Search

Real-world evidence on persistence of interleukin-17 inhibitors (IL-17i) as a drug class among Japanese patients with psoriasis is lacking. Hence, we aimed to describe persistence rates of IL-17is among patients with psoriasis including psoriasis vulgaris (PsO), psoriatic arthritis (PsA), and generalized pustular psoriasis (GPP) or erythrodermic psoriasis (EP) in Japan. We analyzed claims data from the Medical Data Vision database. Patients ≥15 years old with a psoriasis diagnosis and an IL-17i prescription between November 2016 and August 2020 were included and followed through August 2021. Persistence rates of the IL-17i class among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP), and persistence rates of ixekizumab, secukinumab, or brodalumab among patients with PsO or PsA were analyzed using Kaplan-Meier method. Analyses were conducted in the bio-naïve and bio-experienced subgroups. The IL-17i class had >50% persistence rates up to 36 months among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP). 36-Month persistence rates for ixekizumab, secukinumab, and brodalumab were 46.2% to 57.7% in patients with PsO and 43.0% to 48.4% in patients with PsA. Across analyses, bio-naïve patients demonstrated similar or greater persistence rates than bio-experienced patients. IL-17is' persistence rates over 36 months were >50% among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP) in Japan. [ABSTRACT FROM AUTHOR]

Introduction: Atopic dermatitis (AD) is an inflammatory disease causing severe skin itching. Data on patient–physician disconnect on treatment satisfaction in patients with AD in Japan are limited. We investigated patient–physician disconnect on treatment satisfaction in AD and if it influences treatment patterns, clinical characteristics, and patient-reported outcomes (PROs). Methods: Data were drawn from the Adelphi AD Disease Specific Programme (DSP), a real-world, point-in-time survey of physicians and patients with AD conducted in Japan from April to July 2019. Patients and physicians were grouped according to level of treatment satisfaction ("extremely satisfied" to "extremely dissatisfied"); with any level of dissatisfaction recorded as "less than satisfied." Data were collected on treatment patterns, clinical characteristics, and PROs including the Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), EQ-5D-3L questionnaire, and Work Productivity and Activity Impairment (WPAI) questionnaire. Results: Data were provided by 184 patients with AD and 56 physicians; 72.8% of patient–physician pairs reported a fair (kappa coefficient: 0.40) level of agreement on treatment satisfaction, 51.6% of patient–physician pairs were both satisfied, and 21.2% were both less than satisfied. Satisfied physicians prescribed a mean 1.2 fewer treatments than dissatisfied physicians (p < 0.05). Cases where both physician and patient were less than satisfied or where patients were less satisfied than their physicians reported the worst PROs, DLQI (both less than satisfied: mean 10.7 versus patient less satisfied than physician: 10.6 versus overall: 7.9), POEM (19.5 versus 17.3 versus 17.0), EQ-5D-3L (0.82 versus 0.81 versus 0.87) (all, p < 0.05). Work impairment was highest when both patient and physician were less than satisfied (p < 0.05). Physicians cited treatment efficacy and patients cited efficacy and usability as main reasons for dissatisfaction. Conclusion: Overall, 12.0% of patients were less satisfied with their AD treatment than the physician, demonstrating some of the worst PROs, suggesting unmet need that could be improved by better patient–physician communication. [ABSTRACT FROM AUTHOR]

Background: Increasing proportions of smokers in Japan smoke <10 cigarettes per day (CPD). Yet, the health risks of low-intensity smoking in Asia are poorly understood.Methods: We performed a pooled analysis of 410 294 adults from nine population-based prospective cohort studies participating in the Japan Cohort Consortium. Cigarette-use data were collected at each study baseline in 1983-1994. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality were calculated using multivariable-adjusted Cox regression by CPD among current smokers and by age at cessation among former smokers, with never smokers as the referent group. Pooled HRs and CIs were computed using a random-effect model.Results: The smoking prevalence was 54.5% in men and 7.4% in women. About 15.5% of male and 50.4% of female current smokers smoked 1-10 CPD (low-intensity). Both male and female low-intensity smokers had higher all-cause mortality risks than never smokers. Risks were further higher with increasing CPD in a dose-response manner. HRs (95% CIs) were 1.27 (0.97-1.66), 1.45 (1.33-1.59) and 1.49 (1.38-1.62) for 1-2, 3-5 and 6-10 CPD, respectively, in men; 1.28 (1.01-1.62), 1.49 (1.34-1.66) and 1.68 (1.55-1.81) for 1-2, 3-5 and 6-10 CPD, respectively, in women. Similar associations were observed for smoking-related causes of death. Among former low-intensity smokers, younger age at cessation was associated with lower mortality risk.Conclusions: Smoking very low amounts was associated with increased mortality risks in Japan. All smokers should quit, even if they smoke very few CPD. [ABSTRACT FROM AUTHOR]

