Preoperative risk factors for skeletal muscle mass loss in patients with biliary tract cancer.

BACKGROUND: Endoscopic retrograde cholangiography (ERC)-related procedures, usually performed before biliary tract cancer (BTC) surgery, are associated with increased risk for various complications, which can cause sarcopenia. No study has previously elucidated the relationship between preoperative ERC-related procedures and sarcopenia/skeletal muscle mass loss. METHODS: Patients with BTC who underwent radical surgical resection following ERC-related procedures were included. Skeletal muscle mass was evaluated using the psoas muscle mass index (PMI), which was determined using computed tomography images, and the change in PMI before the initial pre-ERC and surgery (ΔPMI) was calculated. Risk factors for advanced skeletal muscle mass loss, defined as a large ΔPMI, were evaluated. RESULTS: The study cohort included 90 patients with a median age of 72 (interquartile range, 65-75) years. The median PMI pre-ERC and surgery was 4.40 and 4.15 cm2/m2, respectively (p < .01). The median ΔPMI was -6.2% (interquartile range, -10.9% to 0.5%). By multivariate analysis, post-ERC pancreatitis and cholangitis before surgery were independent predictive factors for large PMI loss (odds ratio, 4.57 and 3.18, respectively; p = .03 and p = .02, respectively). CONCLUSIONS: Skeletal muscle mass decreases preoperatively in most patients with BTC undergoing ERC. Post-ERC pancreatitis and cholangitis before surgery were independent risk factors for large skeletal muscle mass loss.

Proteomic analysis of serum extracellular vesicles reveals Fibulin-3 as a new marker predicting liver-related events in MASLD.

BACKGROUND: There is a need for novel noninvasive markers for metabolic dysfunction-associated steatotic liver disease (MASLD) to stratify patients at high risk for liver-related events including liver cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) to identify new biomarkers that change with fibrosis progression and can predict the development of liver-related events. METHODS: We analyzed serum EVs from 50 patients with MASLD assessed for liver fibrosis by biopsy and identified proteins that altered with advanced fibrosis. A further evaluation was conducted on another cohort of 463 patients with MASLD with biopsy. RESULTS: Eight candidate proteins were identified by proteomic analysis of serum EVs. Among them, serum levels of Fibulin-3, Fibulin-1, and Ficolin 1 correlated with their EV levels. In addition, serum Fibulin-3 and serum Fibulin-1 levels changed significantly with advanced fibrosis. Using another cohort with biopsy, we found that the serum Fibulin-3 concentration was significantly greater in those with advanced fibrosis but that the serum Fibulin-1 concentration was not significantly different. Multivariate Cox proportional hazards analysis revealed that a higher Fibrosis-4 (FIB-4) index and higher serum Fibulin-3 concentration were independent risk factors for liver-related events. When the cutoff value for the serum Fibulin-3 concentration was 6.0 µg/mL according to the Youden index of AUROCs, patients with high serum Fibulin-3 significantly more frequently developed liver-related events than did other patients. Validation using another cohort of 226 patients with clinically diagnosed MASLD confirmed that high serum Fibulin-3 levels are associated with a greater frequency of liver-related events. CONCLUSIONS: Serum Fibulin-3 was identified as a biomarker for predicting liver-related events in patients with MASLD.

Brief intervention for chronic liver disease patients with alcohol use disorder in a hepatology outpatient unit: Effects and limitations.

AIM: It is not uncommon to encounter outpatients in the hepatology department with harmful alcohol habits. When treating such chronic liver disease (CLD) patients, an adequate intervention method for harm reduction of alcohol use, such as brief intervention (BI) or BI and nalmefene, should be considered. This study aimed to elucidate the clinical effectiveness of BI for CLD patients affected by harmful alcohol use. METHODS: From June 2021 to 2023, 123 Japanese CLD outpatients (hepatitis B virus : hepatitis C virus : alcoholic liver disease : others = 32:18:42:31) with an Alcohol Use Disorders Identification Test (AUDIT) score of ≥8 at the initial interview and a repeat interview with AUDIT 9 months later were enrolled. Clinical features related to patient behavior following the initial AUDIT interview were retrospectively evaluated, and compared between patients without and with BI treatment. RESULTS: For the non-BI and BI groups, baseline AUDIT score (median 10 [interquartile range (IQR) 9-13] vs. 12 [IQR 10-17], p = 0.016) and relative change in AUDIT score (median 0 [IQR -3 to 2] vs. -3 [IQR -7 to 0], p < 0.01) showed significant differences, whereas there was no significant difference between the groups for AUDIT score at the time of the second interview (p = 0.156). Following BI, significant improvements were observed for items 1, 2, 3, 4, 5, 8, and 10 of AUDIT (each p < 0.05). CONCLUSION: Patients with an alcohol use disorder as well as those with alcohol dependency who received BI showed a significant decline in AUDIT score, although the score of the follow-up AUDIT indicated continued alcohol use disorder. In addition to BI, medication with nalmefene should be considered, based on individual factors.

