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Abstract This study evaluated the long-term efficacy and safety of the widely used drugs entecavir (ETV) and tenofovir alafenamide (TAF), as well as the incidence of HCC.A nonrandomized, prospective, observational analysis included 77 patients with chronic hepatitis B who were assigned to continue ETV or switch TAF. After 240 weeks, the mean changes in serum hepatitis B surface antigen (− 0.365 ± 0.069 log IU/mL vs. 0.301 ± 0.039 log IU/mL, p = 0.39) and hepatitis B core-related antigen (− 0.215 ± 0.092 log IU/mL vs. − 0.195 ± 0.056 log IU/mL) were not significantly different between the ETV and TAF groups. There were also no differences between the two groups in estimated glomerular filtration rate (− 5.407 ± 1.660 vs. − 2.666 ± 1.52, p = 0.240), urinary β2-microglobulin β/creatinine (ETV: 2.330 ± 0.374 at baseline and 2.335 ± 0.257 at 240 weeks; TAF: 2.720 ± 0.073 and 2.123 ± 0.310, p = 0.996 and 0.455, respectively) or urinary N-acetyl-β-D-glucosaminidase/creatinine (ETV: 0.040 ± 0.005 at baseline and 0.044 ± 0.004 at 240 weeks; TAF: 0.049 ± 0.005 and 0.053 ± 0.005, p = 0.642 and 0.684, respectively). Finally, no significant difference was found in the incidence of HCC between the ETV and TAF groups (log-rank test, p = 0.08). In conclusion, the long-term observation of this study demonstrated that ETV and TAF have comparable efficacy and safety. Clinical trial registration: UMIN000026465.

Background/Aims This study aimed to evaluate the safety and efficacy of continuous propofol infusion for anesthesia during endoscopic ultrasonography (EUS). Methods A total of 427 consecutive patients who underwent EUS between May 2018 and February 2019 were enrolled in this study. The patients were divided into two propofol infusion groups: continuous (n=207) and intermittent (n=220). The following parameters were compared: (1) propofol dose, (2) respiratory and circulatory depression, (3) body movement requiring discontinuation of the examination, (4) awakening score, and (5) patient satisfaction. Results The median total maintenance dose of propofol was significantly higher in the continuous group than in the intermittent group (160.0 mg vs. 130.0 mg, respectively); however, the reduction in SpO2 was significantly lower in the continuous group (2.9% vs. 13.2%). Body movements occurred less frequently in the continuous group than in the intermittent group (40.1% vs. 49.5%, respectively). The rate of complete awakening was significantly higher in the continuous group than in the intermittent group. Finally, there was a significant difference in the percentage of patients who answered “absolutely yes” when asked about receiving EUS again: 52.7% in the continuous group vs. 34.3% in the intermittent group. Conclusions Continuous infusion resulted in stable sedation and reduced propofol-associated risks.

Abstract Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1–3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1–3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0–2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1–2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group.

Background: Traditional tumor classifications have relied on cellular origin, pathological morphological features, gene expression profiles, and more recently, the tumor immune microenvironment. While these classifications provide valuable insights, incorporating physiological classifications focusing on liver metabolic functions may lead to new discoveries. Summary: We proposed to reclassify benign and malignant hepatocellular neoplasms based on their physiological functions such as albumin production, bile acid production, glycolysis, glycogenesis, and adipogenesis. We further demonstrated the homology between signal pathways activated by the differentiation program of the normal hepatobiliary cells and those activated by genetic abnormalities in tumors. Specifically, Wnt/β-catenin, RAS, NOTCH, and TGF-β signaling not only contribute to cell differentiation via activation of liver-enriched transcription factors but also determine the tumor traits. Examining the distinctions between hepatocellular carcinomas (HCCs) that maintain or lose metabolic functions can yield valuable insights into the drivers of biological malignancy and tumor plasticity. Key Messages: To confirm the homology between the differentiation programs of normal hepatobiliary cells, hepatocellular adenomas (HCA), and HCC we identify liver-specific functions such as catabolism and anabolism within tumors. HCCs and HCAs that have lost these metabolic functions exhibit characteristics such as dedifferentiation, resemblance to biliary cells, or increased glycolysis. Focusing on this underexplored area will likely stimulate active research into new tumor characteristics.

ABSTRACT Background Fibrolamellar hepatocellular carcinoma (FL‐HCC) clinically occurs in young people aged 20–30 years, who often have a normal liver background. We propose a treatment for such cases in which a combination therapy of atezolizumab and bevacizumab is followed by sandwiching radiation therapy to release tumor antigens and then re‐administering the combination therapy of atezolizumab and bevacizumab (ABC conversion therapy). Case The patient is a 15‐year‐old girl. On April 18, 2022, she noticed skin yellowing and visited her local doctor. Computed tomography (CT) revealed a large mass in the right lobe of the liver and bile duct obstruction due to the tumor. She also had a nodule on her chest that appeared to be a metastatic tumor and was referred to Kinki University Hospital in April 2023. She was suspected to have FL‐HCC based on contrast‐enhanced ultrasound and CT scan results. There were findings suggestive of lung metastasis; however, she underwent a right hepatic lobectomy on May 17, 2023, considering the risk of liver failure and intra‐abdominal bleeding due to the large liver tumor. A CT scan conducted on July 25, 2022, showing increased lung metastases, and she started atezolizumab/bevacizumab combination treatment on October 20, 2022. On March 15, 2023, multiple lung metastases and new intrahepatic lesions appeared, which was diagnosed as progressive disease (PD), and lenvatinib was discontinued. On November 17, 2023, radiation therapy (25 Gy/5 Fr) was administered to the lung and intrahepatic lesions to release tumor antigens, and on November 27, 2023, atezolizumab and bevacizumab combination treatment was resumed to control the tumor. Conclusion Combination therapy with atezolizumab, bevacizumab, and radiation therapy may be an option for the treatment of FL‐HCC.

