Tohoku Medical Megabank Organization

Background/Objectives: Trastuzumab deruxtecan (T-DXd) is an effective antibody-drug conjugate for human epidermal growth factor receptor 2-expressing solid tumors; however, interstitial lung disease (ILD) remains a clinically significant adverse event. Although both clinical characteristics and genetic susceptibility have been implicated in drug-induced ILD, the factors specifically associated with T-DXd-induced ILD remain unclear. This study aimed to evaluate clinical and genetic factors associated with the development of ILD in patients treated with T-DXd. Methods: We retrospectively analyzed the clinical data of 54 patients treated with T-DXd. The baseline clinical and treatment-related characteristics of patients with ILD and those without were compared. Genome-wide single-nucleotide polymorphism (SNP) analyses with genotype imputation and targeted candidate SNP analyses were performed to evaluate genetic susceptibility. Results: ILD occurred in 15 patients (27.8%), with a median time to onset of 215 days (range, 48-1187). None of the baseline clinical or treatment-related factors were significantly associated with ILD development. Genome-wide analyses did not reveal any significant SNPs after correcting for multiple testing. Contrarily, a targeted analysis focusing on SNPs previously associated with drug-induced ILD identified one variant rs12625311 that was significantly associated with ILD in this cohort. Conclusions: In this exploratory study, baseline clinical characteristics alone were insufficient to discriminate the risk of ILD among patients treated with T-DXd. Although no high-penetrance genetic variants were identified, candidate-based genetic analyses suggested that host genetic factors may contribute to ILD susceptibility. Integrating genetic information with clinical assessment may help refine the risk stratification for T-DXd-induced ILD in future studies.

This study aimed to evaluate the risk of major congenital malformations (MCMs) associated with first-trimester exposure to antipsychotics, using a large claims database in Japan. This retrospective cohort study was based on data from a large claims database in Japan. We used a large claims database from 2010 to 2019. Dates of pregnancy onset and delivery were estimated using the developed algorithms. Overall MCMs were defined according to the International Classification of Diseases, 10th revision codes. To address confounding by indication, the risk of MCM in relation to first-trimester antipsychotic use was evaluated among pregnant women with psychiatric disorders diagnosed before the end of the first-trimester. We compared the prevalence of MCMs among infants born to pregnant women with or without first-trimester exposure to antipsychotics and estimated the weighted odds ratios (wORs) using propensity-score overlap weights. The prevalence of psychiatric diagnoses before the end of the first-trimester was 6291 women among the 91 390 who delivered between 2010 and 2019. Among the 6291 diagnosed with psychiatric disorders, 317 were exposed to any antipsychotics during the first-trimester of pregnancy. The prevalence of overall MCMs among live births was 411 (6.9%) among women unexposed to any antipsychotics and 24 (7.6%) among those exposed. The first-trimester exposure to any antipsychotics was not significantly associated with overall MCMs when wORs were calculated using propensity-score overlap weights (wOR 1.144, 95% confidence intervals 0.727-1.799). Exposure to any antipsychotics during the first-trimester of pregnancy was not associated with an increased risk of overall MCMs in infants.

Early detection of cancer and precise recurrence monitoring remain major unmet needs in oncology. Conventional screening is limited to a few cancer types, leaving nearly half of cancers without established programs. Multi-cancer early detection (MCED) tests based on circulating tumor biomarkers have shown promise, but sensitivity for early-stage remains a challenge. In parallel, detection of molecular residual disease (MRD) using circulating tumor DNA (ctDNA) has emerged as a powerful prognostic and predictive tool, though current assays remain limited in sensitivity and specificity. This study aims to integrate multi-omics data to develop more refined and highly sensitive MCED and MRD assays. This study leverages clinical information and biospecimens from patients with cancer and cancer-naïve individuals. Samples from patients with cancers will be derived from the MONSTAR-SCREEN-3 study, while those from cancer-naïve individuals will be obtained from the Tohoku Medical Megabank Project. Comprehensive analyses will include whole-genome sequencing (WGS), whole-exome sequencing (WES), whole-transcriptome sequencing (WTS), proteomics, metabolomics, and microbiome profiling using stool and saliva. Artificial intelligence (AI)-based multi-omics integration will be performed to develop novel MCED and MRD assays and to evaluate their clinical performance. The primary endpoints are the sensitivity and specificity of MCED and MRD assays. This is the first large-scale study to integrate comprehensive multi-omics profiling with AI for MCED and MRD assay development. The findings are expected to advance precision oncology by improving early diagnosis and recurrence monitoring. UMIN000053815, approved by the Institutional Review Board of the National Cancer Center Hospital East.

