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Aim: Elderly patients are believed to have a reduced immune capacity, which may make immunotherapy less effective. The aim of this study was to compare the therapeutic outcome of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) for advanced hepatocellular carcinoma (HCC) in patients aged 80 years and older. Methods: From March 2018 to July 2022, 170 and 92 elderly patients who received LEN and Atez/Bev as first‐line treatment, respectively, were retrospectively analyzed. Results: The median ages of the Atez/Bev and LEN groups were 83.0 (8.01–86.0) and 83.0 (82.0–86.0) years (p = 0.3), respectively. Men accounted for approximately 70% of the patients in both groups. The objective response rate was 35.9% in the LEN group and 33.7% in the Atez/Bev group (p = 0.8), whereas the disease control rates in the LEN and Atez/Bev groups were 62.9% and 63.0%, respectively (p = 1.0). The median progression‐free survival (PFS) in the LEN and Atez/Bev groups was 6.3 and 7.2 months, respectively, which were not significantly different (p = 0.2). The median overall survival (OS) was 17.9 months in the LEN group and 14.0 months in the Atez/Bev group. This difference was not statistically significant (p = 0.7). In multivariate analyses, the choice of treatment (LEN vs. Atez/Bev) showed no association with PFS or OS. The Atez/Bev group had a significantly higher rate of postprogression treatment (59.0% vs. 35.7%, p = 0.01) and a lower rate of discontinuation due to adverse events (69 [40.6%] vs. 19 [20.7%], p < 0.001) compared to the LEN group. Conclusions: Atezolizumab plus bevacizumab showed comparable effectiveness to LEN in HCC patients aged 80 years and older. Given the results of postprogression treatment and discontinuation due to adverse events, Atez/Bev could serve as a first‐line treatment even for elderly HCC patients. [ABSTRACT FROM AUTHOR]

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 < 0.001), there was no significant difference in the rate of ALBI score deterioration between the groups (p = 0.06). Subgroup analyses showed that LEN‐treated patients with BCLC advanced stage (p = 0.02) and those who initially received the full dose (p < 0.001) had a significantly greater worsening of ALBI score compared to Atez/Bev. Conclusions: Using a nonlinear mixed‐effects regression approach, which allowed for the inclusion of cases with treatment interruption, we found no significant difference in the trend of liver function deterioration between the Atez/Bev and LEN groups. Caution should be exercised for LEN‐treated patients with BCLC advanced stage or those receiving the full dose of LEN. [ABSTRACT FROM AUTHOR]

Aim: This retrospective study aimed to investigate the impact of proton pump inhibitor treatment (PPI) and antibiotic treatment on the therapeutic outcomes of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev). Methods: The present study included a total of 441 HCC patients who were treated with Atez/Bev in 20 Japanese institutions from September 2020 to April 2022. We adopted the inverse probability of treatment weight to adjust for imbalance in the baseline characteristics of patients with and without PPI treatment as well as patients with and without antibiotic treatment. Results: The progression‐free survival (PFS) and overall survival (OS) of patients with and without PPI treatment did not differ to a statistically significant extent. In the weighted cohort, the difference in PFS and OS between the patients with and without PPI did not reach statistical significance (median PFS, 7.0 vs. 6.5 months, p = 0.07; 1‐year survival rate 66.3% and 73.8%, p = 0.9). The PFS and OS in patients with antibiotic treatment were worse in comparison to patients without antibiotic treatment (median PFS, 3.8 vs. 7.0 months, p = 0.007; 1‐year survival rate 58.8% and 70.3%, p = 0.01). In the weighted cohort, the PFS and OS of the two groups did not differ to a statistically significant extent (median PFS, 3.8 vs. 6.7 months, p = 0.2; 1‐year survival rate, 61.8% and 71.0%, p = 0.6). Conclusions: The therapeutic outcomes of Atez/Bev in HCC patients did not differ between patients with and without PPI treatment or between patients with and without antibiotic treatment. [ABSTRACT FROM AUTHOR]

Aim: This study compared the efficacy and safety of atezolizumab and bevacizumab (Atez/Bev) in patients with viral and non‐viral infection in clinical settings. Methods: We conducted the retrospective cohort study of 323 BCLC stage B or C hepatocellular carcinoma (HCC) patients with Child‐Pugh class A, and a performance status of 0 or 1 who started Atez/Bev from September 2020 to December 2021 at 22 institutions in Japan. Patients with viral infection was defined as those who were either serum anti‐HCV‐ Ab or HBs‐Ag‐positive, while patients with non‐viral infection was defined as those who were both serum anti‐HCV Ab‐ and HBs‐Ag‐negative. We constructed a propensity‐score‐matched cohort to minimize the risk of observable potential confounders. Results: Propensity score matching produced 126 matched pairs for patients with viral versus non‐viral infection. After matching, the significant differences in baseline demographic features did not exist between the two groups. The objective response rate was 20.6% and 24.6% in viral‐ and non‐viral‐related HCC patients, respectively, without a significant difference (p = 0.55). The disease control rate was not also significantly different (68.3% vs 69.0%, p = 1.00). The median progression‐free survival was 7.0 months (95% confidence interval [CI] 6.0–9.6) and 6.2 months (95% CI 5.1–7.8) in patients with viral and non‐viral infection, and the 12‐month survival rates were 65.5% (95% CI 50.8–76.8) and 71.7% (95% CI 57.3–81.9) in those with viral and non‐viral infection, respectively, which were not significantly different (p = 0.33, p = 0.38). No significant difference in treatment‐related adverse events was found between the two groups. Conclusions: Our etiology‐based study demonstrated that Atez/Bev showed good efficacy and safety for HCC patient with non‐viral infection as well as those with viral infection. [ABSTRACT FROM AUTHOR]

Aims: This retrospective study compared the survival between elderly and non‐elderly patients. Methods: A total of 5545 treatment‐naive patients with hepatocellular carcinoma (HCC) who visited 7 different hospitals from January 2000 to December 2018 were included. Patients ≥80 years old were defined as elderly patients. We divided the patients into three groups based on the timing of the initial treatment: Early, middle, and late periods defined as 2000 to 2005, 2006 to 2012, and 2013 to 2018, respectively. Results: There were 132 (8.9%), 405 (17.5%), and 388 (22.2%) elderly patients in the early, middle, and late period, respectively, showing a significant increase over time (p < 0.001). In both elderly and non‐elderly patients, the median albumin‐bilirubin score significantly improved over time and the diagnosis of HCC was made slightly earlier over time. The median overall survival (OS) in elderly patients was 52.8, 42.0, and 45.6 months in the early, middle, and late period, respectively, without a significant improvement (p = 0.17) whereas the OS in non‐elderly patients was significantly improved (p < 0.001). The percentage of elderly patients receiving curative treatments did not significantly increase (p = 0.43), while that of non‐elderly patients did (p = 0.017). Non‐liver‐related death in elderly patients significantly differed among periods (p = 0.023), while liver‐related death did not (p = 0.050). Liver‐ and non‐liver‐related death in non‐elderly patients significantly differed among periods (p < 0.001, p = 0.005). Conclusions: Survival in elderly patients was not improved despite an improvement in their liver function. Curative treatments should be conducted when appropriate after evaluating each elderly patient. [ABSTRACT FROM AUTHOR]

