Veterinary and comparative oncology最新文献

Local treatment for dogs with regional lymph node metastasis secondary to apocrine gland anal sac adenocarcinoma (AGASACA) includes nodal extirpation or radiotherapy. Stereotactic body radiation therapy (SBRT) may provide a definitive intent treatment option for macroscopic nodal disease when surgery is declined or the disease is deemed inoperable. Twenty-five dogs receiving SBRT to the metastatic sacroiliac lymph nodes were retrospectively evaluated. Dogs were staged according to the previously published TNM staging system with 3 stage IIIa, 14 stage 3b, and 8 stage IV. The overall median survival time (MST) was 451 days and the stage did not significantly impact survival (p = 0.31). The overall median event-free survival time was 246 days. Significant positive prognostic factors included male sex, higher dose per fraction, and higher total dose (p = 0.034, 0.0035, 0.0047). Dogs receiving 6-7.5 Gy per fraction with a total dose of 30-37.5 Gy outperformed dogs receiving other protocols. Twelve dogs experienced gait changes in the hind limbs during the late radiation effects period. Resolution of hypercalcemia in 5 dogs was inconsistent and transient. The best response was complete in 21%, partial in 58%, and stable disease in 17% at a median of 100 days. Three dogs (12%) developed progression of treated lymph nodes at 157, 498, and 644 day. Eight dogs (32%) had recurrence of their primary (untreated by radiation) anal sac masses. SBRT was determined to be an effective alternative to surgical excision; however, more investigation is needed to determine the cause of gait changes in the late toxicity period.

Canine multicentric lymphoma (CML) is one of the most common malignancies in dogs. Although breed risk is important, environmental factors such as herbicides have also been implicated. The objective of this study was to determine whether genotoxic exposures to the herbicides 2,4-D and glyphosate are associated with CML, using dogs from the Golden Retriever Lifetime Study cohort. We measured urinary concentrations of glyphosate and 2,4-D in golden retrievers with CML and matched unaffected controls at two time points: at the time of diagnosis and 1 year prior to diagnosis. To assess the genotoxic potential of herbicide exposures, we used reverse dosimetry from urinary concentrations to estimate plasma concentrations. We then assessed the genotoxicity of these herbicide concentrations towards healthy canine peripheral blood mononuclear cells (PBMC's) in vitro using the CometChip assay, with and without canine liver microsomes. All dogs had detectable urinary exposures to 2,4-D (7.3-42.9 ng/mg creat) and glyphosate (0.4-80.7 ng/mg creat), with no differences between cases and controls at either time point. Both 2,4-D and glyphosate were genotoxic to canine PBMCs at concentrations of 0.10 μM and higher, with no consistent effects of canine liver microsomes on herbicide genotoxicity. No dogs reached estimated genotoxic plasma concentrations for glyphosate, but 4 of 30 golden retrievers with CML (13.3%) and 2 of 30 control dogs (6.7%) reached estimated genotoxic 2,4-D exposures (p = 0.67).

Paclitaxel is an antimitotic agent that targets elements of the cancer phenotype, including cell proliferation, DNA repair, and apoptosis, predicting its broad activity in a spectrum of cancers. An oral paclitaxel formulation has been developed to overcome challenges associated with parenteral administration of this drug, notably the development of Cremophor-induced acute hypersensitivity reactions, which are particularly problematic in dogs. The aim of this open-label, dose-escalating study was to evaluate the tolerability and determine the maximum tolerated dosage (MTD) and dose-limiting toxicity (DLT) of oral paclitaxel when co-administered with the P-glycoprotein pump inhibitor, encequidar, in dogs with cancer. Paclitaxel was administered as a 3-consecutive-day course starting at 90 mg/m² with encequidar weekly for 3 weeks, using escalation of 30 mg/m² increments. MTD was established using a rolling-six dose escalation study design, based on the number of dogs experiencing any DLT assessed after each dosing cycle and during a 28-day post-treatment monitoring period. Nineteen client-owned dogs were enrolled. MTD was established at 90 mg/m² and the most frequent adverse events (AEs) were gastrointestinal, followed by hematologic, with the majority being self-resolving and low grade. VCOG Grades 3 and 4 gastrointestinal toxicity, Grade 4 neutropenia, and acute kidney injury were defined as DLTs at 120 mg/m². Conclusions of this study define oral paclitaxel MTD in cancer-bearing dogs at 90 mg/m² when given with encequidar for 3 consecutive days weekly for 3 weeks. Future Phase 2 trials evaluating the therapeutic activity of oral paclitaxel at its MTD co-administered with encequidar in defined tumour histologies are warranted.

