Veterinary and comparative oncology最新文献

Canine cutaneous mast cell tumours (MCTs) are currently staged based on the World Health Organization (WHO) classification, which has remained unchanged since its initial formulation. Our study aimed to assess the reliability of a novel pTNM staging system, which incorporates tumour extent (T), lymph node involvement (N), presence of distant metastases (M) and the two-tier histologic grade. We analysed medical records of dogs with one or more cutaneous/subcutaneous completely staged MCT, undergoing tumour excision with lymphadenectomy, unless distant metastases were present, in which cases, medical therapy was administered. Dogs were categorized into three stages: I (T1-2N0M0), II (T1-2N1M0) and III (distant metastases). Stages I and II were further divided based on histologic grade into 'low' and 'high'. Substage b was defined as the presence of tumour diameter of ≥3 cm and/or ulceration. Of 226 dogs, 87 (38.5%) were in Stage I (I-low, n = 75; I-high, n = 12), 107 (47.3%) in Stage II (II-low, n = 59; II-high, n = 48), and 32 (14.2%) in Stage III. The newly proposed staging system was able to significantly stratify the population for both time to progression and tumour-specific survival. Compared to Stage I-low, the risk of progression increased significantly for Stage I-high (18.3 times), Stage II-low (8.5 times), Stage II-high (41.5 times) and Stage III (110.3 times). The staging system was highly prognostic for both cutaneous and subcutaneous MCTs. Prospective validation studies are essential to compare this new system with the current WHO staging and further validate its accuracy and clinical utility.

Hodgkin-like lymphoma (HLL) is a rare neoplasm in cats that shares characteristics with the human disease. The hallmark of HLL is the presence of Reed-Sternberg (RS) cells expressing CD30 and CD20. This study aimed to elucidate the clinicopathologic features, immunophenotype and clonality patterns of feline HLL. A comprehensive retrospective review of clinicopathologic and molecular data of nodal lymphomas over a 6-year period was conducted in MyLav laboratory. Twenty-four cases were identified. All cats presented with submandibular or retropharyngeal lymphadenopathy. Histopathologic examination revealed a multifocal to diffuse proliferation of medium-to-large lymphoid cells with low mitotic activity, interspersed RS cells, and a heterogeneous inflammatory infiltrate comprising T-cells, plasma cells and neutrophils. In addition, extensive necrosis was a consistent finding. Immunohistochemistry showed a variable membranous CD20 and nuclear PAX5 expression in neoplastic cells, while RS cells displayed only mild to moderate CD20 positivity and were negative to PAX5. In 21/24 cases (87.5%), RS cells were diffusely CD30-positive. PARR analysis demonstrated clonal B-cell expansion in 60% of cases, with the remaining 40% exhibiting polyclonality. For the 10 cats with available follow-up, the prognosis was generally favourable, with only two cats succumbing to progressive disease. In conclusion, diagnosing feline HLL is challenging. The expression of CD30 and CD20 by RS cells should be considered a hallmark of the disease, but only after excluding differential diagnoses such as anaplastic B-cell lymphoma and granulomatous lymphadenopathy.

Prostate cancer continues to be one of the most lethal cancers in men. While androgen deprivation therapy is initially effective in treating prostate cancer, most cases of advanced prostate cancer eventually progress to castration-resistant prostate cancer (CRPC), which is incurable. Similarly, the most aggressive form of prostatic carcinoma occurs in dogs that have been castrated. To identify molecular similarities between canine prostate cancer and human CRPC, we performed a comparative analysis of gene expression profiles. Through this transcriptomic analysis, we found that prostatic carcinoma in castrated dogs demonstrates an androgen-indifferent phenotype, characterised by low-androgen receptor and neuroendocrine-associated genes. Notably, we identified two genes, ISG15 and AZGP1, that were consistently up- and down-regulated, respectively, in both canine prostatic carcinoma and human CRPC. Additionally, we identified several other genes, including GPX3, S100P and IFITM1, that exhibited similar expression patterns in both species. Protein-protein interaction network analysis demonstrated that these five genes were part of a larger network of interferon-induced genes, suggesting that they may act together in signalling pathways that are disrupted in prostate cancer. Accordingly, our findings suggest that the interferon pathway may play a role in the development and progression of CRPC in both dogs and humans and chart a new therapeutic approach.

