Veterinary and comparative oncology最新文献

Stereotactic body radiation therapy (SBRT) has become a non-invasive alternative option for canine adrenal tumours with high surgical risks; however, its clinical benefits and risks are still to be fully understood. The goal of this multi-institutional retrospective study was to describe the clinical outcome and safety of SBRT for the treatment of 21 dogs with adrenal tumours. Ten were suspected pheochromocytomas, two adenocarcinomas, and the diagnosis was unknown in nine dogs. Vascular invasion was present in 81% of cases (17/21). Thirteen dogs received 3 fractions of 6 to 11 Gy, 7 received 5 fractions of 6 to 9 Gy, and 1 received 4 fractions of 6 Gy. For the 20 patients with follow-up imaging, 9 (43%) had partial response, 10 (47%) stable disease, and 1 (5%) progressive disease. Progression-free survival was 16.8 months (95% CI: 3.4-23), and overall survival time was 16.8 months (95% CI: 3.7-23.7). Twelve patients (57%) experienced acute adverse events (AEs); of those, seven were gastrointestinal grade ≥ III, including one grade V. Late AEs were suspected in seven dogs (33%), including gastrointestinal grade V in four of them. A total of five dogs (24%) died from radiation-related toxicities. Although SBRT seems to be effective against adrenal tumours, it was associated with a high morbidity and mortality rate, suggesting that re-evaluation of radiation therapy protocols is necessary for maintaining patient safety.

Human epidermal growth factor receptor 2 (HER2) gene mutations have been reported in 5% to 38% of canine pulmonary adenocarcinomas (cPACs), most commonly as V659E mutations in exon 20. However, their prognostic and predictive significance remains unclear. This retrospective, single-centre cohort study investigated the frequency of HER2 mutations in surgically resected cPACs and their association with clinical outcomes. Between 2005 and 2021, lung masses histologically diagnosed as cPACs were collected and subjected to direct sequencing of HER2 exons 20 and 21. A total of 72 dogs were enrolled, with successful HER2 gene analysis in 69 cases. HER2 exon 20 missense mutations were identified in 20 dogs (29.0%), including 18 harbouring the previously reported V659E hotspot mutation within the transmembrane domain. Homozygous mutations were detected in 13 dogs. Univariable analysis revealed associations between progression-free interval (PFI) and clinical signs, tumour size classification, lymph node metastasis, surgical margin status, and histologic grade. Overall survival time (OST) was associated with age, clinical signs, tumour size > 7 cm, histologic subtype, lymph node metastasis, and margin status. In multivariable analysis, tumour size classification and margin status remained significantly associated with PFI, while age, tumour size > 7 cm, and histologic subtype were independently associated with OST. Notably, the presence of HER2 mutations was significantly associated with prolonged PFI in both univariable and multivariable analyses, although no significant association with OST was observed. These findings suggest that HER2 mutation status may serve as a favourable prognostic marker for disease progression in surgically resected cPACs.

Alkaline phosphatase (ALP) enzymatic activity has been proposed as a marker for distinguishing canine acute leukaemia (AL) subtypes (i.e., myeloid vs. lymphoid). However, ALP enzymatic activity has not been fully evaluated in CD34+ AL. Determine whether ALP enzymatic activity can differentiate CD34+ AL subtypes in dogs and distinguish CD34+ AL from CD34- haematopoietic tumours in tissue/effusion samples. Peripheral blood from 64 dogs with CD34+ AL, 10 with B cell chronic lymphocytic leukaemia (CLL), and 10 healthy controls were prospectively evaluated for ALP enzymatic activity via cytochemical staining; a subset also underwent ALP detection by flow cytometry (FC). Archived cytology slides from 67 tissue/effusion specimens, including 27 CD34+ AL, 22 T cell lymphomas, and 18 B cell lymphomas, were retrospectively assessed. CD34+ AL cases were categorised as acute myeloid leukaemia (AML), acute lymphoid leukaemia (ALL) or acute unclassifiable leukaemia (AUL) by established FC criteria. ALP positivity was defined as > 3% ALP+ neoplastic cells, which was selected based on receiver operating characteristic (ROC) curve analysis. Cytochemical ALP activity was detected in 61/64 (95.3%) CD34+ AL cases, with no significant differences between AML, ALL, and AUL subtypes (p > 0.05). All lymphoma and B cell CLL cases were ALP-negative. FC-based ALP analysis showed poor concordance with cytochemistry, and the correlation between %CD34 + ALP+ cells and %ALP+ neoplastic cells was weak (Spearman's ρ = 0.25). While ALP enzymatic activity is present in most CD34+ AL cases, it does not reliably differentiate CD34+ AL subtypes via cytochemistry. However, ALP may help distinguish CD34+ AL from B and T cell lymphomas. FC-based ALP analysis is not a reliable marker for CD34+ AL classification.