Background & Aims: We compared the clinical performance of the novel GAAD (gender [biological sex], age, alpha-fetoprotein [AFP], des-gamma carboxyprothrombin [DCP]) and GALAD (gender [biological sex], age, AFP, Lens culinaris agglutinin-reactive AFP [AFP-L3], DCP) algorithms to deduce the clinical utility of AFP-L3 for detecting early-stage hepatocellular carcinoma (HCC) from chronic liver disease (CLD). Methods: An algorithm development study (STOP-HCC-ARP) and clinical validation study (STOP-HCC-MCE) were conducted, recruiting adult participants with HCC (confirmed by radiology or pathology) or CLD in an international, multicenter, case-control design. Serum biomarkers were measured using Elecsys assays (GAAD and GALAD [Cobas]) or μTASWAKO assays (GALAD [μTASWAKO]) while blinded to case/control status. Results: In STOP-HCC-ARP (algorithm development cohort), 1,006 patients {297 HCC (41.4% early-stage [Barcelona Clinic Liver Cancer {BCLC} 0/A) and 709 CLD} were included. Area under the curve (AUCs) for discriminating between early-stage HCC vs. CLD were 91.4%, 91.4%, and 90.8% for GAAD (Cobas), GALAD (Cobas), and GALAD (μTASWAKO), respectively. The clinical validation cohort of STOP-HCC-MCE comprised 1,142 patients, (366 HCC cases [48% early-stage], 468 specificity samples and 302 CLD); AUCs for GAAD (Cobas), GALAD (Cobas), and GALAD (μTASWAKO) for discriminating between early-stage HCC vs. CLD were 91.4%, 91.5%, and 91.0%, respectively; AUCs were 94.7–95.0% for all-stage HCC. The GAAD and GALAD algorithms demonstrated similar good performance regardless of disease etiology, presence of cirrhosis, geographical region, and within pan-tumor specificity panels (p

Background & Aims: Atezolizumab/bevacizumab (A/B) is now a standard first-line treatment for advanced hepatocellular carcinoma (HCC), but the optimal second-line regimen is not known. We evaluated real-world treatment patterns and outcomes to investigate factors associated with post-progression survival (PPS). Methods: In this multicenter, international, retrospective study, we examined clinical characteristics and outcomes of patients with advanced HCC who progressed on first-line A/B. The primary outcome of PPS was defined as time from first radiographic progression on A/B to death. Results: A total of 406 patients alive after progression on first-line A/B were included in the final analysis, of whom 45.3% (n = 184) received best supportive treatment (BST) and 54.7% (n = 222) continued active systemic treatment. In the second line, 155 patients were treated with tyrosine kinase inhibitors (TKIs), 45 with immune checkpoint inhibitor (IO)-based regimens, and 3 had missing data. Median PPS of the whole cohort (mPPS) was 6.0 months (95% CI 5.2-7.2). On multivariate Cox regression analysis, absence of portal vein tumor thrombus, ECOG

ABSTRACT Background Immune checkpoint inhibitors have demonstrated efficacy against various cancers; however, there is a rising incidence of immune‐related colitis. Some cases of immune‐related colitis prove resistant to treatment, even with the administration of glucocorticoids or infliximab, and there is currently no established standard treatment for such cases. Case The patient, a 73‐year‐old male, had undergone combination therapy for malignant pleural mesothelioma for 2 years, utilizing both ipilimumab (a CTLA‐4 inhibitor) and nivolumab (a PD‐1 inhibitor). Unfortunately, the treatment led to side effects, specifically immune‐related adverse event (irAE) enterocolitis. Steroid and infliximab treatment failed to improve the patient's condition. Treatment with tacrolimus was attempted, but the patient remained unresponsive. Subsequently, 45 mg of upadacitinib, a Janus kinase (JAK) inhibitor, was administered. Symptoms improved rapidly following upadacitinib administration, and endoscopy also revealed positive results. With the increasing incidence of immune‐related colitis, some patients have become resistant to treatment with glucocorticoids and infliximab. In this case, the irAE enterocolitis was improved by upadacitinib administration. Conclusion In cases where immune‐related colitis proves resistant to treatment with glucocorticoids, infliximab, or tacrolimus, upadacitinib represents a potential option as a JAK inhibitor.

