Veterinary and comparative oncology最新文献

Canine multicentric lymphoma is a common cancer in dogs without evidence-based prevention measures. While breed accounts for part of lymphoma risk, environmental exposures might also contribute. Human non-Hodgkin lymphoma (NHL), which resembles canine lymphoma, is associated with exposures to volatile organic compounds (VOCs) and herbicides. Pet dogs are commonly exposed to these genotoxic chemicals, but it is unknown whether such exposures are associated with in vivo DNA damage as a potential contributor to lymphoma in dogs or whether early DNA damage can be detected before lymphoma diagnosis. The aims of this study were to determine whether DNA strand breaks or oxidised DNA residues precede a diagnosis of canine lymphoma and to assess whether DNA damage events correlate with estimated systemic exposures to the VOCs benzene, xylene and 1,3-butadiene or the herbicides 2,4-D and glyphosate. In a nested case-control study within the Golden Retriever Lifetime Study, we found increased DNA strand breaks in dogs with lymphoma compared to controls at the time of diagnosis (p = 0.004). We also found higher oxidised DNA residues both at the time of diagnosis (p = 0.02) and in the year prior to diagnosis (p = 0.03). DNA strand breaks across all dogs and time points were positively correlated with estimated aggregate blood VOC exposures and estimated plasma 2,4-D and glyphosate concentrations. These data indicate that detectable oxidative DNA damage may precede a diagnosis of canine lymphoma and support the hypothesis that VOC and herbicide exposures might contribute to DNA strand breaks in pet dogs.

This retrospective study evaluated a cyclical, hypofractionated palliative-intent radiotherapy protocol ('quad-shot', QS) in 81 dogs with sinonasal tumours treated between 2011 and 2023. The protocol consisted of a 'cycle' of four fractions of 3.25-4.0 Gy delivered over 48-72 h, repeated every 3-4 weeks, up to three cycles (maximum cumulative dose, 48 Gy). Most were treated with 3D conformal radiation therapy and a small number with a clinical setup. Carcinomas accounted for 78% of cases and tumours were modified Adams stage 1 (n = 5; 6%), 2 (n = 8; 10%), 3 (n = 29; 36%), 4 (n = 33; 41%) or unknown in n = 6 (7%). Ninety percent of patients received three full cycles to a total of 39-48 Gy, and 77% showed clinical improvement at presentation for Cycle 2 and 90% at presentation for Cycle 3. Median progression-free interval (PFI) was 207 days (95% CI: 124-290), and median overall survival time (OST) was 296 days (95% CI: 177-415). One-, two-, and 3-year survival rates were 40.6%, 17.2%, and 9.4%, respectively. Acute toxicity was generally mild, with conjunctivitis (33%), mucositis (7%), and radiodermatitis (6%) being the most frequent. Severe late toxicity was infrequent, but toxicities were considered likely under-reported. In the multivariable analysis, three QS cycles (vs. 1 or 2 cycles only) was a positive prognostic factor. The QS protocol resulted in improvements in nasal clinical signs, with survival outcomes comparable to other palliative radiation protocols. Toxicity was acceptable, despite the poor conformality of the radiation therapy in this population.

Hypofractionated radiotherapy (hRT) is often used to treat dogs with oral malignant melanoma (OMM); however, there is no consensus as to whether clinically uninvolved regional lymph nodes should be prophylactically irradiated. The objective of this retrospective study is to compare outcomes for dogs with OMM treated with hRT+/- elective nodal irradiation (ENI). Dogs with nonmetastatic OMM undergoing hRT+/- ENI with a prescription of ≥ 30 Gy were included. Survival statistics were evaluated with Kaplan-Meier curves and log-rank testing. Univariable and multivariable Cox proportional hazard models were used to assess how survival was impacted by the use of ENI, WHO T-stage, mitotic count, RT technique, and use of Oncept melanoma vaccine. Data from four institutions and 100 dogs (80 with ENI and 20 without) were included. In the ENI group, nodal and distant metastases were documented in 4 and 30 dogs, respectively. In the non-ENI group, nodal and distant metastases were documented in 6 and 4 dogs, respectively. There was no significant difference in the 1-year nodal or distant progression-free intervals (p = 0.174, and 0.563, respectively). The only variable maintaining significance on multivariable analysis was T-stage (overall progression-free survival, HR 1.393, p = 0.006; overall survival time, HR 1.426, p = 0.005; distant progression-free interval, HR 1.521, p = 0.033). ENI did not measurably alter the oncologic outcomes in this study population. Results should be interpreted cautiously given the lack of standardised staging/restaging and the heterogenous nature of this clinical population. Future investigations are needed to clarify the role of ENI in the treatment of canine OMM.

