The off-label uses of pipeline embolization device for complex cerebral aneurysms: Mid-term follow-up in a single center.

OBJECTIVE: To describe the off-label uses of pipeline embolization device for a variety of types of aneurysms including ruptured aneurysms, posterior circulation aneurysms, small aneurysms, distal aneurysms, and recurrent aneurysms. METHODS: Clinical and angiographic data of patients who underwent pipeline embolization device treatment on off-label use at our center were retrospectively reviewed. For categorical variables, Fisher's exact test was used, and a two-sample Wilcoxon rank-sum test was used for patients' age to analyze the correlation with outcomes. RESULTS: In this study, 121 aneurysms in 107 patients received off-label pipeline embolization device treatments. The overall rate of complete aneurysm occlusion was 77.8% (28/36 in 35 patients) for posterior circulation aneurysms and 95.3% (81/85 in 72 patients) for anterior circulation aneurysms. The posterior circulation aneurysms have a lower rate of aneurysm occlusion (p = 0.0372). The small aneurysms have a higher rate of aneurysm occlusion (p = 0.0104). The patient's sex, age, and aneurismal size were associated with ischemic stroke complications (p = 0.0397, 0.0166, and 0.0178). In posterior circulation aneurysm patients, only two basilar apex aneurysms underwent pipeline embolization device treatment, both of whom died of thrombotic complications. There was no difference in mortality between posterior circulation aneurysm patients (8.6%, 3/35) and anterior circulation aneurysm patients (1.4%, 1/72) (p = 0.1015). Patients of older age have a higher risk of death rate (p = 0.0053). CONCLUSIONS: The off-label use of pipeline embolization device is often performed in clinical practice and can achieve efficacy in complex aneurysms. The off-label use of pipeline embolization device was found to carry an increased rate of mortality in older patients. Excluding basilar apex aneurysms, the pipeline embolization device is as safe as anterior circulation aneurysms in the treatment of posterior circulation aneurysms elsewhere.

A Single- and Multiple-Dose Study to Evaluate the Pharmacokinetics of Fixed-Dose Grazoprevir/Elbasvir in Healthy Chinese Participants.

PURPOSE: The burden of hepatitis C virus infection is particularly high in Asian countries, and new treatments are urgently needed. The purpose of this study was to characterize the pharmacokinetics (PK) and safety of the fixed-dose combination tablet of elbasvir/grazoprevir in healthy Chinese participants. PATIENT AND METHODS: In this Phase I, single-site, open-label, 3-period study in healthy Chinese adults, participants received a single tablet of elbasvir 50 mg/grazoprevir 100 mg, followed by blood sampling for up to 96 hrs (http://www.chinadrugtrials.org.cn/ CTR20160034; Protocol PN071). Participants then received 1 tablet daily for 10 days, followed by a minimum 10-day washout, after which participants received a single dose of 2 tablets (elbasvir 100 mg/grazoprevir 200 mg). Elbasvir and grazoprevir PK were assessed following single and multiple doses. Safety and tolerability were also evaluated. RESULTS: Twelve participants (50% male) were enrolled in and completed the study. Following single-dose oral administration of elbasvir 50 mg/grazoprevir 100 mg or elbasvir 100 mg/grazoprevir 200 mg, the median Tmax was 3-4 hrs and elimination half-life was 18 hrs (elbasvir) and 30 hrs (grazoprevir). Multiple-dose administration resulted in AUC0-24 accumulation ratios of 1.58 (elbasvir) and 2.35 (grazoprevir). Both elbasvir 50 mg/grazoprevir 100 mg and 100 mg/200 mg regimens were generally well tolerated. CONCLUSION: Single-dose administration of elbasvir 50 mg/grazoprevir 100 mg or 100 mg/200 mg and once-daily administration of elbasvir 50 mg/grazoprevir 100 mg for 10 days has been adequately characterized, with PK values within the expected range, and was generally well tolerated in healthy Chinese male and female participants.

Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study.

BACKGROUND: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab ± chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented. METHODS: Patients ≥ 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score ≥ 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1-5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy). RESULTS: In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8-24.1) and 17.5 months (range 1.7-20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma. CLINICAL TRIAL: ClinicalTrials.gov NCT02335411.

Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer.