Infiltrative lipomas represent a subcategorisation of rarer, potentially more aggressive, lipoma-related neoplasms. Twenty-one dogs treated with conventionally fractionated radiotherapy (CFRT) for infiltrative lipomas were included in this retrospective study. One patient had no prior surgical excision, 11 patients had one prior surgery and 9 patients had two or more surgeries prior to CFRT. Five patients (24%) had microscopic disease and 16 patients (76%) had macroscopic disease prior to treatment. A complete response or no regrowth was seen in 10 patients (48%), stable disease in 6 patients (29%) and progressive disease or regrowth in 5 patients (24%). Response to treatment of macroscopic tumours was significantly different between dogs that had one prior surgery versus two or more (p = 0.01). Dogs with a single surgery were most likely to result in stable disease compared with dogs with two or more surgeries resulting in a complete response. The dog without surgery developed progressive disease at 211 days, dogs with one surgery had a median progression or recurrence at 1369 days and dogs with two or more surgeries developed progression or recurrence at 826 days (p = 0.04). Twelve dogs were alive at the time of analysis. Overall median survival time (MST) was 1694 days. The prior number of surgeries did not significantly affect MST. While survival time is comparable to previous reports, the number of patients with progressive disease or recurrence of previous microscopic disease requires more investigation into the most appropriate protocol, dose and treated field size.

Canine haemangiosarcoma (HSA) is a highly aggressive cancer often associated with coagulation abnormalities. Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) clinically prescribed for hypercholesterolemia, are also believed to possess antitumour and anticoagulant properties by inhibiting downstream Akt activation. Akt phosphorylation is involved in the mechanism of the antitumour and tissue factor (TF)-lowering effects of statins. In the present study, we aimed to investigate whether statins could inhibit cell viability while concurrently inducing anticoagulant properties by regulating the expression of TFs in canine HSA cells. Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), we initially exclusively detected HMGCR mRNA expression in canine HSA tissues and cell lines but not in normal cephalic vein and spleen tissues. Moreover, treatment with lipophilic statins, including atorvastatin, fluvastatin, and simvastatin, inhibited cell viability in a concentration-dependent manner and decreased TF expression both at the mRNA and protein levels, as evidenced by cell viability assays, RT-qPCR, and immunoblotting, respectively. Further investigation using cell viability assays and flow cytometry revealed that simvastatin decreased Akt phosphorylation, and MK-2206, a specific Akt inhibitor, mirrored the effect of simvastatin on cell viability and cell cycle arrest. However, MK-2206 exhibited different effects on TF expression depending on the cell type, indicating that Akt phosphorylation may not consistently regulate TF expression. Overall, this study provides insights into the potential therapeutic use of statins in targeting tumour growth and coagulation abnormalities in canine HSA. Further research is warranted to fully elucidate the underlying mechanisms and clinical applications of statins in canine HSA treatment.

Ataxia telangiectasia and Rad3-related (ATR) kinase is one of the main regulators of cell response to DNA damage and replication stress. Effectiveness of ATR targeting in human cancers has been confirmed in preclinical studies and ATR inhibitors are currently developed clinically in human oncology. In the presented study, we tested the anticancer efficacy of ATR inhibitor berzosertib in an in vitro model of canine haematopoietic cancers. Using MTT assay and flow cytometry, we assessed the cytotoxicity of berzosertib in four established canine lymphoma and leukaemia cell lines and compared it with its activity against noncancerous canine cells. Further, we estimated the level of apoptosis in berzosertib-treated cells via flow cytometry and assessed H2AX phosphorylation as a marker of DNA damage using western blot technique. In flow-cytometric analysis, we also evaluated potential synergism between berzosertib and chlorambucil and assessed the influence of berzosertib on cell cycle disturbances induced by the drug. The results demonstrated that berzosertib, even without additional DNA damaging agent, can be effective against canine lymphoma and leukaemia cells at concentrations that were harmless for noncancerous cells, although sensitivity of individual cancer cell lines varied greatly. Cell death occurred through caspase-dependent apoptosis via induction of DNA damage. Berzosertib also acted synergistically with chlorambucil, probably by preventing DNA damage repair as a consequence of S-phase arrest abrogation. In conclusion, ATR inhibition may provide a new therapeutic option for the treatment of canine lymphomas and leukaemias, but further studies are required to determine potential biomarkers of their susceptibility.

Radiotherapy (RT) is increasingly utilised for definitive-intent treatment of canine genitourinary carcinomas (CGUC). At our institution, the standard approach is to irradiate tomographically abnormal tissues gross tumour volume (GTV) plus a clinical target volume (CTV) expansion of 2 cm. Cystourethroscopy is often incorporated into the treatment planning workflow, though an optimal approach has yet to be defined. This observational study evaluated cystourethroscopy as a tool for identifying gross lesions that can be targeted with RT. We hypothesised that in most cases, addition of cystourethroscopy would result in a larger GTV than would be drawn with computed tomography (CT) alone. Medical records from 54 dogs diagnosed with CGUC between 2013 and 2023 were reviewed; each had been evaluated before RT using CT and cystourethroscopy. The GTV was initially defined as the tomographically evident disease on a post-contrast sagittal plane CT scan, and then lesions visualised with cystourethroscopy (suspected or confirmed to be tumour) were added. Beyond what was visible on CT, cystourethroscopy extended the GTV by a median of 6.5 cm distally into the urethra (range: 1.5-31.8 cm) and therefore resulted in GTV enlargement in 26 of 54 (48%) cases. Addition of our standard 2 cm CTV expansion to a CT-defined GTV (without use of data from cystourethroscopy) would have underestimated the extent of grossly abnormal tissue in 35% (19/54) of cases. These results suggest that incorporating cystourethroscopy into treatment planning workflows may improve local tumour control by reducing the risk of a geographic miss.