Loss-of-function mutations in nucleotide-binding oligomerization domain 2 (NOD2) constitute the primary risk factors for Crohn’s disease. NOD2 is an intracellular sensor for muramyl dipeptide (MDP), a small molecule derived from the peptidoglycan layer of bacterial cell wall. Although NOD2 is involved in host immune responses, much attention has been paid to the involvement of NOD2 in the maintenance of intestinal homeostasis. Despite the fact that the proinflammatory cytokine and chemokine responses induced by NOD2 activation alone are weaker than those induced by toll-like receptors (TLRs), NOD2 plays a crucial role in host defense against invading pathogens and in the regulation of immune responses. Recent studies have highlighted the importance of negative regulatory functions of NOD2 in TLRs-mediated proinflammatory cytokine responses. MDP-mediated activation of NOD2 induces interferon regulatory factor 4 (IRF4) expression, thereby suppressing nuclear factor-κB-dependent colitogenic cytokine responses through the inhibition of Lys(K)63-linked polyubiquitination on receptor-interacting serine/threonine protein kinase 2. MDP-mediated activation of NOD2 also downregulates TLR9-induced type I IFN responses by inhibiting the K63-linked polyubiquitination of TNF receptor-associated factor 3 via deubiquitinating enzyme A (DUBA) expression. Thus, NOD2 exerts dual negative regulation of TLRs-mediated proinflammatory cytokine and type I IFN responses by inducing the expression of IRF4 and DUBA, respectively. In this review, we summarize the molecular mechanisms whereby NOD2 activation suppresses TLRs-mediated proinflammatory and type I IFN responses. In addition, we discuss the clinical relevance of the NOD2-mediated negative regulation of TLRs in inflammatory bowel disease.

Background/Aim The aim of this study was to compare the therapeutic efficacy of ablation and surgery in solitary hepatocellular carcinoma (HCC) measuring ≤5 cm with a large HCC cohort database. Methods The study included consecutive 2,067 patients with solitary HCC who were treated with either ablation (n=1,248) or surgery (n=819). Th e patients were divided into three groups based on the tumor size and compared the outcomes of the two therapies using propensity score matching. Results No significant difference in recurrence-free survival (RFS) or overall survival (OS) was found between surgery and ablation groups for tumors measuring ≤2 cm or >2 cm but ≤3 cm. For tumors measuring >3 cm but ≤5 cm, RFS was significantly better with surgery than with ablation (3.6 and 2.0 years, respectively, P=0.0297). However, no significant difference in OS was found between surgery and ablation in this group (6.7 and 6.0 years, respectively, P=0.668). Conclusion The study suggests that surgery and ablation can be equally used as a treatment for solitary HCC no more than 3 cm in diameter. For HCCs measuring 3-5 cm, the OS was not different between therapies; thus, ablation and less invasive therapy can be considered a treatment option; however, special caution should be taken to prevent recurrence.

Abstract The number of cancer cases diagnosed during the coronavirus disease 2019 (COVID-19) pandemic has decreased. This study investigated the impact of the pandemic on the clinical practice of hepatocellular carcinoma (HCC) using a novel nationwide REgistry for Advanced Liver diseases (REAL) in Japan. We retrieved data of patients initially diagnosed with HCC between January 2018 and December 2021. We adopted tumor size as the primary outcome measure and compared it between the pre-COVID-19 (2018 and 2019) and COVID-19 eras (2020 and 2021). We analyzed 13,777 patients initially diagnosed with HCC (8074 in the pre-COVID-19 era and 5703 in the COVID-19 era). The size of the maximal intrahepatic tumor did not change between the two periods (mean [SD] = 4.3 [3.6] cm and 4.4 [3.6] cm), whereas the proportion of patients with a single tumor increased slightly from 72.0 to 74.3%. HCC was diagnosed at a similar Barcelona Clinic Liver Cancer stage. However, the proportion of patients treated with systemic therapy has increased from 5.4 to 8.9%. The proportion of patients with a non-viral etiology significantly increased from 55.3 to 60.4%. Although the tumor size was significantly different among the etiologies, the subgroup analysis showed that the tumor size did not change after stratification by etiology. In conclusion, the characteristics of initially diagnosed HCC remained unchanged during the COVID-19 pandemic in Japan, regardless of differences in etiology. A robust surveillance system should be established particularly for non-B, non-C etiology to detect HCC in earlier stages.

Abstract Aim This retrospective study compared the impact of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) on the liver function in patients with hepatocellular carcinoma. Methods We included 526 patients who received Atez/Bev and 731 who received LEN March 2018 and July 2022 in this study. We conducted a 1:1 propensity‐score‐matched analysis and identified 324 patients in each group for inclusion in the present analysis. Nonlinear mixed‐effects regression models were employed, allowing for the evaluation and inclusion of cases where treatment was interrupted due to disease progression, adverse events, or loss to follow‐up. These models were used to compare the ALBI score between the Atez/Bev and LEN groups. Results Following propensity score matching, the mean ALBI scores in the Atez/Bev and LEN groups were −2.41 ± 0.40 and −2.44 ± 0.42 at baseline, and −2.17 ± 0.56 and −2.19 ± 0.58 at 12 weeks, respectively. Although the ALBI score significantly worsened during treatment in both groups (p

