Longevity and mortality in cats: A single institution necropsy study of 3108 cases (1989-2019).

Client-owned cats who underwent a post-mortem examination (n = 3,108) at a veterinary medical teaching hospital between 1989 and 2019 were studied to determine longevity and factors affecting mortality. Demographic factors, environmental factors, age, and causes of death were assessed. Sexes included 5.66% intact females, 39.86% spayed females, 6.95% intact males and 47.49% neutered males. 84.2% were mixed breed cats. Age at death was known for 2,974 cases with a median of 9.07 years. Cancer was the most common pathophysiologic cause of death (35.81%) and was identified in 41.3% of cats. When categorized by organ system, mortality was most attributed to multiorgan/systemic (21.72%). Renal histologic abnormalities were noted in 62.84% of cats but was considered the primary cause of death in only 13.06% of cats. Intact female and male cats had significantly shorter lifespans than their spayed or neutered counterparts. FeLV positive status was associated with decreased longevity (P<0.0001) while FIV status was not. This study reports on risk factors associated with mortality and highlights areas of research that may contribute to improved lifespan in cats.

Inhaled recombinant human IL-15 in dogs with naturally occurring pulmonary metastases from osteosarcoma or melanoma: a phase 1 study of clinical activity and correlates of response.

PURPOSE: Although recombinant human interleukin-15 (rhIL-15) has generated much excitement as an immunotherapeutic agent for cancer, activity in human clinical trials has been modest to date, in part due to the risks of toxicity with significant dose escalation. Since pulmonary metastases are a major site of distant failure in human and dog cancers, we sought to investigate inhaled rhIL-15 in dogs with naturally occurring lung metastases from osteosarcoma (OSA) or melanoma. We hypothesized a favorable benefit/risk profile given the concentrated delivery to the lungs with decreased systemic exposure. EXPERIMENTAL DESIGN: We performed a phase I trial of inhaled rhIL-15 in dogs with gross pulmonary metastases using a traditional 3+3 cohort design. A starting dose of 10 µg twice daily × 14 days was used based on human, non-human primate, and murine studies. Safety, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) were the primary objectives, while response rates, progression-free and overall survival (OS), and pharmacokinetic and immune correlative analyses were secondary. RESULTS: From October 2018 to December 2020, we enrolled 21 dogs with 18 dogs reaching the 28-day response assessment to be evaluable. At dose level 5 (70 µg), we observed two DLTs, thereby establishing 50 µg twice daily × 14 days as the MTD and recommended phase 2 dose. Among 18 evaluable dogs, we observed one complete response >1 year, one partial response with resolution of multiple target lesions, and five stable disease for an overall clinical benefit rate of 39%. Plasma rhIL-15 quantitation revealed detectable and sustained rhIL-15 concentrations between 1-hour and 6 hour postnebulization. Decreased pretreatment lymphocyte counts were significantly associated with clinical benefit. Cytotoxicity assays of banked peripheral blood mononuclear cells revealed significant increases in peak cytotoxicity against canine melanoma and OSA targets that correlated with OS. CONCLUSIONS: In this first-in-dog clinical trial of inhaled rhIL-15 in dogs with advanced metastatic disease, we observed promising clinical activity when administered as a monotherapy for only 14 days. These data have significant clinical and biological implications for both dogs and humans with refractory lung metastases and support exploration of combinatorial therapies using inhaled rhIL-15.

RNA in situ hybridisation as a molecular diagnostic technique targeting IBA-1 and CD204 in canine histiocytic sarcoma.

BACKGROUND: Canine histiocytic sarcoma (HS) is an aggressive cancer with morphologically variable features; therefore, obtaining a definitive diagnosis can be challenging. Two proteins, IBA-1, ionised calcium-binding adapter molecule 1, and CD204, a macrophage scavenger receptor, have been shown to be specific immunohistochemical markers helpful in distinguishing HS from other tumour types with similar morphological features. OBJECTIVES: This study was performed to demonstrate the use of RNA in situ hybridisation (ISH) technology allowing single-molecule RNA visualisation in formalin-fixed paraffin-embedded (FFPE) tissues as a molecular tool for the diagnosis of canine HS. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis for IBA-1 and CD204 were performed to correlate gene expression and protein expression of these two markers in the histiocytic sarcoma DH82 cell line. RNA-ISH for IBA-1 and CD204 was performed on the DH82 cell line to validate the RNA-ISH probes. RNA-ISH and immunohistochemistry (IHC) were performed in clinical HS FFPE samples to demonstrate mRNA and protein expression of IBA-1 and CD204. FFPE archived samples of canine round cell tumours, melanoma and anaplastic sarcoma were used as negative controls. RESULTS: RNA-ISH and IHC showed moderate to strong expression for IBA-1 and CD204 in the neoplastic cells in both the canine DH82 cell line and the archived canine HS samples. RNA-ISH and IHC showed scattered positive staining in the control tumours samples, consistent with macrophagic infiltration. CONCLUSION: RNA-ISH for CD204 and IBA-1 appeared to have a high specificity and sensitivity in our samples and may be an additional valuable diagnostic technique in identifying HS.

