IMpower210:A phase Ⅲ study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer

Objective: IMpower210(NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs.docetaxel as second-line treatment for advanced non-small cell lung cancer(NSCLC) in East Asian patients.Methods: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system(7th edition);Eastern Cooperative Oncology Group performance status of 0 or 1;and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab(1,200 mg) or docetaxel(75 mg/m^(2)). The primary study endpoint was overall survival(OS) in the intention-to-treat(ITT) population with wild-type epidermal growth factor receptor expression(ITT EGFR-WT) and in the overall ITT population.Results: Median OS in the ITT EGFR-WT population(n=467) was 12.3 [95% confidence interval(95% CI),10.3-13.8] months in the atezolizumab arm(n=312) and 9.9(95% CI, 7.8-13.9) months in the docetaxel arm[n=155;stratified hazard ratio(HR), 0.82;95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5(95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1(95% CI, 8.4-14.2) months(n=377) with docetaxel treatment(n=188;stratified HR, 0.87;95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events(TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm.Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

Peginterferon alfa-2a for the treatment of chronic hepatitis C in the era of direct-acting antivirals

BACKGROUND: The availability of novel direct-acting antivirals (DAAs) represents a new era of curative hepatitis C virus (HCV) treatment, with over 95% of patients infected with HCV genotype 1 achieving sustained virological response (SVR). Nevertheless, the majority of patients globally are unable to access these treatments because of cost and infrastructure constraints and, thus, remain untreated and uncured. DATA SOURCE: Relevant articles of peginterferon (PegIFN)-based treatments in HCV and sofosbuvir-based treatments, simeprevir, daclatasvir/asunaprevir, ritonavir-boosted paritaprevir/ombitasvir/dasabuvir, and grazoprevir/elbasvir, were searched in PubMed database, including general population and special population. RESULTS: PegIFN in combination with ribavirin remains an important and relevant option for some patients, achieving SVR rates of up to 79% in genotype 1 and 89% in genotype 2 or 3 infections, which increases for patients with favorable IL28B genotypes. Triple therapy of DAA plus PegIFN/ribavirin is effective in treating difficult-to-cure patients infected with HCV genotype 3 or with resistance-associated variants. Owing to its long history in HCV management, the efficacy, tolerability and long-term outcomes associated with PegIFN alfa-2a are well established and have been validated in large-scale studies and in clinical practice for many populations. Furthermore, emerging data show that IFN-induced SVR is associated with lower incidences of hepatocellular carcinoma compared with DAAs. On the contrary, novel DAAs have yet to be studied in special populations, and long-term outcomes, particularly tumor development and recurrence in patients with cirrhosis and/or hepatocellular carcinoma, and reactivation of HBV in dually infected patients, are still unclear. CONCLUSION: In this interferon-free era, PegIFN-based regimens remain a safe and effective option for selected HCV patients.

Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1α in advanced hepatocellular carcinoma

BACKGROUND Hypoxia-inducible factor 1α(HIF-1α) is a gene that regulates tumor survival,neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma(HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC.AIM To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179.METHODS In the preclinical study of RO7070179 in a HCC xenograft model, the mice wereseparated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment,received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179.RESULTS Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1 b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies(each biopsy was divided into 2 specimens, the tip and the root).CONCLUSION RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity.This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either m RNA level or DCE-MRI within 1 cycle of therapy.

A candidate identification questionnaire for postmenopausal osteoporosis patients switched from daily or weekly bisphosphonate to once-monthly ibandronate: An open, prospective, multicenter study—BONCURE study

A candidate identification questionnaire (CIQ) was tested to determine its predictive value for patient-reported satisfaction in patients switched from once-weekly or once-daily treatment with a bisphosphonate to once-monthly dosing. This was a prospective, open-label, multicenter international study in patients with postmenopausal osteoporosis who had been receiving once-daily or once-weekly alendronate or risendronate for at least 3 months. Patients completed a CIQ, then commenced 150 mg monthly ibandronate for 6 months. Patients completed the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-QTM) at baseline for 6 months. Scores were converted to composite satisfaction scores (CSS, scale 0-100). Totally 677 patients completed a CIQ, 645 were enrolled in the treatment phase and comprised the intent-to-treat (ITT) population, and 630 completed the study. In the ITT population, 68.1% patients answered “yes” to one or more CIQ questions. OPSAT-Q scores increased for the convenience, quality of life and overall satisfaction domains (p scores for the side effects domains were significant (p < 0.001) in the CIQ “yes” group, but not for the degree of bother (decrease in mean of 0.1 points, p = 0.50) or duration (no change, p = 0.84) of non-gastrointestinal side effects. Of 638 patients who completed the preference questionnaire, 93.0% of patients preferred the once-monthly dosing schedule and 563 patients (90.7%) found it more convenient. The most common adverse events were dyspepsia (1.9%), nausea (1.1%), and upper abdominal pain (0.9%). Patients are likely to prefer treatment with monthly ibandronate to a weekly or monthly bisphosphonate irrespective of their stated preference before switching treatment.