Background and Aim: The causal relationship between Helicobacter pylori (H. pylori) infection and gastric cancer has been established. Although the magnitude of the carcinogenic effect of H. pylori is the next concern, it has not been sufficiently evaluated in Japan. Spontaneous disappearance of H. pylori infection may have provoked underestimation of the carcinogenic effect of the infection. To reduce the influence, a comparison should be carried out between subjects with and without the infection history. Cutoff values of H. pylori antibody lower than the manufacturer's recommendation are known to be more appropriate to diagnose history of H. pylori infection. The aim was to evaluate the carcinogenic effect of H. pylori. Methods: A case–control study consisting of 275 gastric cancer patients and 275 age‐ and sex‐matched controls was performed. Serum H. pylori antibody was measured using the "JHM‐Cap" kit with a domestic antigen (cut value of the manufacturer's recommendation was 2.3 EV: ELISA value). Using a conditional logistic model, the odds ratios (ORs) for five cutoff values adjusted for smoking and drinking doses were calculated. Results: For cutoff values of 1.25, 1.5, 1.75, 2.0, and 2.3 EV, the ORs (95% confidence intervals) were 67.7 (9.1, 502), 37.2 (8.8, 157), 21.3 (9.0, 60.2), 25.5 (9.0, 72.7), and 25.9 (9.2, 73.2), respectively. Conclusions: These results suggest that the risk ratio of gastric cancer between subjects with and without history of H. pylori infection in Japan may exceed 20. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) infection is considered the leading cause of gastric cancer. Gastric cancer is currently a common cancer with high incidence and mortality rates, but it is expected that the incidence rate will gradually decrease as the H. pylori infection prevalence decreases in the future. When evaluating the effectiveness of gastric cancer prevention strategies, it is essential to note the differences in long‐term cumulative risks between H. pylori‐infected and uninfected populations, but this has not yet been precisely evaluated. In our study, we aimed to estimate the cumulative incidence risks of developing gastric cancer from birth to 85 years among H. pylori‐infected and uninfected populations by using population‐based cancer registry data and birth year‐specific H. pylori infection prevalence rates. Death from gastric cancer and other causes of death were considered in the estimations of the adjusted cumulative incidence risks stratified by sex and H. pylori infection status. After performing 5000 Monte Carlo simulations with repeated random sampling using observed cancer incidence in selected three prefectures (Fukui, Nagasaki, Yamagata) of prefectural population‐based cancer registry in Japan, the mean adjusted cumulative incidence risk for gastric cancer in the H. pylori‐infected population was 17.0% for males and 7.7% for females and 1.0% for males and 0.5% for females in the uninfected population. These results calculated with Japanese cancer registry data may be useful in considering and evaluating future prevention strategies for gastric cancer in Japan. What's new? Helicobacter pylori infection is considered the leading cause of gastric cancer. This study estimated the cumulative incidence risk for gastric cancer from birth to 85 years of age, stratified by H. pylori infection status, for the first time in Japan. The cumulative risk among H. pylori‐infected individuals was 17.0% in males and 7.7% in females, after adjusting for gastric cancer incidence and other causes of death. The cumulative risk in the population without H. pylori infection was low. These results offer essential information for future cost‐effectiveness and cost‐benefit analyses and new gastric cancer prevention programs in Japan. [ABSTRACT FROM AUTHOR]

Although alcohol consumption is reported to increase the incidence of breast cancer in European studies, evidence for an association between alcohol and breast cancer in Asian populations is insufficient. We conducted a pooled analysis of eight large‐scale population‐based prospective cohort studies in Japan to evaluate the association between alcohol (both frequency and amount) and breast cancer risk with categorization by menopausal status at baseline and at diagnosis. Estimated hazard ratios (HR) and 95% confidence intervals were calculated in the individual cohorts and combined using random‐effects models. Among 158 164 subjects with 2 369 252 person‐years of follow‐up, 2208 breast cancer cases were newly diagnosed. Alcohol consumption had a significant association with a higher risk of breast cancer in both women who were premenopausal at baseline (regular drinker compared to nondrinker: HR 1.37, 1.04‐1.81, ≥23 g/d compared to 0 g/d: HR 1.74, 1.25‐2.43, P for trend per frequency category: P =.017) and those who were premenopausal at diagnosis (≥23 g/d compared to 0 g/d: HR 1.89, 1.04‐3.43, P for trend per frequency category: P =.032). In contrast, no significant association was seen in women who were postmenopausal at baseline or at diagnosis, despite a substantial number of subjects and long follow‐up period. Our results revealed that frequent and high alcohol consumption are both risk factors for Asian premenopausal breast cancer, similarly to previous studies in Western countries. The lack of a clear association in postmenopausal women in our study warrants larger investigation in Asia. What's new? While alcohol consumption is a well‐established risk factor for breast cancer in European populations, associations are less clear for Asian populations. Here, pooled analysis of data for more than 150,000 Japanese women showed that both high frequency alcohol consumption and consumption of large amounts of alcohol are associated with increased breast cancer risk in premenopausal but not postmenopausal women. Associations were evident especially among women who were premenopausal at diagnosis, compared to women who were premenopausal at baseline. Although further study is needed, the findings indicate that among Asian women, alcohol consumption and breast cancer risk have specific associations. [ABSTRACT FROM AUTHOR]

