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Summary To describe the demographics, etiologies, types of status epilepticus ( SE ), and outcomes in people with refractory and super‐refractory SE from around the world, we prospectively collected cases of refractory SE ( RSE ) treated with continuous intravenous anesthetic drugs in an intensive care unit setting through online questionnaires using “active surveillance.” We collected information about 776 cases of RSE in 50 countries over 4 years. Control of SE was achieved in 74% of the cases. Neurologic outcomes were poor in 41% of patients, and 24% died. Good outcome was associated with younger age and a history of epilepsy. Etiology strongly influenced the outcome. Patients from Asia were younger, more frequently presented with convulsive SE , and were more frequently affected by infectious etiologies when compared with patients from Europe and the Americas. Despite these differences, outcomes were similar in all countries. Demographics of patients with RSE in a global audit are similar to those in prior single center series, providing evidence of generalizability of those studies. Important differences exist among patients with RSE from different regions of the world, but these do not seem to significantly influence patient outcomes.

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97–1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03–1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Abstract Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. Patients and Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. Conclusions: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

OBJECTIVES: We assessed the adherence to neuroimaging guidelines and the diagnostically relevant yield of neuroimaging in newly presenting early life epilepsy (ELE). METHODS: There were 775 children with a new diagnosis of epilepsy (<3 years old at onset) who were recruited through the ELE study at 17 US pediatric epilepsy centers (2012–2015) and managed prospectively for 1 year. The data were analyzed to assess the proportion of children who underwent neuroimaging, the type of neuroimaging, and abnormalities. RESULTS: Of 725 children (93.5%) with neuroimaging, 714 had an MRI (87% with seizure protocols) and 11 had computed tomography or ultrasound only. Etiologically relevant abnormalities were present in 290 individuals (40%) and included: an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%). Neuroimaging was abnormal in 160 of 262 (61%) children with abnormal development at diagnosis versus 113 of 463 (24%) children with typical development. Neuroimaging abnormalities were most common in association with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%). In children without spasms or focal semiology with typical development, 29 of 185 (16%) had imaging abnormalities. Pathogenic genetic variants were identified in 53 of 121 (44%) children with abnormal neuroimaging in whom genetic testing was performed. CONCLUSIONS: Structural abnormalities occur commonly in ELE, and adherence to neuroimaging guidelines is high at US pediatric epilepsy centers. These data support the universal adoption of imaging guidelines because the yield is substantially high, even in the lowest risk group.