Veterinary and comparative oncology最新文献

Mammary tumours account for approximately 50% of the neoplasms in female dogs. Even conventionally accepted prognostic indicators often fail to reliably predict the clinical behaviour of these tumours, underscoring the need for more effective prognostic markers. Proteins of the LOX family are associated with tumour invasion and metastasis in several types of tumours. The purpose of this study was to characterise the immunohistochemical expression of LOX and LOXL2 in canine mammary carcinomas and to investigate their prognostic significance. Samples of mammary carcinomas from 80 female dogs with a minimum post-surgical follow-up of 180 days were analysed. Tumour samples were submitted to immunohistochemistry to detect LOX and LOXL2. Immunolabelling was evaluated based on scores for staining intensity and percentage of positive cells, and a combined score was used to classify each protein as having either 'low-' or 'high-expression'. The results were compared with histological types, mortality due to the disease and post-surgical survival. We found that negativity for LOXL2 expression was an indicator of higher risk of death due to the disease. Our results suggest that lysyl oxidases such as LOXL2 are potential prognostic markers in mammary carcinomas of dogs.

Dogs with intracranial tumours routinely receive radiotherapy, yet species-specific dose-volume constraints for normal brain tissue remain undefined. In human radiation oncology, exceeding certain brain dose-volume thresholds markedly increases the risk of radiation-induced injury (e.g., radionecrosis). Current veterinary practice often extrapolates human guidelines without validation in discrete species, creating a gap in evidence-based planning. This study aimed to identify brain dose-volume thresholds associated with overall survival (OS) in canine brain-tumour patients. We pooled data from two prospective randomised trials (n = 105 dogs) treated with 10 daily fractions of 4 Gy (total 40 Gy) for intracranial tumours at a single institution. Semi-automated scripting extracted multiple dose-volume metrics, including generalised equivalent uniform dose (gEUD), for the whole brain and brain minus gross tumour volume (Brain-GTV). An iterative Kaplan-Meier and Cox proportional hazards approach identified optimal dosimetric cutoffs, which were then adjusted for tumour volume and body weight via a regression residual method. A brain-volume-adjusted gEUD threshold was also derived to account for variation in brain size. Exposure to normal brain to doses around 30-40 Gy emerged as the strongest predictor of OS. Brain-GTV V32 Gy ≤ 13 cm³ was associated with longer OS (covariate-adjusted cutoff 13.4 cm³, HR = 1.74; p = 0.022, unadjusted optimal split 11.5 cm³, HR = 2.08; p = 0.001). Whole-brain gEUD > 30 Gy similarly predicted poorer survival (HR = 1.72; p = 0.034). Implementing a personalised gEUD ceiling increased 2-year sensitivity from 31% to 38% with only a three-point drop in specificity. In a 10 × 4 Gy canine intracranial radiotherapy model, limiting Brain-GTV V32 Gy to ≤ 13 cm³ and whole-brain gEUD to ≤ 30 Gy was associated with longer overall survival. A brain-volume-adjusted gEUD ceiling further refined risk prediction. These evidence-based thresholds provide actionable guidance for veterinary treatment planning, with the potential to improve outcomes in canine brain tumour therapy.

Vascular endothelial growth factor receptor 2 (VEGFR2) is a key target for anti-angiogenic oncotherapy, as inhibiting this receptor on tumour vasculature slows tumour development and enhances drug- and immune infiltration, improving therapy outcome. Although VEGFR2 is primarily expressed on endothelial cells (ECs), it is also found on neoplastic cells in both humans and dogs, including canine malignant melanoma (CMM). In this study, we compared current methods for assessing VEGFR2 expression in CMM and healthy tissues to elucidate the targets of anti-VEGFR2 therapy in canines. VEGFR2 protein expression was analysed using various anti-VEGFR2 antibodies for immunohistochemistry, and mRNA expression was analysed using RT-PCR. Surprisingly, a marked difference in the detection of VEGFR2 was observed between the anti-VEGFR2 antibody clones used, despite recognition of the same sequences. Supported by additional Western blot and confocal fluorescence microscopy analysis, we observed two distinct staining patterns: a specific pattern predominantly labelling ECs and a more nonspecific pattern predominantly labelling non-ECs, including neoplastic melanocytes. Notably, the more specific pattern demonstrated significantly more VEGFR2 expression in ECs within CMM. These findings indicate that the interpretation of VEGFR2 expression on neoplastic cells is highly dependent on antibody specificity, leading to potential overestimation in some studies. We therefore suggest that anti-VEGFR2 therapy primarily targets the tumour vasculature rather than the tumour cells. This highlights the need to reconsider the aims of anti-VEGFR2 therapies in companion animals.

