Sapporo Higashi Tokushukai Hospital

There is an increasing need for predictors of clinical outcomes in patients with ulcerative colitis (UC). In this exploratory analysis, we aimed to analyze the gene expression profile of intestinal tissues according to treatment outcome in patients with UC treated with vedolizumab and to develop a treatment outcome prediction model. Transcriptomic analysis of intestinal tissues at the inflammation site (week 0) of patients (N = 10), stratified by mucosal healing status at week 54 after vedolizumab 300 mg treatment, was performed to identify differentially expressed genes (DEGs) with ≥ 1.5-fold difference and P < 0.05. Vedolizumab-related ‘hub’ genes were identified by network analysis (cytoHubba). Candidate biomarkers were selected and a prediction model for mucosal healing was developed using the least absolute shrinkage and selection operator (LASSO) algorithm (a machine learning method that helps to identify the most relevant genes for prediction while avoiding overfitting), which was validated with a public dataset (GSE73661). Transcriptomic analysis revealed 375 DEGs associated with vedolizumab mucosal healing. Gene enrichment analysis revealed terms associated with T cell activation and immune regulation. Eighteen hub genes were identified. A prediction model developed and validated with a public dataset had AUC–ROC values of 0.800 (95% CI, 0.551–1.000) and 0.750 (95% CI, 0.350–1.000) for the week 12 and 52 vedolizumab validation cohorts, respectively. In contrast, the AUC–ROC was 0.575 (95% CI, 0.317–0.833) for the week 4–6 infliximab validation cohort, suggesting that the model is specific for vedolizumab-associated clinical outcomes. We identified hub genes that were related to vedolizumab treatment outcomes. A prediction model of vedolizumab-associated mucosal healing was developed and validated with a public dataset.

767 Background: Pancreatic ductal adenocarcinoma (PDAC) remains lethal. Neoadjuvant therapy (NAT) is increasingly applied to borderline resectable and locally advanced PDAC. However, most patients show only partial or minimal regression. To define molecular correlates of NAT response, we analyzed paired pre-/post-chemotherapy specimens: pre-treatment endoscopic ultrasound-guided fine needle tissue acquisition (EUS-TA) and matched resection tumors. Methods: At Tohoku University Hospital (2010–2020), 220 NAT-treated PDAC resections were graded by the College of American Pathologists (CAP). 75 cases had sufficient DNA; 69 had paired TA–tumor and 6 tumor-only. NAT regimens primarily included gemcitabine plus oral tegafur/gimeracil/oteracil or gemcitabine plus nab-paclitaxel; a minority received single-agent therapy or regimen switches. Detailed distributions of NAC regimens and clinicopathologic variables are summarized in Table. A deep learning framework (DietNet) was applied to pre-treatment TA data to predict response (CAP1–2 vs CAP3) and integrated with post-treatment tumor profiles to assess molecular evolution. Results: DietNet achieved mean cross-validated AUC 0.77 (95% CI 0.57–0.91); permutation p=0.096. Predictive features included amplifications ( AKT1/2, ERBB2, GATA6, HRAS ) and deletions ( CDKN2A/B, SMAD4, MTAP, RNF43) . Delta (tumor–TA) suggested emergent TP53/STK11 mutation loss and GATA6 copy change. CAP3 vs CAP2 was enriched for CDKN2A/IKBKB loss and gains in BCL9; ARNT/SETDB1/MLLT11; NTRK1; FCGR2B/DDR2/PBX1; PRRX1; TLX3; HOXA9; CSMD3; MYC; RAD21/EXT1 —implicating Wnt/β-catenin, chromatin remodeling, receptor tyrosine kinase activation, and stemness programs. Conclusions: Pre-treatment TA-based modeling moderately predicted NAT response. CAP3 tumors showed CDKN2A/IKBKB loss plus multiple oncogenic gains consistent with chemoresistance. Integrating pre-treatment prediction with post-treatment evolution may aid risk stratification and guide therapeutic development. Clinicopathologic characteristics of patients stratified by pathologic response (CAP1/2 vs CAP3). Variable Categories CAP1/2 n = 25 CAP3 n = 50 Total n = 75 p-value Sex Male:Female 13:12 31:19 44:31 0.684 (Chi²) Age (years) Median (range) 67 (50–78) 65 (56–89) – 0.62 (Wilcoxon) NAC Regimen GS:GnP:Multiple:Other 14:3:1:4 39:10:4:0 53:13:5:4 0.421 (Chi²) Recurrence Yes:No 8:17 11:39 19:56 0.355 (Chi²) Prognosis Alive:Dead:non-cancer death 8:10:7 18:29:3 26:43:6 0.675 (Chi²) UICC Grade G1:G2:G3:G4 5:11:9:0 10:26:11:3 15:37:20:3 0.418 (Fisher) UICC 8th Stage IA:IB:IIA:IIB:III:IV 4:0:0:13:2:6 4:6:3:14:19:4 8:6:3:27:21:10 0.0026 (Fisher) Counts shown. GS=gemcitabine+oral tegafur/gimeracil/oteracil; GnP=gemcitabine+nab-paclitaxel; Multiple = regimen switch during treatment. P-value by Chi-square, Fisher, or Wilcoxon as appropriate.

