Fujita Health University

Peritoneal metastasis is the most lethal manifestation of gastric cancer, with a median survival of less than one year, highlighting the need for new therapeutic targets. Through an in vivo genome-wide CRISPR/Cas9 screen, we identified GRIA2, an AMPA-type glutamate receptor subunit, as a key driver of peritoneal metastasis. GRIA2 promotes gastric cancer cell migration, invasion, stemness, and adhesion to mesothelial cells in a glutamate-dependent manner. Mechanistically, glutamate activates GRIA2, enhancing its interaction with GSK-3β and inducing calcium influx, inhibiting GSK-3β kinase activity and stabilizing β-catenin, thereby activating the Wnt/β-catenin signaling pathway. Single-cell RNA sequencing revealed that cancer-associated fibroblasts are the primary source of glutamate in the peritoneal microenvironment, which establishes a paracrine axis that enhances GRIA2-driven metastasis. Pharmacological inhibition of AMPA receptors with NBQX and Selurampanel suppressed peritoneal metastasis in both cell line-derived and patient-derived organoid xenograft (PDOX) mouse models. In clinical analysis, GRIA2 expression in peritoneal metastases correlated with the levels of β-catenin and phosphorylated GSK-3β (serine 9), with high GRIA2 expression predicting poor prognosis. These findings suggest that GRIA2 is a novel therapeutic target, and AMPA receptor antagonists are promising agents for treating gastric cancer peritoneal metastasis.

Post-transplant acute limbic encephalitis (PALE) has been reported, and human herpesvirus 6 (HHV-6) is one of the causes. Reports of PALE in children are still limited. In the present study, the detailed clinico-radiological findings of PALE and the neurological outcomes of four children are reported. Four patients aged three to twelve years of 142 patients who underwent allogeneic hematopoietic stem cell transplantation developed PALE. Underlying disorders were neuroblastoma in three patients and acute lymphoblastic leukemia in one. All four patients showed disorientation, behavioral changes, emotional dysregulation, anterograde amnesia, or decreased level of consciousness between 12 and 22days after transplantation. None had clinical seizures. In all patients, MRI showed hyperintense signals in unilateral or bilateral hippocampi, especially in the CA1 area, on diffusion-weighted imaging (DWI), with a decreased apparent diffusion coefficient. Though the hippocampi were also hyperintense on T2-weighted and fluid-attenuated inversion recovery imaging, signal intensity was higher on DWI by visual inspection. Electroencephalograms showed poorly organized posterior dominant rhythm in all patients and left occipito-centro-parietal slow waves in one without epileptiform discharges. HHV-6 DNA was positive in both cerebrospinal fluid and whole blood by polymerase chain reaction in three of the four patients. Two patients had pharmaco-resistant epilepsy and cognitive impairment three years after PALE, but the other two recovered neurologically from PALE. A DWI abnormality of the hippocampal CA1 area is a good biomarker for the diagnosis of HHV-6-positive or -negative PALE in children. Glutamatergic dysregulation and hippocampal cytotoxic edema may be involved in PALE.

We evaluated the prognostic significance and implications of a major pathologic response (MPR) after preoperative treatment for pancreatic ductal adenocarcinoma (PDAC). Preoperative treatment is increasingly used for PDAC to improve oncologic outcomes. The pathologic response represents a potential indicator of treatment efficacy; however, its prognostic value in PDAC remains unclear. We retrospectively analyzed 739 patients who underwent pancreatectomy for PDAC after preoperative treatment at 21 institutions in Japan. The pathologic response was graded using Evans' classification, with MPR defined as Evans grade III/IV. Survival outcomes and prognostic factors were evaluated, and factors associated with achieving MPR were analyzed to develop a predictive model. MPR was achieved in 11.5% of patients. The MPR group had a significantly longer median overall survival (71.5 vs. 40.9mo) and recurrence-free survival (55.5 vs. 15.2mo) than the non-MPR group. Multivariate analysis identified MPR as an independent prognostic factor for overall survival. In the MPR subgroup, neither overall nor recurrence-free survival differed according to adjuvant chemotherapy administration; multivariate analysis did not identify adjuvant therapy as an independent prognostic factor. Predictive factors for achieving MPR included chemoradiotherapy, preoperative duration ≥6 months, normal carbohydrate antigen 19-9 after preoperative treatment, and complete or partial radiologic response. Finally, we developed a simplified predictive model for achieving MPR. MPR was independently associated with favorable survival in PDAC. The prognostic impact of adjuvant chemotherapy was not observed among patients who achieved MPR, suggesting that MPR may inform individualized postoperative management and warrants prospective validation.

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.

