Malignant transformation and subsequent leptomeningeal carcinomatosis of a gastric polyp in a dog.

Progressive carcinogenesis of a gastric polyp with transformation to gastric adenocarcinoma and subsequent development of leptomeningeal carcinomatosis is described in an adult male Scottish terrier. Presenting clinical signs consisted of vomiting with intermittent hematemesis. Surgical biopsies over the course of 14 months documented the progression from gastric polyp to minimally invasive gastric carcinoma to invasive gastric adenocarcinoma, a pathogenesis not previously documented in veterinary oncology. The patient ultimately developed neurologic pathology and was euthanized, and necropsy evaluation identified widespread carcinomatosis with accompanying leptomeningeal metastasis. As in humans, gastric polyps in dogs rarely have malignant potential.

Quantification of CD3, FoxP3, and granzyme B immunostaining in canine renal cell carcinoma.

Tumor-infiltrating lymphocyte (TIL) density plays an important role in anti-tumor immunity and is associated with patient outcome in various human and canine malignancies. As a first assessment of the immune landscape of the tumor microenvironment in canine renal cell carcinoma (RCC), we retrospectively analyzed clinical data and quantified CD3, FoxP3, and granzyme B immunostaining in formalin-fixed paraffin-embedded tumor samples from 16 dogs diagnosed with renal cell carcinoma treated with ureteronephrectomy. Cell density was low for all markers evaluated. Increased numbers of intratumoral FoxP3 labelled (+) cells, as well as decreased granzyme B+: FoxP3+ TIL ratio, were associated with poor patient outcomes. Our initial study of canine RCC reveals that these tumors are immunologically cold and Tregs may play an important role in immune evasion.

Clinical outcomes in cats with renal carcinoma undergoing nephrectomy: A retrospective study.

Renal carcinomas (RC) are uncommonly encountered in feline medicine. Limited information regarding clinical presentation and postoperative outcomes is available. The purpose of this multi-institutional, retrospective study was to describe the presenting features and clinical outcomes of cats with RC undergoing nephrectomy. Thirty-six client-owned cats were included. Medical records from participating institutions were searched to identify cats that had a histopathologic diagnosis of RC and underwent nephrectomy from January 2001 to October 2021. The most common presenting complaints were weight loss (36.1%) and hyporexia (30.6%). Based on preoperative imaging and intraoperative findings, eight cats had suspected metastasis at the time of surgery (22.2%). Twenty-eight cats survived to discharge (77.8%). Median progression free interval (PFI) could not be determined, as only six cats developed suspected recurrence (16.7%) and seven cats developed suspected metastasis (19.4%). The all-cause median survival time (MST) was 203 days (95% confidence interval [CI]: 84, 1379 days). When cases that died prior to discharge were excluded, MST increased to 1217 days (95% CI: 127, 1641 days). One-year, two-year, and three-year survival rates were all 40.4%. Neither renal tumour histologic subtype nor the presence of preoperative azotemia, anaemia, erythrocytosis, haematuria, or suspected metastasis at diagnosis were found to influence survival. For cats surviving to discharge, prolonged survival times were possible. Further studies are necessary to elucidate other potential prognostic factors, the utility of postoperative adjuvant treatment, and to identify cats at-risk of mortality in the perioperative period.

Evaluation of mechlorethamine, vinblastine, procarbazine, and prednisone for the treatment of resistant multicentric canine lymphoma.

Multi-agent chemotherapy successfully induces remission in most naïve, high-grade canine lymphoma patients; however, disease recurrence is common. MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) is an effective rescue protocol used to re-induce remission, but is associated with gastrointestinal toxicity and can be a less desirable option for patients that previously failed vincristine-containing protocols. Therefore, alternative members of the vinca alkaloid family, such as vinblastine, could be potentially advantageous as substitutes for vincristine to reduce gastrointestinal toxicity and chemoresistance. The objective of this study was to report the clinical outcomes and toxicity of 36 dogs with relapsed or refractory multicentric lymphoma treated with a modified MOPP protocol whereby vincristine was replaced with vinblastine (MVPP). The overall response rate to MVPP was 25% with a median progression free survival of 15 days and a median overall survival of 45 days. MVPP at the prescribed doses resulted in modest and transient clinical benefit, but was well tolerated with no treatment delays or hospitalizations secondary to side effects. Given the minimal toxicity, dose intensification could be considered to improve clinical responses.

Calculation of dose intensity and comparison of published methods using a cohort of canine T-cell lymphoma patients undergoing CHOP-based chemotherapy.