Aim: Atezolizumab plus bevacizumab (atezo + bev) shows a good overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients. However, the OS of patients with nonviral infection is quite worse than that in those with viral infection. The present study investigated the efficacy and safety of lenvatinib in patients with nonviral infection, who were unlikely to obtain benefit from atezo + bev. Methods: We conducted a multicenter retrospective study that included 139 advanced HCC patients treated with lenvatinib between March 2018 and September 2020. Results: The median age was 72 years, and 116 patients (83.5%) were male. Based on the etiology of liver disease, 84 (60.4%) and 55 patients (39.6%) were assigned to the viral infection and nonviral infection groups, respectively. The significant extents in patient characteristics were not observed in both groups. The objective response rate per mRECIST and progression-free survival (PFS) did not differ significantly between the viral infection and nonviral infection groups (36.0 vs. 33.0%, p = 0.85; and 7.6 vs. 7.5 months, p = 0.94, respectively). The 1-year survival rates were 68.7% (95% confidence interval [CI] 57.7–79.7%) in the viral infection group and 59.5% (95% CI 45.2–73.8%) in the nonviral infection group. The viral infection group was not a significant factor associated with the PFS or OS in a multivariate analysis. Conclusions: Lenvatinib shows no significant difference in response between patients with and without viral infection. Treatment strategies based on the etiology of liver disease may lead to good clinical outcome. [ABSTRACT FROM AUTHOR]

Noonan syndrome is a genetic multisystem disorder and is associated with mutation of genes encoding the proteins in the RAS‐MAPK pathway. We reported the first case of Noonan syndrome complicated with hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the predictive factors of objective response rate (ORR) and progression‐free survival (PFS), and the correlation of albumin‐bilirubin (ALBI) grade with decreased appetite and fatigue in hepatocellular carcinoma patients treated with lenvatinib. Methods: From March 2018 to December 2018, a total of 94 patients was included in this retrospective multicenter study. Results: The median age of all patients was 73 years (interquartile range 66–79.3 years), and approximately 78% patients were men. The ALBI grade was 1, 2, and 3 in 27 (28.7%), 64 (68.1%), and three patients (3.2%), respectively. The Barcelona Clinic Liver Cancer stage was early, intermediate, and advanced in one (1.1%), 22 (23.4%), and 71 patients (75.5%), respectively. Best radiological response was determined to complete response, partial response, stable disease, and progressive disease in 0 (0.0%), 24 (30.4%), 38 (48.1%), and 17 patients (21.5%), respectively, giving the ORR of 30.4%. The 3‐, 6‐, and 12‐month PFS was calculated to be 78.7% (95% CI 70.3–87.1%), 46.7% (95% CI 36.1–57.3%), and 17.4% (95% CI 6.6–28.2%). Multivariate analysis showed that the Barcelona Clinic Liver Cancer intermediate stage was shown to be the only significant factor affecting the ORR (odds ratio 3.78, 95% CI 1.14–12.5, P = 0.030) and PFS (hazard ratio 0.49, 95% CI 0.26–0.94, P = 0.030). The incidence of all grades of decreased appetite and fatigue was significantly less in patients with ALBI grade 1 compared with ALBI grade 2 + 3. Conclusions: The Barcelona Clinic Liver Cancer intermediate stage was the predictive factor affecting the ORR and PFS, and ALBI grade was a good predictive factor affecting the incidence of fatigue and decreased appetite. [ABSTRACT FROM AUTHOR]

Aim: In patients with hepatitis C virus, treatment failure of daclatasvir plus asunaprevir combination therapy (DCV + ASV) seems to become intractable due to the induction of resistance‐associated substitutions. This study aimed to investigate the outcomes of retreatment with direct‐acting antivirals (DAAs) in patients with DCV + ASV therapy failure, as well as changes in drug resistance mutations. Methods: We retrospectively analyzed 44 patients re‐treated with DAAs after DCV + ASV failure between December 2015 and April 2018. All patients were analyzed for amino acid substitutions, and additional treatment regimens were selected based on the results and current treatment guidelines. Results: The sustained virological response rate with second‐line treatment was 81.8% (36/44), and relapse occurred in five of 16 patients who received sofosbuvir/ledipasvir and three of seven patients who received DCV/ASV/beclabuvir. Third‐ and fourth‐line treatments were also tried in relapsed cases, and the overall sustained virological response rates were 90.9% (40/44) and 93.2% (41/44), respectively. A high rate of viral clearance was eventually observed. Before second‐line treatment, the prevalence of mutations in the NS5A and NS3/4A regions was 100% (44/44) and 86.4% (38/44), respectively. There was no significant increase in the number of amino acid substitutions in patients for whom second‐line treatment failed. Conclusions: Amino acid substitutions were frequently observed in patients with DCV + ASV failure, but most patients achieved a sustained virological response after retreatment with DAAs. Although the spread of drug‐resistant viruses due to unsuccessful DAA treatment was a matter of concern, most cases of DCV + ASV failure were overcome with additional treatment. [ABSTRACT FROM AUTHOR]

Nuclear receptors (NR) collectively regulate several biological functions in various organs. While NRs can be characterized by activation of the transcription of their signature genes, they also have other diverse roles. Although most NRs are directly activated by ligand binding, which induces cascades of events leading to gene transcription, some NRs are also phosphorylated. Despite extensive investigations, primarily focusing on unique phosphorylation of amino acid residues in different NRs, the role of phosphorylation in the biological activity of NRs in vivo has not been firmly established. Recent studies on the phosphorylation of conserved phosphorylation motifs within the DNA- and ligand-binding domains confirmed has indicated the physiologically relevance of NR phosphorylation. This review focuses on estrogen and androgen receptors, and highlights the concept of phosphorylation as a drug target. [ABSTRACT FROM AUTHOR]

Background: Patients with morbid obesity selected for bariatric surgery have a high prevalence of nonalcoholic steatohepatitis (NASH); however, the incidence is varied and depends on race. The prevalence of NASH in obese Japanese patients is unknown. We evaluated the prevalence of NASH in a prospective cohort of Japanese patients with morbid obesity.Methods: From October 2009 to July 2011, consecutive patients requiring bariatric surgery underwent a liver biopsy during the operation. The indications for bariatric surgery followed the guidelines of the Asia-Pacific Metabolic and Bariatric Surgery Society.Results: One hundred two patients (55 males and 47 females, age 42.7 ± 10.7 years) were analyzed. The mean body mass index was 42.1 ± 8.2 kg/m(2). Among the 102 patients, 84 patients (82.4%) had nonalcoholic fatty liver disease and 79 patients (77.5%) had NASH. The grading and staging of NASH by Brunt's classification were as follows: grade 0 steatosis, one patient; grade 1 steatosis, 35 patients; grade 2 steatosis, 32 patients; grade 3 steatosis, 11 patients; stage 1 fibrosis, 25 patients; stage 2 fibrosis, 38 patients; stage 3 fibrosis, 16 patients, stage 4 fibrosis, no patients. The body weight, waist-hip ratio, visceral fat area, and aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, fasting plasma glucose, fasting plasma insulin, C peptide, hemoglobin A1c, and homeostasis model assessment insulin resistance levels were significantly elevated in the NASH group in comparison with the non-NASH group. The platelet count was significantly decreased in the NASH group. The waist-hip ratio and the alanine aminotransferase, fasting plasma glucose, and homeostasis model assessment insulin resistance levels were found to be independent predictors of NASH in a multivariate analysis.Conclusion: The prevalence of NASH was 77.5% in this prospective Japanese cohort. The prevalence of NASH in Japanese morbidly obese patients was extremely high, and early intervention should be undertaken. [ABSTRACT FROM AUTHOR]

Aim Amino acid transporters play an important role in tumor progression and survival of cancer cells. However, the prognostic significance of L-type amino acid transporter 1 ( LAT1), system ASC amino acid transporter-2 ( ASCT2) and xCT expression in patients with hepatocellular carcinoma ( HCC) remains unclear. The aim of this study is to investigate the clinicopathological significance of these amino acid transporters in patients with HCC. Methods We examined 84 patients with surgically resected HCC. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/ CD98hc ( 4F2hc), Ki-67 and microvessel density ( MVD) determined by CD34. Results LAT1, 4F2hc, ASCT2 and xCT were positively expressed in 61% (50/84), 77% (65/84), 63% (53/84) and 65% (55/84), respectively. Positive LAT1 expression was significantly associated with 4F2hc expression, Ki-67 and the serum albumin. By univariate analysis, LAT1 expression, disease stage and albumin had a significant relationship with overall survival. Tumor size, disease stage, portal vein invasion, albumin and α-fetoprotein had a significant relationship with progression-free survival. Multivariate analysis confirmed that LAT1 expression is an independent and significant prognostic factor for predicting worse outcome after surgery. Conclusion LAT1 can serve as a significant prognostic marker for predicting negative prognosis after surgery. [ABSTRACT FROM AUTHOR]