We aimed to examine the psychometric properties of the second version of the Brief Evaluation of Psychosis Symptom Domains (BE-PSD-V2.0) and its correspondence with the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity scale (CGI-S) scores. This cross-sectional study was conducted at 18 institutes in Japan. We performed correlational analyses to test the convergent and divergent validity of the BE-PSD-V2.0. Inter-rater reliability was assessed using intraclass correlation coefficients (ICCs). The equipercentile equating method was employed to examine the linking of the BE-PSD-V2.0 with the PANSS and the CGI-S. A total of 353 patients with schizophrenia spectrum disorders were included. Spearman's rank correlation coefficients between the BE-PSD-V2.0 item scores and their corresponding PANSS factor scores ranged from 0.64 to 0.86, indicating sufficient convergent validity. These specific correlation coefficients were consistently the highest among all item-to-factor comparisons, indicating sufficient divergent validity. In 34 patients, ICCs for the BE-PSD-V2.0 itemand total scores ranged from 0.60 to 0.94, showing sufficient inter-rater reliability. Conversion tables were established between the BE-PSD-V2.0 total score and the PANSS total score, between the BE-PSD-V2.0 total score and the CGI-S score, and between the BE-PSD-V2.0 item scores and their corresponding PANSS factor scores. A correspondence between symptomatic remission criteria using the PANSS and BE-PSD-V2.0 was confirmed. The BE-PSD-V2.0 possesses sufficient psychometric properties and corresponds to the PANSS and CGI-S. It is a sound and reliable brief rating scale for assessing symptoms in schizophrenia spectrum disorders, and its established conversion correspondences facilitate score interpretation within existing clinical paradigms for both clinical practice and research.

ABSTRACTTo evaluate dysphagia, pharyngeal high‐resolution impedance manometry (P‐HRM‐I) is used in conjunction with videofluoroscopic examination of swallowing (VF) or videoendoscopic evaluation of swallowing to obtain additional objective data that cannot be captured by conventional assessment methods. Based on the Leuven Consensus of the International Pharyngeal Manometry Working Group for diagnosing pharyngeal and upper esophageal sphincter (UES) motility disorders, we present a case series of two patients illustrating the recovery process of dysphagia following lateral medullary syndrome. Two patients with severe dysphagia due to lateral medullary infarction caused by vertebral artery dissection were evaluated. In both patients, the initial P‐HRM‐I showed profound impairment of the UES opening and bolus passage, preventing oral intake. Balloon dilation of the UES, laryngeal elevation exercises, tongue strengthening exercises, and direct swallowing training were performed, and the functions of the pharynx and UES were regularly evaluated using VF and P‐HRM‐I. Following UES dilation, PHRM‐I revealed improved UES opening, enhanced pharyngeal contraction, and restoration of pharyngeal peristalsis. Both patients regained sufficient swallowing function to resume a regular diet. P‐HRM‐I may be a useful tool for quantitatively assessing UES function and bolus propulsion, identifying the pathophysiological components of dysphagia, guiding individualized treatment, and monitoring post‐intervention recovery.

Major depressive disorder (MDD) shows varied treatment responses. Previous Phase 2 and 3 trials demonstrated the efficacy of 2-week oral zuranolone in Japanese MDD patients, but individual symptom trajectories were not analyzed. To address this gap, this study aimed to characterize patterns of depressive symptom trajectories among these patients. We conducted a pooled analysis of Phase 2/3 randomized, double-blind, placebo-controlled trials in Japanese adults with MDD. Participants received zuranolone 30 mg or placebo once daily for 14 days, with a 6-week follow-up. Patients with complete 17-item Hamilton Rating Scale for Depression (HAM-D17) data at baseline and 10 subsequent time points through Day 57 were included. Change from baseline scores underwent Dynamic Time Warping-based k-means clustering identified symptom trajectory patterns in the zuranolone group, with optimal cluster number determined by the elbow method. A Random Forest classifier then assessed scale items linked to symptom worsening trajectories. Four distinct trajectories were identified. Three clusters showed varying degrees of symptom reduction during treatment, stabilizing during follow-up. The fourth cluster showed symptom reduction during the treatment period and a mean increase in HAM-D17 scores after Day 15, primarily due to worsening insomnia. Each Patient Health Questionnaire-9 (PHQ-9) score showed a similar course to the corresponding HAM-D17 scores. No notable differences were observed among clusters in baseline demographics, episode duration, or initial severity. This study reveals diverse symptom trajectories in zuranolone-treated patients and provides clinically relevant insights, highlighting the importance of early post-dosing monitoring-particularly of sleep symptoms-to inform clinical management and future research.

Escherichia coli O157 and O26 are well-known Shiga toxin-producing E. coli (STEC) serotypes, but other serotypes such as O91, O103, O111, O121, O145, and O165 have also emerged as important public health concerns. PCR-based methods, such as multilocus variable-number tandem-repeat analysis (MLVA), are commonly used for rapid genotyping of STEC strains. However, MLVA requires analysis of numerous loci, some of which are serotype-specific, limiting its applicability across multiple STEC serotypes. In this study, we developed a PCR-based open reading frame typing (POT) method for genotyping diverse STEC serotypes. By detecting 22 ORFs using two multiplex PCR assays, STEC genotypes were determined based on the presence or absence of specific ORFs. Most STEC serotypes, except for O121, were classified with high discriminatory power (Simpson's index: 0.95-0.98). STEC-POT represents a rapid, cost-effective, and broadly applicable molecular typing tool. It facilitates timely outbreak detection and enhances public health surveillance by enabling rapid molecular epidemiological investigations.