Clinicopathological differences between EGFR mutated and EGFR wild-type lung adenocarcinoma with papillary predominant pattern.

OBJECTIVES: We aimed to reveal the clinicopathological differences between epidermal growth factor receptor (EGFR)-mutated and wild-type (WT) lung adenocarcinoma (LUAD) focusing on the predominant subtype. METHODS: This study included 352 with EGFR mutation and 370 with WT patients in consecutive stage I LUAD classified by the predominant subtype, and their clinicopathological characteristics and prognosis were analyzed. Using the Cancer Genome Atlas Program (TCGA) cohort, we analyzed differences in gene expression between EGFR mutation and WT groups. Furthermore, we performed immunohistochemical evaluations for 46 with EGFR mutation and 47 with WT patients in consecutive stage I papillary predominant adenocarcinoma (PPA). RESULTS: Compared to the PPA with WT [n = 115], those with EGFR mutation [n = 99] exhibited smaller invasive size (p = 0.03) and less frequent vessel invasion (p < 0.01). However, PPA with EGFR mutation showed significantly worse 5-ys recurrence-free survival (RFS) rates compared to those with WT (70.6 % versus 83.3 %, p = 0.03). Contrarily, no significant differences were observed in other predominant subtypes. In the TCGA cohort, PPA with EGFR mutation tended to show higher expression of galectin-3, which is associated with tumor metastasis and resistance to anoikis, compared to those with WT (p = 0.06). Immunohistochemical evaluation revealed that galectin-3 expression was significantly higher in PPA with EGFR mutation than in those with WT (p < 0.01). CONCLUSIONS: The prognosis of PPA with EGFR mutation proved to be less favorable compared to that with WT, and galectin-3 is highly expressed in EGFR-mutated PPA.

GGT1 is a SNP eQTL gene involved in STAT3 activation and associated with the development of Post-ERCP pancreatitis.

Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP.

Peripheral T Cell Subpopulations as a Potential Surrogate Biomarker during Atezolizumab plus Bevacizumab Treatment for Hepatocellular Carcinoma.

The therapeutic benefits of the immunotherapeutic combination of atezolizumab and bevacizumab (Atez/Bev) in hepatocellular carcinoma (HCC) vary. Therapeutic biomarkers might help improve outcomes for HCC patients receiving Atez/Bev therapy. The role of systemic immune profiles in HCC progression also remains unclear. This study aimed to evaluate the status and dynamics of peripheral T cell subpopulations in HCC patients receiving Atez/Bev treatment and to explore biomarkers predictive of a therapeutic response. We enrolled 83 unresectable advanced HCC patients who commenced Atez/Bev treatment at our hospital between October 2020 and June 2022. Peripheral T cell subpopulations in peripheral blood mononuclear cells at baseline and 3 weeks post-treatment were investigated using flow cytometry and compared with those in control samples from 18 healthy individuals. We retrospectively analyzed the association between peripheral T cell subpopulation profiles and clinical outcomes. Baseline peripheral T cell subpopulations could be profiled in 70 patients with sufficient cell counts, among whom 3-week subpopulations could be evaluated in 51 patients. Multivariate analysis showed that a high baseline proportion of CD8+ central memory T (TCM) cells was independently associated with longer progression-free survival (PFS). Further, overall survival (OS) was significantly prolonged in patients with increased CD8+ effector memory T (TEM) cell proportions. In conclusion, TCM proportion at baseline might be a good indicator of the efficacy of Atez/Bev therapy. Furthermore, observation of increasing TEM proportions might be an early predictor of the potential clinical benefits of treatment.

