Cost-Effectiveness Analysis of Nivolumab Plus Ipilimumab Combination Therapy as First-line Treatment for Advanced Renal Cell Carcinoma in Japan.

OBJECTIVES: The purpose of this study is to examine the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy (NIVO + IPI) compared with the sunitinib (SUN) therapy for Japanese patients with advanced renal cell carcinoma from the perspective of a Japanese health insurance payer. METHODS: A lifetime horizon was applied, and 2% per annum was set as the discount rate. The threshold was set as $ 75 000 per quality-adjusted life-year (QALY) gained. For the analytical method, we used a partitioned survival analysis model to estimate the incremental cost-effectiveness ratio (ICER), which is calculated by dividing incremental costs by incremental QALYs. Progression-free survival, progressive disease, and death were set as health states. Additionally, cost parameters and utility weights were set as key parameters. We set the intermediate/poor-risk population as the base case. Scenario analysis was conducted for the intention-to-treat population and the favorable risk population. Furthermore, one-way sensitivity analysis and probabilistic sensitivity analysis were conducted for each population. RESULTS: In the base-case analysis, the QALYs of NIVO + IPI and SUN were 4.32 and 2.99, respectively. NIVO + IPI conferred 1.34 additional QALYs. Meanwhile, the total costs in the NIVO + IPI and SUN were $692 288 and $475 481, respectively. As a result, the ICER of NIVO + IPI compared with SUN was estimated to be $162 243 per QALY gained. The parameter that greatly affected the ICER was the utility weight of progression-free survival in NIVO + IPI. CONCLUSIONS: NIVO + IPI for advanced renal cell carcinoma seems to be not cost-effective compared with the SUN in the Japanese healthcare system.

Detection bias in open-label trials of anticancer drugs: a meta-epidemiological study.

OBJECTIVES: In anticancer clinical trials, particularly open-label trials, central reviewers are recommended to evaluate progression-free survival (PFS) and objective response rate (ORR) to avoid detection bias of local investigators. However, it is not clear whether the bias has been adequately identified, or to what extent it consistently distorts the results. Therefore, the objective of this study was to evaluate the detection bias in oncological open-label trials by confirming whether local investigators overestimate the PFS and ORR compared with the findings of central reviewers. DESIGN: Meta-epidemiological study. DATA SOURCES: MEDLINE via PubMed from 1 January 2010 to 30 June 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Open-label, parallel-group superiority, randomised trials of anticancer drugs that adjudicated PFS or ORR by both central reviewers and local investigators. REVIEW METHODS: We assessed the values for the same outcome (PFS and ORR) adjudicated by both central reviewers and local investigators. A random-effects model was used to estimate the ratio of HR (RHR) for PFS and the ratio of OR (ROR) for ORR between central reviewers and local investigators. An RHR lower than 1 and an ROR higher than 1 indicated an overestimation of the effect estimated by local investigators. RESULTS: We retrieved 1197 records of oncological open-label trials after full-text screening. We identified 171 records (PFS: 149 records, ORR: 136 records) in which both central reviewers and local investigators were used, and included 114 records (PFS: 92 records, ORR: 74 records) for meta-analyses. While the RHR for PFS was 0.95 (95% CI 0.91 to 0.98), the ROR of ORR was 1.00 (95% CI 0.91 to 1.09). The results remained unchanged in the prespecified sensitivity analysis. CONCLUSIONS: This meta-epidemiological study found that overestimation of local investigators has a small impact on evaluating PFS and ORR in oncological open-label trials. However, a limitation of this study is that it did not include data from all trials; hence, the results may not fully evaluate detection bias. The necessity of central reviewers in oncological open-label trials needs to be assessed by further studies that overcome this limitation. TRIAL REGISTRATION NUMBER: CTR-UMIN000044623.

Social Isolation/Loneliness and Tooth Loss in Community-Dwelling Older Adults: The Sukagawa Study.

