Peripheral-central network analysis of cancer cachexia status accompanied by the polarization of hypothalamic microglia with low expression of inhibitory immune checkpoint receptors.

While the excessive inflammation in cancer cachexia is well-known to be induced by the overproduction of inflammatory mediators in the periphery, microflora disruption and brain dysfunction are also considered to contribute to the induction of cancer cachexia. Hypothalamic microglia play a crucial role in brain inflammation and central-peripheral immune circuits via the production of inflammatory mediators. In the present study, we evaluated possible changes in excessive secretion of gut microbiota-derived endotoxin and the expression timeline of several inflammation-regulatory mediators and their inhibiting modulators in hypothalamic microglia of a mouse model of cancer cachexia following transplantation of pancreatic cancer cells. We demonstrated that the plasma level of lipopolysaccharide (LPS) was significantly increased with an increase in anaerobic bacteria, especially Firmicutes, in the gut at the late stage of tumor-bearing mice that exhibited dramatic appetite loss, sarcopenia and severe peripheral immune suppression. At the early stage, in which tumor-bearing mice had not yet displayed "cachexia symptoms", the mRNA expression of pro-inflammatory cytokines, but not of the neurodegenerative and severe inflammatory modulator lipocalin-2 (LCN2), was significantly increased, whereas at the late "cachexia stage", the level of LCN2 mRNA was significantly increased along with significant decreases in levels of inhibitory immune checkpoint receptors programmed death receptor-1 (PD-1) and CD112R in hypothalamic microglia. In addition, a high density of activated neurons in the paraventricular nucleus (PVN) of the hypothalamus region and a significant increase in corticosterone secretion were found in cachexia model mice. Related to the cachexia state, released corticosterone was clearly increased in normal mice with specific activation of PVN neurons. A marked decrease in the natural killer cell population was also observed in the spleen of mice with robust activation of PVN neurons as well as mice with cancer cachexia. On the other hand, in vivo administration of LPS in normal mice induced hypothalamic microglia with low expression of inhibitory immune checkpoint receptors. These findings suggest that the induction of cancer cachexia may parallel exacerbation of the hypothalamic inflammatory status with polarization to microglia expressed with low levels of inhibitory immune checkpoint receptors following LPS release from the gut microflora.

Safety and pharmacokinetics of thalidomide in tumor-bearing dogs.

Thalidomide, an angiogenesis inhibitor, has recently been used to treat malignant canine tumors. This study retrospectively investigated the adverse events (AEs) of thalidomide administered to tumor-bearing dogs. We investigated the pharmacokinetics of thalidomide after administration and the rate of body weight change before and after administration. The initial thalidomide dose was 5 mg/kg per os once daily, which was increased to 10 mg/kg once daily in dogs with no significant AEs. Pharmacokinetics were measured in four dogs after the 5 mg/kg or 10 mg/kg dose. We evaluated AEs related to clinical signs in 51 patients; 9/51 had lethargy, 6/51 had tremor, 4/51 had dizziness, 31/51 had decreased appetite, 8/51 had vomiting, and 16/49 had soft stool/diarrhea. We evaluated hematologic toxicity in 44 patients with grade 3 or higher adverse events; 1/44 had thrombocytopenia, 1/44 had increased blood urea nitrogen concentrations, and 5/44 had increased alanine aminotransferase activities. The mean thalidomide blood levels were Cmax=1.4 ± 0.7 µg/mL (Area under the curve [AUC]0-24=8.5 ± 4.7 µg•hr /mL) and Cmax=3.2 ± 2.1 µg/mL (AUC0-24=22.0 ± 14.7 µg•hr/mL) in the 5 mg/kg and 10 mg/kg groups, respectively. The Cmax and AUC in the 10 mg/kg group were comparable to the effective blood concentrations seen in humans administered thalidomide. The weight fluctuation rates were assessed in 24 dogs approximately 1 month after the start of thalidomide administration; more than half showed weight maintenance or gain. Most AEs were clinically acceptable; however, peripheral nerve signs were seen in some dogs.

Clinical features and prognosis of retroperitoneal hemangiosarcoma in dogs with surgical resection with or without adjuvant doxorubicin.

Retroperitoneal hemangiosarcoma (RPHSA) is a rare tumor in dogs with a poorly understood prognosis after surgery. The objectives of this study were to investigate the clinical features and prognosis of canine RPHSA that had undergone surgical resection. In this single-center, retrospective cohort study, we reviewed the medical records of dogs that had undergone surgical resection for retroperitoneal tumors and received a histopathologic diagnosis of HSA between 2005 and 2021. The median progression-free survival (PFS) and overall survival (OS) were 77.5 days and 168 days, respectively. In the present study, canine RPHSA had an aggressive biological behavior similar to visceral HSA. Further studies in larger canine populations are needed to evaluate the efficacy of adjuvant chemotherapy.