Prior studies reported the association of reproductive factors with breast cancer (BC), but the evidence is inconsistent. We conducted a pooled analysis of nine cohort studies in Japan to evaluate the impact of six reproductive factors (age at menarche/age at first birth/number of births/age at menopause/use of female hormones/breastfeeding) on BC incidence. We conducted analyses according to menopausal status at the baseline or at the diagnosis. Hazard ratio (HR) and 95% confidence interval (CI) were estimated by applying Cox proportional‐hazards model in each study. These hazard ratios were integrated using a random‐effects model. Among 187,999 women (premenopausal: 61,113, postmenopausal: 126,886), we observed 873 premenopausal and 1,456 postmenopausal cases. Among premenopausal women, use of female hormones significantly increased BC incidence (HR: 1.53 [1.04–2.25]). Although P value for trend was not significant for age at first birth and number of births (P for trend: 0.15 and 0.30, respectively), women giving first birth at ages ≥36 experienced significantly higher BC incidence than at ages 21–25 years, and women who had ≥2 births experienced significantly lower BC incidence than nulliparous women. Among postmenopausal women, more births significantly decreased BC incidence (P for trend: 0.03). Although P value for trend was not significant for age at first birth and age at menopause (P for trend: 0.30 and 0.37, respectively), women giving first birth at ages 26–35 years experienced significantly higher BC incidence than at ages 21–25 years, and women with age at menopause: ≥50 years experienced significantly higher BC incidence than age at menopause: ≤44 years. BC incidence was similar according to age at menarche or breastfeeding history among both premenopausal and postmenopausal women. In conclusion, among Japanese women, use of female hormones increased BC incidence in premenopausal women, and more births decreased BC incidence in postmenopausal women. [ABSTRACT FROM AUTHOR]

Smoking has been consistently associated with the risk of colorectal cancer (CRC) in Western populations; however, evidence is limited and inconsistent in Asian people. To assess the association of smoking status, smoking intensity and smoking cessation with colorectal risk in the Japanese population, we performed a pooled analysis of 10 population‐based cohort studies. Study‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox's proportional hazards model and then pooled using a random‐effects model. Among 363 409 participants followed up for 2 666 004 person‐years, 9232 incident CRCs were identified. In men, compared with never smokers, ever smokers showed higher risk of CRC. The HRs (95% CI) were 1.19 (1.10‐1.29) for CRC, 1.19 (1.09‐1.30) for colon cancer, 1.28 (1.13‐1.46) for distal colon cancer and 1.21 (1.07‐1.36) for rectal cancer. Smoking was associated with risk of CRC in a dose‐response manner. In women, compared with never smokers, ever smokers showed increased risk of distal colon cancer (1.47 [1.19‐1.82]). There was no evidence of a significant gender difference in the association of smoking and CRC risk. Our results confirm that smoking is associated with an increased risk of CRC, both overall and subsites, in Japanese men and distal colon cancer in Japanese women. What's new? Colorectal cancer (CRC) has been included in lists of tobacco‐related cancers. However, this inclusion has been based on data from Western populations. Studies of Asian populations have yielded conflicting results. In the current study, the authors conducted a pooled analysis of 10 cohort studies in Japan. They found that smoking is also associated with an increased risk of CRC (both overall and at subsites) in Japanese men, and of distal colon cancer in Japanese women. This increase in risk was dose dependent. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWASs) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with pancreatic cancer susceptibility. We sought to replicate the associations of 61 GWAS-identified SNPs at 42 loci with pancreatic cancer in Japanese and to develop a risk model for the identification of individuals at high risk for pancreatic cancer development in the general Japanese population. The model was based on data including directly determined or imputed SNP genotypes for 664 pancreatic cancer case and 664 age- and sex-matched control subjects. Stepwise logistic regression uncovered five GWAS-identified SNPs at five loci that also showed significant associations in our case-control cohort. These five SNPs were included in the risk model and also applied to calculation of the polygenic risk score (PRS). The area under the curve determined with the leave-one-out cross-validation method was 0.63 (95% confidence interval, 0.60–0.66) or 0.61 (0.58–0.64) for versions of the model that did or did not include cigarette smoking and family history of pancreatic cancer in addition to the five SNPs, respectively. Individuals in the lowest and highest quintiles for the PRS had odds ratios of 0.62 (0.42–0.91) and 1.98 (1.42–2.76), respectively, for pancreatic cancer development compared with those in the middle quintile. We have thus developed a risk model for pancreatic cancer that showed moderately good discriminatory ability with regard to differentiation of pancreatic cancer patients from control individuals. Our findings suggest the potential utility of a risk model that incorporates replicated GWAS-identified SNPs and established demographic or environmental factors for the identification of individuals at increased risk for pancreatic cancer development. [ABSTRACT FROM AUTHOR]