The goal of this prospective, single-arm pilot study was to assess tolerability and clinical benefit for cats with histologically confirmed lymphocytic lymphoma/chronic inflammatory enteropathy complex (FLL/CIE) treated with low-dose abdominal cavity radiation therapy (RT; 8 Gy total dose administered in four 2 Gy fractions). No cats received steroids or chemotherapy prior to RT. Fourteen cats were enrolled and 13 completed the study. Eight cats had enteropathy-associated T cell lymphoma type II (FLL), and 6 cats had CIE (lymphoplasmacytic enteritis, 3 with concurrent eosinophilic enteritis). Nine of 13 cats (69%) had transient worsening of GI signs in the 1-3 weeks after RT, presumed secondary to RT and/or stress of travel/anaesthesia. Eight were managed as outpatients and one cat died after being syringe fed by the owner. Nine of the 12 remaining cats (75%; N = 6 with FLL and N = 3 with CIE) had a clinical benefit to treatment (resolution or improvement of GI signs as defined by owner surveys and body weight) that was sustained for > 340 days. Three cats experienced presumed or confirmed disease progression at 341, 465 and 449 days after RT and were treated with steroids. Six cats remained asymptomatic (N = 5) or stable (N = 1) at a median of 635 days after RT (range, 447-1014 days). Low-dose abdominal cavity RT could be considered for cats that cannot tolerate steroids and/or for owners that cannot pill cats routinely. Further optimisation of the protocol and use of RT as a rescue treatment for cats that fail traditional therapies are considerations for further study.

Spontaneous canine prostate cancer (PC) is widely considered a pertinent clinical model for the human disease. While over 95% of PC in men are adenocarcinomas, arising from prostatic glandular epithelium, it is increasingly recognised that many canine PC are of urothelial origin, arising within the prostatic urethra or ducts, or through invasion from a primary urinary bladder tumour. At diagnosis, canine prostatic tumours are often poorly differentiated and widely disseminated, masking the primary site and limiting the sensitivity of cellular biomarkers. Consequently, published studies of canine PC show varying representation of glandular versus urothelial tumours, yielding conflicting observations regarding their molecular pathogenesis and clinical behaviour. We characterised DNA sequence mutations and copy number aberrations in 31 canine PC, seeking evidence supporting relevance as a disease model. Only three tumours resembled adenocarcinomas. The remainder were either histologically consistent with urothelial carcinoma (n = 15), showed mixed glandular and urothelial morphology (n = 4), or were carcinomas of undetermined cell type (n = 9). BRAF V588E mutation was detected in 87% of tumours, including all three adenocarcinomas. Urinary bladder involvement was evident in 46% of cases, but none of the adenocarcinomas. Genome-wide DNA copy number instability was apparent throughout the cohort, with chromosome 36 gain significantly associated with urothelial tumours. Hallmark alterations of human PC, such as defects within PI3K and androgen receptor signalling pathways, were not detected. Improved molecular subclassification of canine PC is needed to direct selection of relevant cases for modelling the human disease and to ensure appropriate extrapolation between canine and human studies.