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.

A clear understanding of human and canine osteosarcoma (hOS and cOS) immunobiology is needed to develop effective immunotherapeutic strategies, a promising option to improve outcomes. Previous studies in humans and dogs have underscored the importance of the macrophagic infiltrate. Notably, high M2-like macrophage infiltration has been associated with increased metastatic progression-free survival in hOS treated with surgery and chemotherapy. Given the strong similarities between hOS and cOS, we hypothesized that tumour infiltration by M2-like macrophages would also be associated with an improved prognosis in dogs. Eighty-four dogs with a histological diagnosis of cOS were retrospectively selected from the database of five veterinary institutions and one pathology laboratory. Medical data and associated cOS samples were retrieved from electronic records and original pathology laboratories. Macrophage populations were identified by immunohistochemistry using anti-CD204 and anti-CD206 antibodies. Univariate and multivariate Cox proportional hazard models were performed to identify factors associated with overall survival time (OST) in dogs treated with surgery with (SOC) or without (SxOnly) adjuvant chemotherapy. In dogs treated surgically (SOC + SxOnly), only high CD206+ infiltrate was associated with longer OST in both univariate (p = 0.019) and multivariate analysis (p = 0.014). Within the SOC group, high CD206+ infiltrate (p = 0.006) and lower body weight (p = 0.029) were associated with better outcome in the univariate analysis while high CD206+ infiltrate (p = 0.003) and female sex (p = 0.044) were associated with a longer survival in the multivariate analysis. This observation underscores the role of M2-like macrophages in OS and strengthens the relevance of cOS as a model for hOS in the immunological field.

Feline mammary tumours represent the third most common malignancy in cats, with limited evidence-based tools available for risk assessment and screening guidance. Traditional veterinary approaches rely on subjective clinical judgement, lacking quantitative risk stratification methods that could optimise preventive care delivery. To develop and validate the first comprehensive machine learning-based risk prediction system for feline mammary tumours, providing evidence-based clinical decision support for veterinary practice. We developed a comprehensive synthetic dataset of 4399 feline cases spanning 2002-2022, systematically calibrated against real-world epidemiological data from published literature. The synthetic data incorporated demographic, clinical, reproductive, and environmental variables that precisely replicated actual epidemiological relationships. Five machine learning algorithms (Random Forest, XGBoost, Neural Network, SVM, Logistic Regression) were trained and combined using soft voting ensemble methodology. Model performance was evaluated using area under the curve (AUC), calibration metrics, and clinical utility measures. The ensemble model achieved excellent discrimination capability (AUC = 0.888, 95% CI: 0.873-0.903) with 80.5% accuracy, 85.7% sensitivity, and 76.0% specificity. Risk stratification demonstrated clear clinical utility: low-risk cats (< 30% probability) had 12.4% tumour prevalence, while very high-risk cats (> 80% probability) showed 89.5% prevalence. The machine learning approach substantially outperformed traditional assessment methods, showing 64.8% improvement in discriminative ability and a 163% increase in net clinical benefit. This study establishes the first validated machine learning-based clinical decision support system for feline mammary tumour risk assessment. The risk stratification approach enables personalised screening recommendations while optimising resource allocation, potentially transforming preventive veterinary oncology practice.

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.

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.

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.