Background and Aims The Japan Society for Dialysis Therapy established ' Guidelines for the Treatment of Hepatitis C Virus Infection in Dialysis Patients.' We evaluated the status of HCV infection and the treatment of hemodialysis patients in Gunma prefecture. Methods Questionnaires concerning the infection rate, recognition of the guidelines, and treatment status were sent to all 64 hospitals/clinics that had hemodialysis systems in Gunma prefecture. The hepatitis C virus-infected hemodialysis patients who received pegylated interferon (peg- IFN) were analyzed at Gunma University Hospital. Results The positive rate for hepatitis C virus antibody was 256/2582 hemodialysis patients (9.9%). The positive rate varied between institutions (range 0-40.0%; median 9.0%). All institutes recognized the establishment of the guidelines. Conventional or peg- IFN treatment was being given at 37.5% of the institutions. The other 62.5% institutions answered that they intended to provide the treatment in the future if collaboration with a hepatologist could be arranged. The most common answers regarding the indication for IFN treatment were as follows: few complications, under 60 years of age, more than 10 years of survival expected on hemodialysis. Eighteen patients received peg- IFN treatment. The sustained virological response rate of all patients was 33.3%, 0% in 1b/high viral titer, 50% in genotype 2, and 100% in genotype 2/low viral titer. The sustained virological response rate was worse in the patients with 1b/high viral load and diabetic nephropathy ( P < 0.05). Conclusions Recognition of the publication of the guidelines was high. However, the number of patients treated with peg- IFN was still low. Further enlightenment and cooperation between hemodialysis teams and hepatologists are therefore needed. [ABSTRACT FROM AUTHOR]

Abstract: Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are key regulators of drug-metabolizing enzymes and transporters. These two receptors are closely associated with each other and also have overlapping functions. This study investigated the overall hepatic gene expression profiles and the regulatory roles of these nuclear receptors using CAR/PXR single and double knockout mice. Basal and ligand-stimulated gene expression profiles were obtained in each mouse using cDNA microarrays and a reverse transcriptase–polymerase chain reaction. Enzymes such as Cyp2b10, Cyp3a11, Cdc20 and Cdk1 displayed both CAR- and PXR-dependent induction. Inversely, enzymes such as Cyp4a10, Fos and Mme displayed both CAR- and PXR-dependent repression. Enzymes such as Cyp1a1, Cyp1a2 and c-Myc represented the group of genes only induced by CAR. Enzymes such as Aacs represented the group of genes induced only by the PXR. CAR and PXR are closely associated and have diverse roles, both as positive and negative regulators of hepatic genes including xenobiotic metabolism, apoptosis, cholesterol biosynthesis, lipid metabolism, and cytokine signaling pathways. [Copyright &y& Elsevier]

Background and Aim: This study evaluated whether the assessment of hepatitis C virus (HCV)-RNA at 12 weeks (FW+12) post-treatment follow-up was as applicable as FW+24 to evaluate sustained virological response (SVR) using the highly sensitive real-time polymerase chain reaction (PCR) HCV assay. Methods and Results: Two hundred and twenty-two patients with chronic hepatitis C were included in this study. Pegylated interferon (Peg-IFN) and ribavirin were administered for 24-72 weeks based on the genotype and viral load. Serum HCV-RNA was measured using real-time PCR at pretreatment, the end of treatment, FW+4, FW+8, FW+12, FW+16, FW+20 and FW+24. Two hundred patients had a virological response at the end of treatment. One hundred and forty-eight of 200 (74.0%) patients with a virological response at the end of treatment had an SVR at the FW+24. The positive predictive value (PPV) to identify patients with SVR at FW+4, FW+8, FW+12 was 87.1, 96.1, 98.0%, respectively. The viral load showed a reversion to the basal level as early as 8 weeks in relapse patients. There were only three patients who relapsed after FW+12 and all three of these patients were females with genotype Ib and a high viral load. Conclusion: The assessment of serum HCV-RNA FW+12, using the highly sensitive real-time PCR assay, is almost as effective as FW+24 to predict SVR. However, there are false negatives in female patients with a high viral load of genotype Ib when the SVR is predicted by FW+12. The current standard with FW+24 is reasonable, but the assessment of serum HCV-RNA FW+12 may be effective in most patients. [ABSTRACT FROM AUTHOR]

Endoscopic hemostasis is a useful treatment modality for gastric ulcer bleeding. However, it is sometimes difficult to achieve hemostasis in cases with arterial bleeding, especially those complicated with vascular abnormalities. We describe a case with gastric ulcer bleeding from a variant left gastric artery accompanied by congenital absence of the splenic artery. A 50-year-old female was admitted to our hospital with dizziness and tarry stools. Upper gastrointestinal endoscopy revealed bleeding from a gastric ulcer, and endoscopic hemostasis by endoscopic clipping was carried out. Computed tomography and abdominal angiography revealed the variant left gastric artery running below the gastric ulcer. In spite of endoscopic hemostasis and medication, re-bleeding from the gastric ulcer occurred. A transcatheter coil embolization for the variant left gastric artery was performed and successfully achieved hemostasis. This case was accompanied by congenital absence of the splenic artery, which is an extremely rare condition. We herein describe this rare case and review previously reported cases. [ABSTRACT FROM AUTHOR]

The nuclear receptor constitutive active/androstane receptor (CAR) acts as a sensor of toxic byproducts derived from the endogenous metabolism and exogenous chemicals. We previously reported that CAR is responsible for exacerbating hepatic injury and fibrosis in a dietary model of non-alcoholic steatohepatitis (NASH) via upregulation of lipid peroxidation. In this study, we investigated the pathological roles of the CAR in the development of hepatocellular carcinoma in NASH model. CAR+/+ and CAR−/− mice were fed methionine- and choline-deficient (MCD) diet after tumor initiation with a single dose of the genotoxic carcinogen diethylnitrosamine (DEN) at 2 weeks of age. Interestingly, the MCD diet dramatically promoted DEN-induced hepatocarcinogenesis in CAR+/+ mice. However, the deletion of CAR leads to a significantly lower tumor incidence and smaller tumor diameter. Hepatocytes of MCD-treated-CAR+/+ mice showed a significantly higher staining frequency of Ki-67, a marker of cell proliferation, and exhibited a higher expression of c-Myc and FoxM1 transcripts compared with MCD-treated CAR−/− mice. Immunohistochemistry revealed the nuclear translocation of CAR thus suggesting that the activation of CAR signaling increased in the hepatocytes of CAR+/+ mice fed MCD diet. In addition, in vitro experiments using the CAR stably expressed cell line with TCPOBOP have suggested that CAR activation directly leads to cell proliferation. Survival was significantly lower in the CAR+/+ mice fed the MCD diet in comparison with the CAR−/− mice. Taken together, these results suggest that CAR may therefore play a critical role in the hepatocarcinogenesis of the murine NASH model via the upregulation of cell proliferation. [ABSTRACT FROM AUTHOR]