Background: Intrahepatic cholangiocarcinoma (iCCA) is often diagnosed at an advanced stage, leading to limited treatment options and a poor prognosis. So far, standard systemic therapy for advanced iCCA has been a combination of gemcitabine and cisplatin. However, recent advancements in the understanding of the molecular characteristics of iCCA have opened new possibilities for molecular-targeted therapies and immunotherapy. Summary: Reportedly, 9–36% of iCCA cases have an inflamed tumor immune microenvironment (TME) based on the immune gene expression signature, which is characterized by the presence of immune cells involved in anti-tumor immune responses. The majority of iCCA cases have a non-inflamed TME with a lack of effector T cells, rendering immune checkpoint inhibitors (ICIs) ineffective in these cases. Interestingly, alterations in the fibroblast growth factor receptor (FGFR2) gene and IDH1/2 gene mutations are often observed in the non-inflamed TME in iCCA. Several mechanisms have been reported for the role of driver mutations on the establishment of TME unique for iCCA. For example, IDH1/2 mutations, which cause an increase in DNA methylation, are associated with the downregulation and hypermethylation of antigen processing and presentation machinery, which may contribute to the establishment of a non-inflamed TME. Therefore, inhibitors targeting IDH1/2 may restore the DNA methylation and expression status of molecules involved in antigen presentation, potentially improving the efficacy of ICIs. FGFR inhibitors may also have the potential to modulate immunosuppressive TME by inhibitingthe suppressor of cytokine signaling 1 and activating the interferon-γ signaling as a consequence of inhibition of the FGFR signal. From this perspective, understanding the molecular characteristics of iCCA, including the TME and driver mutations, is essential for the effective application of ICIs and molecular-targeted therapies. Key Messages: Combination approaches that target both the tumor and immune system hold promise for improving the outcomes of patients with iCCA. Further research and clinical trials are needed to validate these approaches and optimize the treatment strategies for iCCA.

Introduction: Immunotherapy is becoming a promising approach for unresectable-hepatocellular carcinoma (HCC); the anti-tumor response is affected by the tumor microenvironment (TME). Although Wnt/β-catenin mutations are reported to cause non-inflamed phenotype, their role on TME remains controversial. We aimed to clarify the heterogeneity of immunophenotype in HCC with Wnt/β-catenin mutations. Methods: This study includes 152 resected HCCs; mutations in the catenin beta-1, adenomatous polyposis coli, or AXIN1, or AXIN2 genes were defined as Wnt/β-catenin mutations. With hierarchical cluster analyses, TME was classified into inflamed or non-inflamed classes based on the gene expressions associated with T-cell activation. Expression profiles of molecules related to cell differentiation and biliary-stem cell markers were compared between the TME classes to investigate whether differences in tumor traits were associated with TME. Results: Forty of 152 (26.3%) HCCs carried the Wnt/β-catenin mutations. Of these, 33 were classified as non-inflamed (33/40, 82.5%) and 7 as inflamed (7/40, 17.5%). Non-inflamed class was characterized by low number of CD3+, CD4+, and CD8+ cells on immunostaining, and high mRNA expressions of AXIN2 and GLUL, which are involved in the canonical Wnt/β-catenin signaling and hepatocyte differentiation, respectively. Non-inflamed tumors showed higher enhancement on the hepatobiliary-phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) compared to inflamed tumors. HCCs classified as inflamed class are revealed to have high numbers of CD3+, CD4+, and CD8+ tumor infiltrating lymphocytes on immunostaining. This class is associated with increased expression of anti-epithelial cell adhesion molecule and FOXM1 accompanied by upregulation of genes related to interferon-gamma signaling, dendritic cell migration, regulatory T cells, and myeloid-derived suppressor cell activation and recognized as low enhancement nodule on Gd-EOB-DTPA-enhanced MRI. Conclusion: Heterogeneity of tumor traits and TME was observed in HCC with Wnt/β-catenin mutation. The potential was indicated that tumor traits and TME are determined not only by the activation of the HNF4A but also by FOXM1, both of which are downstream transcription factor of the Wnt/β-catenin signaling pathway.

Abstract Background and Aim A multicenter, open‐label randomized Phase II trial was conducted to determine whether low‐dose gemcitabine plus nab‐paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard‐dose GnP for elderly patients with metastatic pancreatic cancer. Methods Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low‐ or standard‐dose groups with a 1:1 ratio. Patients in the low‐dose GnP group received gemcitabine at a dose of 250 mg/m2 and nab‐paclitaxel at 125 mg/m2. Results Low‐dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression‐free survival (7.3 vs 8 months) were comparable between the low‐ and standard‐dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non‐hematologic treatment‐related adverse events was comparable between the two groups. Conclusion Low‐dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events.