Methods of calculating and reporting dose intensity (DI) of CHOP-based protocols in the veterinary literature vary. The goal of this retrospective study is to examine the prognostic significance of the average percentage of planned DI received in a cohort of canine T-cell lymphoma patients treated with a modified CHOP protocol with corresponding toxicity and efficacy data. Our data set of 40 dogs was analysed using various previously published methods for calculating DI. Median progression-free survival and overall survival were 91 and 196 days, respectively. Receiving a higher percentage of planned DI was not found to be associated with patient outcome. Outcomes remain poor for dogs with T-cell lymphoma treated with CHOP-based chemotherapy irrespective of received DI. Standard methods of DI calculation and reporting should be adopted in veterinary oncology to enable repeatable and rigorous comparisons of published chemotherapy protocols and to ascertain the potential prognostic relevance of DI in canine lymphoma patients.

Evaluation of the anti-tumour activity of Coriolus versicolor polysaccharopeptide (I'm-Yunity) alone or in combination with doxorubicin for canine splenic hemangiosarcoma.

Canine splenic hemangiosarcoma (HSA) is an aggressive tumour of vascular endothelium that carries a grave prognosis following standard of care treatment with surgery and doxorubicin. A previous pilot study revealed potential anti-tumour activity of I'm-Yunity polysaccharopeptide (PSP) for canine HSA. The aim of this prospective study was to assess patient outcome when treated with PSP alone or in combination with doxorubicin post-splenectomy compared to patients treated with surgery and doxorubicin that received a placebo in place of PSP. Dogs undergoing splenectomy for splenic HSA were eligible. Following splenectomy, owners were offered treatment with PSP alone or adjuvant doxorubicin chemotherapy (unblinded). Patients with owners that selected to proceed with doxorubicin chemotherapy were blindly randomized to receive placebo or PSP. Dogs were evaluated weekly for 15 weeks, then scheduled for monthly visits until death. One hundred and one dogs were included in the final analysis: 51 PSP alone, 25 doxorubicin/placebo, and 25 combination PSP/doxorubicin. On multivariate analysis, dogs treated with single agent PSP, female dogs, decreased haematocrit at diagnosis, and stage III disease were negatively significantly associated with outcome; however, an interaction between treatment group and sex was documented. Gender-specific outcomes revealed no significant difference in survival between treatment groups for male dogs, but female dogs treated with PSP alone had significantly reduced survival compared to females receiving doxorubicin/placebo (HR 0.21; p = .004). Anaemia (HR 5.28; p < .001) and stage III disease (HR 2.9; p = .014) remained negatively associated with survival when controlling for sex and treatment group. The addition of PSP to doxorubicin post-splenectomy did not improve survival in dogs with splenic HSA.

Increased tumor-infiltrating lymphocyte density is associated with favorable outcomes in a comparative study of canine histiocytic sarcoma.

Histiocytic sarcoma (HS) is a rare and aggressive tumor in humans with no universally agreed standard of care therapy. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Previous data allude to the immunogenicity of this disease in both species, highlighting the potential for their successful treatment with immunotherapy. Quantification of CD3 tumor-infiltrating lymphocytes (TIL) in five cases of human HS revealed variable intra-tumoral T cell infiltration. Due to the paucity of human cases and lack of current model systems in which to appraise associations between anti-tumor immunity and treatment-outcome in HS, we analyzed clinical data and quantified TIL in 18 dogs that were previously diagnosed with localized HS and treated with curative-intent tumor resection with or without adjuvant chemotherapy. As in humans, assessment of TIL in biopsy tissues taken at diagnosis reveal a spectrum of immunologically "cold" to "hot" tumors. Importantly, we show that increased CD3 and granzyme B TIL are positively associated with favorable outcomes in dogs following surgical resection. NanoString transcriptional analyses revealed increased T cell and antigen presentation transcripts associated with prolonged survival in canine pulmonary HS and a decreased tumor immunogenicity profile associated with shorter survivals in splenic HS. Based on these findings, we propose that spontaneous canine HS is an accessible and powerful novel model to study tumor immunology and will provide a unique platform to preclinically appraise the efficacy and tolerability of anti-cancer immunotherapies for HS.

Extracellular Vesicles Secreted by Tumor Cells Promote the Generation of Suppressive Monocytes.