Background and Aim: Stricture is a complication that may occur after endoscopic submucosal dissection (ESD) of gastric neoplasms. The goal of the present study was to investigate the incidence, risk factors and management of gastric stricture after ESD. Methods: The medical records of 308 patients who underwent ESD for gastric neoplasms were reviewed. Stricture is defined as having symptoms caused by an obstruction through which a 1-cm diameter endoscopic fiber cannot be passed. Results: Stricture was identified in six of 308 patients (1.9%). Three of the six lesions were located in the prepylorus, two cases in the antrum and one in the cardia. The mean longitudinal distance and the mean area of the resected specimens in the six cases with stricture (7.8 ± 2.0 cm, 34.0 ± 15.8 cm2, respectively) was significantly larger than in those without stricture (4.5 ± 1.4 cm, 12.7 ± 8.3 cm2, respectively, P < 0.01). The ratio of the resected circumference/whole circumference was 83.3 ± 7.5% in those with stricture in comparison to 25.4 ± 16.3% in those without stricture ( P < 0.01). All six patients underwent endoscopic balloon dilations, and obtained relief from stricture. However, one patient experienced a gastric perforation and recovered following conservative therapy. Conclusion: Sub-circumferential resection over 75% of the circumference by ESD in the prepylorus, antrum and cardia is a risk factor for the occurrence of stricture. Early intervention might be considered for this high-risk group to avoid a perforation during balloon dilation. [ABSTRACT FROM AUTHOR]

Background and Aim: Bleeding from ectopic varices, including duodenal varices, is uncommon, but it can be difficult to manage. The clinical data of patients diagnosed and treated for duodenal varices were reviewed to investigate the strategy for treatment. Methods: The present study reviewed the clinical data of 10 patients with duodenal varices (mean age, 58.2 ± 15.6 years) at our associated institutes during the period between January 1996 and December 2008. Results: Nine patients had duodenal varices located in the second portion, whereas in one case they were located in the duodenal bulbus. The underlying diseases included liver cirrhosis in eight patients, and extrahepatic portal vein obstruction in two patients. The lesions were identified with bleeding from varices in eight of 10 patients. Initial hemostasis was achieved in all eight patients. However, among four patients treated endoscopically only, two patients died from rebleeding from varices and two died from hepatic failure resulting from variceal bleeding. Additional interventional radiology (IVR) was used in three patients and additional surgery was carried out in one case. One patient who was treated with balloon-occluded retrograde transvenous obliteration rebled during IVR and died from bleeding. Two patients who underwent double balloon-occluded embolotherapy and one case who had surgery achieved good clinical outcomes. Conclusions: Although endoscopic treatment is useful for initial hemostasis of hemorrhagic duodenal varices, the patients who underwent additional IVR after endoscopic treatment achieved good outcomes. [ABSTRACT FROM AUTHOR]

Background and Aim: The pathophysiological mechanisms leading to the development of non-alcoholic steatohepatitis (NASH) remain unclear. There are differences in the susceptibility to NASH between the different species and sexes. The investigation of the precise mechanism of interstrain differences may provide new means by which the pathophysiological mechanisms of NASH may be understood. Methods: C57BL/6N and C3H/HeN mice were administered a methionine- and choline-deficient (MCD) diet to establish a dietary model of NASH. Results: An elevation of the serum alanine aminotransferase and increased infiltration of inflammatory cells were predominant in C57BL/6N mice at 8 weeks. The increase in the steatosis and lipid contents in the liver was greater in C57BL/6N mice than in C3H/HeN mice. The indices of lipid peroxidation demonstrated by F2-isoprostanes or 8-hydroxy-2′-deoxyguanosine also increased in the livers of C57BL/6N mice. Furthermore, Sirius red staining revealed an increase in the degree of fibrosis in C57BL/6N mice given the MCD diet. As a result, the C57BL/6N strain had a higher susceptibility to NASH than the C3H/HeN mice. The carnitine palmitoyltransferase 1A (in β-oxidation) mRNA and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (in ketogenesis) mRNA were downregulated in the C57BL/6N mice in comparison with C3H/HeN mice. There were no differences in the expression of microsomal triglyceride transfer protein or sterol regulatory element binding protein 1 between the C57BL/6N and C3H/HeN mice. Conclusion: There were interstrain differences in susceptibility to NASH observed in a rodent dietary model. Further evaluations of the precise molecular mechanism of this interstrain difference may provide some indications of the pathophysiological mechanisms of NASH in humans. [ABSTRACT FROM AUTHOR]

Background. The number of patients with morbid obesity is increasing worldwide. However, the prevalence of morbid obesity is still low in Japan, and therefore few systematic investigations of liver dysfunction in this population have so far been carried out. This study aimed to investigate the clinical characteristics in severe obese Japanese patients undergoing laparoscopic Roux-en-Y gastric bypass surgery (LRYGB). Methods. Eighty-four patients with severe obesity, including 61 Japanese and 23 non-Japanese patients, were analyzed. Results. The mean body mass index (BMI) was 43.7 ± 7.8 kg/m2, and there was no difference between Japanese and non-Japanese patients. Nonalcoholic fatty liver disease (NAFLD) was observed in 45/59 (76.2%) of the Japanese patients. Although there were no differences in the BMI and body weight, serum ALT was higher in Japanese patients in comparison to non-Japanese patients ( P < 0.05). The indices for insulin resistance were significantly higher in the Japanese patients in comparison to non-Japanese patients ( P < 0.01). The liver/spleen computed tomography (CT) ratios were lower in Japanese patients ( P < 0.05). The laboratory data and BMI significantly improved at 1 year after LRYGB in both groups. Conclusions. Racial difference may exist difference may exist in NAFLD in patients with severe obesity. When the BMI is similar, liver dysfunction among Japanese patients with severe obesity tends to be higher than in non-Japanese patients. Japanese patients with severe obesity must therefore reduce their body weight to a greater degree in comparison to non-Japanese patients with the same BMI. LRYGB can achieve effective weight control and lower ALT levels in Japanese patients with severe obesity. [ABSTRACT FROM AUTHOR]

Background: Endoscopic submucosal dissection (ESD) has the advantage of permitting en bloc and histologically complete resection for early gastric cancer. Elderly patients often have surgical operative risks due to disease, and the feasibility of this treatment for such patients will improve the quality of life. The aim of the present study is to evaluate the efficacy and safety of ESD in elderly patients. Methods: We reviewed patients who underwent ESD for gastric lesions at Maebashi Red Cross Hospital. Among 251 gastric lesions treated by ESD from 2002 to 2006, 110 lesions were discovered in 93 elderly patients who were 75 years of age or older. The one-piece resection with tumor-free margin rate and the complications were assessed in comparison with younger patients under 75 years old. Results: The average age of the elderly patients was 79.8 years (range 75–92 years). The one-piece resection with tumor-free margin rate was 96.4% (106/110). Immediate bleeding occurred in one lesion (0.9%) and delayed bleeding requiring emergency endoscopy occurred in five lesions (4.5%). Perforation during ESD occurred in two patients (1.8%), and was immediately closed with endoclips and managed by conservative medical treatment. One case (0.9%) complicated with delayed perforation was managed by conservative medical treatment. The one-piece resection with tumor-free margin rate and the complication rate in elderly patients were not significantly different from those of younger patients. Conclusion: The present study shows the technical feasibility of ESD for gastric neoplasms in elderly patients. [ABSTRACT FROM AUTHOR]