Abstract This analysis was conducted to inform dose selection of a combination of nivolumab plus ipilimumab for the treatment of sorafenib‐experienced patients with hepatocellular carcinoma (HCC). CheckMate 040 is an open‐label, multicohort, phase I/II trial in adults with advanced HCC that evaluated nivolumab monotherapy (0.1–10 mg/kg once every 2 weeks [q2w]) and the following three combinations of nivolumab plus ipilimumab: (1) nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (q3w) for four doses, followed by nivolumab monotherapy 240 mg q2w (arm A); (2) nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w (arm B); and (3) nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg every 6 weeks continuously (arm C). Exposure‐response relationships (efficacy and safety) were characterized using nivolumab and ipilimumab concentrations after the first dose (Cavg1) as the exposure measure. Objective tumor response (OTR) and overall survival (OS) improvements were associated with increased ipilimumab exposure (OTR: odds ratio 1.45, 95% confidence interval [CI], 1.13–1.86; OS: hazard ratio 0.86, 95% CI 0.75–0.98), but not nivolumab exposure (OTR: odds ratio 0.99, 95% CI 0.97–1.02; OS: hazard ratio 1.08, 95% CI 0.89–1.32). Hepatic treatment‐related and immune‐mediated adverse events were more common in arm A than in arms B or C. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w had the most favorable benefit:risk profile in patients with advanced HCC.

Abstract Background and Aim Serum leucine‐rich alpha‐2 glycoprotein level has been reported to be a useful biomarker in assessing mucosal healing in patients undergoing biotherapy, where mucosal lesions caused by ulcerative colitis are difficult to assess endoscopically. However, no such reports have been reported in biotherapy‐naïve cases. Methods Sixty‐eight patients with ulcerative colitis (UC) who were biotherapy‐naïve at Kindai University Hospital between October 2021 and October 2022 were enrolled. We prospectively examined the correlation between leucine‐rich alpha‐2 glycoprotein (LRG), C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR), and Geboes scores with clinical endoscopic activity using the Mayo endoscopic subscore (MES). Results Mucosal healing was achieved in 39 (57%) patients. Univariate analysis revealed that the factors associated with mucosal healing were LRG (P = 0.0024), CRP (P = 0.1078), ESR (P = 0.0372), and Geboes scores (P = 0.0075). Logistic regression analysis identified LRG and Geboes scores as independent factors associated with mucosal healing assessed using MES (P = 0.0431 for LRG and P = 0.0166 for Geboes scores). Conclusion LRG was found to be the easiest marker to monitor disease activity and mucosal inflammation in UC patients with biotherapy‐naïve cases, with a performance equivalent to that of Geboes scores.

Abstract Although prednisolone treatment is effective in Cronkhite–Canada syndrome (CCS), its mechanisms of action are poorly understood. We performed analyses of cytokine expression and fecal microbiota in a patient with the concurrent occurrence of CCS and rectal cancer, in whom regression of polyposis was achieved by prednisolone. Regression of CCS polyps was accompanied by downregulation of proinflammatory cytokine expression and alterations in microbiota composition; a decrease in Bacteroides fragilis and Peptostreptococcus anaerobius with the promotion of inflammation. We could not completely exclude the possibility that alterations in fecal microbiota composition might be influenced by the presence of advanced cancer. However, this case suggests that the administration of PSL might lead to the regression of CCS polyps through alterations in gut microbiota composition and suppression of proinflammatory cytokine responses.

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 is equally effective in viral and non-viral patients. Methods We retrospectively analyzed 885 HCC patients treated with first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% non-viral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multi-variate models to explore potential differences on overall survival (OS), time to progression (TTP), disease control rates based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to second-line treatments and outcomes were also reported and compared between etiologies. Results Overall, no statistically significant differences were found in OS (mOS: viral 15.9 months; non-viral 16.3 months), TTP (mTTP: viral 8.3 months; non-viral 7.2 months), and disease control rates (DCR: viral 78.1%; non-viral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and non-viral 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 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 non-viral 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.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73–0.86) but not in female (pooled HR 0.85; 95% CI 0.70–1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59–1.04; 1.02, 95% CI 0.80–1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

IntroductionIntrapancreatic activation of trypsinogen caused by alcohol or high-fat intake and the subsequent autodigestion of the pancreas tissues by trypsin are indispensable events in the development of acute pancreatitis. In addition to this trypsin-centered paradigm, recent studies provide evidence that innate immune responses triggered by translocation of intestinal bacteria to the pancreas due to intestinal barrier dysfunction underlie the immunopathogenesis of acute pancreatitis. Although severe acute pancreatitis is often associated with pancreatic colonization by fungi, the molecular mechanisms linking fungus-induced immune responses to the development of severe acute pancreatitis are poorly understood. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that mediates innate immune responses to fungi and bacteria. Mutations in Lrrk2 is a risk factor for Parkinson’s disease and Crohn’s disease, both of which are driven by innate immune responses to gut organisms.DiscussionIn this Minireview article, we discuss how activation of LRRK2 by the recognition of fungi induces severe acute pancreatitis.

Abstract Background Immune checkpoint inhibitors have been reported to have excellent therapeutic effects on various malignant tumors. However, immune‐related adverse events can occur, targeting various organs. Case presentation A 49‐year‐old male with lung carcinoma was started on carboplatin + pemetrexed + nivolumab (every 3 weeks) + ipilimumab (every 6 weeks), and nivolumab/ipilimumab was administered in the 3rd course. Subsequently, fever and fatigue developed, and grade 3 liver damage was also noted, so he was admitted to Kindai University Hospital. A bone marrow aspirate examination was performed on the third day of illness, and a definitive diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made. It was determined that immediate therapeutic intervention was necessary, and pulse therapy with methylprednisolone was started on the third day of illness. After 3 days of pulse treatment, a rapid recovery of platelet values, a decrease in ferritin levels, and a decrease in lactate dehydrogenase were observed. Subjective symptoms such as fever and fatigue also quickly improved. Conclusion Early diagnosis and treatment for HLH resulted in a positive response. The number of HLH cases may increase in the future due to the expansion of immune checkpoint inhibitor indications.

