Disease Etiology Impact on Outcomes of Hepatocellular Carcinoma Patients Treated with Atezolizumab plus Bevacizumab: A Real-World, Multicenter Study.

Introduction: The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab (A + B) is equally effective in viral and nonviral patients. Methods: We retrospectively analyzed 885 HCC patients treated with the first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% nonviral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multivariate models to explore potential differences on overall survival (OS), time-to-progression (TTP), disease control rates (DCRs) based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to the second-line treatments and outcomes were also reported and compared between etiologies. Results: Overall, no statistically significant differences were found in median OS (mOS: viral 15.9 months; nonviral 16.3 months), TTP (mTTP: viral 8.3 months; nonviral 7.2 months), and DCRs (viral 78.1%; nonviral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and nonviral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e., NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of the second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups. Conclusion: Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and nonviral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice.

A novel histopathological feature of spatial tumor-stroma distribution predicts lung squamous cell carcinoma prognosis.

We used a mathematical approach to investigate the quantitative spatial profile of cancer cells and stroma in lung squamous cell carcinoma tissues and its clinical relevance. The study enrolled 132 patients with 3-5 cm peripheral lung squamous cell carcinoma, resected at the National Cancer Center Hospital East. We utilized machine learning to segment cancer cells and stroma on cytokeratin AE1/3 immunohistochemistry images. Subsequently, a spatial form of Shannon's entropy was employed to precisely quantify the spatial distribution of cancer cells and stroma. This quantification index was defined as the spatial tumor-stroma distribution index (STSDI). The patients were classified as STSDI-low and -high groups for clinicopathological comparison. The STSDI showed no significant association with baseline clinicopathological features, including sex, age, pathological stage, and lymphovascular invasion. However, the STSDI-low group had significantly shorter recurrence-free survival (5-years RFS: 49.5% vs. 76.2%, p < 0.001) and disease-specific survival (5-years DSS: 53.6% vs. 81.5%, p < 0.001) than the STSDI-high group. In contrast, the application of Shannon's entropy without spatial consideration showed no correlation with patient outcomes. Moreover, low STSDI was an independent unfavorable predictor of tumor recurrence and disease-specific death (RFS; HR = 2.668, p < 0.005; DSS; HR = 3.057, p < 0.005), alongside the pathological stage. Further analysis showed a correlation between low STSDI and destructive growth patterns of cancer cells within tumors, potentially explaining the aggressive nature of STSDI-low tumors. In this study, we presented a novel approach for histological analysis of cancer tissues that revealed the prognostic significance of spatial tumor-stroma distribution in lung squamous cell carcinoma.

Efficacy and Safety of Durvalumab/Tremelimumab in Unresectable Hepatocellular Carcinoma as Immune Checkpoint Inhibitor Rechallenge Following Atezolizumab/Bevacizumab Treatment.

BACKGROUND: While guidelines recommend immune checkpoint inhibitor (ICI) rechallenge as second-line therapy for unresectable hepatocellular carcinoma (HCC), data supporting this remain limited, particularly regarding a standard regimen for first- and second-line treatments. Tremelimumab/durvalumab was recently approved but data on ICI rechallenge are lacking. OBJECTIVES: The purpose of this study was to evaluate the early efficacy and safety of tremelimumab/durvalumab for HCC as an ICI rechallenge following initial ICI therapy with atezolizumab/bevacizumab. PATIENTS AND METHODS: This multicenter retrospective study included patients with HCC who underwent treatment with tremelimumab/durvalumab, with relevant available clinical information. We evaluated the safety and efficacy of tremelimumab/durvalumab as ICI rechallenge following initial treatment with atezolizumab/bevacizumab. We analyzed the outcomes in patients who underwent tremelimumab/durvalumab as an ICI rechallenge and those who received tremelimumab/durvalumab as their initial ICI therapy RESULT: A total of 45 patients treated with tremelimumab/durvalumab were included, with 55.6% (25/45) undergoing ICI rechallenge. The objective-response and disease-control rates in patients who underwent ICI rechallenge were 14.3% (3/21) and 47.6% (10/21), respectively, similar to those in patients initially treated with tremelimumab/durvalumab. All patients (n = 3) who experienced the best response to progressive disease (PD) with initial atezolizumab/bevacizumab experienced PD during ICI rechallenge. The incidence rates of adverse events were similar between patient groups treated with tremelimumab/durvalumab as ICI rechallenge and initial ICI. Among patients experiencing immune-related adverse events (irAEs) with atezolizumab/bevacizumab, 75% (3/4) encountered similar irAEs during ICI rechallenge. CONCLUSION: Early safety and efficacy profiles of durvalumab/tremelimumab as ICI rechallenge are satisfactory.