Background: Resistin, an adipose-derived polypeptide hormone, has been proposed to be a candidate in insulin resistance, although its role in humans remains controversial. Liver cirrhosis (LC) is characterized by an elevated number of circulating proinflammatory cytokines, hyperinsulinemia and insulin resistance. The aim of this study was to determine the plasma resistin levels in patients with LC. Methods: Resistin levels were determined in 79 patients with LC and in 31 healthy controls. Patients included 34 with Child–Pugh grade A, 30 with Child's B and 15 with Child's C LC. Fasting plasma glucose, fasting plasma insulin, adiponectin, the homeostatic model assessment insulin resistance (HOMA-IR) index, quantitative insulin sensitivity check index (QUICKI) and biochemical parameters were also determined. Results: Plasma resistin levels were 7.61 ± 6.70 ng/mL in the LC patients and 3.38 ± 1.68 ng/mL in the controls, respectively. The plasma resistin levels were significantly elevated in patients with LC in comparison to the controls ( P < 0.01). The plasma resistin levels increased in a stepwise fashion in line with a higher grade according to Child–Pugh classification. Fasting plasma insulin, adiponectin and HOMA-IR index were also significantly elevated in patients with LC in comparison to controls. Inversely, QUICKI significantly decreased in patients with LC. According to Spearman's rank correlation, log resistin showed significantly positive correlation with fasting plasma insulin, log adiponectin, HOMA-IR index, and a negative correlation with QUICKI ( P < 0.01). The plasma resistin levels did not correlate with sex, body mass index and fasting plasma glucose levels. Conclusion: The plasma resistin levels increased in patients with LC, thus showing a positive correlation with fasting plasma insulin, adiponectin, HOMA-IR index, and a negative correlation with QUICKI. Although a decreased extraction of resistin due to reduced liver function cannot be ruled out, resistin may contribute to insulin resistance in patients with LC. The pathophysiological roles of resistin in LC still require further investigation. [ABSTRACT FROM AUTHOR]

Sjogren's syndrome can cause many organic changes, but is rarely accompanied by pleuritis. We report a 65-year-old patient with primary Sjogren's syndrome who developed bilateral pleuritis with moderately large effusions. He was diagnosed as having Sjogren's syndrome, based on xerophthalmia, xerostomia, positive results for anti-Sjogren's syndrome (anti-SS-A/SS-B) antibodies, the Schirmer test and biopsy findings in the minor salivary glands. The pleural fluid was lymphocyte rich and contained high levels of anti-SS-A/SS-B antibodies. There was no evidence of infection, malignancy or other collagen diseases which cause pleuritis. We conclude that this case adds to the eight previously published reports of primary Sjogren's syndrome complicated by pleural effusion. [ABSTRACT FROM AUTHOR]

Background: Despite the progression of therapeutic approaches, a high frequency of recurrence is what determines the long-term prognosis of patients with hepatocellular carcinoma (HCC). In this study, the chemopreventive effects of vitamin K2 on the recurrence and survival of patients with HCC after curative therapy were evaluated. Methods: Sixty patients who were diagnosed to be free of HCC after radiofrequency ablation therapy or surgery were randomly assigned to either the vitamin K2 group ( n = 30 patients) or the control group ( n = 30 patients). All patients were positive for the hepatitis C virus (HCV) antibody and hepatitis B surface antigen positive patients were excluded from this study. Patients in the vitamin K2 group received an oral dose of menatetrenone at 45 mg per day. Disease recurrence and the survival rates were analyzed in patients with HCC. Results: The cumulative recurrence-free rates in the vitamin K2 group were 92.3% at 12 months, 48.6% at 24 months and 38.8% at 36 months; and those in the control group were 71.7%, 35.9% and 9.9%, respectively ( P = 0.045). The cumulative survival rates in the vitamin K2 group were 100% at 12 months, 95.0% at 24 months and 77.5% at 36 months; and those in the control group were 95.8%, 90.2% and 66.4%, respectively ( P = 0.70). Conclusions: Vitamin K2 may have a suppressive effect on the recurrence of HCC and a beneficial effect on tumor recurrence. However, there was no significant difference in the survival rates. The chemopreventive effects of vitamin K2 are not sufficient. The development of a further regimen such as combination therapy is required. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease is a common liver injury, but the pathophysiological mechanisms leading to the development of non-alcoholic steatohepatitis (NASH) remain unclear. The pathological roles of the nuclear receptor constitutive androstane receptor (CAR), a key regulator of drug-metabolising enzymes, in the development of NASH were investigated. Methods and results: CAR+/+ and CAR-/- mice were given a methionine and choline-deficient (MCD) diet to establish a dietary model of NASH. Increases in serum alanine aminotransferase (ALT) and in infiltration of inflammatory cells were dominant in CAR+/+ mice at 8 weeks. There was no significant difference in the lipid concentration of the liver-namely, the first hit between CAR+/+ and CAR-/- mice. The index of lipid peroxidation increased in liver of the CAR+/+ mice, as demonstrated by 8-iso-prostaglandin F2α (F2-isoprostanes). Western blotting analysis showed that nuclear translocation of CAR occurred in CAR+/+ mice fed the MCD diet. As a result, the CAR activation caused the lipid peroxidation-namely, the second hit. The expressions of cytochrome P450 (CYP)2B10, 2C29, 3A11 all increased considerably in the CAR+/+ mice. Furthermore, α smooth muscle actin immunohistochemistry and Sirius red staining showed an increase in the degree of fibrosis in CAR+/+ mice fed the MCD diet at 16 weeks. The mRNA expressions of collagen α1(1) and the tissue inhibitor of metalloproteinase-1 were found to be elevated in CAR+/+ mice. Conclusion: CAR caused the worsening of the hepatic injury and fibrosis in the dietary model of NASH. Our results suggest that the CAR nuclear receptor may thus play a critical role in the pathogenesis of NASH. [ABSTRACT FROM AUTHOR]

Background: It is important to elucidate the precise mechanism of drug metabolism during hepatic regeneration. Although cytochromes P450 (CYPs) are well known to be down-regulated in growth-stimulated cells, the overall gene expression profile of drug metabolizing enzymes are still not fully understood during hepatic regeneration. In this study, we investigated the gene expression profiles of such enzymes with an overexpression of hepatocyte growth factor (HGF). Methods: Gene expression profiles were obtained using the Affymetrix MOE430A GeneChip oligonucleotide microarray by comparing HGF transgenic mice and wild-type mice. Results: HGF produced a general decrease in mice with the expression of CYP isoforms such as Cyp1a2, Cyp2b10, Cyp2c, Cyp2d9, Cyp3a11, Cyp4a10, and Cyp7a1. Some isoforms of alcohol dehydrogenase, aldehyde dehydrogenase, and carboxylesterase also decreased. In the phase II enzymes, some isoforms of glutathione S-transferase and UDP-glucuronosyl transferase showed a reduced expression, although the sulfotransferase did not. In phase III transporters, some organic anion transporter and organic cation transporters were down-regulated. Among the nuclear receptors that are known to regulate the drug-metabolizing enzymes, small heterodimer partner and constitutive androstane receptor were down-regulated with an HGF overexpression. The protein level and enzymatic activity of Cyp2c decreased with an HGF overexpression. We furthermore investigated the inducibility of Cyp2b10 with xenobiotic inducers. Although the basal expression of Cyp2b10 was repressed, the inducibility was not abolished with the HGF overexpression. Conclusions: HGF down-regulated not only CYPs but also some drug-metabolizing enzymes, transporters, and nuclear receptors. We thus have to take in our mind the low basal expression of drug metabolizing enzymes, when treating patients with a regenerative liver state. [ABSTRACT FROM AUTHOR]

Pancreatic or gastric metastases from other primary malignancies are rare, especially from leiomyosarcoma. We report a case of leiomyosarcoma in the left lower leg with metastases to the pancreas and stomach. A 61-year-old man had liver cirrhosis caused by hepatitis C virus infection and was followed up by his primary physician. Two years before presentation at our hospital, he had undergone surgical resection of leiomyosarcoma in the left lower leg and systemic chemotherapy for multiple metastatic tumors in the lung. On admission, endoscopic examination and computed tomography were performed for a routine checkup to exclude esophageal varices and liver tumor. Although the patient had no specific symptoms, multiple gastric and pancreatic metastases were identified by endoscopy and computed tomography, respectively. In general, metastases to the pancreas and stomach are rare. We discuss the clinical and diagnostic findings of pancreatic and gastric metastases by reviewing previously reported cases. [ABSTRACT FROM AUTHOR]

