Increasing evidence indicates that the tumor microenvironment plays a critical role in regulating the biologic behavior of breast cancer. In veterinary oncology, there is a need for improved prognostic markers to accurately identify dogs at risk for local and distant (metastatic) recurrence of mammary gland carcinoma and therefore would benefit from adjuvant therapy. Collagen density and fiber organization have been shown to regulate tumor progression in both mouse and human mammary tumors, with certain collagen signatures predicting poor outcomes in women with breast cancer. We hypothesized that collagen signatures in canine mammary tumor biopsies can serve as prognostic biomarkers and potential targets for treatment. We used second harmonic generation imaging to evaluate fibrillar collagen density, the presence of a tumor-stromal boundary, tumor associated collagen signatures (TACS) and individual collagen fiber characteristics (width, length and straightness) in grade I/II and grade III canine mammary tumors. Collagen density, as well as fiber width, length and straightness, were inversely correlated with patient overall survival time. Notably, grade III cases were less likely to have a tumor-stromal boundary and the lack of a boundary predicted poor outcome. Importantly, a lack of a defined tumor-stromal boundary and an increased collagen fiber width were associated with decreased survival even when tumor grade, patient stage, ovariohysterectomy status at the time of mammary tumor excision, and histologic evidence of lymphovascular invasion were considered in a multivariable model, indicating that these parameters could augment current methods to identify patients at high risk for local or metastatic progression/recurrence. Furthermore, these data, which identify for the first time, prognostic collagen biomarkers in naturally occurring mammary gland neoplasia in the dog, support the use of the dog as a translational model for tumor-stromal interactions in breast cancer.
Olfactory neuroblastoma (ONB) is a rare intranasal neoplasm in both dogs and humans. Similar clinical presentation and overlapping histologic and immunohistochemical features of ONB with other intranasal neoplasms can make diagnosis and treatment of intranasal neoplasia challenging. Furthermore, in part because of their rarity, there is a lack of reporting on therapeutic regimen for these neoplasms. In humans, initial debulking surgery is usually followed by radiation therapy. Here we report on the histologic, immunohistochemical, and ultrastructural characteristics of canine ONB and report on the clinical progression of cases treated with radiation therapy. In all nine canine ONB examined here, neoplastic cells were arranged in a lobular manner amidst a prominent neurofibrillary matrix and had features consistent with Grade III (high grade) ONB. The neoplastic cells demonstrated positive immunohistochemical staining for TuJ-1, a Class III beta-tubulin neuronal cytoskeletal protein, and variable staining for other markers, including chromogranin, synaptophysin,
Objectives The aims of this study were to evaluate the safety of mustargen, vincristine, procarbazine and prednisone (MOPP) chemotherapy in the treatment of relapsed or refractory feline lymphoma, and to determine the overall response rate and median remission time with this protocol. Methods The medical records of 38 cats with relapsed or refractory lymphoma treated with MOPP chemotherapy at three institutions (University of Pennsylvania, the Animal Medical Center, and VCA Western Veterinary Specialist and Emergency Centre) were examined. Information evaluated included patient signalment, feline immunodeficiency virus/feline leukemia virus status, anatomic location(s) of lymphoma, prior protocols (type and number), MOPP doses, MOPP response, remission duration, hematologic and biochemical parameters, and owner-reported adverse effects. Results Overall, 70.3% of cats responded to MOPP chemotherapy. Among the responders, the median remission duration was 166 days. The most common adverse effects were neutropenia and gastrointestinal upset, which were reported in 18.4% of cats. In 55.3% of cats, no adverse effects were reported. In total, 30.8% of responders continued to respond 6 months following the initiation of MOPP, and 15.4% maintained a response 1 year after starting MOPP. Conclusions and relevance MOPP is a safe protocol for the treatment of relapsed or refractory feline lymphoma, with a promising overall response rate and median remission time.
Sorafenib is a multi-kinase small molecule inhibitor that targets serine/threonine and tyrosine kinases including the RAF kinase family, VEGFR-2, and PDGFR. The aim of this study was to evaluate the systemic pharmacokinetics of a previously defined tolerable oral dose of sorafenib in tumor-bearing dogs. Six client-owned dogs with a cytologic or histologic diagnosis of cancer were enrolled in this open-label, tolerability study. Dogs were administered sorafenib at an intended dose of 3 mg/kg and serum samples were obtained for analysis of sorafenib serum concentrations at 0, 1, 2, 6, 12, 24, 48, 72, 96, and 168 h post-drug administration. Median time to peak serum sorafenib concentration occurred at 4 h (range 2–12 h) resulting in an average serum concentration of 54.9 ± 33.5 ng/mL (118.2 ± 72.1 nM). Mean sorafenib levels declined by over 70% relative to peak serum concentrations by 24 h in all dogs, suggesting the value of at least twice daily administration. Doses of 3 mg/kg were well-tolerated and no patients in the study experienced adverse events that were attributable to sorafenib. Future trials in dogs with cancer are recommended at this dosing schedule to assess the effect of sorafenib administration on anti-tumor efficacy signals and relevant pharmacodynamic target modulation in vivo.