Deciphering metabolic dysfunction-associated steatotic liver disease: insights from predictive modeling and clustering analysis.

BACKGROUND AND AIM: New nomenclature of steatotic liver disease (SLD) including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) has recently been proposed. We investigated clustering analyses to decipher the complex landscape of SLD pathologies including the former nomenclature of nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: Japanese individuals who received annual health checkups including abdominal ultrasonography (n = 15 788, men/women: 10 250/5538, mean age: 49 years) were recruited. RESULTS: The numbers of individuals with SLD, MASLD, MetALD, ALD, NAFLD, and MAFLD were 5603 (35.5%), 4227 (26.8%), 795 (5.0%), 324 (2.1%), 3982 (25.8%), and 4946 (31.3%), respectively. Clustering analyses using t-distributed stochastic neighbor embedding and K-means to visually represent interconnections in SLDs uncovered five cluster formations. MASLD and NAFLD mainly shared three clusters including (i) low alcohol intake with relatively low-grade obesity; (ii) obesity with dyslipidemia; and (iii) dysfunction of glucose metabolism. Both MetALD and ALD displayed one distinct cluster intertwined with alcohol consumption. MAFLD widely shared all of the five clusters. In machine learning-based analyses using algorithms of random forest and extreme gradient boosting and receiver operating characteristic curve analyses, fatty liver index (FLI), calculated by body mass index, waist circumference, and levels of γ-glutamyl transferase and triglycerides, was selected as a useful feature for SLDs. CONCLUSIONS: The new nomenclature of SLDs is useful for obtaining a better understanding of liver pathologies and for providing valuable insights into predictive factors and the dynamic interplay of diseases. FLI may be a noninvasive predictive marker for detection of SLDs.

Adverse Events as Potential Predictive Factors of Activity in Patients with Advanced HCC Treated with Atezolizumab Plus Bevacizumab.

BACKGROUND: In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors. OBJECTIVE: This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting. PATIENTS AND METHODS: The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea). RESULTS: Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13-0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24-0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38-0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65-0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52-0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64-0.98; p = 0.03) as independent prognostic factors for progression-free survival. CONCLUSIONS: As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab.

A homeostatic role of nucleus-actin filament coupling in the regulation of cellular traction forces in fibroblasts.

Cellular traction forces are contractile forces that depend on the material/substrate stiffness and play essential roles in sensing mechanical environments and regulating cell morphology and function. Traction forces are primarily generated by the actin cytoskeleton and transmitted to the substrate through focal adhesions. The cell nucleus is also believed to be involved in the regulation of this type of force; however, the role of the nucleus in cellular traction forces remains unclear. In this study, we explored the effects of nucleus-actin filament coupling on cellular traction forces in human dermal fibroblasts cultured on substrates with varying stiffness (5, 15, and 48 kPa). To investigate these effects, we transfected the cells with a dominant-negative Klarsicht/ANC-1/Syne homology (DN-KASH) protein that was designed to displace endogenous linker proteins and disrupt nucleus-actin cytoskeleton connections. The force that exists between the cytoskeleton and the nucleus (nuclear tension) was also evaluated with a fluorescence resonance energy transfer (FRET)-based tension sensor. We observed a biphasic change in cellular traction forces with a peak at 15 kPa, regardless of DN-KASH expression, that was inversely correlated with the nuclear tension. In addition, the relative magnitude and distribution of traction forces in nontreated wild-type cells were similar across different stiffness conditions, while DN-KASH-transfected cells exhibited a different distribution pattern that was impacted by the substrate stiffness. These results suggest that the nucleus-actin filament coupling play a homeostatic role by maintaining the relative magnitude of cellular traction forces in fibroblasts under different stiffness conditions.

Prognosis of anemic patients with atrial fibrillation undergoing percutaneous coronary intervention.