Doi F, Kakizaki S, Takagi H, Murakami M, Sohara N, Otsuka T, Abe T, Mori M. Long-term outcome of interferon-α-induced autoimmune thyroid disorders in chronic hepatitis C.Liver International DOI: 10.1111/j.1478-3231.2005.01089.x.© Blackwell Munksgaard 2005Autoimmune thyroid disorders are among the well-known adverse effects of interferon-α (IFN-α) therapy in patients with chronic hepatitis C. However, there are few reports regarding the long-term outcome of this complication. We aimed to evaluate the natural history of IFN-α-induced autoimmune thyroid disorders with long-term follow-up.Four hundred and thirty-nine patients with chronic hepatitis C were treated with IFN-α for 24 weeks between March 1993 and April 1998. Seventeen of 439 (3.9%) patients developed symptomatic autoimmune thyroid disorders including nine cases of hyperthyroidism and eight cases of hypothyroidism. The patients with hypothyroidism were all women. These 17 patients were followed up for 71.1±17.8 months (48–120 months) and were evaluated for long-term outcome.Eight patients could discontinue the thyroid medication (2–36 months, median 10 months). Nine patients needed the thyroid medication at the follow-up period. The patients with hyperthyroidism who needed long-term thyroid medication had a significantly high titer of TSH receptor antibody on onset compared with the patients who could discontinue the thyroid medication. There were no significant differences in age, type of IFN, duration from IFN administration to onset, cessation of IFN, genotype of hepatitis C virus and thyroid hormone levels on onset between the patients who needed long-term thyroid medication and the patients who could discontinue the thyroid medication.All patients with IFN-α-induced thyroid disorders could be controlled with medication. However, the IFN-α-induced thyroid disorders are not always reversible. One must be careful about not only the development of autoimmune thyroid disorders during IFN-α therapy but also the outcome of the thyroid disease. [ABSTRACT FROM AUTHOR]

The constitutive active receptor (CAR) regulates the induction of the cytochrome P450 2B6 (CYP2B6) gene by phenobarbital-type inducers, such as 1,4 bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) via the distal phenobarbital-responsive enhancer module (PBREM, at -1732/-1685 bp). Activation of the PBREM by TCPOBOP generated a 10-fold induction of CYP2B6 mRNA in HepG2 cells stably expressing mouse CAR (Ym17). Co-treatment with the protein phosphatase inhibitor okadaic acid (OA) synergistically increased this induction over 100-fold without directly activating CAR or the PBREM. Although OA synergy required the presence of PBREM, deletion assays delineated the OA-responsive activity to a proximal 24-bp (-256/-233) sequence (OARE) in the CYP2B6 promoter. CAR did not directly bind to the OARE in electrophoretic mobility shift assays. However, both DNA affinity and chromatin immunoprecipitation assays showed a significant increase in CAR association with the OARE after co-treatment with TCPOBOP and OA, indicating the indirect binding of CAR to the OARE. The two cis-acting elements, the distal PBREM and the proximal OARE, within the chromatin structure are both regulated by CAR in response to TCPOBOP and OA, respectively, to maximally induce the CYP2B6 promoter. This functional interaction between the two sites expands the current understanding of the mechanism of CAR-mediated inducible transcription. [ABSTRACT FROM AUTHOR]

Phenobarbital (PB) increases hepatic drug/steroid-metabolic capability by coordinately activating transcription of the genes encoding various metabolizing enzymes. The nuclear receptor CAR was first implicated as a transcription factor that activates the cytochrome P450 Cyp2b10 gene. In response to PB, CAR forms a heterodimer with the retinoid X receptor (RXR), binds to a PB response element (typified by DR-4 motif), and activates transcription of the gene. In the CAR-null mouse, PB does not only induce the Cyp2b10 gene, but also induces genes encoding various metabolizing enzymes. Thus, CAR is a general nuclear receptor that is essential for PB induction of drug/steroid metabolizing enzymes. PB also induces amino levulinate synthase 1 (ALAS-1), the rate-limiting enzyme in heme biosynthesis, to increase heme supply. However, PB induction of the synthase occurs in CAR-null mice, suggesting that CAR does not coordinate the heme synthesis for the induction of drug/steroid metabolism. [Copyright &y& Elsevier]

Aims/Background: To determine the relationship between host factors and host response to interferon (IFN) therapy, serum soluble Fas (sFas), soluble Fas ligand (sFas ligand), and tumor necrosis factor-α (TNF-α) were analyzed in 41 patients with chronic hepatitis C (CH-C) treated with IFN-α. Methods: Serum levels of sFas, sFas ligand, and TNF-α were measured at 0, 4, and 24 weeks of IFN therapy. Results: Eighteen patients were complete responders (CR) and 23 patients were non-responders (NR). Serum levels of sFas and TNF-α in patients with CH-C were significantly higher than those in healthy controls (p<0.01 and p<0.01, respectively). Serum sFas ligand levels were significantly lower in CH-C patients than in healthy controls (p<0.01). Before IFN therapy, serum levels of sFas in NR were significantly higher than those in CR (p<0.05). At 4 weeks of IFN therapy, serum levels of sFas of CR were significantly elevated compared with levels before IFN therapy (p<0.05). Serum levels of sFas correlated with the histological activity of the liver (p<0.05) and alanine aminotransferase (p<0.05). None of the three parameters, serum sFas, sFas ligand, or TNF-α levels, correlated with each other, with HCV-RNA genotype or with serum HCV-RNA load. Multiple logistic regression analysis showed that serum sFas levels before IFN therapy were a contributive factor to predict efficacy of IFN therapy. Conclusions: Serum sFas/sFas ligand and TNF-α play a possible role in pathogenesis of CH-C and also in IFN therapy. Serum sFas levels before IFN therapy may be one of the host-related factors used for evaluating the response of CH-C patients to IFN therapy. [ABSTRACT FROM AUTHOR]

Background: Iron overload in the presence of increasing concentrations of iron is one of the indicators of poor response to interferon therapy in chronic hepatitis C. In order to analyze the effect of iron on hepatitis C virus (HCV) replication, we measured replication in an HCV-infected cell line. Methods and Results: Cells from a non-neoplastic HCV-infected human hepatocyte line (PH5CH8) susceptible to HCV infection and supportive of HCV replication were used in this study. The replication of HCV RNA was measured by reverse transcription-nested polymerase chain reaction (RT-nested PCR). PH5CH8 cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. PH5CH8 cells were incubated with 0, 1, 10, 50, and 100 μM of FeSO4 at 37°C with 5% CO2. Forty-eight hours after iron supplementation, the quantity of HCV RNA in the cells incubated in 50 and 100 μM of FeSO4 was approximately ten times that of the cells with no iron supplementation. Similar changes were observed beginning at 12 h from supplementation with FeSO4 and continued for at least 72 h after supplementation. MTT assay indicated that iron did not have cytotoxic effects on the PH5CH8 cells. Conclusion: Iron enhances HCV replication in a hepatocyte cell line. The results suggest that iron deposition in hepatocytes could facilitate HCV infection in the liver. [ABSTRACT FROM AUTHOR]