Travel-associated sexually transmitted infections in Japan: An observational study using imported infectious disease registry data.

International travel is a risk factor for acquiring sexually transmitted infections (STIs) owing to factors such as increased sexual opportunities, a sense of freedom, and the allure of the sex industry. We investigated the incidence of travel-associated STIs in Japan using data from the Japan Registry for Infectious Diseases from Abroad (J-RIDA) reported by 17 participating medical institutions between October 2017 and December 2022. Data were collected on the patients' age, sex, nationality, chief complaint, whether they had visited a travel clinic before travel, travel history, and final diagnosis. Of 4545 cases of travel-associated illness reported, 52 (1.1%) were STIs. Most patients with STIs were male (81%) with a median age of 31 years. HIV (17%), genital herpes (13%), syphilis (13%), and gonorrhea (12%) were the most frequently reported STIs. Only one patient had visited a travel clinic before travel. Promoting awareness and vaccination is crucial for preventing travel-associated STIs.

Positivity of high-sensitivity HBsAg test, not previous HBV infection, indicates poor prognosis in patients with non-HBV-related HCC.

BACKGROUND AND AIMS: The prognostic impact of previous-HBV-infection (pHBV) in non-HBV-related hepatocellular carcinoma (non-HBV-related-HCC) and the prevalence, characteristics and significance of recently developed high-sensitivity HBs antigen positivity (hHBsAg+) in these patients remain unclear. We aimed to close these gaps. METHODS: We retrospectively screened patients with newly diagnosed non-HBV-related-HCC (standard HBsAg-test negative) at Hokkaido University. Patients with complete clinical information and preserved serum for hHBsAg+ were included. We evaluated the prevalence, characteristics and prognostic impact of pHBV and hHBsAg+ in non-HBV-related-HCC. RESULTS: A total of 401 non-HBV-related-HCC patients were included (288 with pHBV/113 without pHBV). In non-HBV-related-HCC, pHBV did not affect overall survival (OS). Among non-HBV-related-HCC patients with pHBV, 11.8% (34/288) were hHBsAg+ and had more advanced stages of HCC, higher AFP levels, higher vascular invasion rates, and significantly shorter OS than others (OS: 19.3 vs. 61.4 months, p = 0.012). Comparison of OS among non-HBV-related-HCC patients without pHBV (group 1), those with pHBV and without hHBsAg+ (group 2), and those with pHBV and hHBsAg+ (group 3) revealed significantly shorter OS in group 3 (19.3, 56.6 and 66.4 months in groups 1, 2 and 3, respectively; p = 0.036). Multivariate Cox regression indicated that compared with group 1, only group 3 was significantly and independently associated with shorter OS (HR: 2.044, p = 0.011). Subgroup analysis revealed that this association was particularly evident in non-HBV-related-HCC patients with non-B-non-C aetiology and advanced HCC. CONCLUSIONS: In non-HBV-related-HCC patients, hHBsAg+, not pHBV, is significantly and independently associated with poor prognosis.

Relationship between body mass index and clinical events in patients with atrial fibrillation undergoing percutaneous coronary intervention.

BACKGROUND: It is still unclear whether body mass index (BMI) affects bleeding and cardiovascular events in patients requiring oral anticoagulants (OAC) for atrial fibrillation (AF) and antiplatelet agents after percutaneous coronary intervention (PCI) for coronary artery disease (CAD). The aim of this study was to evaluate the relationship between BMI and clinical events in patients who underwent PCI under OAC therapy for AF. METHOD: This was a multicenter, observational cohort study conducted at 15 institutions in Japan. AF patients who underwent PCI with drug-eluting stents for CAD were retrospectively and prospectively included. Patients were divided into the Group 1 (BMI <21.3 kg/m2) and the Group 2 (BMI ≥21.3 kg/m2) according to the first-quartile value of BMI. The primary endpoint was net adverse clinical events (NACE), a composite of major adverse cardiovascular events (MACE) and major bleeding events within one year after index PCI procedure. RESULTS: In the 720 patients, 180 patients (25.0%) had BMI value <21.3 kg/m2. While the rates of NACE and MACE were significantly higher in the Group 1 than the counterpart (21.1% vs. 11.9%, p = 0.003 and 17.2% vs. 8.9%, p = 0.004), that of major bleeding did not differ significantly between the 2 groups (5.6% vs. 4.3%, p = 0.54). The cumulative rate of NACE and MACE was significantly higher in the Group 1 than the Group 2 (both log-rank p = 0.002), although that of major bleeding events was equivalent between the 2 groups (log-rank p = 0.41). In multivariable Cox regression analyses, while BMI value <21.3 kg/m2 was not associated with major bleeding events, that cut-off value was an independent predictor for increased NACE and MACE. CONCLUSIONS: Among the patients undergoing PCI for CAD and requiring OAC for AF, BMI value was a useful indicator to predict major adverse clinical events.

