Faculty Bibliography

BACKGROUND: There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a ?hypermutator phenotype?. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily trans- formed IDH-mutant GBMs. Safety-lead-in results will be presented.
METHOD(S): This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE.
RESULT(S): Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5-54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade >= 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade <= 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4-5.7). Median OS was 10.1 (range 6.8-21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual.
CONCLUSION(S): Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen

ONC201, the first bitopic DRD2 antagonist for clinical oncology, has shown efficacy in H3 K27M-mutant glioma. We performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27Mmutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). Elevated DRD2 expression was found in the thalamus of non-malignant brain tissue, leading to the hypothesis that thalamic tumors may be a particularly ONC201-sensitive sub-group. We analyzed thalamic H3 K27Mmutant glioma patients treated with ONC201 as of the 05/22/2019 cutoff date, which included patients who had recurrent disease prior to initiating ONC201 (n=20; 15-73 years old) and post-radiation non-recurrent patients (n=11; 5-19 years old). As of 5/22/2019, 10 of 20 recurrent patients and 9 of 11 non-recurrent patients remain on-treatment. Median PFS has not been reached for either cohort: median follow-up of 2.2 months (range: 0.6-37.9) for recurrent patients and 10.6 months (range: 4.3-20.5) from diagnosis for non-recurrent patients. Best response so far by RANO includes 1 CR, 2 PR, 7 SD, 9 PD, 1 NE for recurrent patients and 1 PR, 7 SD, 3 PD for non-recurrent patients. Additionally, 3 recurrent (-66%, -47%, -34%) and 2 non-recurrent (-40%, -10%) patients experienced regressions but are not yet confirmed PRs. For recurrent patients, median onset of response is 3.5 months (range: 2.2-3.8) and median duration of response has not been reached with a median follow-up of 12.5 months (range: 8.1-32.8). Preliminary analyses demonstrated a strong correlation of cell-free tumor DNA in plasma and CSF with MRI response. In summary, ONC201 demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients, regardless of age. Micro-environmental DRD2 expression may enhance the overall ONC201 response and extend its therapeutic utility beyond H3 K27M-mutant glioma

OBJECTIVE:To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program. METHODS:Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing and the phage-display assay, VirScan, for viral immune responses. An etiological diagnosis was established post-mortem. RESULTS:Using VirScan, enrichment of dengue viral antibodies were detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but post-mortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months ante-mortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency and sequencing of the virus demonstrated wild-type dengue virus in the central nervous system. INTERPRETATION/CONCLUSIONS:Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self-limiting and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Further, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiologies. This article is protected by copyright. All rights reserved.

AIM/OBJECTIVE:To assess the accuracy of consumer available wrist-based and hip-based activity trackers in quantitatively measuring ambulation in children with cerebral palsy (CP). METHOD/METHODS:Thirty-nine children (23 males, 16 females; mean age [SD] 9y 7mo [3y 5mo]; range 4-15y) with CP were fitted with trackers both on their wrist and hip. Each participant stood for 3 minutes, ambulated in a hallway, and sat for 3 minutes. The number of steps and distance were recorded on trackers and compared to manually counted steps and distance. Pearson correlation coefficients were determined for the number of steps during ambulation from each tracker and a manual count. Mean absolute error (MAE) and range of errors were calculated for steps during ambulation for each tracker and a manual count and for distance for each tracker and hallway distance. RESULTS:For the number of steps, a weak inverse relationship (r=-0.033) was found for the wrist-based tracker and a strong positive relationship (r=0.991) for the hip-based tracker. The MAE was 88 steps for the wrist-based and seven steps for the hip-based tracker. The MAE for distance was 0.06 miles for the wrist-based and 0.07 miles for the hip-based tracker. INTERPRETATION/CONCLUSIONS:Only the hip-based tracker provided an accurate step count; neither tracker was accurate for distance. Thus, ambulation of children with CP can be accurately quantified with readily available trackers.

