Kawasaki Medical School

Currently, there are no established treatments for esophagogastric junction outflow obstruction (EGJOO). In this study, we evaluated the efficacy and safety of acotiamide for EGJOO by targeting impaired lower esophageal sphincter (LES) function. This investigator-initiated, multicenter, randomized, double-blind, placebo-controlled phase II trial enrolled 35 patients with EGJOO between December 2021 and December 2023. Patients were randomized to receive either placebo (n = 11) or acotiamide (300mg/day, n = 12; 600mg/day, n = 12) for 4weeks (placebo-controlled period). Subsequently, all patients received 600mg/day acotiamide for an additional 4weeks (open-label period). As a primary endpoint, during the placebo-controlled period, the improvement rate of food-sticking symptoms in the chest was 12.5% and 0.0% in the acotiamide and placebo groups, respectively (p = 0.3092). In terms of secondary endpoints, the integrated relaxation pressure (IRP) normalization rate was significantly higher in the acotiamide group (41.7%) than in the placebo group (0.0%) (p = 0.0107). No other secondary endpoints showed significant differences between the groups. Regarding the exploratory endpoints, during the open-label period, among the 24 patients treated with ≥ 300mg/day of acotiamide for 8weeks, the improvement rate of food-sticking symptoms in the chest increased to 37.5%, and the IRP normalization rate rose to 54.2%. Acotiamide is effective in normalizing impaired LES relaxation in patients with EGJOO and may improve food-sticking symptoms in the chest. Japan Registry of Clinical Trials ( https://jrct.mhlw.go.jp/en-top ); registration number jRCT2071210072.

Radiographic progression (RP) without prostate-specific antigen (PSA) elevation has emerged as a clinically important pattern in the androgen receptor pathway inhibitors (ARPI) era, but its prevalence and prognostic significance in real-world metastatic hormone-sensitive prostate cancer (mHSPC) cohorts remain unclear. To assess the prevalence and prognostic implications of RP alone progression in mHSPC patients treated with first-line ARPIs. We retrospectively analyzed 518 mHSPC patients treated with abiraterone acetate plus prednisolone, enzalutamide, or apalutamide. PSA progression was defined using PCWG3 criteria. Patients were categorized into PSA progression or RP alone progression groups, and clinical outcomes were compared. Among 169 patients who developed castration-resistant prostate cancer (CRPC), 34 (20.1%) experienced RP alone. RP alone patients had significantly worse overall survival compared to those with PSA progression (median 21 vs. 39 months, p = 0.007), despite exhibiting deeper biochemical responses-PSA nadir (0.055 vs. 0.86 ng/mL, p < 0.001) and a higher rate of PSA nadir < 0.2 ng/mL (61.8% vs. 27.4%, p < 0.001). The baseline characteristic differing between groups was CHAARTED volume classification; high volume disease was markedly more common in RP alone patients (94.1% vs. 77.8%). In univariate and multivariate analyses of the overall cohort, CHAARTED high volume disease was identified as an independent risk factor for RP alone (HR 10.3, 95% CI 1.20-89.3; p = 0.034). RP alone progression occurred in approximately one-fifth of patients and was associated with significantly poorer survival despite excellent PSA responses, underscoring the limitation of PSA-based monitoring and supporting routine imaging for early detection of PSA-incongruent disease progression in mHSPC.

Primary Percutaneous Coronary Intervention (PCI) has significantly contributed to reducing the mortality of patients with ST segment elevation myocardial infarction (STEMI) even in cardiogenic shock and is now the standard of care in most of Japanese institutions. The Task Force on Primary PCI of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) proposed an expert consensus document for the management of acute myocardial infarction (AMI) focusing on procedural aspects of primary PCI in 2018 and updated in 2022 (Ozaki et al. in Cardiovasc Interv Ther 33:178-203, 2018), (Ozaki et al. in Cardiovasc Interv Ther 37:1-34, 2022). Following the publication of the 2023 European Society of Cardiology (ESC) Guidelines for the management of acute coronary syndromes, the CVIT Task Force released another revised version in 2024 (Ozaki et al. in Cardiovasc Interv Ther 39:335-375, 2024). In light of new clinical evidence and technological advances that have emerged since then, the Task Force now proposes an updated expert consensus document for the management of ACS focusing on procedural aspects of primary PCI in 2026 version.