Monocytes are among the first cells to infiltrate the tumor microenvironment. The conversion of monocytes to suppressor cells in the tumor microenvironment is crucial in evasion of the immune response and tumor maintenance. Tumor cells may secrete products that promote the conversion of monocytes to suppressor cells. Cells secrete extracellular vesicles (EVs) containing cargos of genetic materials and proteins as a way to communicate with neighboring cells. During pathologic conditions like cancers, tumor cells increase their EVs production containing microRNA, RNA, and proteins that may affect the immune cell response, contributing to the immunosuppressive microenvironment. Our studies show that EVs secreted by a wide range of murine tumor cells, including osteosarcoma, glioma, colon carcinoma, sarcoma, and melanoma, can be taken up by bone marrow-derived monocytes. The monocytes that took up the EVs secreted by tumor cells matured toward an immune-suppressive phenotype by upregulating the expression of suppressive cytokines and effector molecules. The monocytes also downregulated MHC class II and costimulatory molecules while increasing the expression of PD-L1 on their surface after taking up EVs from tumor cells. Most importantly, monocytes exposed to EVs secreted by tumor cells suppressed activated Ag-specific CD4+ T cells. These results show that tumor cells from several different tumor types secrete EVs which promote the conversion of monocytes into suppressor cells, thus promoting immune evasion. These studies suggest that EVs secreted by tumors are potentially a new target for future cancer therapy.

Response-based modification of CHOP chemotherapy for canine B-cell lymphoma.

Despite high initial response rates, a subset of dogs with B-cell lymphoma responds less robustly to CHOP-based chemotherapy and experiences shorter survival. One hundred and four dogs with nodal B-cell lymphoma were treated with a response-based CHOP (RBCHOP) protocol modified based on response to individual drugs during the first chemotherapy cycle. Dogs achieving complete (CR) or partial response (PR) at week 3, following treatment with vincristine and cyclophosphamide, received RBCHOP 1 (n = 72), a protocol sequentially rotating vincristine, cyclophosphamide, and doxorubicin. Dogs without a detectable response at week 3 that subsequently achieved CR or PR following treatment with doxorubicin received RBCHOP 2 (n = 14), in which four doses of doxorubicin were given consecutively followed by vincristine and cyclophosphamide. Dogs that failed to respond at week 3 and then to doxorubicin at week 5 assessment were offered rescue chemotherapy (RBCHOP 3, n = 18). Median progression free survival (PFS) and overall survival time (OST) were similar between RBCHOP 1 (PFS 210 days, OST 354 days) and RBCHOP 2 (PFS 220 days, OST 456 days), but significantly shorter for RBCHOP 3 (PFS 34 days, OST 80.5 days, P < 0.001). No presenting signalment nor hematologic variable differentiated patient cohort, however, dogs in RBCHOP 2 and RBCHOP 3 were more likely to have a lymphocytosis at diagnosis (P = 0.02 and 0.04, respectively). Protocol modification based on response during the first cycle resulted in similar toxicity profiles and outcomes to previously published variants of CHOP, and prognosis remained poor for dogs failing to respond during the first treatment cycle.

Sarcomas-A barren immunological wasteland or field of opportunity for immunotherapy?

Key advances in our understanding of immunobiology and the immunosuppressive mechanisms of the tumour microenvironment have led to significant breakthroughs in manipulating the immune system to successfully treat cancer. Remarkable therapeutic responses have occurred with tumours that carry a high mutational burden. In these cases, pre-existing tumour-specific T cells can be rejuvenated via checkpoint inhibition to eliminate tumours. Furthermore, durable remissions have been achieved in haematological malignancies following adoptive transfer of T cells that specifically target cell surface proteins where expression is restricted to the malignancy's cell of origin. Soft tissue sarcomas and bone sarcomas have a paucity of non-synonymous somatic mutations and do not commonly express known, targetable, tumour-specific antigens. Historically, soft tissue sarcomas have been considered immunologically 'cold' and as such, unlikely candidates for immune therapy. Here, we review the immune landscape of canine and feline sarcomas and the immunotherapeutic strategies that have been employed in veterinary clinical trials to improve patient outcome. We also provide insight into immunotherapeutic approaches being used to treat human sarcomas. Together, current data indicates that, rather than a barren immunological wasteland, sarcomas represent a field of opportunities for immunotherapies. Furthermore, we and others would suggest that strategic combinations of immunotherapeutic approaches may hold promise for more effective treatments for high grade soft tissue sarcomas and bone sarcomas.

Aortic tear and dissection related to connective tissues abnormalities resembling Marfan syndrome in a Great Dane.

Aortic tears and acute aortic dissection are rarely reported in dogs. This report describes a case of aortic dissection and probable sinus of Valsalva rupture in a young Great Dane with associated histopathologic findings suggestive of a connective tissue abnormality.