Mechanics of serotonin-producing human entero-endocrine cells

The gastrointestinal(GI)tract's primary role is food digestion,relying on coordinated fluid secretion and bowel movements triggered by mechanosensation.Enteroendocrine cells(EECs)are specialized mechanosensitive cells that convert mechanical forces into electrochemical signals,culminating in serotonin release to regulate GI motility.Despite their pivotal role,knowledge of EEC mechanical properties has been lacking due to their rarity and limited accessibility.In this brief report,we present the first single-cell mechanical characterization of human ECCs isolated from healthy intestinal organoids.Using single-cell optical tweezers,we measured EEC stiffness profiles at the physiological temperature and investigated changes following tryptophan metabolism inhibition.Our findings not only shed light on EEC mechanics but also highlight the potential of adult stem cell-derived organoids for studying these elusive cells.

Weighted Youden index and its two-independent-sample comparison based on weighted sensitivity and specificity

Background Most indices for evaluating a diagnostic test can be expressed as functions of sensitivity （SEN） and specificity （SPE）. Practically, all existing methods suffer from the inability to weight sensitivity and specificity relative to their importance. In this paper, we developed a novel index, the weighted Youden index, that allows Youden index to be a combination of sensitivity and specificity with user-defined weights. Methods The weighted Youden index Jw is defined as Jw=2（wxSEN＋（1-w）SPE）-I （0 〈w 〈1）. It has three properties： （1） the sum of the weights which are attached to sensitivity and specificity should be equal to 1; （2） the range of Jw should be within [-1, 1], which is the range of the Youden index J; （3） Jw should be equal to J when sensitivity and specificity have equal weights. According to the central limit theorem, we obtain the standard error of Jw, and propose a statistical inference method to compare two weighted Youden indices. The monotonicity of the test statistic was discussed. Results An example of comparing two diagnostic tests for pheochromocytoma was used to demonstrate the weighted Youden index method. Weighted Youden index, the confidence interval for each test and the hypothesis test of comparing two independent diagnostic tests were presented. Assigning the weights is essential to the weighted Youden index approach. Conclusion The weighted Youden index can broaden further research in weighting sensitivity and specificity exp ts applications in diagnostic test development and motivate icitly.

Safety and efficacy of obinutuzumab in Chinese patients with B-cell lymphomas: a secondary analysis of the GERSHWIN trial

Background:Patients with relapsed/refractory B-cell lymphomas have limited treatment options.GERSHWIN is an open-label,single-arm,phase Ib study of obinutuzumab monotherapy in Chinese patients with histologically docu-mented CD20+relapsed/refractory chronic lymphocytic leukemia(CLL),diffuse large B-cell lymphoma(DLBCL),or follicular lymphoma(FL).The primary outcome measure of pharmacokinetics has been previously reported.We now present data on the secondary endpoint measures(e.g.,safety,and efficacy and pharmacodynamics).Methods:Patients received 1000 mg obinutuzumab intravenously on days 1,8,and 15 of cycle 1(CLL patients;first dose split over 2 days),and on day 1 of cycles 2-8.Each cycle lasted for 21 days;the treatment period was 24 weeks.All subjects receiving at least one dose of obinutuzumab were included in the analysis of safety,efficacy,as well as pharmacodynamics.Results:A total of 48 patients(>18 years of age)were enrolled(CLL:12;DLBCL:23;FL:13).The subjects received a median of two lines of anticancer treatment prior to the enrollment.Thirty-five patients(72.9%)had at least one adverse event(AE).The most frequent AE was infusion-related reactions(15 patients;31.3%),followed by pyrexia(11 patients;22.9%).Treatment-related AEs were reported in 28 patients(58.3%),and included one death(interstitial lung disease).End-of-treatment(EoT)response rate was 33.3%.Best overall response rate was 47.9%.Most CLL patients achieved a partial response at EoT(58.3%).CD19+depletion occurred in 75.0%of the patients with CLL,and all patients with FL and DLBCL.Conclusions:The safety and efficacy of obinutuzumab monotherapy in Chinese patients with B-cell lymphomas were similar to that observed in previous studies in non-Chinese patients;no new safety signals were observed.