Chronic background mucosal inflammation contributes to colorectal cancer (CRC) development in ulcerative colitis (UC), but its prognostic impact is unclear. We evaluated whether background mucosal inflammation documented at cancer diagnosis is associated with oncologic outcomes. This retrospective study analyzed 1189 UC patients diagnosed with CRC using a nationwide, multicenter database in Japan. Patients were classified as CRC within the UC-involved area (within-area) or outside the UC-involved area (outside-area), based on tumor location relative to the UC disease extent documented endoscopically at cancer diagnosis. The primary end point was 5-year recurrence-free survival (RFS), and the secondary end point was 5-year cancer-specific survival (CSS). In within-area cases, inflammation severity was assessed using the Mayo Endoscopic Score (MES), stratified as Inactive, Mild-Moderate, and Severe. Of the 723 eligible patients, 683 had within-area and 40 outside-area CRC. Five-year RFS was significantly lower in within-area than outside-area CRCs (75.1% vs 87.6%, P = 0.022). Multivariable Cox regression analysis of RFS revealed this classification as an independent prognostic factor (hazard ratio = 2.99, 95% confidence interval: 1.09-8.18, P = 0.030). A significant difference was also observed in 5-year CSS (P = 0.038). Among within-area cases, higher MES was associated with stepwise declines in RFS (P = 0.150), and a similar, statistically significant gradient in CSS (P = 0.048). Background mucosal inflammation at cancer diagnosis is associated with significantly worse prognosis of CRC in UC patients. Systematic endoscopic assessment at cancer diagnosis may aid prognostic stratification and inform management.

Abstract Background Patients with advanced renal cell carcinoma (RCC) undergoing hemodialysis are often excluded from clinical trials. We aimed to evaluate real-world outcomes of first-line molecular targeted therapy (MTT) and immuno-oncology (IO) combination therapies in patients with advanced RCC receiving hemodialysis. Methods We retrospectively analyzed data from 88 patients undergoing hemodialysis who received first-line systemic therapy for advanced RCC at 18 institutions in Japan between 2008 and 2023. Patients were divided into three groups by first-line regimen: MTT (n = 53), IO–IO (n = 18), or IO-tyrosine kinase inhibitor (IO–TKI, n = 17). Treatment response, progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were evaluated. Prognostic factors were identified using univariate and multivariate Cox regression analyses. Results The median PFS and OS were 3.9 and 18.9 months, respectively. IO–IO and IO–TKI groups achieved significantly longer PFS than the MTT group (median PFS 3.5, 5.4, and 7.5 months, respectively; p = 0.003); OS did not differ significantly among groups. Grade ≥ 3 TRAEs occurred in 30.2%, 33.3%, and 41.2% of MTT, IO–IO, and IO–TKI groups, respectively. Multivariate analysis identified poor Eastern Cooperative Oncology Group performance status, longer hemodialysis duration (≥ 10 years), and first-line regimen as independent PFS predictors. International Metastatic RCC Database Consortium risk classification and hemodialysis duration independently predicted OS. Conclusions Systemic therapy, including MTT and IO combination therapy such as IO–IO and IO–TKI, demonstrated acceptable safety profiles for patients with advanced RCC undergoing hemodialysis. IO combination therapy significantly improved PFS, supporting its utility as a first-line treatment option.