BACKGROUND: There are limited data regarding whether anemia is associated with adverse clinical outcomes in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). METHODS: Patients with AF undergoing PCI at 15 institutions between January 2015 and March 2021 were included in this analysis. Based on the baseline hemoglobin levels, moderate to severe anemia was defined as hemoglobin levels <11 g/dL, and mild anemia was defined as hemoglobin levels 11-12.9 g/dL for men and 11-11.9 g/dL for women. Clinical outcomes within 1 year, including major adverse cardiovascular events (MACE: all-cause death, myocardial infarction, stent thrombosis, and stroke) and major bleeding events (BARC 3 or 5), were compared among patients with moderate/severe anemia, mild anemia, and no anemia. RESULTS: In a total of 746 enrolled patients, 119 (16.0%) and 168 (22.5%) patients presented with moderate/severe and mild anemia. The incidence of MACE (22.5%, 11.0%, and 9.1%, log-rank p < 0.001), all-cause death (20.0%, 7.2%, and 4.8%, log-rank p < 0.001), and major bleeding events (10.7%, 6.5%, and 2.7%, log-rank p < 0.001) were the highest in the moderate/severe anemia group compared with the mild and no anemia groups. Multivariable Cox regression analyses determined moderate/severe anemia as an independent predictor for MACE (p = 0.008), all-cause death (p = 0.005), and major bleeding events (p = 0.031) at 1 year after PCI. CONCLUSION: Moderate/severe anemia was significantly associated with the higher incidence of MACE and all-cause death as well as major bleeding events compared with mild and no anemia in AF patients undergoing PCI.

Whole-transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential.

Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies.

Impact of body mass index on the prognosis of unresectable HCC patients receiving first-line Lenvatinib or atezolizumab plus bevacizumab.

INTRODUCTION: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment. METHODS AND MATERIAL: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests. RESULTS: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis. CONCLUSION: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib.

Deep learning reconstruction for high-resolution computed tomography images of the temporal bone: comparison with hybrid iterative reconstruction.

PURPOSE: We investigated whether the quality of high-resolution computed tomography (CT) images of the temporal bone improves with deep learning reconstruction (DLR) compared with hybrid iterative reconstruction (HIR). METHODS: This retrospective study enrolled 36 patients (15 men, 21 women; age, 53.9 ± 19.5 years) who had undergone high-resolution CT of the temporal bone. Axial and coronal images were reconstructed using DLR, HIR, and filtered back projection (FBP). In qualitative image analyses, two radiologists independently compared the DLR and HIR images with FBP in terms of depiction of structures, image noise, and overall quality, using a 5-point scale (5 = better than FBP, 1 = poorer than FBP) to evaluate image quality. The other two radiologists placed regions of interest on the tympanic cavity and measured the standard deviation of CT attenuation (i.e., quantitative image noise). Scores from the qualitative and quantitative analyses of the DLR and HIR images were compared using, respectively, the Wilcoxon signed-rank test and the paired t-test. RESULTS: Qualitative and quantitative image noise was significantly reduced in DLR images compared with HIR images (all comparisons, p ≤ 0.016). Depiction of the otic capsule, auditory ossicles, and tympanic membrane was significantly improved in DLR images compared with HIR images (both readers, p ≤ 0.003). Overall image quality was significantly superior in DLR images compared with HIR images (both readers, p < 0.001). CONCLUSION: Compared with HIR, DLR provided significantly better-quality high-resolution CT images of the temporal bone.

Spatial intratumor heterogeneity of programmed death-ligand 1 expression predicts poor prognosis in resected non-small cell lung cancer.

OBJECTIVE: We quantified the pathological spatial intratumor heterogeneity (ITH) of programmed death-ligand 1 (PD-L1) expression and investigated its relevance to patient outcomes in surgically resected non-small cell lung carcinoma (NSCLC). MATERIALS AND METHODS: This study enrolled 239 consecutive surgically resected NSCLC specimens of pathological stage IIA-IIIB. To characterize the spatial ITH of PD-L1 expression in NSCLC tissues, we developed a mathematical model based on texture image analysis and determined the spatial heterogeneity index of PD-L1 (SHIP) for each tumor. The correlation between the SHIP values and clinicopathological characteristics, including prognosis, was analyzed. Furthermore, an independent cohort of 70 cases was analyzed for model validation. RESULTS: Clinicopathological analysis showed correlations between high SHIP values and histological subtype (squamous cell carcinoma, p < .001) and vascular invasion (p = .004). Survival analysis revealed that patients with high SHIP values presented a significantly worse recurrence-free rate than those with low SHIP values (5-year RFS 26.3% vs 47.1%, p < .005). The impact of SHIP on cancer survival rates was verified through validation in an independent cohort. Moreover, high SHIP values were significantly associated with tumor recurrence in squamous cell carcinoma (5-year RFS 29.2% vs 52.8%, p < .05) and adenocarcinoma (5-year RFS 19.6% vs 43.0%, p < .01). Moreover, we demonstrated that a high SHIP value was an independent risk factor for tumor recurrence. CONCLUSIONS: We presented an image analysis model to quantify the spatial ITH of protein expression in tumor tissues. This model demonstrated that the spatial ITH of PD-L1 expression in surgically resected NSCLC predicts poor patient outcomes.

