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.
BACKGROUND:Anastomotic leakage (AL) remains a major postoperative complication after rectal cancer surgery, even with advances in minimally invasive techniques. Indocyanine green (ICG) fluorescence imaging is widely used to assess bowel perfusion, but conventional methods rely heavily on subjective visual interpretation. The SPY-QP software enables quantitative evaluation of ICG fluorescence, potentially improving the accuracy of perfusion assessment. METHODS:The SPECTACLE study is a multicenter, prospective, single-arm trial designed to evaluate whether SPY-QP-based quantitative blood flow assessment can reduce AL rates compared with historical controls from the EssentiAL study. Perfusion assessment is performed according to an algorithm we developed based on our previous retrospective analysis. We plan to enroll 400 patients undergoing laparoscopic or robotic rectal cancer resection with anastomosis. The primary endpoint is the incidence of AL (Grades A-C) within 30 days postoperatively. Secondary endpoints include changes in surgical strategy based on perfusion findings, operative time, intraoperative complications, and other postoperative outcomes. DISCUSSION:This study aims to provide robust evidence on whether objective perfusion assessment using SPY-QP can reduce AL after rectal cancer surgery, potentially leading to broader adoption of quantitative imaging in colorectal surgery. TRIAL REGISTRATION:Japan Registry of Clinical Trials: jRCTs032230212.
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.
BACKGROUND:Patients with heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV)-pulmonary arterial (PA) uncoupling, as assessed by a decrease ratio of tricuspid annular plane systolic excursion (TAPSE) to PA systolic pressure (PASP) on echocardiography, have poorer outcomes than patients without RV-PA uncoupling. METHODS AND RESULTS:The MONACO trial was an adaptive, randomized, double-blind, placebo-controlled study that enrolled hospitalized patients with HFpEF admitted to 12 centers in Japan. Patients who had left ventricular ejection fraction ≥50% and TAPSE/PASP <0.57 mm/mmHg at discharge were randomized 1 : 1 to receive pimobendan 1.25 mg b.i.d. or placebo. The primary objective was to evaluate changes from baseline (day 0) to day 30 in exercise capacity measured by the 6-minute walking test. Enrollment was terminated due to the invalid result of the planned interim analysis. The median age of participants was 82 years and 46% were women. Pimobendan (n=24) or placebo (n=26) was administrated orally. At day 30, mean changes in 6-minute walking distance in patients who received pimobendan (+26.9 m [95% confidence interval; -2.0, +55.8]) or placebo (+21.4 m [95% confidence interval; -14.3, +57.2]) were not significantly different (P=0.402). CONCLUSIONS:Among patients with HFpEF and RV-PA uncoupling, administration of pimobendan for 30 days did not result in significant improvement in exercise capacity compared with placebo.