Quantification of Gremlin 1 throughout the tumor stroma using whole slide imaging and its clinicopathological significance in gastric cancer.

Gremlin 1 (GREM1) is an antagonist of bone morphogenetic protein (BMP). GREM1 is expressed in the stromal cells of various carcinomas and promotes tumor progression by suppressing BMP signaling. We designed this study to establish an evaluation strategy for GREM1 expression, focusing on the tumor stroma, and to examine its clinicopathological significance in gastric cancer (GC) progression. We employed RNA in situ hybridization (ISH) to evaluate the prognostic value of GREM1 expression in a cohort of 104 surgically resected GC cases and assessed ISH scores according to previous reports. GREM1 expression was observed in tumor stromal cells, including fibroblasts. We defined GREM1-positive cells as those expressing ISH score ≥ 3 and quantified the number of GREM1-positive cells using image analysis software. We examined the relationship between the number of GREM1-positive cells in the tumor stroma and clinicopathological features. The number of GREM1-positive cells per tumor stroma ranged from 0 to 714.7 cells/mm2 (median, 1.65 cells/mm2). We divided the 104 GC cases into GREM1-High and GREM1-Low expression groups based on the abovementioned median value. GREM1-High expression group was significantly associated with a more advanced pT grade, pN grade, lymphatic invasion, and venous invasion. Kaplan-Meier analysis showed significantly poorer survival in the GREM1-High expression group than in the GREM1-Low expression group. These results indicated that GREM1 expression in GC is localized in tumor stromal cells, and that high GREM1 expression in the tumor stroma could be a poor prognostic factor.

Trace element partitioning in a deep magma ocean and the origin of the Hf-Nd mantle array.

Crystallization in Earth's deep magma ocean could have caused trace element fractionation in the lower mantle that might be inherited to the isotopic compositions of the present-day mantle. However, the trace element partitioning has been experimentally investigated only up to the uppermost lower-mantle pressures. Here, we determined the bridgmanite/melt partition coefficients D of La, Nd, Sm, Lu, and Hf from 24 to 115 gigapascals, covering the wide pressure range of the lower mantle. Results demonstrate substantial reductions in DLu and DHf from >1 to ≪1 with increasing pressure to 91 gigapascals. We also found DLu/DHf > 1 and DSm/DNd < 1 under deep lower-mantle conditions, evolving melts toward low Lu/Hf and high Sm/Nd ratios by crystallizing bridgmanite. If residual melts form a dense hidden reservoir in the lowermost mantle, the complementary accessible mantle has the Hf and Nd isotopic compositions matching the observed terrestrial mantle array that deviates from the bulk silicate Earth reference.

Predicting lymph node recurrence in cT1-2N0 tongue squamous cell carcinoma: collaboration between artificial intelligence and pathologists.

Researchers have attempted to identify the factors involved in lymph node recurrence in cT1-2N0 tongue squamous cell carcinoma (SCC). However, studies combining histopathological and clinicopathological information in prediction models are limited. We aimed to develop a highly accurate lymph node recurrence prediction model for clinical stage T1-2, N0 (cT1-2N0) tongue SCC by integrating histopathological artificial intelligence (AI) with clinicopathological information. A dataset from 148 patients with cT1-2N0 tongue SCC was divided into training and test sets. The prediction models were constructed using AI-extracted information from whole slide images (WSIs), human-assessed clinicopathological information, and both combined. Weakly supervised learning and machine learning algorithms were used for WSIs and clinicopathological information, respectively. The combination model utilised both algorithms. Highly predictive patches from the model were analysed for histopathological features. In the test set, the areas under the receiver operating characteristic (ROC) curve for the model using WSI, clinicopathological information, and both combined were 0.826, 0.835, and 0.991, respectively. The highest area under the ROC curve was achieved with the model combining WSI and clinicopathological factors. Histopathological feature analysis showed that highly predicted patches extracted from recurrence cases exhibited significantly more tumour cells, inflammatory cells, and muscle content compared with non-recurrence cases. Moreover, patches with mixed inflammatory cells, tumour cells, and muscle were significantly more prevalent in recurrence versus non-recurrence cases. The model integrating AI-extracted histopathological and human-assessed clinicopathological information demonstrated high accuracy in predicting lymph node recurrence in patients with cT1-2N0 tongue SCC.

The SCRUM-MONSTAR Cancer-Omics Ecosystem: Striving for a Quantum Leap in Precision Medicine.

The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multi-omics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% confidence interval, 13.4-16.3), for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83).

Prognostic value of the international association for the study of lung cancer grading system and its association with the tumor microenvironment in stage I EGFR-muted lung adenocarcinoma.