Background: The rise of the cardio-renal-metabolic syndrome concept and broader use of SGLT2 inhibitors in non-diabetics mark a shift toward earlier intervention in kidney care. We conducted a study to assess whether glomerular hyperfiltration (GHF) or hyperinsulinemia, estimated by the TG/HDL-C ratio (TGR), more strongly predicts renal function decline in this population. Methods: This single-center observational study included individuals aged ≥18 years who underwent annual health checkups with serum creatinine measurements from 2012 to 2024. Participants were stratified by age and sex; strata with ≥200 subjects were included. GHF was defined as estimated glomerular filtration rate (eGFR) above the 95th percentile within each stratum; controls were those with eGFR >60 mL/min/1.73 m2 excluding GHF. The index date was the first checkup with GHF or the initial checkup during the study for controls. Hyperinsulinemia was estimated using TGR (cut-off: 2.1), and subjects were stratified into high and low TGR groups. Exclusion criteria were age <18, missing TG/HDL-C values, or HbA1c ≥6.5%. The primary outcome was time to a 30% eGFR decline, analyzed by Kaplan-Meier curves and Cox proportional hazards models. Results: A total of 5,654 individuals (mean age 48.7 years; 48.8% male; mean eGFR 79.0) were analyzed. GHF was observed in 611 subjects (mean eGFR 102.3), and 1,615 were categorized as high TGR. During follow-up, 183 participants (3.2%) experienced ≥30% eGFR decline. Kaplan-Meier analysis, adjusted for age and sex, showed significantly higher risk in the GHF group vs controls (log-rank p<0.001), while no significant difference was observed between high and low TGR groups (p=0.7). Cox regression showed a markedly elevated risk with GHF, while high TGR alone showed no significant association (Figure). Conclusion: GHF significantly increased renal risk regardless of TGR, while elevated TGR alone was not associated with additional risk. These findings suggest hyperfiltration is a dominant factor in renal decline among non-diabetic individuals, whereas surrogate hyperinsulinemia markers contribute little.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a new spectrum of autoimmune inflammatory nervous system disorders associated with infection, neoplasm, or drug use. We present the first pediatric case of GFAP astrocytopathy caused by an influenza A infection. The patient manifested meningoencephalitis, central respiratory failure, quadriplegia, elimination disorders, and syndrome of inappropriate antidiuretic hormone secretion. Methylprednisolone pulse therapy led to a good prognosis. In cases of progressive atypical complications of influenza infection, immunotherapy-reactive GFAP astrocytopathy should be considered as a differential diagnosis for prompt treatment.

BackgroundComparative data on early- (G2) vs newer-generation (G4) MitraClip transcatheter edge-to-edge repair (TEER) systems remain limited.ObjectivesThe authors compared procedural and clinical outcomes of both devices in patients with degenerative mitral regurgitation (DMR) or functional mitral regurgitation (FMR).MethodsUsing the OCEAN (Optimized Catheter Valvular Intervention)-Mitral registry, 3,738 patients undergoing TEER with either G2 (n = 1,481) or G4 (n = 2,257) MitraClips were analyzed. Outcomes included procedural metrics, echocardiographic parameters, and clinical events.ResultsDespite being older (P = 0.010) and higher-risk (EuroSCORE [European System for Cardiac Operative Risk Evaluation] II: P = 0.002), the newer-generation group achieved comparable procedural success (residual MR ≤2+) with shorter procedure time and fewer clips, resulting in significantly lower transmitral mean pressure gradients (TMPG) (DMR: median: 3.0 [Q1-Q3: 2.0-4.0] mm Hg vs 2.7 [Q1-Q3: 2.0-3.8] mm Hg; P = 0.009; FMR: median 3.0 [Q1-Q3: 2.0-4.0] mm Hg vs 2.5 [Q1-Q3: 1.9-3.5] mm Hg; P < 0.001) in both DMR and FMR cohorts. Rates of mechanical complications, such as single leaflet device attachment and leaflet tear, were rare across both device generations but were further reduced in the newer-generation device. The newer-generation device was associated with reduced heart failure (HF) rehospitalization in DMR (adjusted HR: 0.51; 95% CI: 0.33-0.77; P = 0.001) and FMR (adjusted HR: 0.76; 95% CI: 0.61-0.93; P = 0.009), with a greater risk reduction in DMR (Pinteraction < 0.001). A causal mediation analysis revealed that postprocedural TMPG modestly mediated the association between device generation and HF rehospitalization risk (proportion mediated = 1.8% [Q1-Q3: 0.3%-4.0%]; P = 0.016).ConclusionsThe newer-generation TEER system offers a safer and more efficient procedure, with shorter procedural time, fewer mechanical complications, fewer clips, and a lower postprocedural TMPG, contributing to reduced HF rehospitalization risk, particularly in DMR.