An optimal protocol of adding wide-field irradiation to multi-agent chemotherapy for dogs with lymphoma has not been established. The aim of this retrospective case-control study was to evaluate the efficacy of a protocol combining chemotherapy and half-body irradiation (HBI) for dogs with high-grade lymphoma. Dogs in the treatment group received cranial HBI 2 weeks after completing the second cycle of the multi-agent chemotherapy protocol. The radiation therapy protocol consisted of 4 Gy/fraction once per day for 2 consecutive days for the cranial half body, followed by the same protocol for the caudal half 2 weeks later. The control group only received multi-agent chemotherapy. All patients were required to have cytological confirmation of high-grade lymphoma and achieve complete remission after two cycles of multi-agent chemotherapy. Fourteen patients receiving HBI and 11 patients in the control group were included. The median progression-free interval (PFI) in the HBI group (1143 days) was significantly longer than that in the control group (316 days, p = 0.004). In the HBI group, dogs with T cell lymphoma had statistically shorter PFI (292 days) than dogs with B cell lymphoma (2127 days, p = 0.0013). The median survival time in the HBI group (1924 days) was significantly longer than that in the chemotherapy-only group (566 days, p = 0.0077). The predictive factors for longer PFI and ST were found in the patients who received HBI and chemotherapy (p = 0.0062 and 0.0252, respectively). For chemotherapy-responding patients that completed a multi-agent protocol, HBI significantly prolonged the time to tumour relapse compared with the chemotherapy-only group.

Inflammatory mammary carcinoma (IMC) is the most aggressive variant of invasive mammary tumours in dogs and in women. Decorin is an extracellular matrix molecule whose expression can be reduced or absent in various human cancers, which is associated with a poor prognosis. E-cadherin is a cell adhesion protein whose expression is reduced in several neoplasms. However, it is overexpressed in inflammatory breast cancers of women. EGFR is also associated with cancer development and is commonly overexpressed in aggressive neoplasms. This study aimed to characterise the expressions of Decorin, E-cadherin, and EGFR in canine inflammatory and non-inflammatory mammary carcinomas (IMC and non-IMC) and to evaluate their expression levels as prognostic indicators for survival and occurrence of metastases. Thirty-three IMC and 43 non-IMC cases were analysed retrospectively and submitted to immunohistochemical analysis. The reactions were quantified in five high-power field images from areas of the highest intensity and frequency of immunostaining (hot spots). We found significantly lower expression of Decorin and higher of E-cadherin and EGFR in canine IMCs. Patients with tumours that exhibited Decorin expression in less than 26.35% of epithelial cells had shorter survival (p = 0.0410) and a higher occurrence of distant metastases (p = 0.0115). E-cadherin is overexpressed in canine IMCs (p < 0.0001), similar to what occurs in women, reinforcing that dogs can be used as a study model for human IMC. EGFR overexpression in canine IMCs (p = 0.0322) provides evidence for potential targeted therapy with tyrosine kinase inhibitors.

The treatment of canine transmissible venereal tumour (CTVT) has evolved since its initial description in 1810. Initially considered untreatable in the early 20th century, extensive research over time has significantly advanced our understanding of its aetiopathogenesis. This led to successful chemotherapy treatments, which have shown superior outcomes compared to surgical interventions. Vincristine, in particular, has proven effective in treating CTVT. However, the development of chemoresistance underscores the need to explore alternative therapeutic options. This systematic review provides a comprehensive analysis of CTVT treatment practices from 1950 to 2023, aiming to establish a gold standard and enhance clinical decision-making. Initially, 3633 studies were identified, with 42 meeting the eligibility criteria. Our findings suggest that vincristine sulphate monotherapy is the recommended first-line treatment for CTVT. Administering vincristine intravenously at a dosage of 0.5-0.75 mg/m² weekly for 4-6 sessions resulted in a 93.1% (67.4%-100%) complete response rate in dogs. Extending the treatment to eight sessions increased the complete response rate to 98.9% (83.3%-100%). Radiation therapy, lomustine and doxorubicin are viable second-line treatment options; however, extensive cohort studies are required to confirm their efficacy in achieving remission in vincristine-resistant cases. Additionally, no clear criteria could be established for initiating treatment with drugs other than vincristine in previously untreated dogs. Surgery is considered a third-line option. Notably, complete remission is anticipated following recommended systemic and local therapies in nearly all cases. Despite concerns about chemoresistance, current guidelines indicate a favourable response to suggested treatments even in resistant cases.

Early-delayed side effects (EDSEs) following treatment of canine intracranial meningiomas with 1-3-fraction stereotactic radiation therapy (SRT) can cause worsening neurologic signs, and one potential method of mitigating this toxicity is reducing the dose per fraction. Twenty dogs with imaging-diagnosed intracranial meningiomas and telephone follow-up of at least 6 months received a protocol of 6 Gy × 5, daily (30 Gy). A 'possible EDSE' was defined as mental dullness, neurologic exacerbation of existing neurologic signs or new neurologic signs occurring within 1-4 months of completing SRT, regardless of the response to steroids and even if an MRI was not performed. A 'probable EDSE' was defined as mental dullness, neurologic exacerbation of existing neurologic signs or new neurologic signs occurring within 1-4 months of completing SRT. These signs were either reversible with the initiation or increased doses of prednisolone, or follow-up MRI revealed no evidence of an alternate explanation. No dogs experienced acute radiotoxicity or clinical signs compatible with EDSEs. The protocol appears to result in limited acute radiotoxicity, and further evaluation of the frequency of long-term toxicities and relative efficacy should be undertaken.

