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.

Identification of novel genetic variants, including PIM1 and LINC01491, with ICD-10 based diagnosis of pulmonary arterial hypertension in the UK Biobank cohort.

Pulmonary arterial hypertension (PAH) is characterized by remodeling and narrowing of the pulmonary vasculature which results in elevations of pulmonary arterial pressures. Here, we conducted a genome-wide association study (GWAS) using the UK Biobank, analyzing the genomes of 493 individuals diagnosed with primary pulmonary hypertension, based on ICD-10 coding, compared to 24,650 age, sex, and ancestry-matched controls in a 1:50 case-control design. Genetic variants were analyzed by Plink's firth logistic regression and assessed for association with primary pulmonary hypertension. We identified three linked variants in the PIM1 gene, which encodes a protooncogene that has been garnering interest as a potential therapeutic target for PAH, that were associated with PAH with genome wide significance, one (rs192449585) of which lies in the promoter region of the gene. We also identified 15 linked variants in the LINC01491 gene. These results provide genetic evidence supporting the role of PIM1 inhibitors as a potential therapeutic option for PAH.

Survival time of juvenile dogs with oral squamous cell carcinoma treated with surgery alone: A Veterinary Society of Surgical Oncology retrospective study.

OBJECTIVE: To report the signalment, staging, surgical treatment, and survival time of juvenile dogs treated surgically for oral squamous cell carcinoma (OSCC). STUDY DESIGN: Retrospective study. ANIMALS OR SAMPLE POPULATION: Twenty-five dogs, <2 years of age with OSCC treated with surgery. METHODS: Cases were solicited from the Veterinary Society of Surgical Oncology. Data retrieved included sex, breed, age, weight, clinical signs, tumor location, preoperative diagnostics and staging, histopathological diagnosis with margin evaluation, disease-free interval, and date and cause of death. A minimum follow-up time of 3 months was required for inclusion. RESULTS: Eighteen dogs were <12 months of age, and seven were <24 months. Various breeds were represented, with a mean body weight of 22.3 ± 14.4 kg. No dogs had evidence of metastatic disease prior to surgery. All dogs underwent partial maxillectomy or mandibulectomy. Histological margins were complete in 24 dogs and incomplete in one. No dogs had evidence of metastatic disease or tumor recurrence. The median follow-up time was 1556 days (92 to 4234 days). All dogs were alive at the last follow-up except for one documented death, due to dilated cardiomyopathy. Median disease-specific survival time was not reached. CONCLUSION: The prognosis after wide surgical excision of OSCC in juvenile dogs was excellent. CLINICAL SIGNIFICANCE: OSCC in juvenile dogs can be effectively treated with surgery alone.

The effect of prednisone on histologic and gross characteristics in canine mast cell tumors.

The objective of the study was to determine whether neoadjuvant prednisone therapy affects histological features of cutaneous and subcutaneous mast cell tumors. Twenty-eight dogs with a treatment naïve > 1-cm diameter mast cell tumor (MCT) were randomly assigned (Random number generator; Random.org, Dublin, Ireland) in a blinded fashion to receive either prednisone or placebo (Quality Food Center Pharmacy, Kirkland, Washington, USA). Volumes of mast cell tumors were calculated before incisional and excisional biopsies. Following incisional biopsy, patients received either prednisone (1 mg/kg body weight) daily or a placebo for 7 to 14 days leading up to excisional biopsy. Tumor grade for cutaneous MCT, and mitotic count and atypia for all tumors were reported. Perioperative treatment with prednisone had no significant effect on tumor grade, atypia, or mitotic count. Tumor volume was significantly decreased with prednisone treatment. The use of neoadjuvant prednisone to decrease MCT volume in order to facilitate tumor excision, can be considered without significant concern for change of tumor histologic features in the common population of low- to intermediate-grade MCT.