Introduction: RATIONALE-301 (NCT03412773) was a global, phase 3 study comparing the efficacy and safety of tislelizumab with sorafenib as first-line (1L) treatment in adult patients with unresectable hepatocellular carcinoma (HCC) that met its primary endpoint of noninferiority in overall survival (OS). This analysis compared health-related quality-of-life (HRQOL) outcomes between the arms. Methods: Systemic therapy–naive adults with HCC were randomized 1:1 to receive tislelizumab n = 342) or sorafenib (n = 332). HRQOL was assessed using EORTC QLQ-C30, QLQ-HCC18, and EQ-5D-5L. At cycles 4 and 6, a mixed model for repeated measures was performed using key prespecified patient-reported outcome (PRO) endpoints of the QLQ-C30 and the QLQ-HCC18. Time to deterioration was analyzed with the Kaplan-Meier method using the PRO endpoints. Results: At cycles 4 and 6, patients in the tislelizumab arm had better HRQOL outcomes than the patients in the sorafenib arm per mean-change differences in GHS/QOL, QLQ-C30 physical functioning and fatigue, and QLQ-HCC18 symptom index; however, no differences for pain were observed. Patients in the tislelizumab arm had lower risk of deterioration in GHS/QOL (HR, 0.68; 95% CI, 0.49-0.94), QLQ-C30 physical functioning (HR, 0.46; 95% CI, 0.33-0.64) and fatigue (HR, 0.48; 95% CI, 0.37-0.63), QLQ-HCC18 symptom index (HR, 0.53; 95% CI, 0.34-0.81), and HCC-specific fatigue (HR, 0.60; 95% CI, 0.46-0.80). For pain, both arms had similar risk of deterioration (HR, 0.78; 95% CI, 0.56-1.09). At cycle 4 and 6, patients in the tislelizumab arm maintained in EQ-5D-5L visual analog scale, whereas scores decreased for the patients in the sorafenib arm. Conclusion: Patients with 1L HCC treated with tislelizumab had better HRQOL outcomes compared with patients treated with sorafenib, particularly in fatigue and physical functioning. These results, along with favorable safety profile, better response rate, and OS noninferiority, support tislelizumab as a potential 1L treatment option for unresectable HCC.

Introduction: In REFLECT, lenvatinib was noninferior to sorafenib in terms of overall survival (OS) in patients with unresectable hepatocellular carcinoma (uHCC; median 13.6 vs 12.3 months; HR 0.92, 95% CI 0.79-1.06). The objective response rate (ORR) with lenvatinib was 18.8% by blinded independent imaging review (IIR) per Response Evaluation Criteria in Solid tumors version 1.1 (RECIST v1.1); per modified RECIST (mRECIST), the ORR was 40.6%. We sought to further characterize these tumor responses and explore ORR’s importance among outcomes for patients with HCC. Methods: Efficacy assessments included all patients randomized to receive lenvatinib treatment (body weight ≥60 kg, 12 mg/day;

Clostridium perfringens bacteremia is a rare but rapidly fatal condition, especially in patients exhibiting massive intravascular hemolysis (MIH), gas gangrene, and septic shock. Herein, we present an autopsy case of C. perfringens septicemia exhibiting MIH, gas gangrene, and cytokine storm. The patient was an 84-year-old female with a history of biliary reconstruction surgery for congenital biliary dilatation. She developed MIH, elevated inflammatory mediator levels, thrombocytopenia, and coagulopathy. She went into shock within 1 h of the presentation and died within a few hours. Rapid progression was associated with the transformation of liver abscesses into gas-filled abscesses on computed tomography scan, suggesting the rapid outgrowth of gas-producing bacteria. The patient was finally diagnosed with MIH and gas gangrene due to C. perfringens infection based on the presence of this bacterium in the blood and bile. On autopsy, gas gangrene was observed in almost all organs, originating from the bile duct. Polymerase chain reactions targeting C. perfringens toxins identified the isolated bacterium as C. perfringens type A expressing α-toxin (CPA), perfringolysin O (PFO), and collagenase (ColA). Elevated interleukin 6 and tumor necrosis factor-α expression levels were observed in the serum, and such proinflammatory responses were partially mediated by Toll-like receptor 2. This study elucidated the association between the toxin profiles of clinically isolated C. perfringens and the host cytokine responses in the patient.

Background: Treatment with lenvatinib (dosing for patients who weigh ≥60 kg was 12 mg/day; for patients who weigh

With the development of more advanced methods for the diagnosis and treatment of diseases, the data required for medical care are becoming complex, and misinterpretation of information due to human error may result in serious consequences. Human error can be avoided with the support of artificial intelligence (AI). AI models trained with various medical data for diagnosis and management of liver diseases have been applied to hepatitis, fatty liver disease, liver cirrhosis, and liver cancer. Some of these models have been reported to outperform human experts in terms of performance, indicating their potential for supporting clinical practice given their high-speed output. This paper summarizes the recent advances in AI for liver disease and introduces the AI-aided diagnosis of liver tumors using B-mode ultrasonography.

