Background Hereditary transthyretin (ATTRv) amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We aimed to assess the efficacy and safety of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with ATTRv amyloidosis with polyneuropathy. MethodsThis multi-country, multi-centre, open-label extension (OLE) trial enrolled patients at 43 sites in 19 countries as of 24 September 2018. Patients were eligible if they had completed the phase 3 APOLLO (randomised, double-blind, placebo-controlled [2:1], 18-month study) or phase 2 OLE (single-arm, 24-month study) parent studies and tolerated the study drug. Eligible patients from APOLLO (APOLLO-patisiran [received patisiran during APOLLO] and APOLLO-placebo [received placebo during APOLLO] groups) and the phase 2 OLE (phase 2 OLE patisiran group) studies enrolled in this Global OLE trial and receive patisiran 0•3 mg/kg by intravenous infusion every 3 weeks for up to 5 years. Efficacy assessments include measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress. Patients included in the current efficacy analyses are those who had completed 12-month efficacy assessments as of the data cut-off. Safety analyses included all patients who received ≥1 dose of patisiran up to the data cut-off. The Global OLE is ongoing with no new enrolment, and current findings are based on the 12-month interim analysis. The study is registered with ClinicalTrials.gov, NCT02510261.

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Pancreatic islet transplantation is a curable treatment for type 1 diabetes and has been put into practice in various countries. In this study, we analyzed the pharmacokinetic characteristics of sirolimus and tacrolimus in six Japanese patients with pancreatic islet transplants immediately after surgery, and monitored efficacy and toxicity. The patients were treated with immunosuppressive therapy based on the Edmonton protocol, that is, sirolimus and low-dose tacrolimus. Pharmacokinetic analyses were performed using the nonlinear mixed-effects modeling program NONMEM. Large inter- and intra-individual variability was observed in the pharmacokinetics of sirolimus and tacrolimus. A model with increased apparent clearance in the postoperative period explained well the intra-individual variability in the pharmacokinetics of both drugs. The most frequent drug-induced toxicity was a decrease in the white blood cell count, and two of six patients required the administration of granulocyte colony-stimulating factor. Clinical laboratory tests immediately before the transplantation and cytochrome P450 3A5 genotype were not related to the high blood concentrations of sirolimus after the loading dose. From these results, the apparent clearance of sirolimus and tacrolimus might temporally decline immediately after pancreatic islet transplantation. A high trough concentration of sirolimus might increase the risk of hematological toxicy, and adjustment of the dosage for immunosuppressive treatment will be necessary in Japanese patients.

The standard treatment for ovarian serous carcinoma is maximum debulking surgery and platinum-based chemotherapy. Despite the high response rate for chemotherapy, the majority of patients will be resistant to first-line agents and the prognosis for these patients is particularly poor. Currently there are no reliable methods to determine or predict platinum resistance. Uncoupling protein 2 (UCP2) is widely expressed in cancer cells and regulates the production of mitochondrial reactive oxygen species (ROS). A reduction in ROS is associated with carcinogenesis and chemoresistance. Downregulation of UCP2 significantly causes increased cell death following chemotherapy. The present study investigated the association between UCP2 expression and platinum sensitivity. The study included 54 patients with ovarian serous carcinoma (FIGO stages III and IV) who were treated at Osaka City University Hospital between January 2005 and December 2012. Patients were divided into a platinum-sensitive group (n=27) and platinum-resistant group (n=27) based on the platinum-free interval, which was calculated from the time of last platinum administration to the time of recurrence. UCP2 expression in human ovarian serous carcinoma cells was inhibited by genipin, and changes in carboplatin sensitivity were examined. The UCP2 weighted score was lower in the platinum-sensitive group than in the platinum resistant-group (P=0.005). In addition, patients in the low UCP2 expression group were more sensitive to platinum-based chemotherapy than those in the high UCP2 expression group (P=0.001). Sensitivity to carboplatin was significantly increased when UCP2 was inhibited in human ovarian serous carcinoma cells . UCP2 expression may be a predictive marker of the efficacy of platinum-based chemotherapy for patients with ovarian serous carcinoma.