Summary: Background: Atezolizumab plus bevacizumab (Atezo/Bev) is frequently selected as the primary systemic therapy for hepatocellular carcinoma (HCC). Aims: To investigate the outcomes of patients with HCC treated with Atezo/Bev in a real‐world setting based on whether they met the inclusion criteria for the phase 3 IMbrave150 trial. Methods: A total of 936 patients were enrolled. There were 404 patients who met the inclusion criteria of the phase 3 IMbrave150 trial (IMbrave150 group) and 532 who did not (non‐IMbrave150 group). Results: Median progression‐free survival (PFS) in the IMbrave150 and non‐IMbrave150 groups was 7.4 months and 5.6 months (p = 0.002). Multivariable analysis revealed that non‐B, non‐C HCC aetiology (hazard ratio [HR], 1.173), α‐fetoprotein ≥100 ng/mL (HR, 1.472), Barcelona Clinic Liver Cancer stage ≥ C (HR, 1.318), and modified albumin–bilirubin (mALBI) grade 2b or 3 (HR, 1.476) are independently associated with PFS. Median overall survival (OS) in the IMbrave150 and non‐Imbrave150 groups was 26.5 and 18.8 months (p < 0.001). Multivariable analysis revealed that Eastern Cooperative Oncology Group performance status ≥2 (HR, 1.986), α‐fetoprotein ≥100 ng/mL (HR, 1.481), and mALBI grade 2b or 3 (HR, 2.037) are independently associated with OS. In subgroup analysis, there were no significant differences in PFS or OS between these groups among patients with mALBI grade 1 or 2a. Conclusions: Patients who are treated with Atezo/Bev and meet the inclusion criteria for the phase 3 IMbrave150 trial, as well as those who do not meet the inclusion criteria but have good liver function, have a good prognosis for survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Many drugs has become available for the advanced hepatocellular carcinoma and sequential systemic therapies play an important role in the clinical settings. Because the key eligibility criteria for post-progression treatment included the performance status of ≦1 and Child-Pugh score of ≦6, to clarify the eligibility for post-progression treatment will provide meaningful information. The aim of this multicenter retrospective study was to investigate the predictive factors of progression to Child-Pugh class B, the formation of ascites and the candidates for post-progression treatment. Authors confirmed that male, ALBI grade 1, Child-Pugh score 5 (CP5A) and BCLC early or intermediate stage were favorable factors related to sustaining liver function and the patients with ALBI grade 1 and CP5A were eligible for the post-progression treatment. Careful screening for ascites was needed in patients with low platelet count and Child-Pugh score 6. The aim of this multicenter retrospective study was to assess the change in liver function in patients with hepatocellular carcinoma treated with lenvatinib. Among 139 consecutive patients receiving lenvatinib treatment between March 2018 and July 2019, 28 patients with Child-Pugh class B and one patient with inadequate patient information were excluded. Remaining 110 patients with Child-Pugh class A were analyzed. The median age of 110 patients was 73 years (IQR 66.7–80) and 88 patients (80.0%) were men. Child-Pugh score was 5 (CP5A) and 6 (CP6A) in 58 (52.7%) and 52 patients (47.3%), and ALBI grade was 1 and 2 in 38 (34.5%) and 72 patients (65.5%), respectively. The deterioration to Child-Pugh class B was found in 43 patients (39.1%) during the lenvatinib treatment. The favorable factors related to preserving liver function were significantly shown to be male, ALBI grade 1, CP5A and BCLC early or intermediate stage in the multivariate analysis. The formation of ascites was found in 32 patients (28.6%). The significant unfavorable factors associated with the formation of ascites were found to be low platelet count and CP6A. Among the 79 patients, there were 36 (45.6%) and 11 patients (13.9%) who fulfilled the criteria for candidate for the post-progression treatment and ramucirumab treatment, respectively. The predictive factors of the post-progression treatment were shown to be ALBI grade 1 and CP5A in multivariate analysis. In conclusion, male, ALBI grade 1, CP5A and BCLC early or intermediate stage were favorable factors related to sustaining liver function and the patients with ALBI grade 1 and CP5A were eligible for the post-progression treatment. Careful screening for ascites was needed in patients with low platelet count and CP6A. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusion Direct‐acting antivirals (DAAs) have been accessible in Japan since 2014. The aim of this study is to compare how the prognosis of patients with hepatitis C virus (HCV)‐associated hepatocellular carcinoma (HCV‐HCC) changed before and after DAA development.A retrospective analysis of 1949 Japanese HCV‐HCC patients from January 2000 to January 2023 categorized them into pre‐DAA (before 2013, n = 1169) and post‐DAA (after 2014, n = 780) groups. Changes in clinical features and prognosis were assessed.Despite no significant differences in BCLC stage between groups, the post‐DAA group exhibited higher rates of sustained virological response (SVR) (45.6% vs. 9.8%), older age (73 vs 69 years), lower levels of AST (40 vs 56 IU/L), ALT (31 vs 46 IU/L), and AFP (11.7 vs 23.6 ng/mL), higher platelet count (13.5 vs 10.8 × 104/μL), better prothrombin time (88.0% vs 81.9%), and better ALBI score (−2.54 vs −2.36) (all P < 0.001). The post‐DAA group also showed higher rates of curative treatments (74.1% vs 65.2%) and significantly improved recurrence‐free survival (median 2.8 vs 2.1 years). Adjusted for inverse probability weighting, overall survival was superior in the post‐DAA group (median 7.4 vs 5.6 years, P < 0.001). Subanalysis within the post‐DAA group revealed significantly shorter overall survival for patients without SVR (median 4.8 years vs NA vs NA) compared to pre‐SVR or post‐SVR patients (both P < 0.001). No significant difference in OS was observed between the pre‐SVR and post‐SVR groups (P = 1.0).The development of DAA therapy has dramatically improved the prognosis of HCV‐HCC patients. [ABSTRACT FROM AUTHOR]

Summary: Background: The precise estimation of cases with significant fibrosis (SF) is an unmet goal in non‐alcoholic fatty liver disease (NAFLD/MASLD). Aims: We evaluated the performance of machine learning (ML) and non‐patented scores for ruling out SF among NAFLD/MASLD patients. Methods: Twenty‐one ML models were trained (N = 1153), tested (N = 283), and validated (N = 220) on clinical and biochemical parameters of histologically‐proven NAFLD/MASLD patients (N = 1656) collected across 14 centres in 8 Asian countries. Their performance for detecting histological‐SF (≥F2fibrosis) were evaluated with APRI, FIB4, NFS, BARD, and SAFE (NPV/F1‐score as model‐selection criteria). Results: Patients aged 47 years (median), 54.6% males, 73.7% with metabolic syndrome, and 32.9% with histological‐SF were included in the study. Patients with SFvs.no‐SF had higher age, aminotransferases, fasting plasma glucose, metabolic syndrome, uncontrolled diabetes, and NAFLD activity score (p < 0.001, each). ML models showed 7%–12% better discrimination than FIB‐4 to detect SF. Optimised random forest (RF) yielded best NPV/F1 in overall set (0.947/0.754), test set (0.798/0.588) and validation set (0.852/0.559), as compared to FIB4 in overall set (0.744/0.499), test set (0.722/0.456), and validation set (0.806/0.507). Compared to FIB‐4, RF could pick 10 times more patients with SF, reduce unnecessary referrals by 28%, and prevent missed referrals by 78%. Age, AST, ALT fasting plasma glucose, and platelet count were top features determining the SF. Sequential use of SAFE < 140 and FIB4 < 1.2 (when SAFE > 140) was next best in ruling out SF (NPV of 0.757, 0.724 and 0.827 in overall, test and validation set). Conclusions: ML with clinical, anthropometric data and simple blood investigations perform better than FIB‐4 for ruling out SF in biopsy‐proven Asian NAFLD/MASLD patients. [ABSTRACT FROM AUTHOR]

Background & Aims: The study goal was to compare the outcomes of patients with intermediate‐stage (Barcelona Clinic Liver Cancer [BCLC]‐B) hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first‐line systemic therapy. Methods: A total of 358 patients with BCLC‐B HCC treated with Atezo/Bev (n = 177) or LEN (n = 181) as first‐line systemic therapy were included. Results: The median progression‐free survival (PFS) times in the Atezo/Bev and LEN groups were 10.8 months (95% confidence interval [CI], 7.8–12.6) and 7.3 months (95% CI, 6.3–8.5), respectively (p =.019). In the propensity score‐matched cohort, the median PFS times in the Atezo/Bev (n = 151) and LEN (n = 151) groups were 10.2 months (95% CI, 7.0–12.3) and 6.9 months (95% CI, 5.9–8.1), respectively (p =.020). Restricted mean survival times of PFS were significantly higher in the Atezo/Bev group than in the LEN group at landmarks of 12 and 18 months (p =.031 and.012, respectively). In a subgroup analysis of patients with HCC beyond the up‐to‐seven criteria, the median PFS times in the Atezo/Bev (n = 134) and LEN (n = 117) groups were 10.5 months (95% CI, 7.0–11.8) and 6.3 months (95% CI, 5.5–7.3), respectively (p =.044). Conclusions: The use of Atezo/Bev as first‐line systemic therapy in patients with BCLC‐B HCC is expected to result in good PFS. [ABSTRACT FROM AUTHOR]