Pertuzumab in combination with trastuzumab and chemotherapy for Chinese patients with HER2-positive metastatic gastric or gastroesophageal junction cancer:a subpopulation analysis of the JACOB trial

Background:The JACOB trial(NCT01774786)was a double-blinded,placebo-controlled,randomized,multicenter,international,phase III trial evaluating the efficacy and safety of adding pertuzumab to trastuzumab and chemo-therapy in first-line treatment of human epidermal growth factor receptor 2(HER2)-positive metastatic gastric cancer/gastroesophageal junction cancer(GEJC).The aim of this analysis was to investigate efficacy and safety outcomes in the Chinese subpopulation from the JACOB trial.Methods:This post hoc subpopulation analysis included all patients recruited in China's Mainland(n=163;20.9%)between June 2013 and January 2016.The patients were randomly assigned in a 1:1 ratio to receive pertuzumab plus trastuzumab and chemotherapy(pertuzumab group;n=82)or placebo plus trastuzumab and chemotherapy(con-trol group;n=81).Intravenous pertuzumab(840 mg)and trastuzumab(8 mg/kg loading and 6 mg/kg maintenance doses)were given every 3 weeks until disease progression or unacceptable toxicity.Chemotherapy was given as per standard regimens/doses of capecitabine or 5-fluorouracil plus cisplatin.The primary endpoint was overall survival(OS);secondary efficacy endpoints included progression-free survival(PFS),and overall objective response rate(ORR).Results:The median OS was 18.7 months in the pertuzumab group and 16.1 months in the control group(hazard ratio[HR]0.75;95%confidence interval[CI]0.49 to 1.14).The median PFS was 10.5 and 8.6 months in the pertuzumab and control groups,respectively(HR 0.85;95%CI 0.60 to 1.21),and the median ORRs were 68.9%and 55.7%,respectively.The treatment effect in this Chinese subpopulation showed consistency with that in the global ITT population with numerically lower HR for OS and PFS compared with the control group.The safety profiles of the pertuzumab and control groups in this Chinese subpopulation analysis were generally comparable.The most common grade 3-5adverse events were neutropenia,anemia,and leukopenia.However,due to the nature of being a post hoc subgroup analysis,the results presented here are descriptive only and need to be interpreted with caution.Conclusions:OS and PFS were numerically improved by adding pertuzumab to trastuzumab and chemotherapy as first-line treatment in Chinese HER2-positive gastric cancer/GEJC patients,and this regimen demonstrated an acceptable safety profile.

A Potential Functional Cure in Chinese HBeAg-negative Chronic Hepatitis B Patients Treated with Peg-interferon Alpha-2a

Background and Aims:Data are limited on the use of pegylated-interferon alpha-2a(peg-IFNα)in Chinese patients with chronic hepatitis B virus(HBV)infection(CHB).We evaluated the effectiveness and safety of peg-IFNαin Chinese patients with hepatitis B envelope antigen-negative CHB in routine clinical practice.Methods:In this prospective,multicenter,observational,non-interventional cohort study,patients were assessed for up to 1 year after peg-IFNαtreatment cessation.Treating physicians established the dosing and treatment duration according to Chinese clinical practice.Effectiveness of peg-IFNαtreatment was measured by the percentage of:patients with HBV DNA<2000 IU/mL and loss of hepatitis B surface antigen(commonly known as HBsAg);HBV DNA level at end of treatment(EOT),and 6 months and 1 year posttreatment;and time course change in quantitative HBV DNA and HBsAg.Results:At EOT,6 months posttreatment,and 1 year posttreatment,the percentage of patients with HBV DNA<2000 IU/mL was 90.0%,81.8%,and 82.2%,and that of patients with HBsAg loss was 6.5%,9.4%,and 9.5%,respectively.The HBV DNA level decreased from 5.61 log IU/mL at baseline to 2.48 log IU/mL at EOT and 2.67 log IU/mL at 1 year posttreatment.The HBsAg level decreased from 3.08 log IU/mL at baseline to 2.24 log IU/mL at EOT and 2.10 log IU/mL at 1 year posttreatment.The incidence of adverse events was 52.0%.Conclusions:Peg-IFNαhas the potential to provide functional cure(HBsAg loss)for CHB and is well tolerated in hepatitis B envelope antigen-negative CHB patients in routine clinical practice in China.