Effet de la prednisone sur les caractéristiques histologiques et macroscopiques des mastocytomes canins. L'objectif de la présente étude était de déterminer si une thérapie néoadjuvante avec de la prednisone affecte les caractéristiques histologiques des mastocytomes cutanés et sous-cutanés. Vingt-huit chiens avec un mastocytome (MCT) ayant un diamètre > 1 cm avant le traitement furent répartis de manière aléatoire (Random number generator; Random.org, Dublin, Irlande) à l'aveugle pour recevoir soit de la prednisone ou un placebo (Quality Food Center Phamacy, Kirkland, Washington, USA). Les volumes des MCT furent calculés avant les biopsies d'incision et d'excision. À la suite des biopsies d'incision, les patients reçurent soit de la prednisone (1 mg/kg de poids corporel) quotidiennement ou un placebo pour 7 à 14 jours menant à la biopsie d'excision. Le grade des tumeurs pour les MCT cutanés, ainsi que le dénombrement mitotique et l'atypie pour toutes les tumeurs furent rapportés. Le traitement préopératoire avec de la prednisone n'a pas eu d'effet significatif sur le grade des tumeurs, l'atypie ou le dénombrement mitotique. Le volume des tumeurs était réduit significativement avec le traitement à la prednisone. L'utilisation néoadjuvant de prednisone afin de diminuer le volume des MCT dans le but de faciliter l'excision des tumeurs peut être considérée sans préoccupation significative pour des changements dans les caractéristiques histologiques des populations habituelles de MCT de grade bas à intermédiaire.(Traduit par Dr Serge Messier).

Lower urinary tract transitional cell carcinoma in cats: Clinical findings, treatments, and outcomes in 118 cases.

BACKGROUND: Lower urinary tract transitional cell carcinoma (TCC) is an important but rarely described disease of cats. OBJECTIVES: To report the clinical characteristics, treatments, and outcomes in a cohort of cats with lower urinary tract TCC and to test identified variables for prognostic relevance. ANIMALS: One-hundred eighteen client-owned cats with lower urinary tract carcinoma. METHODS: Medical records were retrospectively reviewed to obtain information regarding clinical characteristics, treatments, and outcomes. Recorded variables were analyzed statistically. RESULTS: Median age of affected cats was 15 years (range, 5.0-20.8 years) and median duration of clinical signs was 30 days (range, 0-730 days). The trigone was the most common tumor location (32/118; 27.1%) as assessed by ultrasound examination, cystoscopy, or both. Treatment was carried out in 73 of 118 (61.9%) cats. Metastatic disease was documented in 25 of 118 (21.2%) cats. Median progression-free survival and survival time for all cats were 113 days (95% confidence interval [CI], 69-153) and 155 days (95% CI, 110-222), respectively. Survival increased significantly (P < .001) when comparing cats across the ordered treatment groups: no treatment, treatment without partial cystectomy, and treatment with partial cystectomy. Partial cystectomy (hazard ratio [HR], 0.31; 95% CI, 0.17-0.87) and treatment with nonsteroidal anti-inflammatory drugs (HR, 0.55; 95% CI, 0.33-0.93) were significantly associated with longer survival times. CONCLUSIONS AND CLINICAL IMPORTANCE: The results support treatment using partial cystectomy and NSAIDs in cats with TCC.

Immunomodulatory Effects of Surgery, Pain, and Opioids in Cancer Patients.

Surgery is the mainstay of therapy for canine and human solid cancers. Alarmingly, evidence suggests that the process of surgery may exacerbate metastasis and accelerate the kinetics of cancer progression. Understanding the mechanisms by which cancer progression is accelerated as a result of surgery may provide pharmacologic interventions. This review discusses surgery-induced cancer progression. It focuses on immunomodulatory properties of anesthesia and opioids and evidence that studies evaluating the role of opioids in tumor progression are indicated. It concludes by discussing why companion animals with spontaneously arising cancer are an ideal model for clinical trials to investigate this phenomenon.

Apocrine gland anal sac adenocarcinoma with perineural metastasis in a cat.