CONTEXT.­: Regulatory approval of pembrolizumab for treatment of gastric and gastroesophageal junction (G/GEJ) adenocarcinoma required a reproducible scoring method for use of programmed death ligand-1 (PD-L1) protein expression as a companion diagnostic to identify likely responders to therapy. OBJECTIVE.­: To develop an immunohistochemical scoring algorithm that includes PD-L1 expression for tumor and immune cells, that is, the combined positive score. DESIGN.­: Four previously treated tumor types in the KEYNOTE-012 and KEYNOTE-028 studies were analyzed descriptively with a version of the PD-L1 immunohistochemical 22C3 pharmDx assay labeled for investigational use only to determine the relative importance of PD-L1 expression in tumor versus immune cells as a biomarker for pembrolizumab response. A combined positive score was developed as a novel scoring method and was compared with the tumor proportion score in cohort 1 from the KEYNOTE-059 study (G/GEJ cancer). External reproducibility was assessed. RESULTS.­: Per combined positive score cutoff of 1 or more, the prevalence of PD-L1 expression in patients with G/GEJ cancer was 57.6% (148 of 257 patients), with reasonable enrichment of responses (odds ratio, 2.8). Per tumor proportion score cutoff of 1% or more, prevalence was 12.5% (32 of 257 patients), with minimal enrichment (odds ratio, 1.4). External reproducibility assessments demonstrated interpathologist overall agreement of 96.6% (591 of 612; 95% CI, 94.0%-98.7%) and intrapathologist overall agreement of 97.2% (595 of 612; 95% CI, 95.3%-98.9%). CONCLUSIONS.­: Combined positive score is a robust, reproducible PD-L1 scoring method that predicts response to pembrolizumab in patients with G/GEJ cancer. This novel scoring method supported US Food and Drug Administration approval of pembrolizumab as third-line therapy for G/GEJ cancer and has facilitated investigation in other indications.

A Phase I, Single- and Multiple-dose Study to Evaluate the Pharmacokinetics of Elbasvir and Grazoprevir in Healthy Chinese Participants.

PURPOSE: This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals. METHODS: This study was a 2-part, parallel-arm, open-label trial. In part 1, single-dose PK variables of elbasvir 10/50/100 mg and grazoprevir 50/100/200 mg were evaluated in 10 participants per drug. In part 2, 10-day multiple-dose PK variables of elbasvir 50 mg and grazoprevir 100 mg administered once daily alone and in combination were evaluated in 12 participants. Summary and inferential statistics of the PK parameters are reported. Elbasvir and grazoprevir PK parameters were also compared between Chinese participants and historical data from white participants. FINDINGS: Single-dose elbasvir and grazoprevir median Tmax were 2.9 to 4.0 and 1.9 to 3.0 hours after administration, respectively. Elbasvir AUC0-∞ and Cmax increased in a dose-proportional manner (slope estimate [90% CI], 0.92 [0.84-1.01] and 0.98 [0.86-1.09], respectively), whereas grazoprevir AUC0-∞ and Cmax increased in a greater-than-dose-proportional manner (slope estimate [90% CI], 1.42 [1.27-1.57] and 1.96 [1.64-2.29]). After repeated administration, the accumulation ratios for AUC0-24, 24-hour concentration, and Cmax were 1.55, 1.57, and 1.38 for elbasvir and 2.03, 1.23, and 2.51 for grazoprevir. Co-administration of elbasvir 50 mg and grazoprevir 100 mg once daily did not have a clinically relevant effect on the PK variables of either drug. Median Tmax after co-administration versus alone was 3.0 hours versus 3.0 hours for elbasvir and 3.1 hours versus 3.0 hours for grazoprevir. Geometric mean ratios (90% CI) for elbasvir and grazoprevir AUC0-24 (Chinese/white participants) were 1.58 (1.03-2.42) and 1.21 (0.76-1.92). Elbasvir and grazoprevir, administered alone or concomitantly, were well tolerated. IMPLICATIONS: In healthy Chinese individuals, administration of elbasvir and grazoprevir, alone or concomitantly, was generally well tolerated, with a thoroughly characterized PK profile. Elbasvir and grazoprevir exposures may trend higher in Chinese healthy participants relative to white healthy participants. Protocol number MK-8742 PN022.

Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial.

Importance: Therapeutic options are needed for patients with advanced gastric cancer whose disease has progressed after 2 or more lines of therapy. Objective: To evaluate the safety and efficacy of pembrolizumab in a cohort of patients with previously treated gastric or gastroesophageal junction cancer. Design, Setting, and Participants: In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016. Median (range) follow-up was 5.8 (0.5-21.6) months. Intervention: Patients received pembrolizumab, 200 mg, intravenously every 3 weeks until disease progression, investigator or patient decision to withdraw, or unacceptable toxic effects. Main Outcomes and Measures: Primary end points were objective response rate and safety. Objective response rate was assessed by central radiologic review per Response Evaluation Criteria in Solid Tumors, version 1.1, in all patients and those with programmed cell death 1 ligand 1 (PD-L1)-positive tumors. Expression of PD-L1 was assessed by immunohistochemistry. Secondary end points included response duration. Results: Of 259 patients enrolled, most were male (198 [76.4%]) and white (200 [77.2%]); median (range) age was 62 (24-89) years. Objective response rate was 11.6% (95% CI, 8.0%-16.1%; 30 of 259 patients), with complete response in 2.3% (95% CI, 0.9%-5.0%; 6 of 259 patients). Median (range) response duration was 8.4 (1.6+ to 17.3+) months (+ indicates that patients had no progressive disease at their last assessment). Objective response rate and median (range) response duration were 15.5% (95% CI, 10.1%-22.4%; 23 of 148 patients) and 16.3 (1.6+ to 17.3+) months and 6.4% (95% CI, 2.6%-12.8%; 7 of 109 patients) and 6.9 (2.4 to 7.0+) months in patients with PD-L1-positive and PD-L1-negative tumors, respectively. Forty-six patients (17.8%) experienced 1 or more grade 3 to 5 treatment-related adverse events. Two patients (0.8%) discontinued because of treatment-related adverse events, and 2 deaths were considered related to treatment. Conclusions and Relevance: Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment. Durable responses were observed in patients with PD-L1-positive and PD-L1-negative tumors. Further study of pembrolizumab for this group of patients is warranted. Trial Registration: clinicaltrials.gov Identifier: NCT02335411.