Abstract Background/Aim A comparison of therapeutic efficacy between atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib treatment given as first‐line therapy for unresectable hepatocellular carcinoma (u‐HCC) in regard to progression‐free survival (PFS) overall survival (OS) has not been reported. We aimed to elucidate which of those given as initial treatment for u‐HCC has greater prognostic impact on PFS and OS of affected patients, retrospectively. Materials/Methods From 2020 to January 2022, 251 u‐HCC (Child–Pugh A, ECOG PS 0/1, BCLC‐B/C) treated were enrolled (Atez/Bev‐group, n = 194; lenvatinib‐group, n = 57). PFS and OS were analyzed following adjustment based on inverse probability weighting (IPW). Results There was a greater number of patients with macro‐vascular invasion in Atez/Bev‐group (22.7% vs. 8.8%, p = 0.022). In lenvatinib‐group, the frequencies of appetite loss (38.6% vs. 19.6%, p = 0.002), hypothyroidism (21.1% vs. 6.7%, p = 0.004), hand foot skin reaction (19.3% vs. 1.0%, p

Abstract Background Lenvatinib was approved for use in unresectable hepatocellular carcinoma (uHCC) in Japan in 2018. Patients with diverse clinical characteristics receive lenvatinib treatment in clinical practice. Thus, it is crucial to evaluate the safety and effectiveness of lenvatinib in real-world clinical settings. Objective This study aimed to evaluate the real-world safety and effectiveness of lenvatinib for uHCC in clinical practice in Japan. Patients and Methods Between July 2018 and January 2019, patients with uHCC who were administered lenvatinib for the first time were enrolled in this prospective, multicenter, observational post-marketing study (NCT03663114). Patients were orally administered lenvatinib and followed up for 12 months. For safety, adverse drug reactions (ADRs) were evaluated. For effectiveness, the objective response rate (ORR) was calculated to evaluate tumor response. Overall survival (OS) was estimated using the Kaplan–Meier method. Results Data of 703 patients (median age, 73 years; 80.2% males) were analyzed. The median (range) treatment duration was 25.3 (0.3–68.9) weeks. The mean ± standard deviation initial dose was 7.37 ± 1.65 mg in patients with body weight 10%) were decreased appetite, fatigue, hypertension, proteinuria, palmar-plantar erythrodysesthesia, hypothyroidism, and diarrhea. The median OS of the 703 patients was 498.0 days. In 494 patients assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), the ORR was 39.5% (95% confidence interval: 35.1–43.9%). Patients with better liver or renal function at baseline achieved significantly higher ORR than those with worse liver or renal function. Conclusions In patients with uHCC in real-world clinical practice in Japan, treatment with lenvatinib was generally well tolerated, and no new safety concerns were identified. The ORR and median OS were similar to or better than the results of the Japanese subset of the global Phase III REFLECT trial. Our results demonstrated that clinically meaningful treatment responses were achieved with lenvatinib in real-world clinical practice.

Introduction: Ustekinumab is an IgG1 kappa monoclonal antibody directed against the common p40 subunit of interleukin-12 and interleukin-23, which activate Th1- and Th17-mediated immune responses, respectively. It has proven efficacy for the treatment of moderate to severe ulcerative colitis (UC) in the UNIFI Phase III clinical trial; however, data on its efficacy in the real world is limited. In this study, we aimed to assess the real-world efficacy of ustekinumab. Methods: This observational study included 30 patients with UC who received ustekinumab from April 2020 to April 2022. We examined demographic information, disease type and activity (Mayo score, partial Mayo score [PMS]), use of biologics, concomitant use of predonisolone (PSL), 8-week ustekinumab clinical response rate, remission induction rate, 44- and 152-week remission maintenance rate, continuation rate, and 44-week steroid-free remission rate. The primary outcomes were the short- and long-term efficacy of ustekinumab. Results: Included patients (53% women; mean age: 41.2 years [16–80 years]) had an average disease duration of 86 weeks. Mayo’s score (median) was 7.4 and the PMS was 5.4. Two (7%), 24 (80%), and four (13%) patients had a Mayo endoscopic sub-score (MES) of MES1, MES2, and MES3, respectively. The median serum CRP was 1.0 mg/dL. Five patients had no history of biotherapy (naive), while 8 and 17 had a history of one and two or more biologic agents, respectively. Eight patients were PSL-resistant and 22 were PSL-dependent. The 8-week clinical response rate was 73%, and the clinical remission induction rate was 70%. The remission maintenance rates at 44 and 152 weeks were 67% and 63%, respectively. The ustekinumab retention rate was 67% (86-week mean follow-up period). Regarding biologic failure cases, the clinical response rate in the failure group with up to one biologic agent (including naive cases) was 84.6%, which was higher than the 58.0% rate in the failure group with two or more biologic agents (p=0.06). Steroid-free remission rates at 44 and 152 weeks were 63% each. In the logistic regression analysis parameters for discontinuation of ustekinumab, only PMS remained significant after multivariate analysis (p=0.018). Conclusion: Our study showed short-term and long-term ustekinumab effectiveness, especially with comparative low disease activity.

