Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

High-dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a nonhuman primate model.

OBJECTIVE: Chemotherapy infusions directly into the fourth ventricle may play a role in treating malignant fourth-ventricular tumors. This study tested the safety and pharmacokinetics of short-term and long-term administration of MTX110 (soluble panobinostat; Midatech Pharma) into the fourth ventricle of nonhuman primates. METHODS: Four rhesus macaque monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In group I (n = 2), catheters were externalized and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term infusions. MTX110 (0.5 ml of 300 µM panobinostat solution) was infused into the fourth ventricle daily for 5 consecutive days. Serial CSF and serum panobinostat levels were measured. In group II (n = 2), fourth-ventricle catheters were connected to a subcutaneously placed port for subsequent long-term infusions. Four cycles of MTX110, each consisting of 5 daily infusions (0.5 ml of 300 µM panobinostat solution), were administered over 8 weeks. Animals underwent detailed neurological evaluations, MRI scans, and postmortem histological analyses. RESULTS: No neurological deficits occurred after intraventricular MTX110 infusions. MRI scans showed catheter placement within the fourth ventricle in all 4 animals, with extension to the cerebral aqueduct in 1 animal and into the third ventricle in 1 animal. There were no MRI signal changes in the brainstem, cerebellum, or elsewhere in the brains of any of the animals. Histologically, normal brain cytoarchitecture was preserved with only focal mild postsurgical changes in all animals. Panobinostat was undetectable in serum samples collected 2 and 4 hours after infusions in all samples in both groups. In group I, the mean peak panobinostat level in the fourth-ventricle CSF (6242 ng/ml) was significantly higher than that in the lumbar CSF (9 ng/ml; p < 0.0001). In group II, the mean peak CSF panobinostat level (11,042 ng/ml) was significantly higher than the mean trough CSF panobinostat level (33 ng/ml; p < 0.0001). CONCLUSIONS: MTX110 can be safely infused into the fourth ventricle in nonhuman primates at supratherapeutic doses. Postinfusion CSF panobinostat levels peak immediately in the fourth ventricle and then rapidly decrease over 24 hours. Panobinostat is detectable at low levels in CSF measured from the lumbar cistern up to 4 hours after infusions. These results will provide background data for a pilot clinical trial in patients with recurrent medulloblastoma.

Strangles, convalescent Streptococcus equi subspecies equi M antibody titers, and presence of complications.

BACKGROUND: Streptococcus equi subspecies equi infection elicits M protein antibody titers in equids. Interpretation of titers is not generally accepted. HYPOTHESIS: The magnitude of S. equi M protein (SeM) antibody titer after infection (titer ≥1:12 800) will be useful to monitor for the presence of complications or the risk of development of complications. ANIMALS: Forty-eight horses on 1 farm involved in strangles outbreak. METHODS: Clinical and observational study. S. equi M protein antibody titers were measured on all horses 8 weeks after infection and select horses 12 and 28 weeks after infection. Horses were categorized: no disease, uncomplicated case, persistent guttural pouch (GP) infection, or complicated cases (metastatic abscesses, purpura hemorrhagica, secondary infections, and dysphagia). Category was compared to titer. RESULTS: Twenty-eight of 48 (58%) developed clinical signs of S. equi infection. Of those, 11 (39%) had uncomplicated strangles, 9 (21%) had persistent GP infection, 5 (18%) were complicated cases, and 3 (11%) had both persistent GP infection and complications. Thirty-three percent of horses (16 of 48) had SeM antibody titers ≥1:12 800 eight weeks after infection. Of horses with titers ≥1:12 800, 6 of 16 had evidence of complications. Of complicated cases, 6 of 8 had titers ≥1:12 800. In this outbreak, the sensitivity (75%; 95% CI [confidence interval] 45-105) for a SeM antibody titer ≥1:12 800 detecting complications was higher than the specificity (43%; 95% CI 23-64). CONCLUSIONS AND CLINICAL IMPORTANCE: This outbreak demonstrates that SeM antibody titers can be increased after infection (≥1:12 800) in the absence of complications of strangles.

Seroprevalence, frequency of leptospiuria, and associated risk factors in horses in Kansas, Missouri, and Nebraska from 2016-2017.

Leptospirosis is a worldwide veterinary and public health concern, and well recognized infectious disease of horses. Seroprevalence rates vary with geography, but many studies have confirmed a high exposure rate. The correlation between seropositivity and shedding status has not been made in horses, however. The aims of this study were to use semi-nested PCR on urine from apparently healthy horses to determine period prevalence of leptospiral shedding and to correlate these findings with MAT results to establish associations with client based survey data regarding horse management and environment. Serum and free-catch urine were collected from 204 healthy horses between May 2016-December 2017. Serum was used to determine GGT, creatinine concentrations, and six serovar MAT. Urine samples were submitted for PCR testing of leptospiral 23S rRNA. Client consent and survey data were collected for all subjects. Potential risk factors included drinking water source, exposure to livestock and dogs, geographical location, season, and precipitation. Two horses were positive on urine PCR for leptospirosis (shedding prevalence 1%), yet only one had a high reciprocal MAT titer of ≥ 800. Both horses were negative on urine PCR one month later without treatment. Approximately 77% of horses (157/204) were seroreactive (MAT reciprocal titer ≥ 100) with titers to serogroup Australis detected more frequently than others (47.5%; (97/204)). Apparently healthy horses infrequently shed Leptospira spp. in urine, yet seroreactivity in clinically normal horses is high (77%), confirming high exposure rates to Leptospira spp. in the Central Midwest.