Objective: To investigate differences in the association of parental history of diabetes with the risk of type 2 diabetes mellitus (T2DM) in the offspring according to the sex of the parent and the offspring's body weight.Methods: A prospective cohort study of 4446 middle-aged non-diabetic Japanese men and women were followed in Aichi Prefecture, central Japan, from 2002 to 2011. Subjects were categorized by their self-reported parental history of diabetes ("no parental history," "father only," "mother only," and "both"). The association of parental history of diabetes and incidence in the offspring was examined according to overweight status adjusted for age, sex, birth weight, smoking, alcohol consumption, physical activity, total energy intake, body mass index, and number of metabolic syndrome components.Results: During follow-up (median 8.9 years), 277 subjects developed T2DM. Parental history of diabetes was positively associated with T2DM incidence. However, stratified analysis by overweight status revealed that only maternal history was associated with increased T2DM incidence in non-overweight subjects (hazard ratio=2.35, 95% confidence interval: 1.41-3.91). While in overweight subjects, paternal history was significantly associated with higher T2DM incidence (hazard ratio=1.98, 95% confidence interval: 1.19-3.28).Conclusions: Our results suggest that parental history of diabetes mellitus is associated with the incidence of T2DM in offspring differently according to the sex of the affected parent and the offspring's body weight. [ABSTRACT FROM AUTHOR]

Background: Metronidazole is an antiprotozoal drug used to treat a broad spectrum of infectious diseases, including Helicobacter pylori (H pylori) infections. In Japan, metronidazole is approved for the eradication therapy of H pylori as a second‐line regimen among adults, but it has not yet been approved for use among children and adolescents. Materials and Methods: To perform this narrative review, we searched the relevant literature on important events in the history of the use of metronidazole, its mechanisms of action, its efficacy, and the adverse effects reported in clinical trials or cohort studies in Japan. Results: At present, metronidazole resistance has not been a serious issue in Japan in large part due to its restricted use. Emerging evidence from randomized controlled trials demonstrates higher eradication rates for metronidazole than for clarithromycin, supporting its use in both first‐line and second‐line eradication therapies. Among the reported adverse effects, there has been lingering concern over the potential carcinogenicity of metronidazole in humans. However, the possibility of an increased cancer risk is not limited to metronidazole; the long‐term use of antibiotics has been linked to increased risk for some site‐specific cancers. However, recent prospective studies have suggested that short‐term exposure to antibiotics is not associated with an increased cancer risk. Conclusion: Sensible use of metronidazole backed by research evidence could maximize the benefits associated with H pylori eradication in Japan. [ABSTRACT FROM AUTHOR]

