Veterinary and comparative oncology最新文献

Canine mucosal melanoma (CMM) is the most common oral malignancy in dogs and is significantly more aggressive than its cutaneous counterpart (CCM), yet the reasons for this disparity remain unclear. Cancer-associated stroma (CAS) plays a crucial role in tumour progression, but a detailed understanding of CAS in canine melanoma is missing. To assess stromal reprogramming, we analysed CAS from 21 CMM, 14 CCM and normal stroma from 10 skin and 9 oral mucosa samples by laser-capture microdissection followed by RNA sequencing. Results were assessed in relation to subtypes, prognostic factors including mitotic count (MC), ulceration, necrosis, pigmentation and immune cell infiltration (CD3, CD20 and CD68), scored using immunohistochemistry and RNA in situ hybridisation. Stromal reprogramming was evident in both subtypes but significantly more pronounced in CMM. Immune-excluded tumours exhibited higher MC than desert/cold ones. MC strongly correlated with genes associated with B-cells, T-helper cells and CTLA4 in CCM, suggesting CAS reprogramming to depend on tumour malignancy. Finally, we identify an immune-suppressive stromal signature in a subset of CMM characterised by the downregulation of key immune checkpoints and pathways. Together, these findings provide a solid foundation for understanding the role of CAS in canine melanoma, specific to cutaneous and mucosal subtypes.

Pre-metastatic niche (PMN) formation is essential for metastatic development and drives organotropism. Tumour-derived extracellular vesicles and soluble factors remodel the microenvironment of distant metastatic organs before subsequent metastasis. Dogs with osteosarcoma (OS) have proven to be excellent disease models for their human companions. Here, we show evidence of PMN formation in dogs with OS before metastasis. We necropsied and sampled lung tissues from dogs with naturally occurring treatment-naïve OS (n = 15) and control dogs without cancer (n = 10). We further divided dogs with OS into those having lung metastases (n = 5) and those without (n = 10). We stained formalin-fixed paraffin-embedded tissues using multiplex immunofluorescence to quantify the number of bone marrow-derived cells, monocytes and macrophages in the lung samples from each dog. The numbers of CD204⁺ macrophages, CD206⁺ macrophages and monocytes and CD11d⁺ bone marrow-derived cells (BMDCs) were significantly higher in the pre-metastatic lung of dogs with OS (n = 10) than in control dogs without cancer (n = 10). Furthermore, the total nucleated cell (DAPI⁺) density was higher before metastasis than in healthy lungs. In dogs with established metastases, the number of CD11d⁺ BMDCs was significantly lower than in the pre-metastatic lung, suggesting this recruitment is transient. Our study provides evidence of PMN existence in a naturally occurring cancer model similar to those observed in pre-clinical murine models. BMDCs are recruited to the lungs before metastases have developed. Dogs with OS may represent ideal candidates for assessing new PMN-targeting therapies.

CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosurea), lomustine, is an oral alkylating agent in the nitrosourea subgroup. The dose-limiting toxicity of CCNU is neutropenia most frequently documented 7 days after its administration. Use of prophylactic antimicrobials to prevent chemotherapy-related febrile neutropenia (FN) and its associated morbidity and mortality has been well-documented in human oncology, but this information is limited in the veterinary literature. The purpose of this multi-institutional retrospective study was to assess whether antimicrobial prophylaxis reduced the risk of FN approximately 7 days after CCNU administration in tumour-bearing dogs. A secondary goal was to identify risk factors for fever development in neutropenic dogs. Two hundred dogs were included in the study. One hundred and fifty-three dogs (76.5%) were neutropenic at the first post-CCNU recheck. One hundred and six (69.3%) dogs received prophylactic antimicrobials and 47 (30.7%) did not. Of the 106 dogs on prophylactic antimicrobials, 8 (7.5%) developed FN. Of the 47 dogs in the no-prophylactic antimicrobials group, 4 (8.5%) developed FN. Use of prophylactic antimicrobials did not reduce the risk of development of FN (p = 0.84). Older age (> 9 y), lower weight and body surface area, and pre-treatment with chemotherapy or radiation therapy were significantly associated with development of FN (p = 0.009, p = 0.023, p = 0.015 and p = 0.01). Patients with a lower absolute neutrophil count, and a higher VCOG-CTCAE v2 neutropenia grade were also at an increased risk of developing FN (p = 0.01, p < 0.001). Additional studies may help establish guidelines for antimicrobial prophylaxis in dogs treated with CCNU, especially for those at high-risk for FN.

Canine lymphoma represents a biologically and metabolically heterogeneous group of neoplasms that arise from malignant transformation of lymphoid cells. An accurate diagnosis is crucial because of its impact on survival. Current diagnostic methods include clinical laboratory tests and imaging, most of which are invasive and lack sensitivity and specificity. Interestingly, recent work in cancer patients focuses on the search for biomarkers for diagnosis, investigation of treatment response mechanisms, treatment efficacy and prognosis and the discovery of tumour metabolic pathways using metabolomic analysis. In this study, we compare the metabolite profiles in serum from 37 dogs with multicentric lymphoma (22 B-cell lymphomas/LB, 9 CD45+ T-cell lymphomas/LTCD45+, 6 CD45- T-cell lymphomas/LTCD45-) and 25 healthy dogs using ¹H nuclear magnetic resonance spectroscopy (NMR). ¹H NMR-based metabolite profiling analysis recognised lipids and 22 metabolites, with 16 of them altered, and was shown to be an effective approach for differentiating samples from dogs with lymphoma and healthy controls based on principal component analysis of the NMR data. We also investigated variations in the serum metabolome between immunophenotypes and the control group through pairwise comparisons of the healthy against the LB, LTCD45+ and LTCD45- groups, respectively which showed similar metabolomic profiles. In addition, there were significant differences in the levels of five individual metabolites based on the univariate statistical analysis. Our results showed alterations in energy, protein and lipid metabolism, suggesting glucose, lactate, N-acetyl glycoproteins (NAGs), scyllo-inositol and choline as possible new candidate biomarkers in canine multicentric lymphoma.