Mast cell tumours (MCTs) are common in dogs. Treatment options include surgery, radiation therapy, and cytotoxic chemotherapy; however, in cases of inoperable or metastatic tumours, tyrosine kinase inhibitors (TKIs) can be used. Imatinib mesylate has been used in the treatment of solid tumours in both human and veterinary medicine. Previous studies have shown some efficacy in dogs with MCTs; however, additional data are needed to better define the optimal dosage, toxicity profile, and clinical outcomes associated with its use. Dogs with a cytological or histopathological diagnosis of mucosal, cutaneous or subcutaneous MCTs were included. Medical records from 2017 to 2024 were reviewed for clinical presentation, results of staging procedures, diagnostic tests, and treatment. Inclusion required the presence of macroscopic disease and administration of imatinib, either as a sole treatment or in combination with surgery. Thirty-five cases were included, all receiving medical treatment with or without surgical excision. Imatinib was administered as first-line treatment in 8 dogs (22.8%) and as a rescue treatment in 27 dogs (77.1%), achieving an overall clinical benefit, including complete response, partial response, and stable disease of 77%. Median progression-free survival was 37 days (range 13-770 days), while the overall median survival time (MST) was 270 days (range 83-1396 days). Following imatinib treatment, the MST was 105 days (range 22-1145 days). Gastrointestinal and haematological adverse events were recorded in 2 (5.7%) and 3 (8.6%) dogs, respectively, and were self-limiting. Imatinib treatment was generally well tolerated, with measurable clinical responses observed and only a limited spectrum of toxicities. Further studies are warranted to better characterise its safety and efficacy in dogs with MCTs.

Intra-operative staging of canine mast cell tumour (MCT) currently relies on routine cytology to determine nodal metastasis. While frozen section nodal histopathology is commonly used in humans, its applicability to veterinary settings is poorly characterised. The goal of this study was to determine the diagnostic performance of frozen section (FS) histopathology for diagnosing metastatic MCT, as compared to a formalin-fixed histopathologic gold standard. Performances of imprint cytology (IC) and fine needle aspirates (FNA) were also evaluated. Forty-one lymph nodes from 20 dogs with MCT were collected and stained with haematoxylin and eosin (HE) and Giemsa (formalin-fixed and frozen tissues), and Wright Giemsa and toluidine blue (IC and FNA). Nineteen out of 20 primary tumours were low grade. Frozen HE sections had poor agreement as compared to formalin-fixed HE histopathology (κ = 0.15); however, diagnostic performance increased to a good level of agreement when interpretation was combined with Giemsa (κ = 0.46). FNA and IC using Wright Giemsa had agreement comparable to combined frozen section histopathology (κ = 0.51 and 0.43, respectively). Combined frozen sections had a sensitivity of 65% and specificity of 93%, which was the same as FNA. Challenges encountered in morphologic interpretation of frozen sections included inadequate sectioning quality, architectural disruption, ruptured cells, and background metachromatic staining. These data provide support for FS histopathology as a feasible strategy for intra-operative detection of metastatic MCT, with diagnostic agreement similar to conventional cytology. Performance of FS histopathology is conditional upon a metachromatic stain evaluated in parallel with HE.