A 3-year-old male castrated Boxer was referred to the University of California-Davis William R. Pritchard Veterinary Medical Teaching Hospital to further evaluate episodes of epistaxis of 1-year duration. The dog was adopted at approximately 6 months of age in the northern region of California (Petaluma, CA) and had no travel history outside of this region. Additional clinical history included urinary incontinence, resolved chronic pancreatitis, and waxing and waning allergic dermatitis, which was considered most likely seasonal. According to anamnesis, the only instituted therapy was cetirizine hydrochloride. Upon physical examination, moderate bilateral mandibular and superficial cervical lymphadenomegaly (up to 3.5 cm) was noted. There was alopecia with erythema and mild lichenification along the distal limbs, but no other overt clinical abnormalities were observed. Ultrasonographic examination of the abdominal cavity revealed mild generalized abdominal lymphadenopathy and hypoechoic hepatomegaly. The thoracic radiographic examination was unremarkable. A CBC (ADVIA 120 automated analyzer, Siemens Healthcare Diagnostics, Munich, Germany) revealed microcytic (MCV = 60 fL, RI 65-75) normochromic nonregenerative (19 500 reticulocytes/ µL, RI 7000-65 000) moderate anemia (PCV = 29%, RI 40-55) and moderate lymphopenia (438 cells/µL, RI 1000-4000). On serum biochemistry (Cobas 6000 C501 analyzer, Roche, Basel, Switzerland), marked hyperglobulinemia (10.9 g/dL, RI 1.7-3.1), moderate hypoalbuminemia (2.1 g/dL, RI 3.4-4.3), and mild hypocholesterolemia (129 mg/dL, IR 139-353) were noted. Protein electrophoresis revealed a broad-based peak bridging the beta and gamma globulin regions, indicating a polyclonal gammopathy for which the presence
Cyclophosphamide (CP) is an alkylating agent commonly included in multi-drug treatment protocols for canine cancer. As a prodrug, CP requires hepatic metabolism for activation to the intermediate compound 4-hydroxycyclophosphamide (4-OHCP) which then spontaneously forms alkylating phosphoramide mustard. CP is frequently administered in a fractionated manner, with the total dose given over multiple days.CP is reported to cause auto-induction of metabolism in humans, with faster CP clearance and relatively increased 4-OHCP formation following fractionated versus bolus dosing, however canine pharmacokinetic studies of CP dose fractionation are lacking. The study objective was to evaluate the pharmacokinetics of fractionated oral CP dosing at a dose of 200-250 mg/m 2 over 3 to 4 days in a prospectively identified population of cancer-bearing dogs. Plasma concentrations of CP and 4-OHCP were measured by ultra-high performance liquid chromatography tandem-mass spectrometry in eight dogs following the first and last doses to assess for auto-induction of CP metabolism. No significant difference in the rate of CP elimination between first and last doses were detected (0.73 ± 0.46 vs. 1.22 ± 0.5 h À1 ; p = .125). Additionally, no significant difference in dose-normalized 4-OHCP exposure was identified between first and last doses (5.9 ± 2.1 vs. 7.9 ± 6.4 h  ng/ml; p = .936). These results suggest that fractionated dosing may not increase exposure to the active metabolite of CP in dogs as it does in humans. As such, standard bolus dosing and fractionated dosing may be equivalent in terms of bio-activation of CP in dogs administered a dose of 200-250 mg/m 2 .
The cover image is based on the SHORT COMMUNICATION Clinical outcomes, ultrastructure and immunohistochemical features of canine high‐grade olfactory neuroblastoma by Molly E. Church et al., https://doi.org/https://doi.org/10.1111/vco.12512.
Background While rare, multiple individual case reports have described mixed thyroid tumours in dogs containing both epithelial and mesenchymal neoplastic components. Objectives In this retrospective case series, we describe the clinical presentation, treatment and outcome of 14 dogs of canine thyroid tumours with concurrent mesenchymal and epithelial neoplastic populations. Methods Fourteen cases were retrospectively abstracted from nine institutions. Histopathologic samples and reports were collected from 10/14 dogs and reviewed by a single board‐certified anatomic pathologist. Results All 14 dogs had curative‐intent surgery to remove the thyroid neoplasm. The most common surgery performed was a unilateral thyroidectomy (10/14 dogs). Postoperatively, systemic therapy was administered in eight dogs. Six dogs developed local recurrence with a median time to loco‐regional recurrence of 53 days. Ten dogs developed metastatic disease with the most common metastatic site being the lungs (6/10 dogs), with a median time to metastasis of 93 days. Ten dogs were euthanised due to locoregional or distant progression of their mixed thyroid neoplasm. The overall median survival time was 156 days (95%CI: 49–244). The median survival time for dogs treated with adjuvant therapy was 189 days (95%CI: 24–244), whereas dogs without adjuvant therapy had a median survival time of 156 days (95%CI: 35‐upper limit could not be calculated; p = 0.62). Conclusion The thyroid tumours with both mesenchymal and epithelial components in this small sample set were associated with a poor prognosis after surgical excision with or without adjunctive therapy.
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