OBJECTIVE:The aim of this study was to identify specific ictal hand postures (HPs) as localizing signs of the epileptogenic zone (EZ) in patients with frontal or temporal lobe epilepsy. METHODS:In this study, we retrospectively analyzed ictal semiology of 489 temporal lobe or frontal lobe seizures recorded over a 6-year period at the Seizure Disorder Center at University of California, Los Angeles in the USA (45 patients) or at the C. Munari Epilepsy Surgery Center at Niguarda Hospital in Milan, Italy (34 patients). Our criterion for EZ localization was at least 2 years of seizure freedom after surgery. We analyzed presence and latency of ictal HP. We then examined whether specific initial HPs are predictive for EZ localization. RESULTS:We found that ictal HPs were present in 72.5% of patients with frontal and 54.5% of patients with temporal lobe seizures. We divided HPs into 6 classes depending on the reciprocal position of the fingers ("fist," "cup," "politician's fist," "pincer," "extended hand," "pointing"). We found a striking correlation between EZ localization and ictal HP. In particular, fist and pointing HPs are strongly predictive of frontal lobe EZ; cup, politician's fist, and pincer are strongly predictive of temporal lobe EZ. INTERPRETATION:Our study offers simple ictal signs that appear to clarify differential diagnosis of temporal versus frontal lobe EZ localization. These results are meant to be used as a novel complementary tool during presurgical evaluation for epilepsy. At the same time, they give us important insight into the neurophysiology of hand movements. ANN NEUROL 2019;86:793-800.

Cerebellar abnormalities are commonly reported in autism spectrum disorder (ASD). Dentate nuclei (DNs) are key structures in the anatomical circuits linking the cerebellum to the extracerebellum. Previous resting-state functional connectivity (RsFc) analyses reported DN abnormalities in high-functioning ASD (HF-ASD). This study examined the RsFc of the DN in young adults with HF-ASD compared with healthy controls (HCs) with the aim to expand upon previous findings of DNs in a dataset using advanced, imaging acquisition methods that optimize spatiotemporal resolution and statistical power. Additional seed-to-voxel analyses were carried out using motor and nonmotor DN coordinates reported in previous studies as seeds. We report abnormal dentato-cerebral and dentato-cerebellar functional connectivity in ASD. Our results expand and, in part, replicate previous descriptions of DN RsFc abnormalities in this disorder and reveal correlations between DN-cerebral RsFc and ASD symptom severity.

Rituximab is a chimeric anti-CD20 monoclonal antibody that is an effective therapy for multiple sclerosis. Rituximab has been associated with the development of serum sickness (type III hypersensitivity) characterized by arthralgia, fever, and rash during the treatment of other conditions, such as rheumatoid arthritis. Here we describe serum sickness associated with rituximab in multiple sclerosis patients and discuss both the management of serum sickness itself and implications for utilizing alternative anti-CD20 monoclonal antibodies for disease management in this patient population.

BACKGROUND:Psychiatric comorbidity is highly prevalent in general medicine inpatient settings and is associated with increased duration and cost of hospitalization. OBJECTIVE:To evaluate the impact of integrated, proactive psychiatric care on hospital medicine length of stay (LOS), expanding upon methods from earlier studies. METHODS:A full-time psychiatrist was dedicated to a single hospital medicine unit to focus on early case finding and intensified treatment, interdisciplinary communication, and discharge planning. To a pre-post intervention design, we added a simultaneous usual care comparison. We also added adjustments for age, sex, insurance type, and whether the patient was discharged home or to a facility. We included a sensitivity analysis to remove outliers for whom LOS was ≤30 days. RESULTS:Statistically significant differences in LOS occurred on the pilot unit in the pre-post analysis (-1.66 d, P = 0.04) and on the pilot versus control units in the intervention year (-1.91 d, P = 0.003). The differential pre-post change in LOS on the pilot versus control units revealed a positive trend but was not statistically significant (-1.59 d, P = 0.14). This more rigorous test approached statistical significance when patients with LOS >30 days were excluded (-1.15 d, P = 0.07). CONCLUSION/CONCLUSIONS:This analysis strengthens existing evidence that dedicated, proactive psychiatric services integrated into hospital medicine units lower LOS more than does usual psychiatric consultation upon request, particularly in patients with an LOS ≤30 days.