Background: Oxaliplatin-containing adjuvant regimens (folinic acid, fluorouracil, and oxaliplatin/capecitabine and oxaliplatin [FOLFOX/CAPOX]) are used after curative resection of colorectal cancer (CRC). However, real-world evidence regarding treatment sequences and outcomes in patients with early recurrence CRC after adjuvant chemotherapy is limited., Objective: We aimed to describe the patient characteristics, treatment sequence, and overall duration of second-line (2L) therapy in patients with early recurrence CRC who received adjuvant chemotherapy (FOLFOX/CAPOX) followed by folinic acid, fluorouracil, and irinotecan (FOLFIRI) + anti-angiogenesis drugs (AA) or FOLFIRI + anti-epidermal growth factor receptor (EGFR) antibodies., Methods: This retrospective study analyzed Japanese administrative data from November 2014 to March 2023 of adult patients who underwent CRC resection surgery, started FOLFOX/CAPOX ≤3 months (mo) after surgery, and had early CRC recurrence. Early recurrence was defined as initiation of FOLFIRI+AA or FOLFIRI+anti-EGFR antibodies as 2L therapy, ≤12 mo of discontinuing adjuvant chemotherapy. Patient characteristics, treatment sequence, median time to treatment discontinuation (mTTD), i.e., duration between the start and end dates of 2L therapy (Kaplan-Meier method), and factors associated with 2L time to treatment discontinuation constituted the study outcomes (Cox regression model). Subgroup analyses were performed for timing of early CRC recurrence (≤6 mo and 6-12 mo) and tumor sidedness., Results: Among the 832 selected patients (median age [minimum-maximum] 67 (24-86) years, 56.4% male), CAPOX (71.3%) was more commonly used than FOLFOX (28.7%) as adjuvant therapy. FOLFIRI+AA (72.5%) was used more commonly than FOLFIRI+anti-EGFR antibodies (27.5%) in 2L. AA and anti-EGFR antibodies groups had similar mTTD: 6.2 mo (95% confidence interval 5.8, 6.9) and 6.1 mo (95% confidence interval 5.2, 7.4). Age ≥70 years showed significant association with shorter 2L treatment duration (hazard ratio 1.2, 95% confidence interval 1.0, 1.4; p = 0.03). The AA cohort's mTTD was numerically shorter in the ≤6 mo recurrence subgroup compared with the 6-12 mo recurrence subgroup (6.1 mo vs 8.1 mo); the anti-EGFR antibodies cohort had similar mTTD (5.8 mo vs 6.2 mo). The AA and anti-EGFR antibodies cohorts also had similar mTTD in the left-sided CRC subgroup (6.5 mo vs 6.2 mo), but not in the right-sided subgroup (5.6 mo vs 3.9 mo)., Conclusions: This is the first administrative data-based real-world evidence on treatment sequence and outcomes for patients with early recurrence CRC treated with FOLFIRI+AAs or FOLFIRI+ anti-EGFR antibodies after adjuvant FOLFOX/CAPOX therapy in Japan. Both regimens had similar TTD, but relapse timing and tumor sidedness may influence their efficacy., (© 2024. The Author(s).)

Introduction: Bowel urgency (BU) is among the most disruptive of inflammatory bowel disease (IBD) symptoms. However, data on its prevalence and association with disease activity are limited. This real-world study of Japanese patients with IBD evaluated BU prevalence and compared clinical outcomes and health-related quality of life (HRQoL) between patients with and without BU., Methods: Data were drawn from the Adelphi IBD Disease Specific Programme™, a cross-sectional survey of physicians and their patients with ulcerative colitis (UC) and Crohn's disease (CD). Physicians reported demographic and clinical data, including disease activity measures (Mayo score and CD Activity Index [CDAI]), for consulting patients, who voluntarily completed a patient-reported questionnaire, including HRQoL measures (Short IBD Questionnaire [SIBDQ] and EQ-5D-5L). Outcomes were compared between patients with and without BU using t-, Fisher exact and Mann-Whitney U tests as appropriate., Results: Of 120 UC patients, 27.5% (n = 33) self-reported BU; physicians were unaware of BU in 54.5% (n = 18) of these patients. Patients with BU had higher mean Mayo scores (p < 0.01) and lower mean SIBDQ scores (47.9 vs 56.6, p < 0.01) than patients without BU, with mean EQ-5D-5L scores 0.83 and 0.87, respectively (p = 0.06). Physicians were satisfied with treatment but believed better control could be achieved for 39.4% of patients with BU and 35.6% without. Of 114 CD patients, 17.5% (n = 20) self-reported BU; physicians were unaware of BU in 75.0% (n = 15) of these patients. Patients with BU had higher mean CDAI scores (p < 0.01) and lower mean SIBDQ (48.7 vs 56.2, p < 0.01) and EQ-5D-5L scores (0.81 vs 0.88, p < 0.01) than patients without BU. Physicians were satisfied but believed better control could be achieved for 40.0% of patients with BU vs 19.1% without., Conclusions: Patients with BU have worse clinical outcomes and HRQoL than patients without, underlining the need for improved physician-patient communication regarding BU and new IBD therapeutic options., (© 2023. The Author(s).)