Canine and human brain tumours exhibit similar incidence rates and prognoses. Recent studies have demonstrated that extracellular vesicles derived from human patients (PDEVs) can be loaded with contrast agents and exhibit tumour tropism in murine models. We showed in a previous study that gadolinium-labelled EVs derived from canine gliomas (cPDEVs) can selectively targets murine glioblastoma cells in animal models. As a further step, we investigated the potential heterologous and cross-species tumour tropism of cPDEVs with brain tumours. With the perspective of imminent clinical application as both markers and drug delivery tools, we have successfully established the isolation protocol for cPDEVs and confirmed the aseptic conditions of the procedure and therefore the sterility of the isolated EVs. To assess the functionality of cPDEVs as drug delivery tool, they were loaded with indocyanine green (ICG) and injected into murine models of cancer for in vivo fluorescence biodistribution studies. Biodistribution analysis in mice revealed that ICG-loaded cPDEVs injected into murine models of subcutaneous tumours accumulated exclusively in the neoplastic tissue, even when evaluated 24 h post-injection, thus showing the cross-species and heterologous selective tumour tropism of the nanoparticles. With these tests, we have established a safe protocol for isolating and loading autologous cPDEVs with various markers, thereby paving the way for the clinical testing phase. These significant findings suggest the potential use of cPDEVs as a theranostic tool in the management of canine brain tumours, with promising implications for translational medicine applications in the future.

Neutropenia is a common chemotherapy-associated adverse event (AE) in dogs and a significant cause of decreased relative dose intensity. Dose reductions (DRs) and treatment delays (TDs) are frequently applied to decrease the risk of further neutropenic events (NEs) and AEs, but there is no standardised approach. The two main objectives of this retrospective study were to determine: (1) the failure rate of a 10% DR to prevent a subsequent inadequate absolute neutrophil count (ANC), defined as a nadir ANC <0.75 × 10⁹/L or pretreatment ANC <1.5 × 10⁹/L; and (2) if the duration of TDs due to pretreatment neutropenia affects the occurrence of subsequent NEs. A total of 1056 chemotherapy treatments were recorded for 128 dogs that developed at least one NE. In 75 of 124 (60.5%, 95% CI: 51.2%-69%) evaluable NEs, a nadir ANC of ≥0.75 × 10⁹/L and pretreatment ANC of ≥1.5 × 10⁹/L were achieved after a single 10% chemotherapy DR, while a 10% DR failed to prevent a subsequent inadequate ANC in the remaining 49/124 (39.5%, 95% CI: 30.1%-48.3%). The only variable associated with failure was the drug prescribed. DR failure occurred in 22/39 (56.4%, 95% CI: 40.9%-70.6%) lomustine DRs, 14/27 (51.9%, 95% CI: 33.9%-69.2%) cyclophosphamide DRs, but only 2/22 (9.1%, 95% CI: 2.5%-27.8%) doxorubicin DRs and 2/24 (8.3%, 95% CI: 2.3%-25.8%) vincristine DRs. Seventy-three evaluable TDs (mean: 5 days, SD ± 2.2 days) were prescribed. There was no association between TD duration and subsequent NEs (p = 0.11).

Mammary gland tumours are common neoplasms that affect female dogs and cats. We compared the accuracy of pre-surgical fine-needle aspiration (FNA) and core needle biopsy (CNB) diagnosing feline (n = 64) and canine (n = 83) mammary gland tumours with excisional histopathology as the gold standard for the definitive diagnosis. We also explored the impact of CNB needle sizes (18G and 16G). FNA, 18G CNB and 16G CNB demonstrated similar accuracy regarding the diagnosis of feline mammary tumours, ranging from 90% to 97.7% (p > 0.05). However, these techniques displayed lower diagnostic accuracy for canine mammary gland tumours: 46.7%-50.9% for FNA, 63.3% for 18G CNB and 73.6% for 16G CNB. In conclusion, FNA and CNB can be used optionally as pre-surgical diagnostic methods for feline and canine mammary gland tumours. However, factors that affect diagnostic accuracy, such as species and diagnostic techniques, should be considered.