Introduction-The metabolic syndrome and insulin resistance represent growing concerns related to atypical antipsychotic (AAP) use as their incidence in the schizophrenia population is two to four fold higher than the general population. Reduced methylenetetrahydrofolate reductase (MTHFR) activity, resulting in aberrant folate metabolism and hyperhomocysteinemia, has been linked to cardiovascular disease and is unstudied in relation to AAP associated metabolic complications.Purpose-To examine the relationship between MTHFR, metabolic syndrome, and insulin resistance in schizophrenia subjects receiving AAPs for ≥ 12 months.Methods-Fifty-eight subjects were included in this cross-sectional analysis and screened for the metabolic syndrome, insulin resistance and MTHFR 677C/T and 1298 A/C genotype.Results-Overall, 23 subjects (40%) met metabolic syndrome criteria. There were no differences in age, gender, race, or AAP exposure between genotype groups. For the 677 T allele carriers, 53% met metabolic syndrome criteria, compared to 23% in the CC genotype group, giving an OR = 3.7, (95% CI = 1.24 -12.66, p = 0.02). Thus, for T allele subjects, the risk was almost four times greater, despite similar antipsychotic exposure. Both waist circumference and MTHFR genotype significantly predicted insulin resistance (F = 8.35, df = 5, 51, p < 0.0001), with these two terms interacting (F = 8.6, df = 2, p = 0.0006) suggesting TT subjects are at greater risk for insulin resistance with increasing central adiposity, which is independent of age, gender, BMI, or metabolic syndrome diagnosis. Conclusion-Resultsshould be taken cautiously due to the small sample size, but suggest the MTHFR 677C/T variant may predispose patients to AAP metabolic complications.

IMPORTANCE Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. OBJECTIVE To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. DESIGN, SETTING, AND PARTICIPANTS Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. INTERVENTIONS Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. MAIN OUTCOMES AND MEASURES Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form-physical functioning subscale score (SF-36), and the change in the Berg Balance Test. RESULTS Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improvedfrom13.2(95%CI,12.2-14.3)to11.3(95%CI,10.0-12.5);themeanbetween-groupdifference was-2.5 units (95% CI,-3.7 to-1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI,-0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. CONCLUSIONS AND RELEVANCE Among patients with chorea associated with Hun...

Background: The majority of NSCLC patients treated with immunecheckpoint inhibitors (ICI) develop acquired resistance. Conventional cytotoxic chemotherapy remains the treatment of choice for those patients. There are case reports on re-administration of ICIs for advanced NSCLC; however, these case series are difficult to draw definitive conclusions. We therefore retrospectively reviewed the efficacy of retreatment with ICI in our hospital. Method: Patients with pathologically confirmed advanced NSCLC who were treated with ICI in Kindai University hospital were retrospectively reviewed from December 2015 to July 2017. Among 212 NSCLC patients treated with ICIs, 10 patients (4.7 %) were retreated with ICI. Result: Number of patients treated with Nivolumab, Pembrolizumab and Atezolizumab were four, five and one, respectively. The best response of initial treatment with ICIs among 10 patients were five partial response (PR), two stable disease (SD) and three progressive disease (PD). Whereas, three patients (30%) showed SD and the others (70%) had PD to ICI retreatment. No severe adverse events attributable to the ICIs were noted. Conclusion: In the limited number of retrospective study, we could not find good responders for retreatment with ICIs. Best overall response during the previous treatment period is not related to the efficacy of retreatment with ICIs. At present, former responder to ICI therapy may not be the proper candidate for ICI re-challenge treatment strategy. Further biomarker analysis and treatment strategy is warranted for the patients and physicians to retreat with ICIs.

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Background Deutetrabenazine is approved in the USA, China, Australia, Israel, Brazil, and South Korea for the treatment of chorea associated with Huntington disease. Objective We aimed to evaluate the long-term safety and tolerability of deutetrabenazine for the treatment of Huntington disease. Methods This open-label, single-arm, multi-center study included patients who completed a double-blind study (Rollover) and patients who converted overnight from a stable tetrabenazine dose (Switch). Exposure-adjusted incidence rates (adverse events per person-year) were calculated. Efficacy was analyzed using a stable post-titration timepoint (8 weeks). Changes in the Unified Huntington's Disease Rating Scale total motor score and total maximal chorea score from baseline to week 8, as well as those from week 8 to week 145 (or the last visit on the study drug if that occurred earlier), were evaluated as both efficacy and safety endpoints during the study. Results Of 119 patients (Rollover, n = 82; Switch, n = 37), 100 (84%) completed ≥ 1 year of treatment. End-of-study exposure-adjusted incidence rates for adverse events in Rollover and Switch, respectively, were: any, 2.57 and 4.02; serious, 0.11 and 0.14; leading to dose suspension, 0.05 and 0.04. Common adverse events (≥ 4% either cohort) included somnolence (Rollover, 20%; Switch, 30%), depression (32%; 22%), anxiety (27%; 35%), insomnia (23%; 16%), and akathisia (6%; 11%). Adverse events of interest included suicidality (9%; 5%) and parkinsonism (4%; 8%). Mean dose at week 8 was 38.1 mg (Rollover) and 36.5 mg (Switch). Mean dose across cohorts after titration was 37.6 mg; at the final visit, mean dose across cohorts was 45.7 mg. Patients showed minimal change in the Unified Huntington's Disease Rating Scale total maximal chorea scores with stable dosing from weeks 8-145 or at the end of treatment, but total motor score increased versus week 8 (mean change [standard deviation]: 8.2 [11.9]). There were no unexpected adverse events upon drug withdrawal, and mean (standard deviation) total maximal chorea scores increased 4.7 (4.6) units from week 8 to 1-week follow-up. Conclusions Adverse events observed with long-term deutetrabenazine exposure were consistent with previous studies. Reductions in chorea persisted over time. Upon treatment cessation, there was no unexpected worsening of chorea. Clinical Trial Registration ClinicalTrials.gov identifier: NCT01897896.The members of "The Huntington Study Group/ARC-HD Investigators and Coordinators" are listed in the Acknowledgements section.