Background and Objectives: The relationship between social isolation/loneliness and oral health is unclear. This study investigated the association between social isolation/loneliness and tooth loss in older Japanese adults. Research Design and Methods: This was a cross-sectional study of a population-based cohort (the Sukagawa Study); 5,490 cohort study participants aged ≥75 years and who were independent answered a self-administered questionnaire in 2018. Social isolation was defined based on the 6-item Japanese version of the Lubben Social Network Scale. Loneliness was measured by the 3-item Japanese version of the University of California, Los Angeles (UCLA) Loneliness Scale version 3. The primary outcome was tooth loss, defined as having fewer than 20 teeth. The secondary outcomes were decreased toothbrushing frequency and diminished ability to chew food. Prevalence ratios (PRs) were estimated using a modified Poisson regression analysis in 2 models-Model 1, which adjusted for age, gender, smoking status, alcohol consumption, low annual income, and short education period, and Model 2, which added history of depression, history of diabetes mellitus, history of stroke, and cognitive impairment to Model 1. Results: The primary analysis included 4,645 participants. Adjusted PRs of social isolation and loneliness for tooth loss (Model 1) were 0.97 (95% confidence interval [CI] 0.92-1.01) and 1.06 (95% CI 1.01-1.12), respectively; those for decreased toothbrushing frequency were 1.13 (95% CI 0.95-1.36) and 1.56 (95% CI 1.26-1.92), respectively; and those for chewing difficulty were 1.61 (95% CI 1.06-2.43) and 2.94 (95% CI 1.91-4.53), respectively. The adjusted PRs in Model 2 demonstrated results similar to that of Model 1. Discussion and Implications: Loneliness is associated with tooth loss among older adults, whereas social isolation is not. Our findings can inform plans for policymakers, professionals, and organizations to identify lonely older adults and provide social prescriptions to improve their access to oral health care services.

Phase II study of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as second-line treatment for metastatic colorectal cancer and exploratory analysis of associations between DNA methylation status and the efficacy of the anti-EGFR antibody: T-CORE1201.

Background: Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for KRAS exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment. Methods: Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay. Results: Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in RAS/BRAF wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) vs. 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) vs. 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months]. Conclusions: Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC.

Association between exposure to secondhand aerosol from heated tobacco products and respiratory symptoms among current non-smokers in Japan: a cross-sectional study.

OBJECTIVES: To investigate the association between secondhand-aerosol exposure from heated tobacco products (HTPs) and respiratory symptoms among current non-smokers. DESIGN: Cross-sectional study. SETTING: Internet survey conducted between 8 and 26 February 2021 in Japan. PARTICIPANTS: Non-smoking respondents at the survey aged 15-80 years. EXPOSURE: Self-reported secondhand-aerosol exposure. PRIMARY AND SECONDARY OUTCOMES: We defined asthma/asthma-like symptoms as a primary outcome and persistent cough as a secondary outcome. We examined the association between secondhand-aerosol exposure from HTPs and respiratory symptoms (asthma attacks/asthma-like symptoms and persistent cough). The prevalence ratio (PR) and 95% CI were calculated by using weighted, multivariable 'modified' Poisson regression models. RESULTS: Of the 18 839 current non-smokers, 9.8% (95% CI 8.2% to 11.7%) and 16.7% (95% CI 14.8% to 18.9%) of those who were exposed to secondhand aerosols reported asthma attacks/asthma-like symptoms and persistent cough, whereas 4.5% (95% CI 3.9% to 5.2%) and 9.6% (95% CI 8.4% to 11.0%) of those who were not, respectively. Secondhand-aerosol exposure was associated with respiratory symptoms (asthma attacks/asthma-like symptoms: PR 1.49, 95% CI 1.21 to 1.85; persistent cough: PR 1.44, 95% CI 1.21 to 1.72) after adjusting for covariates. CONCLUSION: Secondhand-aerosol exposure from HTPs was associated with both asthma attacks/asthma-like symptoms and persistent cough. These results provide policymakers with meaningful information in the regulation of HTP use for the protection of current non-smokers.

Strong chu-hai, a Japanese ready-to-drink high-alcohol-content beverage, and hazardous alcohol use: A nationwide cross-sectional study.

