David I. Sandberg, Natasha Kharas, Bangning Yu, Christopher F. Janssen, Amanda Trimble, Leomar Y. Ballester, Rajan Patel, Afroz S. Mohammad, William F. Elmquist and Rachael W. Sirianni
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.
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.
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).
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.
Ludovic P. Pao, Liang Zhu, Sarah Tariq, Christine A. Hill, Bangning Yu, Mariana Kendrick, Magdalena Jungman, Emilie L. Miesner, Surya N. Mundluru, Stacey L. Hall, Glendaliz Bosques, Nivedita Thakur and Manish N. Shah
Selective dorsal rhizotomy (SDR) is a surgical procedure used to treat spasticity in children with spastic cerebral palsy. Currently, there is a lack of work examining the efficacy of optimizing pain management protocols after single-level laminectomy for SDR. This pilot study aimed to compare the clinical outcomes of SDR completed with a traditional pain management protocol versus one designed for opioid dosage reduction.
The Texas Comprehensive Spasticity Center prospective database was queried for all patients who underwent SDR between 2015 and 2018. Demographic, surgical, and postoperative data for all patients who underwent SDR were collected from medical records. The study was designed as a retrospective study between the patient-controlled analgesia (PCA) and dexmedetomidine infusion (INF) groups with 80% power to detect a 50% difference at a significance level of 0.05. Patients in the INF group received perioperative gabapentin, intraoperative dexmedetomidine infusion, and scheduled acetaminophen and NSAIDs postoperatively.
Medication administration records, pain scores, and therapy notes were collected for 30 patients. Patients who underwent SDR between June 2015 and the end of December 2017 received traditional pain management (PCA group, n = 14). Patients who underwent SDR between January 2018 and the end of December 2018 received modified pain management (INF group, n = 16). No patients were lost to follow-up. Differences in age, weight, height, preoperative Gross Motor Function Classification System scores, operative duration, hospital length of stay, and sex distribution were not statistically different between the 2 groups (p > 0.05). Analysis of analgesic medication doses demonstrated that the INF group required fewer doses and lower amounts of opioids overall, and also fewer NSAIDs than the PCA group. When converted to the morphine milligram equivalent, the patients in the INF group used fewer doses and lower amounts of opioids overall than the PCA group. These differences were either statistically significant (p < 0.05) or trending toward significance (p < 0.10). Both groups participated in physical and occupational therapy similarly postoperatively (p > 0.05). Pain scores were comparable between the groups (p > 0.05) despite patients in the INF group requiring fewer opioids.
Infusion with dexmedetomidine during SDR surgery combined with perioperative gabapentin and scheduled acetaminophen and NSAIDs postoperatively resulted in similar pain scores to traditional pain management with opioids. In addition, this pilot study demonstrated that patients who received the INF pain management protocol required reduced opioid dosages and were able to participate in therapy similarly to the control PCA group.