The effect of body mass index (BMI) on esophageal and gastric carcinogenesis might be heterogeneous, depending on subtype or subsite. However, findings from prospective evaluations of BMI associated with these cancers among Asian populations have been inconsistent and limited, especially for esophageal adenocarcinoma and gastric cardia cancer. We performed a pooled analysis of 10 population-based cohort studies to examine this association in 394,247 Japanese individuals. We used Cox proportional hazards regression to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs), then pooled these estimates to calculate summary HRs with a random effects model. During 5,750,107 person-years of follow-up, 1569 esophageal cancer (1038 squamous cell carcinoma and 86 adenocarcinoma) and 11,095 gastric (728 cardia and 5620 noncardia) cancer incident cases were identified. An inverse association was observed between BMI and esophageal squamous cell carcinoma (HR per 5-kg/m 2 increase 0.57, 95% CI 0.50-0.65), whereas a positive association was seen in gastric cardia cancer (HR 1.15, 95% CI 1.00-1.32). A nonsignificant and significant positive association for overweight or obese (BMI ≥25 kg/m 2 ) relative to BMI <25 kg/m 2 was observed with esophageal adenocarcinoma (HR 1.32, 95% CI 0.80-2.17) and gastric cardia cancer (HR 1.24, 95% CI 1.05-1.46), respectively. No clear association with BMI was found for gastric noncardia cancer. This prospective study-the largest in an Asian country-provides a comprehensive quantitative estimate of the association of BMI with upper gastrointestinal cancer and confirms the subtype- or subsite-specific carcinogenic impact of BMI in a Japanese population., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Standard treatment has not been established for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after discontinuation of covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. This retrospective, administrative database (Medical Data Vision) study described the patient characteristics, treatment patterns, and factors associated with receiving post-first-cBTKi treatment in Japanese patients with CLL/SLL. Patients aged ≥18 years with confirmed CLL/SLL diagnosis and treated with anti-neoplastic drugs indicated for CLL/SLL between March 2013 and February 2022 were included. Patient characteristics at baseline (first line), first cBTKi exposure (first-cBTKi), post-first-cBTKi treatment received, and the treatment sequence of CLL drugs received first line through third line, were described. Time-to-event analyses used the Kaplan-Meier method. Multivariable logistic regression analysis was used to explore factors associated with receiving post-first-cBTKi treatment among patients who discontinued first-cBTKi treatment. Among 2,424 eligible patients (median age: 72.0 years, 61.9% male), 450 (18.6%) received cBTKi in any treatment line. Among patients treated with cBTKi, 273 (60.7%) discontinued treatment; 56.0% of them (n = 153/273) received subsequent treatment. Median duration of post-first-cBTKi treatment was 2.2 months (95% confidence interval [CI]: 1.8, 3.5). The most common regimens post-first-cBTKi were cBTKi therapy (47.7%), bendamustine-based therapy (17.0%), and venetoclax-based therapy (13.1%). Patients aged <75 years (odds ratio [OR] [95% CI]: 2.0 [1.2, 3.4]) and those who did not receive blood transfusion during cBTKi treatment (OR [95% CI]: 2.3 [1.3, 4.1]) were more likely to receive post-first-cBTKi treatment. In conclusion, Japanese patients with CLL/SLL received various treatments for short duration after first-cBTKi discontinuation.

The aim of this study was to further examine the relationship between milk intake and stroke mortality among the Japanese population. We used data from the Japan Collaborative Cohort (JACC) Study (total number of participants = 110,585, age range: 40-79) to estimate the posterior acceleration factors (AF) as well as the hazard ratios (HR) comparing individuals with different milk intake frequencies against those who never consumed milk at the study baseline. These estimations were computed through a series of Bayesian survival models that employed a Markov Chain Monte Carlo simulation process. In total, 100,000 posterior samples were generated separately through four independent chains after model convergency was confirmed. Posterior probabilites that daily milk consumers had lower hazard or delayed mortality from strokes compared to non-consumers was 99.0% and 78.0% for men and women, respectively. Accordingly, the estimated posterior means of AF and HR for daily milk consumers were 0.88 (95% Credible Interval, CrI: 0.81, 0.96) and 0.80 (95% CrI: 0.69, 0.93) for men and 0.97 (95% CrI: 0.88, 1.10) and 0.95 (95% CrI: 0.80, 1.17) for women. In conclusion, data from the JACC study provided strong evidence that daily milk intake among Japanese men was associated with delayed and lower risk of mortality from stroke especially cerebral infarction.