Abstract Background: Tumor-infiltrating lymphocytes (TILs) reflect host immune response and are associated with prognosis and treatment response in HER2-positive and triple-negative breast cancer (TNBC). While the International Immuno-Oncology Biomarker Working Group recommends evaluating stromal TILs in tumor areas, intratumoral heterogeneity and small sample size in core needle biopsy (CNB) specimens limit consistent assessment. It remains unclear whether central tumor (CT) or invasive margin (IM) regions should be prioritized and what cut-off values are clinically relevant. Ultrasonographic (US) features may also reflect the immune microenvironment. We previously proposed a TILs-US score based on three US features that predicts lymphocyte-predominant breast cancer (LPBC). This study evaluated the clinical utility of TILs assessment from CT and IM regions, appropriate cut-off values for predicting response in HER2-positive and TNBC using CNB, and explored optimal biopsy targeting through pathologic and US comparisons. Methods: In this multicenter retrospective study, we analyzed 239 patients (124 HER2-positive, 115 TNBC) with cT1-3/cN0-2 breast cancer who underwent surgery after neoadjuvant chemotherapy (NAC). TILs were evaluated using CNB specimens obtained before NAC and assessed separately in the central tumor (CT) and invasive margin (IM) regions. The IM was defined as a 1-mm-wide area centered on the interface between the tumor and surrounding stroma, while the CT was defined as the remaining intratumoral area within the IM boundary. TILs were analyzed using binary cut-offs of 30% and 50%, as well as a three-tier classification: low (0-10%), intermediate (11-49%), and high (≥50%). Pre-treatment ultrasound (US) findings included tumor shape (scored 0-2), internal echo (0-2), and posterior echo (0-3), which were used to calculate a composite TILs-US score ranging from 0 to 7. Associations between TIL levels, US features, and pathological complete response (pCR) were analyzed. Results: Overall, 104 patients achieved pCR (HER2-positive: 39; TNBC: 65). Using a 30% cut-off, TILs were evenly distributed both CT and IM, while ≥50% cases were relatively rare especially CT (CT: 10%; IM: 20%). CT TILs ≥30% was significantly associated with pCR (p=0.001), whereas the ≥50% cut-off was not (p=0.128). In contrast, both 30% and 50% cut-offs in the IM region were predictive of pCR (p&amp;lt;0.001 and p=0.009, respectively). Subtype analysis revealed that in TNBC, TILs ≥30% in both CT and IM regions were significantly correlated with pCR. In HER2-positive cases, however, only IM TILs ≥30% was predictive of pCR. Similar trends were observed with the three-tier classification. Among US features, a small lobulated shape was associated with high TILs levels in both CT and IM regions, while an enhanced posterior echo was correlated with high TILs in the IM region. Conclusion: Our findings suggest that TILs assessment should include the IM in addition to the CT, especially in CNB specimens as provide valuable information. Given the limited tissue area available in CNB specimen, using a 30% cut-off for TILs may offer a clinically meaningful threshold to predict treatment response. In cases where US findings suggest central fibrosis, targeting only the tumor center may result in sampling fibrotic areas with sparse immune and tumor cells, potentially hindering proper evaluation. Therefore, selecting the biopsy target based on US imaging is essential. Especially in HER2-positive breast cancer, as well as TNBC, it is important for operators to consider the optimal needle insertion angle and sampling site to ensure appropriate sampling of viable tumor tissue and immune microenvironment for accurate pathological and immunological evaluation. Citation Format: Y. Kimura, R. Yamaguchi, K. Fukui, A. Kanou, M. Noma, S. Akashi-Tanaka, K. Arihiro, N. Iwamoto, Y. Ohta, T. Okuno, S. Kashiwagi, Y. Kamei, Y. Tanada, S. Nakano, A. Nagata, A. Murakami, Y. Mochitomi, A. Yamakawa, M. Yamaguchi, H. Shima, A. Emi. Ultrasound-guided biopsy-based tils assessment at tumor margins as a predictive biomarker of neoadjuvant treatment response in early her2-positive and triple-negative breast cancer: a multicenter study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-13-18.