BackgroundClinical Practice Guidelines (CPGs) support evidence-based, shared decision-making by providing recommendations based on the best available evidence, including systematic reviews, clinical trials, and expert consensus. Despite their potential to improve the quality of healthcare and reduce unnecessary interventions, CPGs remain inadequately disseminated and implemented. Key barriers include limited awareness and poor perception among patients and the general public. To inform strategies to improve CPG dissemination, this study aimed to investigate the association between socioeconomic factors and the awareness, reading, and perceptions of CPGs among the Japanese general population.MethodsA nationwide cross-sectional anonymous mail survey (INFORM Study 2023) was conducted among 10,000 randomly selected Japanese adults aged ≥20 years using stratified two-stage random sampling. This study was conducted as part of the INFORM Study 2023, with items related to CPGs included as an approved module. Logistic regression models were used to identify respondent characteristics associated with the awareness and reading experience of CPGs, and to assess the association between reading CPGs and eight perceptions held about them.ResultsThe response rate was 35.3% (n = 3,452). After excluding cases with missing data on CPG awareness, the remaining responses were included in the analysis (n = 3,343). Among these, 82.5% were unaware of CPGs, 9.9% were aware of CPGs but had never read one, and 7.6% were aware of CPGs and had read one. Awareness was significantly higher among individuals with higher education (adjusted odds ratio [aOR]: 2.060 for vocational school; 1.813 for university graduates), higher household income (aOR: 1.882 for ≥8 million yen), excellent health (aOR: 1.373), and frequent healthcare visits (aOR: 1.741 for ≥10 visits/year). Household size of ≥2 members (aOR: 0.591) was associated with lower awareness. Reading CPGs was associated with a self-history of cancer (aOR: 1.858). Of eight perceptions, respondents who had read CPGs correctly disagreed with the notion that CPGs harm patient-provider relationships. Among other respondents, misconceptions about CPGs persisted, particularly regarding their limitations and recommendations.ConclusionsAmong the general population in Japan, awareness of CPGs is associated with demographic and socioeconomic characteristics. Tailored dissemination strategies—particularly for individuals with lower income or education levels and other groups identified in this study—are essential to improving awareness and supporting informed healthcare decision-making. These findings also highlight the need to integrate CPG literacy into national health education initiatives to enhance public access to evidence-based care.

BackgroundMore research is needed to clarify the health effects of dietary carotenoid intakes, and this requires the use of high-quality assessments of habitual dietary intake. Cohort studies from the Tohoku Medical Megabank Organization included a self-administered food frequency questionnaire (TMM-FFQ) for community-dwelling adults. This study evaluated the validity of carotenoid intakes derived from the TMM-FFQ using serum carotenoid concentrations as the gold standard.MethodsIn Miyagi Prefecture, 88 men and 124 women aged ≥20 years voluntarily agreed to participate in the study and provided completed TMM-FFQs and blood samples in 2019 and 2021. Carotenoids examined included α-carotene, β-carotene, β-cryptoxanthin, and lycopene. Intraclass correlation coefficients (ICCs) were calculated to assess correlations between serum concentrations in 2019 and 2021. Spearman’s rank correlation coefficients were calculated to evaluate the correlations between energy-adjusted dietary carotenoid intakes from the TMM-FFQ in 2021 and the average serum carotenoid concentrations in 2019 and 2021, with correction for the attenuating effect of random within-individual variation.ResultsThe ICCs between serum concentrations over the 2 years were >0.50 for all carotenoids. Among men, correlation coefficients were 0.33 for α-carotene, 0.42 for β-carotene, 0.50 for β-cryptoxanthin, and −0.09 for lycopene. Among women, the coefficients were lower than those for men, except for lycopene: 0.11 for α-carotene, 0.23 for β-carotene, 0.21 for β-cryptoxanthin, and 0.28 for lycopene.ConclusionThe TMM-FFQ demonstrated reasonable validity for assessing intakes of α-carotene, β-carotene, and β-cryptoxanthin among men, but not among women, in the TMM cohort studies when using serum concentrations as the gold standard.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated blood pressure (BP)-lowering effects; however, most studies included patients taking antihypertensive medications. Using real-world Japanese data, we assessed factors associated with SGLT2 inhibitor-mediated BP reduction in patients not taking antihypertensive therapy. After excluding those taking antihypertensive medications, we retrospectively analyzed 6,988 patients newly prescribed SGLT2 inhibitors (2014‒2023). BP was evaluated using health check-up data before and after SGLT2 inhibitor prescription. The mean patient age was 61.6 years, and 66.8% were male. Systolic/diastolic BP were reduced by 2.3±7.6/2.3±8.4%, respectively, following SGLT2 inhibitor initiation. Multiple regression analysis identified baseline systolic BP as the strongest predictor (R2 = 8.83%), while BMI change was substantially associated with SBP reduction (R2 = 2.76%). Compared with a propensity score-matched cohort of DPP-4 inhibitor new users, greater BP reduction was observed in the SGLT2 inhibitor group, with differences of 2.3%/2.1% for systolic/diastolic BP. An ≈2% BP reduction may occur following SGLT2 inhibitor initiation.

Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a congenital disorder characterized by lymphedema, telangiectasia, and hypotrichosis or alopecia, caused by mutations in the SRY-related high-mobility group box (SOX) 18 gene. We report the case of a 10-year-old boy who presented with aortic valve regurgitation, marbled skin, minor anomalies, and iron-deficiency anemia due to frequent mucosal bleeding. At 5 years of age, he experienced significant hemostatic difficulties following the extraction of a deciduous tooth. The usual doses of iron supplementation did not cure his iron-deficiency anemia. Blood coagulation analysis revealed a decreased platelet agglutination capacity, associated with reduced von Willebrand factor (vWF) antigen levels and activity. Whole-genome sequencing at the age of 15 years did not identify any pathogenic variants in the VWF gene. However, this analysis revealed a heterozygous pathogenic variant of SOX18 (NM_018419.3: c.481C>T, p.Gln161Ter), which led to the diagnosis of HLTS. SOX18 plays a significant role in VWF expression in stem cells. vWF replacement therapy facilitated safe tooth extraction and stabilized hemoglobin levels. Decreased vWF may be a complication of HLTS, and vWF replacement therapy can significantly improve patients' quality of life.