INTRODUCTION: The International Association for the Study of Lung Cancer (IASLC) grading system predicts early lung adenocarcinoma outcomes. METHODS: The purpose of this study is to examine prognostic value of the IASLC grading system and its association with the tumor microenvironment (TME) in Stage I EGFR-muted lung adenocarcinoma. Based on the IASLC grading system, we compared the clinicopathological characteristics of EGFR-mutated lung adenocarcinoma (n = 296). In addition, we examined the expression level of E-cadherin in tumor cells and counted the number of tumor-infiltrating lymphocytes (TILs; CD8, CD20, CD138, and Foxp3), tumor-associated macrophages (TAMs; CD204), and cancer-associated fibroblasts (CAFs; podoplanin) using semi-automatic digital pathology image analysis. RESULTS: Recurrence-free survival (RFS) curve showed that survival of grade 3 was significantly shorter than that of grade 1 (P < 0.01) and grade 2 (P = 0.03). Multivariate analysis of RFS revealed the invasive size, lymphatic permeation, and grade 3 (P < 0.01) as independent poor prognostic factors. The number of CD204 +TAMs and PDPN+CAFs was significantly higher in grade 3 than in grade 1 or 2 (all P < 0.01). Among the intermediate grade by the predominant subtype based classification, cases classified as grade 3 by the new classification had higher number of CD204 +TAMs (P < 0.01) and PDPN+CAFs (P = 0.02) than those classified as grade 2. CONCLUSION: The IASLC grading system correlated with the outcomes of EGFR-mutated lung adenocarcinoma. Grade 3 was found to have the TME that most contributes to tumor progression, which probably explained their poor prognosis.

Prognostic significance of micronest in cancer stroma in resected lung squamous cell carcinoma.

Tumor budding in the cancer stroma has been reported to be a prognostic factor in non-small cell lung cancer. Micronest in cancer stroma (MICS) is often observed as a formation that is larger and more conspicuous than budding, but its clinicopathologic significance is unclear. In this study, we aimed to examine the clinicopathological significance of MICS in lung squamous cell carcinoma (LSqCC). A total of 198 consecutive patients with pathologically diagnosed LSqCC (anyT N0-1M0) were enrolled in this study. MICS were defined as those that met the following criteria: (1) consisting of 5-200 tumor cells or less than 200 µm in diameter and (2) more than 200 µm away from the adjacent main lesion. The prognostic impact of the presence or absence of MICS and the characteristics of MICS-forming cancer cells were evaluated by immunohistochemistry (IHC). MICS was observed in 57 patients (28.8%), and overall survival (OS) and recurrence-free survival (RFS) were significantly shorter in the MICS-positive group (OS: 44.4% vs. 84.4%, p < 0.001; RFS: 30.0% vs. 82.6%, p < 0.001). Univariate and multivariate analyses revealed that the presence of MICS was an independent poor prognostic factor for OS (hazard ratio [HR] 3.54, p < 0.001) and RFS (HR 4.99, p < 0.001). Immunohistochemistry showed that the expression levels of the cell-cell adhesion molecule E-cadherin and hypoxia-induced protein GLUT-1 were significantly decreased in cancer cells forming MICS lesions compared to the tumor component excluding MICS within the same tumor (non-MICS lesions). Our data show that MICS is a distinct morphological feature with important biological and prognostic significance.

Successful Isavuconazole Treatment for Pulmonary Mucormycosis in a Patient Intolerant to Liposomal Amphotericin B with Pharmacokinetic Insights: A Case Report.

INTRODUCTION: Mucormycosis presents a diagnostic challenge characterized by high morbidity and mortality rates due to its swift and pervasive nature, which leads to extensive tissue destruction and dissemination. Immunocompromised individuals, notably those with hematological malignancies, are at a heightened risk. First-line antifungal agents include liposomal amphotericin B (L-AMB), posaconazole, and isavuconazole (IVZ), which offer advantages, such as minimal drug interactions and a favorable safety profile. However, the necessity and efficacy of therapeutic drug monitoring (TDM) of IVZ remain unclear. CASE PRESENTATION: We report a successful case of IVZ therapy in a patient who was intolerant of L-AMB, highlighting the efficacy and pharmacokinetics of IVZ in treating pulmonary mucormycosis. Pharmacokinetic analysis revealed steady plasma IVZ concentrations, emphasizing the importance of monitoring IVZ levels, particularly in patients undergoing renal replacement therapy. CONCLUSION: This case highlights the efficacy of IVZ therapy for mucormycosis and the potential utility of TDM in a specific patient population. Further research is needed to elucidate the optimal IVZ dosing and monitoring strategies to ensure safe and efficacious treatment.

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.

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.

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.

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.