Prognosis of primary pulmonary adenocarcinoma after surgical resection in small-breed dogs: 52 cases (2005-2021).

BACKGROUND: Tumor size is an important prognostic factor in lung cancer in dogs, and the canine lung carcinoma stage classification (CLCSC) recently has been proposed to subdivide tumor sizes. It is unclear if the same classification scheme can be used for small-breed dogs. OBJECTIVES: To investigate whether the tumor size classification of CLCS is prognostic for survival and progression outcomes in small-breed dogs with surgically resected pulmonary adenocarcinomas (PACs). ANIMALS: Fifty-two client-owned small-breed dogs with PAC. METHODS: Single-center retrospective cohort study conducted between 2005 and 2021. Medical records of dogs weighing <15 kg with surgically resected lung masses histologically diagnosed as PAC were examined. RESULTS: The numbers of dogs with tumor size ≤3 cm, >3 cm to ≤5 cm, >5 cm to ≤7 cm, or >7 cm were 15, 18, 14, and 5, respectively. The median progression-free interval (PFI) and overall survival time (OST) were 754 and 716 days, respectively. In univariable analysis, clinical signs, lymph node metastasis, margin, and histologic grade were associated with PFI, and age, clinical signs, margin, and lymph node metastasis were associated with OST. Tumor size classification of CLCS was associated with PFI in all categories, and tumor size >7 cm was associated with OST. In multivariable analysis, tumor size >5 cm to ≤7 cm and margin were associated with PFI, and age was associated with OST. CONCLUSIONS AND CLINICAL IMPORTANCE: The tumor size classification of CLCS would be an important prognostic factor in small-breed dogs with surgically resected PACs.

Evaluation of adverse events in small-breed dogs treated with maropitant and a single dose of doxorubicin.

BACKGROUND: The recommended doxorubicin (DOX) dose for small dogs is 1 mg/kg. Recent data suggest that DOX-induced gastrointestinal (GI) toxicosis can be reduced with maropitant treatment. OBJECTIVES: To investigate the incidence of adverse events (AEs) in small-breed dogs administered a single 25 mg/m2 DOX followed by administration of maropitant (DOX25). The primary aim was to assess myelo- and GI toxicoses for 2 weeks after DOX administration. The secondary aim was to compare the incidence and grades of AEs found in the DOX25 group with a historical control group (DOX 1 mg/kg without administration of antiemetic or antidiarrheal medications). ANIMALS: Nineteen small-breed tumor-bearing dogs. METHODS: A prospective, observational study of tumor-bearing dogs, weighing 5 to 10 kg, administered a single 25 mg/m2 dose of DOX IV, followed by administration of maropitant for the next 5 days. RESULTS: Inappetence, vomiting, and diarrhea were found in 7/19, 2/19, and 6/19 of the DOX25 dogs, respectively. Neutropenia and thrombocytopenia was 12/19 and 3/19, respectively. Most AEs were grades 1 and 2, except for grades 3 and 4 inappetence and neutropenia in 3 and 4 dogs, respectively. Furthermore, febrile neutropenia occurred in 3/19 dogs in the DOX25 group. All AEs between the DOX25 and historical control groups were not significantly different. CONCLUSIONS AND CLINICAL IMPORTANCE: Vomiting and diarrhea were deemed acceptable with 25 mg/m2 DOX followed by maropitant treatment in 5 to 10 kg dogs; however, additional supportive care might be needed for dogs with inappetence and neutropenia.

Long-term survival in a dog with primary hepatic neuroendocrine tumor treated with toceranib phosphate.

Primary hepatic neuroendocrine tumors (PHNETs) are rare in dogs, and limited information exists about the treatment of these tumors. A 12-year-old castrated male French bulldog was presented to our clinic with gastrointestinal signs. Diagnostic tests revealed increased hepatic enzyme levels, a mass in the hepatic quadrate lobe, multiple intrahepatic nodules, and enlarged hepatic hilar lymph nodes. The liver mass was diagnosed cytologically as a malignant epithelial tumor suspected to be of neuroendocrine origin. The dog was treated with single-agent toceranib phosphate (TOC) and survived 25.1 months after the initial presentation. On necropsy, a liver mass was found and was subsequently diagnosed as a PHNET on histopathology. To the best of our knowledge, this is the first report of long-term survival in a dog with PHNET treated with TOC.