treated with a response‐based CHOP (RBCHOP) protocol modified based on response to individual drugs during the first chemotherapy cycle. Dogs achieving complete (CR) or partial response (PR) at week 3, following treatment with vincristine and cyclophosphamide, received RBCHOP 1 (n = 72), a protocol sequentially rotating vincristine, cyclophosphamide, and doxorubicin. Dogs without a detectable response at week 3 that subsequently achieved CR or PR following treatment with doxorubicin received RBCHOP 2 (n = 14), in which four doses of doxorubicin were given consecutively followed by vincristine and cyclophosphamide. Dogs that failed to respond at week 3 and then to doxorubicin at week 5 assessment were offered rescue chemotherapy (RBCHOP 3, n = 18). Median progression free survival (PFS) and overall survival time (OST) were similar between RBCHOP 1 (PFS 210 days, OST 354 days) and RBCHOP 2 (PFS 220 days, OST 456 days), but significantly shorter for RBCHOP 3 (PFS 34 days, OST 80.5 days, P < 0.001). No presenting signalment nor hematologic variable differentiated patient cohort, however, dogs in RBCHOP 2 and RBCHOP 3 were more likely to have a lymphocytosis at diagnosis (P = 0.02 and 0.04, respectively). Protocol modification based on response during the first cycle resulted in similar toxicity profiles and outcomes to previously published variants of CHOP, and prognosis remained poor for dogs failing to respond during the first treatment cycle.

Objectives Constipation is a common complaint in cats presenting to the emergency room and can become a frustrating recurrent condition. Despite widespread anecdotal reports of risk factors for constipation, at the time of writing there have been no studies supporting these associations or assessing treatment outcomes. The aim of this study was to identify risk factors in the signalment, history, physical examination and clinicopathologic findings of cats presenting to the emergency room for constipation. In addition, we aimed to assess factors contributing to the success or failure of enemas administered to these cats. Methods A medical record search identified 189 cats with a diagnosis of constipation/obstipation that were treated and discharged by the emergency service at an academic veterinary hospital. Data regarding signalment, medical history, physical examination and clinicopathologic findings, as well as treatments performed, were recorded. Ninety-nine cats presenting to the emergency room for other reasons were identified as controls. Statistical analysis was performed to assess risk factors for constipation, as well as success/failure of enema treatments. Results Older, overweight cats and cats with chronic kidney disease or previous episodes of constipation were found to be at increased risk of constipation ( P <0.0001, P = 0.0004, P = 0.0046 and P <0.0001, respectively). Ionized calcium levels were significantly higher in constipated cats, though varied significantly within the cohort ( P = 0.0133). Cats noted to be painful on abdominal palpation were less likely to defecate following an enema. Adjunctive treatments (fluids, laxatives) increased the likelihood of a successful enema but were not statistically significant. Conclusions and relevance Older, overweight cats with a history of constipation or chronic kidney disease are more likely to present for constipation. Further studies are needed to determine the most appropriate treatment protocol in an urgent care setting.

Methods of calculating and reporting dose intensity (DI) of CHOP‐based protocols in the veterinary literature vary. The goal of this retrospective study is to examine the prognostic significance of the average percentage of planned DI received in a cohort of canine T‐cell lymphoma patients treated with a modified CHOP protocol with corresponding toxicity and efficacy data. Our data set of 40 dogs was analysed using various previously published methods for calculating DI. Median progression‐free survival and overall survival were 91 and 196 days, respectively. Receiving a higher percentage of planned DI was not found to be associated with patient outcome. Outcomes remain poor for dogs with T‐cell lymphoma treated with CHOP‐based chemotherapy irrespective of received DI. Standard methods of DI calculation and reporting should be adopted in veterinary oncology to enable repeatable and rigorous comparisons of published chemotherapy protocols and to ascertain the potential prognostic relevance of DI in canine lymphoma patients.