Mechlorethamine is commonly prescribed to dogs at 3 mg/m². The minimal toxicity observed indicates that higher doses of mechlorethamine are likely tolerable. The primary objective of this study was to determine the maximally tolerated dose (MTD) of mechlorethamine in dogs with lymphoma. The secondary objectives were to describe the toxicity associated with increased mechlorethamine dose and to evaluate the response in treatment-naive dogs treated at the MTD. Dogs with histologically or cytologically confirmed intermediate to large cell lymphoma were enrolled using a 3 + 3 dose escalation model, starting at 3.5 mg/m² mechlorethamine IV, with planned dose increments of 10%-15% between cohorts. Adverse events were monitored per VCOG-CTCAE guidelines. Dose-limiting toxicity was defined as any grade 3 or 4 adverse event. Thirty dogs were enrolled across nine cohorts. Two dogs treated at 12.3 mg/m² developed asymptomatic grade 4 neutropenia 7 days after mechlorethamine administration, leading to a MTD of 10.7 mg/m². Low-grade vomiting, diarrhoea, and inappetence were recorded amongst dogs at several dose levels and were managed with supportive medications. Six of 10 chemotherapy-naïve dogs treated at the MTD, representing a separate cohort, showed partial responses (PR) 7 days post-administration; however, PR was also observed at dosages ranging from 3.5 to 12.3 mg/m² in pre-treated patients. A higher dose of mechlorethamine than previously reported can be safely administered as a single agent to dogs. Increasing the dose of mechlorethamine in combination therapies might offer greater therapeutic benefits.

Intraoperative surgical margin evaluation is not routine in veterinary medicine. Polarisation-sensitive optical coherence tomography (PS-OCT) is a variant of spectral domain optical coherence tomography (SD-OCT) that can provide real-time cross-sectional imaging of surgical margins with additional information about the polarisation of light in tissues. The aims of this study were (1) to compare PS-OCT surgical margin images to histopathology of excised canine skin and subcutaneous tumour specimens, and (2) to determine if the addition of PS-OCT images improved the diagnostic accuracy of surgical margin assessment. The authors hypothesised that PS-OCT image features would resemble histopathologic tissue features and the addition of PS-OCT images would improve the accuracy of margin assessment. Sixty-one dogs with 79 skin and subcutaneous tumours were prospectively enrolled. Tumours were excised, the surgical margins were imaged with OCT and then submitted for histopathology. Six masked readers first received image interpretation training in SD-OCT only, followed by training in combined SD-OCT and PS-OCT 1 week later. The readers interpreted each image or video for the presence of cancer and the results were compared to histopathology. PS-OCT imaging features of surgical margin tissues were consistent with tissue histopathologic features at low power. The overall reader median sensitivity and specificity were 90.9% and 95.6% for SD-OCT only and 90.9% and 91.3% for combined SD-OCT and PS-OCT. The addition of PS-OCT images did not improve the diagnostic accuracy of the surgical margin assessment for skin and subcutaneous tumours but resulted in high accuracy of margin interpretation with readers of varying experience.

Mammary carcinomas are aggressive neoplasms and a significant cause of mortality in female cats. Despite surgical removal, feline mammary carcinoma (FMC) often recurs or metastasizes. Specific tumour biomarkers are necessary for early detection, prognosis and therapy selection. This study aims to identify candidate biomarkers for FMC by comparing tissue proteomic profiles among grades of 31 FMC cats and six normal mammary tissues (control) using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Candidate proteins identified by LC-MS/MS were validated by Western blotting and LC-MS/MS. Prognostic values of candidate proteins were evaluated using immunohistochemistry and survival analysis. Protein-chemotherapy drug interaction networks were also evaluated. Among the 268 differential proteins observed, dermatopontin (DPT) expression was significantly downregulated, while sorting nexin 5 (SNX5) expression was elevated in cancerous tissues compared to controls (p < 0.05). Immunohistochemistry results revealed a significant association of DPT and SNX5 with stages (DPT, p < 0.0001; SNX5, p = 0.046) and grades of FMC (DPT, p < 0.0001; SNX5, p = 0.04). Low DPT expression was associated with poor overall survival (p = 0.02), along with Stage 4 FMC (p = 0.0001), high mitotic count (p = 0.003) and the presence of lymphovascular invasion (p = 0.003). Moreover, protein-chemotherapy drug interaction showed a relationship of DPT with doxorubicin, lapatinib and neratinib. This study identified DPT and SNX5 as potential diagnostic and therapeutic targets for FMC, with DPT emerging as a promising prognostic biomarker.

