Prospective, Longitudinal Study of Clinical Outcome and Morphometric Posterior Fossa Changes after Craniocervical Decompression for Symptomatic Chiari I Malformation.

BACKGROUND AND PURPOSE: The time course of changes in posterior fossa morphology, quality of life, and neurologic function of patients with Chiari I malformation after craniocervical decompression requires further elaboration. To better understand the pace of these changes, we longitudinally studied patients with Chiari I malformation, with or without syringomyelia, before and after the operation for up to 5 years. MATERIALS AND METHODS: Thirty-eight symptomatic adult patients (35 women, 3 men) diagnosed with Chiari I malformation only (n = 15) or Chiari I malformation and syringomyelia (n = 23) and without previous Chiari I malformation surgery were enrolled in a clinical study. Patients underwent outpatient study visits and MR imaging at 7 time points (ie, initial [before the operation], 3 months, 1 year, 2 years, 3 years, 4 years, and 5 years) during 5 years. The surgical procedure for all patients was suboccipital craniectomy, C1 laminectomy, and autologous duraplasty. RESULTS: Morphometric measurements demonstrated an enlargement of the CSF areas posterior to the cerebellar tonsils after the operation, which remained largely stable through the following years. There was a decrease in pain and improved quality of life after the operation, which remained steady during the following years. Reduction in pain and improved quality of life correlated with CSF area morphometrics. CONCLUSIONS: Most changes in MR imaging morphometrics and quality of life measures occurred within the first year after the operation. A 1-year follow-up period after Chiari I malformation surgery is usually sufficient for evaluating surgical efficacy and postoperative MR imaging changes.

Long-term safety of MRI-guided administration of AAV2-GDNF and gadoteridol in the putamen of individuals with Parkinson's disease.

Direct putaminal infusion of adeno-associated virus vector (serotype 2) (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene was studied in a phase I clinical trial of participants with advanced Parkinson's disease (PD). Convection-enhanced delivery of AAV2-GDNF with a surrogate imaging tracer (gadoteridol) was used to track infusate distribution during real-time intraoperative magnetic resonance imaging (iMRI). Pre-, intra-, and serial postoperative (up to 5 years after infusion) MRI were analyzed in 13 participants with PD treated with bilateral putaminal co-infusions (52 infusions in total) of AAV2-GDNF and gadoteridol (infusion volume, 450 mL per putamen). Real-time iMRI confirmed infusion cannula placement, anatomic quantification of volumetric perfusion within the putamen, and direct visualization of off-target leakage or cannula reflux (which permitted corresponding infusion rate/cannula adjustments). Serial post-treatment MRI assessment (n = 13) demonstrated no evidence of cerebral parenchyma toxicity in the corresponding regions of AAV2-GDNF and gadoteridol co-infusion or surrounding regions over long-term follow-up. Direct confirmation of key intraoperative safety and efficacy parameters underscores the safety and tissue targeting value of real-time imaging with co-infused gadoteridol and putative therapeutic agents (i.e., AAV2-GDNF). This delivery-imaging platform enhances safety, permits delivery personalization, improves therapeutic distribution, and facilitates assessment of efficacy and dosing effect.

Cytokine Microdialysis for Real-Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade.

BACKGROUND: Glioblastoma is the most common primary malignancy of the brain, with a dismal prognosis. Immunomodulation via checkpoint inhibition has provided encouraging results in non-CNS malignancies, but prediction of responders has proven to be challenging in glioblastoma patients. OBJECTIVE: To determine the proportion of patients who have a measurable increase of interferon gamma levels in brain tumor tissue after their first dose of nivolumab, and to evaluate the safety of using brain tumor microdialysis to monitor for immune response while evaluating the safety of the combination of anti-programmed death 1 (PD-1) and anti-lymphocyte activation gene 3 (LAG-3) checkpoint inhibition. METHODS: The study design is a single-center, nonrandomized phase 1 clinical trial. Up to 15 adult patients with recurrent glioblastoma will be enrolled with the goal of 10 patients completing the trial over an anticipated 18 mo. Patients will undergo biopsy; placement of microdialysis catheters and lumbar drains; treatment with anti-PD-1 checkpoint inhibition; comprehensive immune biomarker collection; tumor resection; and then treatment with anti-PD-1 and anti-LAG-3 checkpoint inhibition until progression. EXPECTED OUTCOMES: We expect interferon gamma levels to increase in the brain as measured via microdialysis in treated patients. Based on published reports, microdialysis in this patient population is expected to be safe, and anti-LAG-3 and anti-PD-1 combined will likely have a similar side effect profile to other checkpoint inhibitor combinations. DISCUSSION: The failure of recent trials of immune therapies in glioblastoma underscores the need to appropriately measure response in the treated tissue. This trial may provide insight on indicators of which patients will respond to immune therapy.

Audiologic Natural History of Small Volume Cochleovestibular Schwannomas in Neurofibromatosis Type 2.

OBJECTIVE: To characterize the audiometric natural progression in patient-ears with small volume (<1,000 mm), treatment-naïve cochleovestibular schwannomas (CVSs) in Neurofibromatosis Type 2 (NF2). STUDY DESIGN: Prospective, longitudinal cohort study. SETTING: Quaternary medical research institute. PATIENTS: One hundred eleven ears in 71 NF2 patients with small, treatment-naïve CVSs observed from July 2006 to July 2016. INTERVENTION: Serial audiometric testing, including pure tone audiometry, speech audiometry, and magnetic resonance imaging (MRI). OUTCOME MEASURES: Four-frequency pure tone average (4f-PTA) of 0.5, 1, 2, and 4 kHz and word recognition score (WRS) were recorded. Their changes were compared with MRI changes in CVS volume over time. Times to significant hearing loss (10 dB loss in 4f-PTA) and WRS based on 95% critical difference were measured. RESULTS: Linear regression analysis showed a significant correlation with baseline hearing level (4f-PTA) and internal auditory canal (IAC) tumor volume to annual hearing decrease rate (AHDR) (p = 0.003, p = 0.0004). Hearing level at baseline and tumor volume correlate with AHDR while tumor volume growth rate does not. Two-way analysis of variance found significant differences in AHDR, risk of significant hearing loss, and risk of critical difference in WRS based on baseline hearing level (abnormal or normal) and IAC tumor volume (greater or less than 200 mm). CONCLUSION: Subjects with normal baseline hearing and small IAC tumor component had a low AHDR and low risk of significant hearing loss and may warrant conservative management while the presence of baseline hearing loss and large IAC volume resulted in higher ADHR and greater risk for further hearing loss and may benefit from early treatment interventions.