BACKGROUND: A new ready-to-drink premixed high-alcohol-content beverage, called strong chu-hai, was launched in Japan, and more recently, in Taiwan and Australia. We aimed to examine the popularity and association of strong chu-hai with individual alcohol use, both of which remained unclear. METHODS: We conducted a cross-sectional study using data from the Japan "Society and New Tobacco" Internet Survey conducted from February 1 to 28, 2022, in Japan. We enrolled 27,993 respondents (aged 15 to 81 years; male 48.5%), including 15,083 current alcohol users. Using inverse probability weighting of data from the 2016 Comprehensive Survey of Living Conditions on Health and Welfare, we estimated the weighted proportions of strong chu-hai users among all respondents and constructed multivariable logistic regression models to estimate the weighted odds ratios (OR) and 95% confidence intervals (CI) of strong chu-hai use for hazardous and harmful alcohol use, defined as a score ≥8 of the Alcohol Use Disorder Identification Test, among current alcohol users. RESULTS: Among all respondents, 56.2% (weighted proportions: past, 35.9%; and current, 20.3%) drank strong chu-hai. Among drinkers, both past and current strong chu-hai use, compared to never use, were associated with hazardous and harmful alcohol use (past, OR 1.73, 95% CI 1.42 to 2.12; current, OR 2.19, 95% CI 1.79 to 2.69). CONCLUSIONS: Our study found that more than half of the respondents experienced strong chu-hai consumption, suggesting that it is widely used in Japan. In addition, both past and current strong chu-hai use were associated with hazardous and harmful alcohol use among current alcohol users.

Burnout and its associated factors among healthcare workers and the general working population in Japan during the COVID-19 pandemic: a nationwide cross-sectional internet-based study.

OBJECTIVES: To examine the prevalence and the associated factors of burnout among both healthcare workers (HCWs) and the general working population, which has not yet been unknown, using large-scale, nationwide data. DESIGN: Cross-sectional internet-based study. SETTING: Nationwide internet survey conducted between 8 and 26 February 2021 in Japan. PARTICIPANTS: Workers aged 20-64 years. We classified the workers as HCWs and the general working population. EXPOSURES: Demographic characteristics (age, sex and marital status), socioeconomic status (education, employment and income), health-related, work-related and industry-related factors (smoking, alcohol use, physical and psychiatric comorbidities, working hours, types of healthcare professionals, experience on the COVID-19 frontline and working industries). MAIN OUTCOME MEASURES: Burnout defined as a score of ≥3 points on the Mini-Z Single-Item Burnout Scale. RESULTS: Of the included 12 650 workers, 1087 were HCWs. After inverse probability weighting on data from the 2016 Comprehensive Survey of Living Conditions, burnout in HCWs and the general working population was 33.5% (95% CI 29.2% to 38.0%) and 31.0% (95% CI 29.7% to 32.4%), respectively. In the weighted multivariable modified Poisson regression models, working 60 hours or more was associated with burnout in all workers (HCWs: prevalence ratio (PR) 2.52, 95% CI 1.68 to 3.76; general population: PR 1.26, 95% CI 1.07 to 1.48). Widowed/separated compared with married was associated with burnout only among HCWs (PR 1.69, 95% CI 1.16 to 2.47), whereas presence of physical or psychiatric comorbidities was associated with burnout among the general working population (PR 1.14, 95% CI 1.03 to 1.28; and PR 1.65, 95% CI 1.45 to 1.87, respectively). CONCLUSIONS: Burnout was prevalent in both HCWs and the general working population in Japan. Both common and specific risk factors were observed. Our findings highlight the need for the general workplace policy and targeted interventions for burnout prevention.

Inadequate reporting of adjudicators in open-label trials of anticancer drugs between 2017 and 2021: a methodological review.

OBJECTIVES: In open-label trials, the details of the adjudicators are essential to evaluate the risk of detection bias. We aimed to describe how the adjudicators of progression-free survival (PFS) and objective response rate (ORR) have been reported in open-label trials of anticancer drugs. STUDY DESIGN AND SETTING: A literature search was conducted using MEDLINE via PubMed. We included open-label, parallel-group superiority randomized trials that investigated the PFS and ORR of anticancer drugs for solid tumors. After screening based on the titles and abstracts, 200 articles were randomly selected from 2017 to 2021. The researchers independently checked the eligibility and collected the adjudicators' information in the protocol, registry, and original article. RESULTS: One hundred fifty five studies reported the PFS and ORR. Approximately half of the studies did not report adjudicators (47.7% in PFS and 47.6% in ORR) in the published articles. The inconsistency between the protocol/registry and the published article was 31.0% for PFS and 33.5% for ORR. The prespecified outcomes were not reported in 5.2% of the studies evaluating PFS and 4.5% evaluating ORR. CONCLUSION: This methodological review found that adjudicators were poorly and inconsistently reported between the protocol/registry and the final publication in open-label trials of anticancer drugs.