Glomerular filtration rate (GFR) predicts carboplatin clearance and myelotoxicity in humans and cats. This relationship is unknown in dogs. In canines, elevated serum symmetric dimethylarginine (SDMA) correlates with reduced GFR. This study prospectively evaluated whether dogs with elevated SDMA (> 14 μg/dL) are at increased risk of hematologic and gastrointestinal toxicity following carboplatin chemotherapy. Plasma samples were collected to determine if SDMA or other factors are significant determinants of carboplatin pharmacokinetics. Thirty client-owned dogs weighing > 15 kg with confirmed neoplasia were enrolled. Dogs received carboplatin intravenously (300 mg/m²). SDMA was measured on the day of treatment. Nonlinear mixed effects modelling was done to identify possible covariates affecting pharmacokinetic parameters. Adverse effects were monitored with weekly complete blood counts and owner assessment forms. Five dogs had elevated SDMA; four had significantly reduced carboplatin clearance (mean 93.9, range 76.1-116.8 mL/h/kg) compared with dogs with SDMA ≤ 14 μg/dL (mean 185.4, range 114.3-268.3 mL/h/kg, p < 0.001). Three dogs with elevated SDMA experienced grade 4 neutropenia; one was euthanized due to sepsis. Two additional dogs with elevated SDMA were euthanized 5- and 13-days post treatment due to severe gastrointestinal signs. Twenty-five dogs had SDMA ≤ 14 μg/dL: 10 had asymptomatic grade 3 or 4 neutropenia, 3 had grade 3 or 4 GI toxicity, and none died. Elevated SDMA was associated with decreased carboplatin clearance in dogs and predicted risk for treatment-related toxicity and death in our study population.

Cancer is a leading cause of mortality in older dogs. Despite the prevalence of chemotherapy in canine oncology, a good understanding of owners' observations of side effects and clinical signs in real time is still lacking. Owners' perceptions and reporting of clinical signs play an important role in monitoring a dog's condition during treatment and the use of digital owner-reported outcome measures could prove efficient in tracking chemotherapy side effects in the home environment. This could improve care and draws inspiration from the human use of patient-reported outcome measures in oncology. We aimed to develop and test a prototype digital measure for monitoring clinical signs and health-related quality of life in dogs undergoing chemotherapy, designed to facilitate owner participation in monitoring and support veterinary care. A rapid literature review was conducted to identify existing measures and their methodological limitations. Items were generated based on the Veterinary Comparative Oncology Group-Common Terminology Criteria for Adverse Events, existing client-reported outcome measures, and expert veterinary opinion. Proof-of-Concept testing was performed with 29 dog owners with pets undergoing chemotherapy. Participants completed daily assessments of their dog's clinical signs and weekly quality of life surveys over a 21-day period. A sub-sample participated in cognitive interviews to assess content validity and acceptability. Descriptive statistics were used to assess clinical signs and quality of life scores. Internal consistency and item discrimination were evaluated, and qualitative data were analyzed thematically. High adherence was reported, with a median of 21 daily and 3 weekly assessments completed. Participants found the assessments acceptable and beneficial. Fatigue, polydipsia, and anorexia were the most frequently reported clinical signs. Dogs experienced a median of 3 different clinical signs. The quality-of-life scale showed good internal consistency (Cronbach's α = 0.84). Participants appreciated the daily assessments, found them easy to complete, and believed the measure could help improve monitoring and decision-making during chemotherapy. The prototype tool, the Canine Cancer Outcome Measure (CAN-COM), demonstrated feasibility and acceptability for use by owners in the home environment for dogs undergoing chemotherapy. With further refinement and validation, such a tool could improve the monitoring of adverse events and support decision-making in veterinary oncology, enhancing the welfare of canine cancer patients.