Lynch syndrome (LS) is an autosomal-dominant hereditary disorder caused by germline pathogenic variants in mismatch repair (MMR) genes, predisposing individuals to multiple malignancies. In Japan, universal screening for LS, such as through microsatellite instability (MSI) testing, is not widely implemented. Moreover, MMR genetic testing is not covered by insurance, often leading to missed diagnoses. We present a rare case of a 72-year-old woman with LS who developed nine metachronous cancers over 35 years, including colorectal, endometrial, gastric, breast, and skin cancers, one of the highest numbers reported in a single patient. She had a family history of cancer. MSI testing of colorectal cancer tissues revealed MSI-high status; therefore, LS was suspected. The definitive diagnosis was established through germline genetic testing, which identified pathogenic MLH1 variants. Each cancer was treated with curative resection. The patient remained disease-free for 3.8 years after her most recent skin cancer surgery. This case underscores the importance of early detection, systematic surveillance, and timely intervention in achieving long-term survival in patients with LS. It highlights the potential for early diagnosis, optimal management, and improved outcomes through comprehensive cross-organ monitoring and emphasizes the need for expanded LS screening, including MMR genetic testing.
Abstract Background High microsatellite instability (MSI-H) is an established prognostic marker in various cancers, including colorectal, gastric, and endometrial cancers. However, comprehensive real-world data from universal screening in Asian populations remain limited. We aimed to evaluate the clinicopathological and prognostic impact of MSI-H status in Japanese patients with colorectal cancer (CRC). Methods This retrospective cohort study was conducted at Osaka General Medical Center, Japan. A total of 346 consecutive patients with CRC who underwent MSI testing between January 2021 and December 2022 were retrospectively analyzed. MSI status and associated clinicopathological features were assessed. Overall survival (OS) and recurrence-free survival (RFS) were analyzed using Kaplan–Meier survival curves and Cox regression models. Results Among the 346 patients, 29 (8.4%) had MSI-H tumors, which were more frequently right-sided (p <0.0001) and poorly differentiated (p <0.0001) compared with non-MSI-H. Genomic analysis revealed that MSI-H tumors had significantly fewer RAS mutations (p = 0.024) and more BRAF mutations (p <0.0001) compared with non-MSI-H tumors. Survival analysis showed no significant differences in RFS (HR, 0.67; 95% CI, 0.26–1.90; p = 0.40) or OS (HR, 0.64; 95% CI, 0.30–1.58; p = 0.78) between patients with MSI-H and non–MSI-H tumors. Multivariate analysis identified MSI-H as a potential independent predictor of favorable OS (HR, 0.07; 95% CI, 0.005–0.90; p = 0.04), whereas BRAF mutations were associated with poor OS (HR, 7.39; 95% CI, 1.32–41.50; p = 0.02). Conclusions This real-world study suggests that MSI-H status is associated with distinct clinicopathological characteristics and may be associated with improved overall survival in Japanese patients with CRC undergoing universal MSI screening. These findings support the clinical relevance of MSI testing in routine clinical practice and highlight the need for further validation in a larger cohort.
BACKGROUND:The EARNEST-PVI trial showed that left atrial ablation in addition to pulmonary vein isolation (PVI) reduced atrial fibrillation (AF) recurrence after catheter ablation for persistent AF; however, the efficacy of left atrial additional ablation in patients with diabetes mellitus (DM) is not well known. The aim of this study was to evaluate the efficacy of left atrial additional ablation after PVI in patients with and without DM. METHODS AND RESULTS:This study, a subanalysis of the EARNEST-PVI trial, a multicenter, prospective, randomized, controlled trial, analyzed 493 consecutive patients undergoing initial radiofrequency catheter ablation for persistent AF. Patients were randomized to PVI alone (PVI-alone group) or PVI plus linear and/or complex fractionated atrial electrogram ablation (PVI-plus group). The primary outcome was defined as AF recurrence during the 12-month follow-up period after ablation. A total of 84 (17%) patients had DM. The primary outcome occurred in 120 (24%) patients. In patients without DM, freedom from AF recurrence was significantly higher in the PVI-plus group than in the PVI-alone group (80.0% vs. 71.1%, P=0.034). In contrast, in patients with DM, freedom from AF recurrence was similar between the PVI-plus and PVI-alone groups (75.4% vs. 72.9%, P=0.696). CONCLUSIONS:The efficacy of left atrial additional ablation after PVI in reducing AF recurrence following catheter ablation for persistent AF was diminished in patients with DM.
BACKGROUND: Tertiary lymphoid structures (TLSs) maturity and cellular composition shape resistance or sensitivity to immune-checkpoint blockade (ICB) across cancers. Single-cell spatial resolution data for the endothelial compartment of TLSs are lacking; therefore, we investigated the cellular composition, endothelial dynamics, and cell-cell interactions within TLS regions. METHODS: We applied high-resolution Xenium In Situ spatial transcriptomics to eight samples collected from non-small-cell lung cancers (NSCLC) (four after chemoimmunotherapy, four untreated), extracted 90 TLS regions, generated approximately 320,000 single-cell profiles from those regions, and analyzed the endothelial compartment within each TLS. We independently assessed the exploratory findings using multiplex immunofluorescence and survival analysis in a separate cohort of 45 patients receiving immunotherapy. RESULTS: Spatial mapping revealed a reproducible, B-cell-dominant TLS architecture across all samples. Mature TLSs contained CXCL13-rich follicular cores and were associated with a favorable prognosis. Within the endothelial compartment, high endothelial cells (HECs) forming high-endothelial venules (HEVs) segregated from other endothelial cells; in mature TLSs these HECs exhibited high inhibitor of DNA binding 1 (ID1) expression and an adhesion molecular signature, promoting lymphocyte recruitment. Patients with tumors harboring ID1-high HEVs showed higher response rates and pronounced survival advantage; multivariable analysis confirmed ID1-high status as an independent prognostic factor. Conversely, ICB exposure eventually reduced ID1 expression and adhesion molecule levels in HECs, impaired lymphocyte trafficking, and promoted a shift toward a remodeled endothelial state. CONCLUSIONS: ID1expression, linked to HEC differentiation during TLS maturation or ICB exposure, marks a functionally mature, lymphocyte-recruiting HEV that predict durable response to immunotherapy. These findings provide a novel mechanistic framework and practical biomarkers for HEV-centered immuno-oncology strategies in NSCLC.