The fraction size in canine pelvic tumours has traditionally been limited to minimisze radiation toxicity. However, advancements in precision radiotherapy techniques have enabled the use of larger fraction sizes, thereby facilitating a reduction in the overall treatment course. This study assessed the radiation toxicity risks of a 10-fraction radiation protocol for canine prostatic carcinoma by calculating normal tissue complication probabilities (NTCPs). Computed tomography data from 22 dogs with prostatic carcinoma were analysed. The new protocol was designed to deliver 43 Gy in 10 fractions over 2 weeks (Monday-Friday), with a biologically effective dose similar to that of standard protocols. Compared to the standard 20-fraction protocol, the 10-fraction protocol demonstrated comparable toxicity risks in most organs except for some rectal endpoints and the urethra, while also offering advantages in treatment time and patient convenience. Nevertheless, under the 10-fraction protocol, the relatively high NTCPs for late rectal toxicities and the identification of patients at high risk of toxicity support the recognition of the rectum as a primary organ at risk in hypofractionated radiotherapy. Rectal toxicity risks were higher in patients with trigonal invasion, dorsal rectal displacement or rectal narrowing. Higher tumour length/L6 height and maximal tumour diameter/L6 height ratios were associated with increased rectal NTCPs. Relative tumour size indices effectively predicted patients at high risk for rectal toxicity. Cut-off values were identified for acute rectal toxicity (Grade ≥ 2; tumour height/pelvic inlet ratio: 0.62), rectal bleeding (Grade 2; tumour height/L6 height: 4.03) and proctitis (Grade 2; maximal tumour diameter/pelvic inlet ratio: 0.82). These findings highlight the importance of relative tumour size indices as predictive markers for rectal toxicity risk in the 10-fraction protocol. The results suggest that the 10-fraction, 43 Gy protocol may be safely applied when tumour size remains below specific thresholds.

Steroids provide rapid clinical improvement in dogs with multicentric diffuse large B-cell lymphoma (DLBCL). However, their use before chemotherapy can induce chemoresistance and compromise diagnostic yield due to increased apoptotic cells. This retrospective study assessed the impact of steroid dose and duration on flow cytometry (FC) diagnostic yield and clinical outcomes in dogs with DLBCL subsequently treated with chemotherapy. Of 273 dogs diagnosed with DLBCL between January 2014 and March 2024, 67 (24.5%) received steroids before treatment (median dose: 1 mg/kg, range: 0.5-3 mg/kg; median duration 8 days, range: 1-1080 days). In 94.0% of cases, steroids were administered for lymphoma management. All dogs received CHOP-based chemotherapy, and 38 (56.7%) also received immunotherapy. Median time to progression (TTP) and lymphoma-specific survival (LSS) were 143 days (95% CI: 111-175) and 196 days (95% CI: 152-240), respectively. Steroid dose, duration, and cumulative dose had no significant impact on TTP or LSS. However, the addition of immunotherapy was associated with longer LSS (p = 0.023). FC diagnostic yield was lower in steroid-treated dogs compared to 67 non-pre-treated dogs (p = 0.042). However, within the pre-treated group, neither dose nor duration impacted diagnostic yield (p > 0.05). In addition, TTP (p = 0.003) and LSS (p < 0.001) were significantly longer in non-pre-treated dogs compared to steroid-treated dogs. These findings suggest that the detrimental effects of upfront steroids are independent of dose or duration. Given their potential to compromise diagnosis and treatment outcomes, corticosteroids should be used with caution and reserved for cases where clinical benefits clearly outweigh the risks.