Objective: The Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL) is a widely used semi-structured diagnostic interview in child and adolescent psychiatry. However, given the extensive use of the K-SADS-PL in clinical practice and research and its adaptation for use in many languages and cultures, validation studies of the instrument are scarce. This study was designed to examine the inter-rater reliability, criterion validity and construct validity of the updated instrument, the K-SADS-PL for DSM-5, in Japanese outpatients totaling 95 children and adolescents., Method: We translated and adapted the updated instrument into Japanese using a standard forward-backward translation procedure. Two of nine experienced clinicians independently made diagnoses using the interview for each patient in a conjoint session. Discrepancies in diagnosis between two clinicians were resolved by consensus, and the consensus diagnosis was compared with a "best-estimate" diagnosis made by five experienced clinicians using all available data sources for patients who were blinded to the diagnosis using the K-SADS-PL for DSM-5. The "best-estimate" diagnosis of ASD was also based on the Diagnostic Interview for Social and Communication Disorders., Results: The inter-rater reliability was very good, as shown by κ ≥ 0.8 for all disorders examined: autism spectrum disorder (ASD), attention-deficit hyperactivity disorder, tic disorders, selective mutism, enuresis and encopresis. The criterion validity was good, as shown by κ ≥ 0.6 for all disorders examined, except for ASD (κ = 0.59). This study also revealed good construct validity of the instrument by confirming the expected associations with each scale from the Social Responsiveness Scale-2nd edition and the Strengths and Difficulties Questionnaire., Conclusion: These results suggest that the K-SADS-PL for DSM-5 generates valid diagnoses in child and adolescent psychiatry., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 have been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31 230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (p-value < 5.0 × 10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5140 Japanese individuals (p-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2. Our study has confirmed that a functional ALDH2 variant, rs671, most strongly influences on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Changing trends in the prevalence of H. pylori infection in the general population over time are thought to be the main driving force behind the declining gastric cancer mortality in Japan. However, whether the prevalence of H. pylori infection itself shows a birth-cohort pattern needs to be corroborated. We performed a systematic review of studies that reported the prevalence of H. pylori infection among Japanese individuals. Meta-regression was conducted in the framework of a generalized additive mixed model (GAMM) to account for heterogeneity in the prevalence of H. pylori infection as a function of birth year. The prevalence of H. pylori infection confirmed a clear birth cohort pattern: the predicted prevalence (%, 95% CI) was 60.9 (56.3-65.4), 65.9 (63.9-67.9), 67.4 (66.0-68.7), 64.1 (63.1-65.1), 59.1 (58.2-60.0), 49.1 (49.0-49.2), 34.9 (34.0-35.8), 24.6 (23.5-25.8), 15.6 (14.0-17.3), and 6.6 (4.8-8.9) among those who were born in the year 1910, 1920, 1930, 1940, 1950, 1960, 1970, 1980, 1990, and 2000, respectively. The present study demonstrated a clear birth-cohort pattern of H. pylori infection in the Japanese population. The decreased prevalence of H. pylori infection in successive generations should be weighed in future gastric cancer control programs.

Breast cancer is the most common cancer in women. However, it remains unproven whether psychological factors have an influence on breast cancer incidence. In our earlier study, subjects possessing two personality traits, decisiveness and "ikigai" (a Japanese word meaning something that makes one's life worth living), showed a significantly lower risk of developing breast cancer, although no psychological factors have been convincingly demonstrated to have an influence on breast cancer development in other studies. Therefore, we conducted this follow-up analysis to confirm the association between breast cancer incidence and psychological traits, using the final dataset of a large-scale prospective cohort study in Japan. We identified 209 cases of incident breast cancer out of a maximum 21-year follow-up of 29,098 Japanese women. Cox proportional hazard regression analysis, adjusted for the same potential confounders used in our previous study, did not reveal any significant relationships between breast cancer incidence and four psychological traits: having "ikigai", decisiveness, ease of anger arousal, and perceived stress. Our finding is consistent with previous studies, and suggests that the psychological traits are unlikely to be an important risk factor for breast cancer.

Background: Skipping breakfast has been suspected as a risk factor for type 2 diabetes (T2DM), but the associations are not entirely consistent across ethnicities or sexes, and the issue has not been adequately addressed in the Japanese population., Methods: We followed 4631 participants (3600 men and 1031 women) in a work-site cohort of participants aged 35-66 years in 2002 through 2011 for T2DM development. Frequency of eating breakfast was self-reported and was subsequently dichotomized to breakfast skippers, who eat breakfast 3-5 times/week or less, and to eaters. Cox proportional hazards models were used to adjust for potential confounding factors, including dietary factors, smoking and other lifestyles, body mass index (BMI), and fasting blood glucose (FBG) at baseline., Results: During 8.9 years of follow-up, 285 T2DM cases (231 men and 54 women) developed. Compared to participants who reported eating breakfast every day, maximally-adjusted hazard ratios and 95% confidence intervals (CI) of those with the frequency of almost every day and 3-5, 1-2, and 0 days/week were: 1.06 (95% CI, 0.73-1.53), 2.07 (95% CI, 1.20-3.56), 1.37 (95% CI, 0.82-2.29), and 2.12 (95% CI, 1.19-3.76), respectively. In a dichotomized analysis, breakfast skipping was positively associated with T2DM incidence (maximally-adjusted hazard ratio 1.73; 95% CI, 1.24-2.42). The positive associations were found in both men and women, current and non-current smokers, normal weight and overweight (BMI ≥ 25 kg/m(2)), and normal glycemic status and impaired fasting glycemic status (FBG 110 to <126 mg/dL) individuals at baseline (Ps for interaction all >0.05)., Conclusions: The present study in middle-aged Japanese men and women suggests that skipping breakfast may increase the risk of T2DM independent of lifestyles and baseline levels of BMI and FBG.