Constructing Structure Ensembles of Intrinsically Disordered Proteins from Chemical Shift Data.

Modeling the structural ensemble of intrinsically disordered proteins (IDPs), which lack fixed structures, is essential in understanding their cellular functions and revealing their regulation mechanisms in signaling pathways of related diseases (e.g., cancers and neurodegenerative disorders). Though the ensemble concept has been widely believed to be the most accurate way to depict 3D structures of IDPs, few of the traditional ensemble-based approaches effectively address the degeneracy problem that occurs when multiple solutions are consistent with experimental data and is the main challenge in the IDP ensemble construction task. In this article, based on a predefined conformational library, we formalize the structure ensemble construction problem into a least squares framework, which provides the optimal solution when the data constraints outnumber unknown variables. To deal with the degeneracy problem, we further propose a regularized regression approach based on the elastic net technique with the assumption that the weights to be estimated for individual structures in the ensemble are sparse. We have validated our methods through a reference ensemble approach as well as by testing the real biological data of three proteins, including alpha-synuclein, the translocation domain of Colocin N, and the K18 domain of Tau protein.

Pharmacokinetic interaction of finasteride with tamsulosin hydrochloride: an open-label, randomized, 3-period crossover study in healthy Chinese male volunteers.

PURPOSE: The primary aim of this study was to evaluate whether there was clinically significant pharmacokinetic (PK) interaction between finasteride and tamsulosin in healthy Chinese male subjects. METHODS: This was an open-label, randomized, 3-period, crossover study. Subjects received single and multiple doses of 5 mg finasteride alone, single and multiple doses of 0.2 mg tamsulosin hydrochloride sustained-release capsule alone, and single and multiple doses of 5 mg finasteride with 0.2 mg tamsulosin hydrochloride, in an order determined by a computerized randomization schedule. Blood samples were collected up to 48 hours after dosing on study day 1 and up to 24 hours after dosing on study day 9 for determination of plasma concentrations with a validated LC-MS/MS method. Pharmacokinetic parameters were estimated via noncompartmental methods. Tolerability was evaluated by monitoring adverse events, laboratory assays, vital signs, and 12-lead ECG. FINDINGS: Fifteen subjects were enrolled, and 14 completed the study. The geometric mean ratios (GMRs) (90% CIs) of AUC(τ,ss) and C(max,ss) values of finasteride at steady state between coadministration of finasteride and tamsulosin hydrochloride and finasteride alone were 1.14 (1.05-1.23) and 1.06 (0.99-1.14), respectively. The GMRs (90% CIs) for AUC(0-t) and C(max) values of finasteride for a single dose of coadministration of finasteride and tamsulosin hydrochloride and finasteride alone were 1.02 (0.94-1.11) and 1.06 (1.01-1.11), respectively. The GMRs (90% CIs) for AUC(τ,ss) and C(max,ss) values of tamsulosin at steady-state for coadministration of finasteride and tamsulosin hydrochloride and tamsulosin hydrochloride alone were 1.18 (1.05-1.33) and 1.23 (1.06-1.43), respectively. The GMRs (90% CIs) for AUC(0-t) and C(max) values of tamsulosin for a single dose of coadministration of finasteride and tamsulosin hydrochloride and tamsulosin hydrochloride alone were 1.04 (0.97-1.10) and 1.04 (0.98-1.11), respectively. Statistical analyses confirmed that the 90% CIs for these PK parameters were within the predefined not clinically significant PK drug-drug interaction effect boundaries (0.5-2.0) in this study. If comparing the findings with narrower boundaries (0.8-1.25), the conclusion may not be supportive for tamsulosin hydrochloride. During the study, a total of 4 adverse events were reported in 3 subjects including allergic reaction, abnormal findings on an ECG, a slight increase in alanine aminotransferase, and a positive result on glucose urine test. IMPLICATIONS: Both finasteride and tamsulosin hydrochloride were well tolerated. Coadministration of finasteride and tamulosin hydrochloride seems unlikely to lead to a clinically significant PK drug-drug interaction, after a single dose and at steady state.