Surveillance esophagogastroduodenoscopy using linked color imaging and narrow-band imaging: A multicenter randomized controlled trial.

BACKGROUND AND AIM: There has been no report on a direct comparison between linked color imaging (LCI) and second-generation narrow-band imaging (2G-NBI) for surveillance of epithelial neoplasms in the upper gastrointestinal tract (UGIT). The aim of this study was to verify the superiority of LCI to 2G-NBI for surveillance esophagogastroduodenoscopy and to clarify how each endoscopic system should be used. METHODS: This study was conducted as an open-label, two-arm-parallel (1:1), multicenter, randomized controlled trial at six institutions. Patients aged 20-85 years with a treatment history of epithelial neoplasms in the UGIT were recruited. Patients were assigned to a 2G-NBI group and an LCI group, and esophagogastroduodenoscopy was performed with primary image-enhanced endoscopy followed by white light imaging (WLI). The primary endpoint was the detection rate of one or more epithelial neoplasms in the primary image-enhanced endoscopy. A WLI-detected epithelial neoplasm was defined as a lesion that was detected in only WLI. RESULTS: A total of 372 patients in the 2G-NBI group and 378 patients in the LCI group were analyzed. Epithelial neoplasms in the UGIT were detected by 2G-NBI in 18 patients (4.6%) and were detected by LCI in 20 patients (5.3%) (P = 0.87). WLI-detected epithelial neoplasms were in 11 patients in the 2G-NBI group (3.0%) and in 1 patient in the LCI group (0.27%) (P = 0.003). CONCLUSIONS: Linked color imaging did not show superiority to 2G-NBI for the detection of epithelial neoplasms. Also, the percentage of WLI-detected epithelial neoplasms in primary NBI was significantly higher than that in primary LCI.

Extracting interpretable features for pathologists using weakly supervised learning to predict p16 expression in oropharyngeal cancer.

One drawback of existing artificial intelligence (AI)-based histopathological prediction models is the lack of interpretability. The objective of this study is to extract p16-positive oropharyngeal squamous cell carcinoma (OPSCC) features in a form that can be interpreted by pathologists using AI model. We constructed a model for predicting p16 expression using a dataset of whole-slide images from 114 OPSCC biopsy cases. We used the clustering-constrained attention-based multiple-instance learning (CLAM) model, a weakly supervised learning approach. To improve performance, we incorporated tumor annotation into the model (Annot-CLAM) and achieved the mean area under the receiver operating characteristic curve of 0.905. Utilizing the image patches on which the model focused, we examined the features of model interest via histopathologic morphological analysis and cycle-consistent adversarial network (CycleGAN) image translation. The histopathologic morphological analysis evaluated the histopathological characteristics of image patches, revealing significant differences in the numbers of nuclei, the perimeters of the nuclei, and the intercellular bridges between p16-negative and p16-positive image patches. By using the CycleGAN-converted images, we confirmed that the sizes and densities of nuclei are significantly converted. This novel approach improves interpretability in histopathological morphology-based AI models and contributes to the advancement of clinically valuable histopathological morphological features.

Effectiveness of transabdominal ultrasonography in predicting clinical relapse of Crohn's disease.