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The double-guidewire method has been increasingly used in endoscopic procedures for biliary and pancreatic diseases in recent years, including endoscopic retrograde cholangiopancreatography and endoscopic ultrasonography-related procedures. In addition, double-lumen catheters with uneven distal and proximal lumen openings have been introduced, making it possible to easily create a double-guidewire situation, and the usefulness of the double-guidewire technique using uneven double-lumen cannulas has been widely reported. Although the advantages of using two guidewires depend on the particular situation and the appropriate use of the two guidewires, deepening the knowledge of the double-guidewire method will contribute greatly to troubleshooting in daily practice. In this review, the usefulness of the double-guidewire technique is discussed with respect to two main areas: selective insertion of guidewires and devices and biliary cannulation.

Background & aims: The objective of this systematic literature review (SLR) and network meta-analysis (NMA) is to compare randomised controlled trial evidence for atezolizumab-bevacizumab with globally relevant pharmacological comparators for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Methods: Randomised controlled trials investigating first-line treatment of HCC in adults with no prior systemic treatment were eligible for inclusion into the SLR and were retrieved from Embase, MEDLINE, and Evidence Based Medicine (EBM) Reviews. Interventions of interest for the NMA included atezolizumab-bevacizumab, sorafenib, lenvatinib, durvalumab (including in combination with tremelimumab), cabozantinib (including in combination with atezolizumab), camrelizumab (including in combination with rivoceranib), pembrolizumab (including in combination with lenvatinib) and tislelizumab. Random effects NMA was conducted for survival endpoints within a Bayesian framework with an informative prior distribution for between study heterogeneity. The hazard ratios for relative treatment effect were estimated with 95% credible intervals (CrIs). Results: The SLR identified 49 studies, of which eight formed a connected evidence network permitting the indirect treatment comparison of atezolizumab-bevacizumab with comparators of interest. The indirect comparisons suggested an improved overall survival (OS) with atezolizumab-bevacizumab versus most comparators. All indirect treatment comparison results for atezolizumab-bevacizumab included the null value within the 95% CrI (n=1) for OS and progression free survival (PFS). Conclusions: The results of the NMA indicate atezolizumab-bevacizumab is associated with superior or comparable OS and PFS together with a manageable safety profile compared with globally relevant comparators in the unresected HCC indication. The findings support that atezolizumab-bevacizumab remains standard of care for the management of first-line unresectable HCC patients.

Background: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present phase II, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better ORR than sorafenib (jRCTs031180074). Patients and Methods: Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy, and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14–21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child-Pugh A liver function, 0–2 prior TACE sessions, tumor size ≤10 cm, number of tumors ≤10, and ECOG performance status 0–1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was PFS by RECICL, and secondary endpoints were time to untreatable progression, objective response rate (ORR), OS, and safety. Results: A total of 62 HCC patients were enrolled in this trial. The median age was 72 years, 77.4% of patients were men, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (95% CI 25.1–31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (95% CI 35.5 months–NR). LEN-TACE achieved a high response rate and high CR rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR) were similar, and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the nonsimple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR/ORR by LEN-TACE. No new safety concerns were observed. Conclusion: The results of this trial provide encouraging evidence supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy.

Introduction Programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) signaling blockade is the most effective strategy for the treatment of immune evading hepatocellular carcinoma (HCC). While immune checkpoint inhibitor (ICI) has revolutionized the concept of cancer treatment, it has also led to unexpected tumor growth. Regulatory T cells express PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptors, which are proliferated and activated by antibody binding, and their ratio to CD8+ T cells is altered, which is one of the causes for hyper progressive disease (HPD). We examined the frequency of HPD in anti-PD-1/PD-L1 monotherapy and combination therapy with vascular endothelial growth factor (VEGF) antibody and anti-CTLA-4 antibodies. Methods This was a prospective and retrospective cohort study which enrolled 198 patients with unresectable HCC from January, 2015 to December, 2021 at the Kindai University Hospital. Fifty-eight patients received anti-PD-1/PD-L1 monotherapy, 119 patients combination with VEGF antibody, and 21 patients combination with anti-CTLA-4 antibody. We defined HPD as tumor growth rate (TGR) ratio ≥4, ΔTGR ≥40% and tumor growth kinetics ratio ≥4. Results The HPD rate was 10.3% (6/58) in anti-PD-1/PD-L1 monotherapy, 1.7% (2/119) in combination with VEGF antibody, and 4.8% (1/21) in combination with anti-CTLA-4 antibody (P=0.034). The odds ratio for HPD in the combined anti-CTLA-4 antibody group was 0.433 (95% CI: 0.05-3.83) when compared to the anti-PD-1/PD-L1 monotherapy group, and 2.93 (95% CI: 0.25-33.79) when compared to the combined VEGF antibody group. Conclusion The frequency of HPD in unresectable HCC compared to anti-PD-1/PD-L1 monotherapy was decreased with the combination with anti-VEGF antibody, and not increased with anti-CTLA-4 antibody. Anti-PD-1/PD-L1 combined with anti-CTLA-4 antibody is now available in real-world and needs to be further validated with accumulated clinical practice.