Cisplatin Plus Capecitabine After Adjuvant S-1 in Metastatic Gastric Cancer: A Phase II T-CORE1102 Trial.

BACKGROUND/AIM: This phase II study assessed the efficacy of capecitabine plus cisplatin in patients with advanced gastric cancer refractory to adjuvant S-1. PATIENTS AND METHODS: This single-arm, open-label, multicenter, phase II study was conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE) in Japan. Patients aged ≥20 years with advanced HER2-negative gastric cancer that was refractory to S-1 were enrolled. Patients received 80 mg/m2 cisplatin on day 1 intravenously and 1,000 mg/m2 capecitabine twice daily from day 1 to day 14, in 3-week cycles. The primary endpoint was progression-free survival (PFS). The threshold overall response rate (ORR) was estimated to be 15%. The secondary endpoints were overall survival (OS), time to treatment failure, ORR, and toxicities. RESULTS: In total, 21 patients were enrolled from seven hospitals. The median patient age was 63 years. Nineteen patients received the protocol treatment. Median PFS was 3.7 months [90% confidence interval (CI)=2.7-5.6 months], which did not reach the predefined threshold of 4.0 months. ORR was 5.9% (95%CI=0.0-17.1%). Median OS was 11.9 months (95% CI 6.3-19.4 months). Febrile neutropenia was observed in 5.3% of patients. The most frequently observed grade 3 non-hematologic toxicities were nausea (15.8%) and hyponatremia (15.8%). CONCLUSION: The addition of a fluoropyrimidine to a platinum agent after adjuvant therapy is not suitable for gastric cancer.

Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction.

Cancer stem cells (CSCs) have high tumor-initiating capacity and are resistant to chemotherapeutic reagents; thus eliminating CSCs is essential to improving the prognosis. Recently, we reported that dexamethasone increases the effects of gemcitabine on pancreatic CSCs; however, the mechanism involved remains to be fully elucidated. In this study, we explored the role of reactive oxygen species (ROS) in the dexamethasone-induced chemosensitization of CSCs. Dexamethasone increased the growth-inhibitory effects of gemcitabine and 5-fluorouracil, whereas N-acetyl-cysteine, a ROS scavenger, abolished this effect. Although dexamethasone alone did not increase ROS levels, dexamethasone promoted the increase in ROS levels induced by gemcitabine and 5-fluorouracil. Dexamethasone treatment reduced the expression of NRF2, a key regulator of antioxidant responses, which was attenuated by siRNA-mediated knockdown of the glucocorticoid receptor. Furthermore, brusatol, a suppressor of NRF2, sensitized pancreatic CSCs to gemcitabine and 5-fluorouracil. Of note, essentially, the same mechanism was functional in ovarian and colon CSCs treated by the combination of dexamethasone and chemotherapeutic agents. Our study suggests that dexamethasone can sensitize CSCs to chemotherapeutic agents by promoting chemotherapy-induced ROS production through suppressing NRF2 expression.

Lurasidone Sensitizes Cancer Cells to Osimertinib by Inducing Autophagy and Reduction of Survivin.

BACKGROUND/AIM: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are key drugs in cancer treatment due to their minor adverse effects and outstanding anticancer effects. However, drugs for overcoming EGFR-TKI resistance are not in clinical use so far. Therefore, to overcome resistance, we focused on lurasidone, a new antipsychotic drug, due to its mild adverse effect profile from the viewpoint of drug repositioning. MATERIALS AND METHODS: We explored the effects of lurasidone alone or in combination with EGFR-TKI on the growth of osimertinib-resistant cancer cells the anti-apoptotic marker expression such as survivin, and autophagy levels by LC-3B expression. RESULTS: Within a non-toxic concentration range in normal cells, lurasidone and osimertinib combination therapy showed a growth-inhibitory effect in osimertinib-resistant cancer cells in vitro and in vivo. Furthermore, lurasidone decreased survivin expression and mildly induced autophagy. CONCLUSION: Lurasidone may increase the sensitivity to osimertinib in osimertinib-resistant cancer cells in drug repurposing.