Radiation therapy (RT) is the treatment of choice for canine intracranial gliomas. Recently, modern advanced radiation techniques, including intensity modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), have become widely available in veterinary medicine. However, the glioma-specific therapeutic outcomes of patients treated with modern RT remain unclear. This study aimed to describe survival outcomes and tumour response and to identify whether any treatment, clinical, and imaging factors were predictive of prognosis in dogs with intracranial gliomas treated with definitive-intent IMRT alone. Medical records of dogs with presumed intracranial gliomas that underwent definitive-intent IMRT were retrospectively reviewed. Fifty-five dogs were included. Amongst them, 29 and 26 underwent fractionated RT (FRT) and stereotactic RT (SRT), respectively. In the 44 dogs that underwent follow-up magnetic resonance imaging (MRI), the overall measurable response rate was 77.3%. Clinical improvement was observed in 92% of the dogs. Local tumour regrowth and drop metastases were observed in 17 (30.9%) and 10 dogs (18.2%), respectively. The median overall survival, disease-specific survival, and progression-free survival were 432, 670, and 441 days, respectively. Seven dogs (12.7%) died during RT or within 6 weeks. There was no statistically significant difference in the survival times between FRT and SRT. In the multivariate analysis, poor performance status, tumour location in the diencephalon, and fluid-attenuated inversion recovery heterogeneity were significantly associated with shorter survival times. These findings suggest that definitive-intent RT results in tumour shrinkage and prolonged survival (432 days) with minimal radiation toxicity regardless of the RT protocol used. Performance status and MRI findings can be useful for predicting prognosis.

As computed tomography (CT) becomes more commonly used in clinical practice for staging and surgical planning of dogs with adrenal tumours, there remain few reports on CT characteristics of malignant adrenal tumours and none that correlate imaging findings with survival. This retrospective study attempts to evaluate preoperative CT characteristics that are associated with malignancy and those that may be associated with shorter survival in dogs with surgically addressed adrenal tumours. CT scans performed at a single tertiary care facility were examined by a single blinded radiologist, and the findings were correlated with histopathology results as well as short- and long-term survival. A total of 226 adrenal tumours were assessed from 201 individual patients. The overall median survival time for adrenal tumours was 671 days. Dogs undergoing unilateral versus bilateral adrenalectomies had longer survival, with a median survival time of 697 versus 623 days (p = 0.02). Consensus histopathologic diagnosis as malignant versus benign was not associated with a significantly shorter survival time, 952 versus 1514 days, p = 0.04, q = 0.25. No CT features were associated with shortened long-term survival times on multivariate analysis. Excluding deaths within 24 h of surgery, splenectomy was predictive for hazard of death and was retained on multivariate analysis p = 0.03, HR = 2.33. Age (p = 0.0001, HR = 1.23) and concurrent ureteronephrectomy at the time of adrenalectomy (p = 0.042, HR = 2.45) were shown to affect long-term survival and were retained on multivariate analysis. This information may be useful when prognosticating outcomes for pet owners presenting for surgery.

The subtle sequence diversity and mutually exclusive expression patterns of T cell receptor beta chain constant genes, TRBC1 and TRBC2, in mature human T cells, provide the basis for immune-targeting strategies designed to eliminate clonally expanded malignant T cells while sparing a subset of normal T cells capable of maintaining immunocompetence. The evolutionarily conserved gene arrangement and regulation of TRBC loci in mammals make these genes attractive targets for translational immune-targeting strategies in companion species, including dogs. However, available TRBC sequence data relevant to common dog breeds remains limited. In this study, we investigated the sequence diversity and mRNA expression profiles of canine TRBC1 and TRBC2 genes in peripheral blood mononuclear cell (PBMC) samples representing 14 different dog breeds, and in six established canine haematopoietic cell lines of both T-cell and non-T-cell origin (i.e., B and NK cell lines). Our analysis uncovered a previously unreported variation in the TRBC1 sequence encoding the transmembrane region but found no sequence diversity in the extracellular domain of TRBC1 and TRBC2. A nearly equal mRNA expression of TRBC1 and TRBC2 was consistently observed in bulk samples of canine PBMCs across all breeds, in contrast to canine cell lines, which exhibited a more skewed expression profile. Unexpectedly, germline mRNA expression of TRBC was present in some (i.e., CLB70, GL1) but not other (i.e., CLBL1) canine cell lines of B cell origin. In conclusion, our findings indicate that the fully conserved amino acid sequence in the extracellular domain of canine TCR beta chain variants presents a challenge for the development of differential therapeutic antibodies. Additionally, the presence of germline TRBC transcripts in certain canine B-cell neoplasms, but not others, may provide additional insights into the developmental stages from which these neoplasms originate.