Chemokine (C-C motif) ligand 2 (CCL2) is a strong monocyte chemoattractant that has been shown to be increased in humans and dogs with neoplasia. Although in human urothelial carcinoma (UCa) CCL2 levels increase with metastatic disease, a previous study showed an opposite trend in dogs. The aim of this study was to assess serum CCL2 levels in dogs with mast cell tumours (MCT) and insulinoma with or without metastasis. The second aim was to evaluate any correlation between CCL2 serum levels and circulating monocyte counts in UCa, MCT and insulinoma. Serum CCL2 levels were significantly higher in dogs affected with MCT or insulinoma compared to healthy dogs (p = 0.002 and p = 0.017, respectively). Furthermore, low levels of serum CCL2 were associated with metastasis in insulinoma-affected dogs (p = 0.04) similarly to UCa-affected dogs. However, in the MCT group, low levels of serum CCL2 were associated with non-metastatic disease (p = 0.0045). Based on receiver operating characteristic (ROC) curves, optimal cut-off values were determined for CCL2 concentration in order to calculate sensitivity and specificity of the test. Good accuracy was reached for CCL2 as a diagnostic marker, but it was poor as a staging marker. In conclusion, a dual role of CCL2 has been shown in different tumour types. A low level of CCL2 was associated with metastatic disease in dogs with insulinoma similarly to UCa-affected dogs. In contrast, a low level of CCL2 was associated with a non-metastatic disease in dogs with MCT. There was only a moderate correlation between CCL2 and circulating monocyte count in our study in both Uca and MCT, and a fair opposite correlation in insulinoma, leading to hypothesise that the influx of monocytes may be better observed in the tumour itself rather than in the circulation. These results could help to further understand CCL2 in the tumour microenvironment and its possibility as a therapeutic target.

For human and canine invasive urothelial carcinoma (InvUC), there is growing interest in using the molecular characteristics of a tumour to guide individualised treatment strategies. The objective of this study was to use a non-invasive, urine-based method to characterise gene expression signatures in dogs with InvUC. RNA was isolated from canine InvUC tumour samples, urine sediment from dogs with InvUC, normal canine bladder mucosa, and normal canine urine sediment and queried using the nCounter Canine Immuno-Oncology Panel. Differential gene expression profiles were characterised for tissue and urine samples, and nCounter results were compared to bulk RNA-seq gene expression profiles. The effect of spiking normal urine with white blood cells (WBCs) from the same dog was also assessed. Key genes involved in antitumor immune responses and oncogenic signalling pathways, including potential small molecule inhibitor targets, were differentially expressed in tumour and urine samples from dogs with InvUC, compared to normal samples. nCounter-generated gene expression profiles for tumour tissue and urine from dogs with InvUC were highly correlated, whereas the correlation between the nCounter IO panel and bulk RNA-seq results for InvUC tissue was moderate. The addition of WBCs to normal urine affected the gene expression profiles. Analysis of canine urine using the nCounter canine IO panel has good potential for revealing gene expression patterns in InvUC. Additional studies are warranted to determine the extent to which WBC infiltration affects the results related to immune response patterns and the expression of other genes.

Canine oral melanoma (OM) exhibits poor prognosis and limited treatment options. The success of immune checkpoint inhibitors (ICIs) in human melanoma has driven interest in similar therapeutic approaches in the dog, although the immunosuppressive mechanisms adopted by canine OM remain unclear. This study aimed to evaluate the expression of the immune checkpoints PD-1/PD-L1 and CTLA-4 by RNAscope in situ hybridization (ISH) in canine OM, to investigate their expression pattern and explore their potential role in melanoma progression. Twenty-four formalin-fixed, paraffin-embedded canine OM were included in the study. PD-L1 expression by tumour cells was detected in 100% melanomas (score 1-3), especially at the host-tumour interface. PD-1 and CTLA-4 expression by tumour cells was detected in 13/24 (54%, score 1-2) and 18/24 (75%, score 1) melanomas, respectively. Dual ISH-immunohistochemistry with Melanoma Triple Cocktail, CD3, CD20 and Iba1 demonstrated the expression of tested immune checkpoints in neoplastic and immune cells. Notably, PD-1 and CTLA-4 were predominantly expressed by tumour-infiltrating T lymphocytes, while PD-L1 was primarily expressed by tumour-associated macrophages. PD-1 expression in neoplastic cells was significantly correlated with mitotic count (p < 0.05), while no associations were found between immune checkpoint expression and disease-free interval or overall survival. Whole tumour PD-L1 and PD-1 expression, assessed by image analysis, correlated to PD-L1 scores in neoplastic cells and the grade of tumour-infiltrating lymphocytes, respectively. Collectively, PD-L1, PD-1 and CTLA-4 likely contribute to immunosuppression in canine OM. Further studies are warranted to investigate whether ISH can serve as a biomarker for selecting patients suitable for ICI treatment.