Background: Findings regarding the association between milk consumption and all-cause mortality reported by studies carried out in Western populations have been inconsistent. However, no studies have been conducted in Japan on this issue. The present study aimed to investigate the association of milk drinking with all-cause, cardiovascular, and cancer mortality in Japan., Methods: The data were obtained from the Japan Collaborative Cohort (JACC) study. A total of 94 980 Japanese adults aged 40-79 years who had no history of cancer, stroke, or chronic cardiovascular diseases were followed between 1988 and 2009. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of mortalities were assessed using a Cox proportional hazard regression model and taking the lowest milk consumption group as the reference., Results: During a median of 19 years of follow-up, there were 21 775 deaths (28.8% and 35.3% from cardiovascular diseases and cancer, respectively). Drinking milk 1-2 times a month was associated with lower all-cause mortality in men compared to those who never drank milk (multivariable-adjusted HR 0.92; 95% CI, 0.85-0.99). In women, those who drank 3-4 times a week also had a lower mortality risk compared with those who never drank milk (HR 0.91; 95% CI 0.85-0.98). Inverse associations between drinking milk and mortality from cardiovascular diseases and cancer were found only in men., Conclusions: Drinking milk at least 1-2 times a month was associated with lower all-cause mortality in men compared to never drinking milk. An inverse association was also found between drinking milk and mortality from both cardiovascular diseases and cancer. However, lower all-cause mortality in women was found only in those who drank milk 3-4 times/week.

Background: Although the association between cigarette smoking and risk of type 2 diabetes is well established, its mechanisms are yet to be clarified. This study examined the possible mediating effects of adiponectin, leptin, and C-reactive protein (CRP) concentrations on the smoking-diabetes association., Methods: Between 2002 and 2011, we followed 3338 Japanese workers, aged 35-66 years, who were enrolled in the second Aichi workers' cohort study. We used multivariable-adjusted Cox regression models to determine the hazard ratios and respective 95% confidence intervals (CIs) of the association between smoking status and risk of diabetes. A multiple mediation model with bootstrapping was used to estimate the magnitude and the respective bias-corrected (BC) 95% CIs of the indirect effects of smoking on diabetes through the three biomarkers., Results: Relative to never smokers, the risk of diabetes was significantly elevated in current (hazard ratio 1.75, 95% CI 1.25-2.46) and ex-smokers (hazard ratio 1.54, 95% CI 1.07-2.22). The indirect effects of smoking on diabetes through adiponectin levels were statistically significant among light (point estimate 0.033, BC 95% CI 0.005-0.082), moderate (point estimate 0.044, BC 95% CI 0.010-0.094), and heavy smokers (point estimate 0.054, BC 95% CI 0.013-0.113). In contrast, neither the indirect effects of smoking on diabetes through leptin nor CRP levels were significant, as the corresponding BC 95% CIs included zero., Conclusions: In our analysis, adiponectin concentration appeared to partially mediate the effect of smoking on diabetes, while leptin and CRP levels did not.

Background: Elevated high-sensitivity C-reactive protein (hs-CRP), a marker of low-grade systemic inflammation, may be involved in the etiology of type 2 diabetes mellitus (T2DM). However, whether inflammation precedes development of T2DM independent of cigarette smoking and obesity remains to be confirmed., Methods: We studied 4213 civil servants in a local government in Japan aged 35-66 years at baseline in 2002, who donated blood samples and were followed 6 years. Hazard ratios (HR) of T2DM according to the hs-CRP quartiles [range Q1: 0.02-0.18 (reference), Q2: 0.18-0.33, Q3: 0.33-0.67 and Q4: 0.67-9.62 mg/L) were estimated by Cox proportional hazards model adjusted for gender, age, body mass index, alcohol intake, smoking status (current, past and never), number of cigarettes per day, physical activity, family history of diabetes (Model 1) and variables in Model 1 + glucose (Model 2)., Results: The geometric mean [95% confidence interval (CI)] of hs-CRP was 0.36 mg/L (0.34-0.37). During the follow-up, 156 new T2DM cases were confirmed. In total sample, Model 2 HRs (95% CIs) for hs-CRP quartiles Q2-Q4 compared with Q1 were 0.69 (0.36-1.26), 1.47 (0.91-2.39) and 1.78 (1.10-2.88), respectively (p for linear trend = 0.014). Stratified analysis revealed that a statistically significant association was observed only in normal weight non-current smokers with Model 2 HRs (CIs) being 0.79 (0.29-2.17), 2.63 (1.25-5.56) and 3.19 (1.49-6.86) for Q2-Q4 compared with Q1, respectively (p for linear trend = 0.0006). The relationship did not change materially after further adjusting for log-homeostasis model assessment or exclusion of past smokers., Conclusions: These findings imply that higher hs-CRP itself or existence of chronic systemic inflammation precedes onset of T2DM independent of obesity and smoking., (Copyright © 2013 John Wiley & Sons, Ltd.)