Introduction: Chronic constipation is common, but its characteristics and impact on various aspects of daily life remain unclear. This study examined patient characteristics and assessed how background factors, constipation symptoms, and defecation status impact daily life dissatisfaction, quality of life (QOL), and psychological states. Methods: A multicenter, prospective, observational study on outpatients with moderate to severe chronic constipation was conducted. The Chronic Constipation-Therapeutic Efficacy and Satisfaction Test (CC-TEST) and validated questionnaires such as the Hospital Anxiety and Depression Scale (HADS) and Short Form Health Survey-8 (SF-8) were administered to assess symptoms, defecation status, and daily life. Correlation and multiple regression analyses explored factor relationships. Results: The analysis included 201 participants. Despite treatment, with over half using magnesium oxide, many patients remained dissatisfied. Younger patients and females reported more severe abdominal symptoms, while older patients experienced greater defecation difficulty. All constipation symptoms correlated with daily life dissatisfaction, with abdominal discomfort showing the strongest association. Abdominal symptoms were significantly associated with the Mental Component Summary (MCS) of the SF-8, HADS anxiety, and HADS depression scores. Most defecation status components showed no correlation with SF-8 MCS, HADS anxiety, or HADS depression scores. Multivariate analysis revealed that abdominal symptoms, especially discomfort, significantly impacted daily life dissatisfaction, and reduced SF-8 MCS scores. Conclusions: Many patients with moderate to severe chronic constipation experience long-term symptoms and remain dissatisfied with treatment. Abdominal symptoms such as discomfort and pain significantly affect their daily life, QOL, and psychological well-being. Reducing abdominal symptoms may be crucial for improving treatment outcomes.

ABSTRACTBackgroundRare pathogenic variations of desmosomal genes, particularly in plakophilin‐2 (PKP2) and desmoglein‐2 (DSG2), have been implicated in arrhythmogenic cardiomyopathy (ACM); however, their potential polygenic contribution remains unclear.MethodsWe performed a genome‐wide association study of 104 Japanese patients with ACM and 46 527 controls, adjusting for case–control imbalance.ResultsThe strongest association was observed upstream of DSG2 (rs182626537, p = 2.3 × 10−42), but the signal was abolished after excluding carriers of pathogenic DSG2 variants, suggesting a synthetic association driven by linkage disequilibrium.ConclusionsThese findings highlight a population‐specific genetic architecture of ACM, with DSG2 predominating in the Japanese population.

We report a case of cold agglutinin disease (CAD) considered as other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD) in a patient with rheumatoid arthritis (RA) and Sjögren’s disease. A 69-year-old woman developed hemolytic anemia and renal dysfunction after long-term methotrexate and infliximab therapy. Laboratory findings demonstrated monoclonal IgM-κ paraproteinemia and a high cold agglutinin titer, confirming CAD, while imaging studies and bone marrow evaluation revealed no evidence of overt malignancy. Renal biopsy revealed membranoproliferative glomerulonephritis–like lesions with C3-dominant deposition, consistent with C3 glomerulonephritis (C3GN). These findings suggest that both CAD and C3GN may represent manifestations of OIIA-LPD associated with long-term immunosuppressive therapy. Rituximab combined with glucocorticoids led to a prompt and marked improvement in anemia and renal lesions, resulting in sustained remission of both CAD and C3GN while maintaining RA remission. This case suggests the dual pathogenesis of B-cell dysregulation and complement activation and indicates that B-cell–targeted therapy may contribute to controlling both abnormalities. Accumulation of similar cases will be essential to refine disease classification and to optimize therapeutic strategies for immune-mediated overlap disorders.