Outcome of intensity-modulated radiation therapy-based stereotactic radiation therapy for treatment of canine nasal carcinomas.

Stereotactic radiation therapy (SRT) has emerged as a convenient definitive treatment modality in veterinary medicine, but few studies exist evaluating outcome with treatment for canine nasal tumors, and no studies report the treatment of one single tumor histotype. This retrospective, observational study evaluates toxicity, response, and survival in 17 dogs with nasal carcinomas treated with SRT. Dogs received a median of 3000 centigray in three fractions via 6-MV linear accelerator. Eighty-eight percent of patients (n = 15) demonstrated clinical benefit. Of dogs with repeated CT imaging (n = 10), 60% (n = 6) achieved a partial response and 10% (n = 1) achieved a complete response. Median progression-free survival (PFS) was 359 days. Median survival time (MST) was 563 days. Among dogs evaluable for acute toxicity, 50% (n = 10) developed low grade toxicity (grade 1, n = 4; grade 2, n = 1). No patients developed grade 3 toxicity. 16 dogs (87%) evaluable over the long term developed signs consistent with possible late toxicity. The majority of late toxicities were mild (alopecia, hyperpigmentation, and leukotrichia n = 10; ocular discharge and keratoconjunctivitis sicca n = 5). Thirty-seven percent of patients (n = 6) developed seven possible grade 3 late toxicities (blindness, n = 3; fistula, n = 1; seizures, n = 3), which were difficult to distinguish from progressive disease in most patients. Of the prognostic factors evaluated (demographics, tumor stage, dosimetric data, epistaxis, facial deformity, clinical response, image-based response, nonsteroidal anti-inflammatory drugs, and chemotherapy), only clinical response was a positive prognostic factor on MST (P < .00). No factors were found to be significantly associated with PFS.

Plasma ammonia concentration after L-asparaginase therapy in 27 dogs with high-grade lymphoma or leukemia.

OBJECTIVES: To establish the occurrence of increased plasma ammonia concentration after L-asparaginase (L-asp) administration in dogs with high-grade lymphoma or leukemia; to identify risk factors for the development of hyperammonemia after L-asp administration; and to determine occurrence of adverse events related to hyperammonemia. DESIGN: Prospective case controlled study of sequentially enrolled dogs between May 2011 and March 2012. SETTING: A university veterinary teaching hospital. ANIMALS: Twenty-seven dogs with high-grade lymphoma or leukemia. INTERVENTIONS: All dogs received L-asp intramuscularly at a median dose of 400 IU/kg. MEASUREMENTS AND MAIN RESULTS: Plasma ammonia concentrations were measured at baseline, 16 hours, and 48 hours after L-asp therapy. Clinicopathological abnormalities were assessed to determine risk factors for the development of hyperammonemia. Adverse events following L-asp were recorded. Median plasma ammonia concentrations at baseline, 16 hours, and 48 hours were 26 µmol/L (44 µg/dL), 98 µmol/L (166.9 µg/dL), and 67 µmol/L (114 µg/dL), respectively. Median plasma ammonia concentrations at 16 and 48 hours after administration were significantly increased compared to baseline. Six dogs had adverse events following L-asp administration. No significant clinical signs were noted that could clearly be attributed to hyperammonemia. No risk factors for developing hyperammonemia were identified; however, there was a positive correlation between the development of hyperammonemia at 16- and 48-hour time points. CONCLUSIONS: Subclinical hyperammonemia in dogs with lymphoma or leukemia after L-asp administration appears to be common. No risk factors were identified for the development of hyperammonemia after L-asp treatment, and severe adverse events were rare.