CASE SUMMARY: A 15-year-old female spayed domestic shorthair cat was presented for hyporexia and acute development of L4-Cd myelopathy (urinary incontinence, pelvic limb paresis with hyporeflexia and absent tail tone). Humane euthanasia was elected owing to the rapid neurological deterioration and necropsy was performed. Post-mortem examination identified a right-sided anal sac mass and medial iliac lymphadenopathy. No gross lesions were evident in the cauda equina or peripheral nerves. Histopathology and immunohistochemistry utilizing wide-spectrum cytokeratin confirmed apocrine gland carcinoma of the anal sac with lymph node, peripheral nerve and cauda equina metastasis. RELEVANCE AND NOVEL INFORMATION: This is the first report of feline anal sac adenocarcinoma metastasizing to perineural tissue. In addition, it provides a novel differential diagnosis for L4-Cd myelopathy and urinary incontinence in a cat.

Biological implant-associated granulomatous inflammation resulting in secondary hypercalcemia and azotemia in a dog.

Implant associated granulomatous inflammation causing hypercalcemia can occur following use of commercial xenogeneic pericardial tissue patches in dogs. Removal of the implant can result in resolution of the hypercalcemia, suggesting a causal relationship between the tissue reaction to a xenogeneic implant and development of hypercalcemia.

Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation.

The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient's tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies. Cancer Res; 77(11); 2869-80. ©2017 AACR.

Long digital extensor tendon mineralization and cranial cruciate ligament rupture in a dog.

OBJECTIVE: To report clinical and histopathologic features of long digital extensor (LDE) tendon mineralization with concurrent cranial cruciate ligament (CCL) rupture in a dog. STUDY DESIGN: Case report. ANIMAL: 1.5-year-old, male castrated, English bulldog mix weighing 31.5 kg. METHODS: Pre- and postoperative orthogonal radiographs, arthroscopic evaluation, arthrotomy with en bloc surgical excision, and histopathologic analysis of the excised LDE tendon. RESULTS: There was radiographic evidence of mineralization in the region of the proximal LDE and stifle instability suggestive of CCL rupture. Arthroscopy, and subsequent arthrotomy, showed complete tearing of the CCL and an intact but grossly thickened LDE. No evidence of avulsion or bony proliferation associated with the LDE was appreciated. Tibial plateau leveling osteotomy (TPLO) and tenectomy of the LDE returned the dog to normal weight-bearing. No evidence of ectopic mineralization in the affected limb or similar clinical signs in the contralateral limb have been observed in 12 months follow-up. CONCLUSIONS: LDE tenectomy followed by stabilization of the stifle by TPLO resulted in a functional outcome. Mineralization without concurrent avulsion of the LDE has not been reported in dogs; however, posterolateral tendon injury in people has been linked to knee instability and cruciate ligament rupture.

Monoclonal immunoglobulin protein production in two dogs with secretory B-cell lymphoma with mott cell differentiation.

CASE DESCRIPTION: A 9-year-old castrated male mixed-breed dog and a 7-year-old spayed female Boston Terrier, with clinical histories of a liver mass (dog 1) and bloody vomitus, diarrhea, and weight loss (dog 2), respectively, were referred for further evaluation. CLINICAL FINDINGS: At the time of referral, each dog had differing laboratory abnormalities; however, the serum total protein and globulin concentrations were within reference range in both dogs. Cytologic examination of fine-needle aspirates obtained from affected organs (a liver mass [dog 1] and enlarged submandibular lymph node [dog 2]) revealed 2 main nucleated cell types: atypical lymphoid cells and lesser numbers of Mott cells. With the use of serum immunofixation electrophoresis and serum immunoglobulin quantification, a monoclonal immunoglobulin protein was identified in both dogs and a final diagnosis of secretory B-cell lymphoma with Mott cell differentiation (MCL) was made. TREATMENT AND OUTCOME: Both dogs received chemotherapy for their disease. The first dog was euthanized 8.5 months after diagnosis because of acute respiratory distress of unknown etiology, and the second was euthanized 7 days after diagnosis for worsening clinical disease and quality of life. CLINICAL RELEVANCE: To our knowledge, this report is the first of a secretory form of MCL in dogs. Findings indicate that in dogs with suspect MCL, even in patients that lack characteristic hyperproteinemia or hyperglobulinemia, serum protein content should be fully evaluated for the presence of a monoclonal immunoglobulin protein. Such an evaluation that uses immunofixation electrophoresis and immunoglobulin quantification will aid in the diagnosis of MCL in dogs.