Canine mast cell tumours (MCTs) are one of the most common skin cancers of dogs. Surgical removal is the primary treatment, but recurrence and metastasis can occur even with low-grade tumours. As a result, new treatment strategies are being sought. We tested the potential of several oncolytic viruses (OVs) to infect and kill a cell line isolated from a canine MCT. Employing a resazurin-based metabolic assay and flow cytometry technology, we used recombinant vesicular stomatitis virus (rVSV-Δm51), avian orthoavulavirus-1 (AOaV-1), and Orf viruses in our assessment. Our study aimed to evaluate the potential of oncolytic virotherapy in treating canine cancers. We found that MCT-1 cells showed different sensitivities to the OVs, with rVSV-Δm51 showing the most promising results in vitro. These findings suggest that further investigation into using OVs for treating canine MCTs is needed, although clinical efficacy is yet to be determined.

The standard of care treatment for localised feline nasal lymphoma (FeNL) is radiation therapy (RT). Early local or systemic failure occurs in 17%-45% of cats treated with RT with or without chemotherapy. The aim of this study was to determine if pre-treatment biopsy characteristics could predict early tumour progression in FeNL. Inclusion criteria consisted of histologically confirmed FeNL, available paraffin blocks of diagnostic quality, localised to the sinonasal cavity on staging pre-RT, treated with IMRT/IGRT (10 × 4.2 Gy) without chemotherapy and at least 1 year follow-up. All pre-RT biopsies were reviewed and evaluated with CD3, CD20, CD79a, pan-CK and Ki-67 immunohistochemistry and the mitotic activity index was determined. The primary endpoint was progression-free survival (PFS) at 1 year and hazard-ratios (HR) with confidence interval (CI) were calculated. Twenty-eight cats fit the inclusion criteria, and all had diffuse large B-cell lymphoma. Seventeen cats (61%) were progression free at 1 year. Of the 11 cats that progressed in the first year, two had local progression, two had both local and systemic progression and seven had systemic progression. The mitotic index (HR: 1.03, CI 0.9-1.19, p = 0.645), Ki-67 (HR: 1.00, CI 0.98-1.02, p = 0.845) and > 30% of tumour-infiltrating T cells (HR: 0.38, CI 0.09-1.56, p = 0.175) were not significantly associated with PFS. In this uniformly RT treated population of FeNL, none of the evaluated pre-RT histologic parameters could predict early treatment failure.

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.

In human medicine, the choice of medical terminology influences patients' choice of management options and associated anxiety levels in relation to their diagnoses. The objective of this study was to determine the association between canine caregiver's treatment choices and anxiety levels when papillary thyroid cancer is described with or without the term cancer. This randomised cross-sectional study surveyed 683 people over 18 years old over 8.5 months. Respondents ranked their treatment preference (total thyroidectomy, active surveillance, medical therapy, or radiation therapy) following a scenario-based diagnosis of papillary thyroid cancer (PTC), thyroid papillary lesion (TPL) or abnormal cells (AC) in their canine pet. Respondents stated their level of anxiety associated with the diagnosis and treatment choice. Of 683 respondents, 622 (91.7%) were female. When presented with a diagnosis of PTC, TPL or AC, 78.1%, 34.2% and 59.3% of participants, respectively, reported being anxious or very anxious about this diagnosis (p < 0.01). Surgery was chosen as a first-choice treatment for PTC, TPL and AC by 71.8%, 39.8% and 53.8% of respondents, respectively, whereas active surveillance was chosen as a first-choice treatment by 24.5%, 57.5% and 43.9% of respondents, respectively. There was a statistically significant difference in first-choice treatment selection (p < 0.01) and anxiety levels related to treatment (p < 0.01) between the three different terms. The terminology used when presenting caregivers with a diagnosis of PTC influences treatment choices and levels of anxiety.

Feline oral squamous cell carcinoma (FOSCC) is the most common oral malignancy in cats. In general, FOSCC develops rapidly and is highly locally invasive. The existing treatments for treating FOSCC are limited. The objective of this single-centre retrospective cohort study was to report the prognosis and surgical complications in cats that underwent total glosso-mandibulectomy (TGM) for feline oral squamous cell carcinoma (FOSCC). We investigated the medical records of 20 cats diagnosed with FOSCC by histopathologic examination and treated with TGM. The locations of FOSCC were in the mandible and tongue in 12 and 8 cats, respectively. All cats underwent percutaneous endoscopic gastrostomy. Postoperative complications of TGM were observed in 18 (90.0%) cats; incisional swelling was noted in 11 cats, including three cats with airway obstruction requiring management by tracheal intubation for several days. Postoperative anaemia was observed in 10 cats; two cats required blood transfusions. No cats died during the postoperative period. Progression-free interval (PFI) and overall survival time (OST) were 914 and 533 days, respectively. The 1- and 2-year survival rates were 50.2% and 37.8%, respectively. On univariate analysis, only histopathologic margin was associated with PFI and OST. TGM was successful in achieving long-term survival for FOSCC. Conversely, lifelong nutritional support via a gastrostomy tube and routine home care, including the removal of secretions from the palate and throat, was needed. There were no perioperative deaths, but serious complications occurred in some cats. The histopathologic margin was an important prognostic factor.

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.