BACKGROUND/AIMS: Transabdominal ultrasonography (US) helps evaluate Crohn's disease (CD) activity. We investigated whether the US could predict subsequent adverse outcomes for patients with CD in clinical remission. METHODS: This single-center retrospective study included patients with CD in clinical remission who underwent US between April 2011 and April 2021, focusing on the predictability of subsequent adverse outcomes within 5 years. We used the US-CD, which was calculated using multiple US findings. Predictive variables were assessed using Cox proportional hazards regression analysis, and the predictive value was evaluated using receiver operating characteristic curves. RESULTS: Seventy-three patients were included. During a median follow-up of 1,441 days (range, 41-1,825 days), 16.4% (12/73) experienced clinical relapse, 9.6% (7/73) required endoscopic balloon dilation (EBD), 58.9% (43/73) required enhanced treatment, and 20.5% (15/73) underwent surgery. In the multivariate analysis, US-CD was significantly associated with clinical relapse (P= 0.038) and the need for enhanced treatment (P= 0.005). The area under the receiver operating characteristic curve for predicting clinical relapse and the need for EBD was 0.77 and 0.81, respectively, with US-CD (cutoff value = 11), and that for requiring enhanced treatment was 0.74 with US-CD (cutoff value = 6). Patients with US-CD ≥ 11 demonstrated a significantly higher occurrence of clinical relapse (P= 0.001) and EBD (P= 0.002) within 5 years. Patients with US-CD ≥ 6 experienced a significantly higher likelihood of requiring enhanced treatment (P< 0.001) within 5 years. CONCLUSIONS: High US-CD is associated with subsequent adverse outcomes in patients with CD.

Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies. RESULTS: The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial. CONCLUSIONS: We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.

Safety and Efficacy of Lenvatinib in Very Old Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Data concerning the use of lenvatinib in very old patients (≥ 80 years) are limited, although the incidence of hepatocellular carcinoma (HCC) in this patient population is constantly increasing. OBJECTIVE: This analysis aimed to evaluate the efficacy and safety of lenvatinib in a large cohort of very old patients (≥ 80 years) with unresectable HCC. PATIENTS AND METHODS: The study was conducted on a cohort of 1325 patients from 46 centers in four Western and Eastern countries (Italy, Germany, Japan, and the Republic of Korea) who were undergoing first-line treatment with lenvatinib between July 2010 and February 2022. Patients were stratified according to age as very old (≥ 80 years) and not very old (< 80 years). RESULTS: The median overall survival (OS) was 15.7 months for patients < 80 years old and 18.4 months for patients ≥ 80 years old [hazard ratio (HR) = 1.02, 95% confidence interval (CI) 0.84-1.25, p = 0.8281]. Median progression free survival (PFS) was 6.3 months for patients < 80 years old and 6.5 months for patients ≥ 80 years old (HR = 1.07, 95% CI 0.91-1.25, p = 0.3954). No differences between the two study groups were found in terms of disease control rate (DCR; 80.8% versus 78.8%; p = 0.44) and response rate (RR; 38.2% versus 37.9%; p = 0.88). Patients < 80 years old experienced significantly more hand-foot skin reaction (HFSR) grade ≥ 2 and decreased appetite grade ≥ 2. Conversely, patients ≥ 80 years old experienced significantly more fatigue grade ≥ 2. In the very old group, parameters associated with prognosis were AFP, albumin-bilirubin (ALBI) grade, Barcelona Clinic Liver Cancer (BCLC), and Child-Pugh score. BCLC stage was the only independent predictor of overall survival (OS; HR = 1.59, 95% CI 1.11-2.29, p = 0.01115). CONCLUSIONS: Our study highlights the same efficacy and safety of lenvatinib between very old and not very old patients.

Establishment of a novel overlay culture method that enables immune response assessment using gastric cancer organoids.

Organoid technology, a novel 3D cell culture system, can reproduce a patient's cancer and may be a novel immunotherapy experimental model. However, currently no gastric cancer organoid (GCO) models in which the organoid and immune cells are in free contact and sufficiently react with each other exist. In this study, we aimed to create a coculture model in which immune cells can move freely and stay in contact with GCOs. We coated the bottom surface of the plate with Matrigel and adhered stem cells to the Matrigel surface, instead of completely embedding them in Matrigel to culture organoids. This method allowed GCOs to grow on the Matrigel surface while maintaining a three-dimensional structure and reproducing the characteristics of the patient's cancer. We cocultured GCOs and immune cells. Using this model, immune cells could freely move and were in sufficient contact with the cultured GCOs. Our model allowed real-time observation of the immune response and tumor destruction with time. In addition, the GCO killing assay was assessed with natural killer cells from the same patient. This organoid culture model enabled repeated evaluation of the GCO killing assay with various immune cells in vitro. We established a new experimental model that allowed free movement of immune cells and sufficient contact with GCOs. Using this model, it may be possible to predict the effects of immune checkpoint inhibitors in vitro (using GCOs) before administering them to patients.