Use of a nitinol stent to palliate a colorectal neoplastic obstruction in a dog.

CASE DESCRIPTION: A 12-year-old castrated male Labrador Retriever was evaluated for clinical signs associated with colorectal obstruction. CLINICAL FINDINGS: The dog had a 2-week history of tenesmus and hematochezia. On rectal examination, an annular colorectal mass was palpable extending orad into the pelvic canal. The original diagnosis of the colorectal mass was a mucosal adenoma. The dog was maintained on a low-residue diet and fecal softeners for a period of 13 months after initial diagnosis. At that time, medical management was no longer effective. TREATMENT AND OUTCOME: Placement of a colonic stent was chosen to palliate the clinical signs associated with colorectal obstruction. By use of fluoroscopic and colonoscopic guidance, a nitinol stent was placed intraluminally to open the obstructed region. Placement of the stent resulted in improvement of clinical signs, although tenesmus and obstipation occurred periodically after stent placement. At 212 days after stent placement, the patient had extensive improvement in clinical signs with minimal complications; however, clinical signs became severe at 238 days after stent placement, and the dog was euthanized. Histologic evaluation of the rectal tumor from samples obtained during necropsy revealed that the tumor had undergone malignant transformation to a carcinoma in situ. CLINICAL RELEVANCE: A stent was successfully placed in the colon and rectum to relieve obstruction associated with a tumor originally diagnosed as a benign neoplasm. Placement of colorectal stents may be an option for the palliation of colorectal obstruction secondary to neoplastic disease; however, clinical signs may persist, and continuation of medical management may be necessary.

Monoclonal gammopathy without hyperglobulinemia in 2 dogs with IgA secretory neoplasms.

Two dogs, an 8.5-year-old intact male Golden Retriever and a 10-year-old spayed female English Springer Spaniel, each with varied clinical histories, were referred to the Colorado State University Veterinary Teaching Hospital for evaluation of hypercalcemia and severe anemia, respectively. In each dog, serum total protein and globulin concentrations were within reference intervals. Cytologic examination of bone marrow aspirates from both dogs revealed moderate to marked numbers of atypical lymphoid cells with plasma cell features. Using serum immunofixation and serum immunoglobulin (Ig) quantification, a monoclonal Ig protein was identified. In conjunction with other clinicopathologic and molecular findings, IgA secretory neoplasms, B-cell lymphoma with plasmacytoid features and multiple myeloma (MM), were diagnosed. To our knowledge, these cases represent the first descriptions of IgA-secreting neoplasms in dogs that lacked hyperglobulinemia. In cases of suspected B-cell lymphoma or MM in dogs, serum proteins should be fully evaluated for the presence of a monoclonal Ig even in dogs that lack characteristic hyperproteinemia or hyperglobulinemia. This evaluation will aid in the diagnosis of secretory B-cell lymphoma or MM leading to appropriate clinical and therapeutic case management.

Dendritic cells from malaria-infected mice are fully functional APC.

Malaria infection has long been associated with diminished T cell responses in vitro and more recently in experimental studies in vivo. Suppression of T cell-proliferative responses during malaria has been attributed to macrophages in a variety of murine and human systems. More recently, however, attention has been directed at the role of dendritic cells in this phenomenon, with several studies suggesting that maturation of dendritic cells is inhibited in vitro by the presence of malaria-infected E. In the studies reported here, we have examined the function of dendritic cells taken directly from infected mice. We found that they express high levels of costimulatory proteins and class II MHC, can activate naive T cells to produce IL-2 as efficiently as dendritic cells from uninfected mice, and support high levels of IFN-gamma production by naive T cells through an IL-12-dependent mechanism. Dendritic cells from infected mice also support higher levels of TNF-alpha production by naive T cells. These same dendritic cells present parasite Ag to a malaria-specific T cell hybridoma, a finding that demonstrates that dendritic cells participate in the generation of Ag-specific immunity during infection. Our findings challenge the contention that dendritic cell function is inhibited by malaria infection.