Background: Bevacizumab inhibits vascular endothelial growth factor-A (VEGF-A), though is known to increase bleeding risk as an adverse event (AE). This study examined whether atezolizumab/bevacizumab (Atez/Bev) for unresectable hepatocellular carcinoma (uHCC) can be used for patients with esophageal–gastric varices (EGV). Methods: From October 2020 to December 2022, 506 uHCC patients (median 74 years) underwent an upper gastrointestinal endoscopy examination were enrolled, after exclusion of those with portal vein tumor thrombus (PVTT). Patients with EGV (≧ F1) were defined as EGV positive, and the cohort was divided into non-EGV (n = 355) and EGV (n = 151). Before introducing Atez/Bev, endoscopic treatment was performed, when necessary. Prognosis was evaluated, retrospectively. Results: The EGV group had significantly worse hepatic function, lower platelet count, elevated alpha-fetoprotein, and lower rate of extrahepatic metastasis, and lower rate of first-line use (each P < 0.05) than the other. However, progression-free survival (PFS) was also not a significantly difference between the EGV and non-EGV groups in analyses with (PFS rate at 6/12/18 months: 60%/38%/30% vs. 65%/46%/34%, P = 0.29) or without inverse probability weighting adjustment [median: 10.6 months (95% CI 8.3–14.0) vs. 10.5 months (95% CI 7.8–13.7), P = 0.79]. As for AEs, diarrhea was more frequent in the EGV group (≧ G3: 2.0% vs. 0.3%, P = 0.036), while no significant difference was noted for EGV hemorrhage (≧ G3: 1.3% vs. 0.6%, P = 0.345). Of 28 patients who underwent endoscopic treatments before introducing Atez/Bev, none showed EGV-associated hemorrhage. Conclusions: Atez/Bev might be an effective therapeutic option in patients with EGV, when appropriate endoscopic treatment for EGV is performed. [ABSTRACT FROM AUTHOR]

Introduction: Lack of an established methodology for post-progression systemic treatment following atezolizumab plus bevacizumab (Atez/Bev) administration is an important clinical issue. The present study aimed to elucidate the potential of lenvatinib as a second-line treatment option after Atez/Bev failure. Methods: From 2020 to 2022, 101 patients who received lenvatinib as second-line treatment were enrolled (median 72 years, males 77, Child-Pugh A 82, BCLC-A:B:C:D = 1:35:61:4), while 29 treated with another molecular targeting agent (MTA) during the period as second-line treatment were enrolled as controls. The therapeutic efficacy of lenvatinib given as second-line treatment was retrospectively evaluated. Results: Median progression-free survival/median overall survival for all patients was 4.4/15.7 months and for those with Child-Pugh A was 4.7 months/not-reached. When prognosis was compared with patients who received another MTA, there was no significant difference for PFS (3.5 months, p = 0.557) or OS (13.6 months, p = 0.992), and also no significant differences regarding clinical background factors. mRECIST findings showed that objective response and disease control rates in patients treated with lenvatinib were 23.9% and 70.4%, respectively (CR:PR:SD:PD = 3:14:33:21), while those shown by RECIST, ver. 1.1, were 15.4% and 66.2%, respectively (CR:PR:SD:PD = 1:10:36:24). Adverse events (any grade ≥10%) were appetite loss (26.7%) (grade 1:2:3 = 2:15:10), general fatigue (21.8%) (grade 1:2:3 = 3:13:6), protein in urine (16.8%) (grade 1:2:3 = 0:4:13), and hypertension (13.9%) (grade 1:2:3 = 1:8:5). Conclusion: Although lenvatinib treatment might not provide a pseudo-combination immunotherapy effect following Atez/Bev failure, lenvatinib when used as second-line treatment after Atez/Bev failure might be expected to be comparable as compared to its use as first-line treatment. [ABSTRACT FROM AUTHOR]

Aim: The present study focused on Geriatric Nutritional Risk Index (GNRI), which is based on bodyweight and serum albumin, and known as an easy‐to‐use nutritional assessment tool in clinical settings, to elucidate the prognostic predictive ability of GNRI in patients treated with atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC). Methods: A total of 525 HCC patients treated with Atez/Bev, based on their classification of unsuitable status for curative treatments and/or transarterial catheter chemoembolization, were enrolled (Child–Pugh A:B:C = 484:40:1, Barcelona Clinic Liver Cancer stage 0:A:B:C:D = 7:25:192:283:18). Prognosis was evaluated retrospectively using GNRI. Results: Atez/Bev was used in 338 of the present cohort as first‐line systemic chemotherapy (64.4%). Median progression‐free survival based on GNRI indicating normal, mild decline, moderate decline, and severe decline was 8.3, 6.7, 5.3, and 2.4 months, respectively, whereas median overall survival was 21.4, 17.0, 11.5. and 7.3 months, respectively (both p < 0.001). The concordance index (c‐index) values of GNRI for predicting prognosis (progression‐free survival/overall survival) were superior to those of Child–Pugh class and albumin‐bilirubin grade (0.574/0.632 vs. 0.527/0.570 vs. 0.565/0.629). As a subanalysis, muscle volume loss was observed in 37.5% of 256 patients with computed tomography data available. Along with GNRI decline, frequency of muscle volume loss became progressively larger (normal vs. mild vs. moderate vs. severe = 17.6% vs. 29.2% vs. 41.2% vs. 57.9%, p < 0.001), and a GNRI value of 97.8 was predictive of its occurrence (AUC 0.715, 95% CI 0.649–0.781; specificity/sensitivity = 0.644/0.688). Conclusion: These findings indicate that GNRI is an effective nutritional prognostic tool for predicting prognosis and muscle volume loss complication in HCC patients treated with Atez/Bev. [ABSTRACT FROM AUTHOR]

Introduction: Systemic treatment is generally recommended for Child-Pugh (CP) A status patients with an unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate differences regarding therapeutic efficacy between lenvatinib (LEN), a multi-molecular target agent, and atezolizumab plus bevacizumab (Atez/Bev), a newly developed immune-combined therapeutic regimen for CP-B patients affected by uHCC. Methods: From April 2018 to July 2022, 128 patients with uHCC treated with Atez/Bev (n = 29) or LEN (n = 99) as the initial systemic treatment were enrolled (median age 71 years; males 97; CP score 7:8:9 = 94:28:6; median albumin-bilirubin score −1.71). Therapeutic response was evaluated using RECIST, version 1.1. Clinical features and prognosis were retrospectively examined. Results: There were no significant differences between the Atez/Bev and LEN groups in regard to best response (CR:PR:SD:PD = 0:5:12:7 vs. 5:22:25:20, p = 0.415), progression-free survival (PFS) (median 5.0 [95% CI: 2.4–7] vs. 5.5 [95% CI: 3.4–7.9] months, p = 0.332), or overall survival (OS) (5.8 [95% CI: 4.3–11] vs. 8.8 [95% CI: 6.1–12.9] months, p = 0.178). Adverse events (any grade/≥ grade 3) were observed in 72.4%/17.2% (n = 21/5) of patients treated with Atez/Bev and 78.8%/25.3% (n = 78/25) of those treated with LEN (p = 0.46/0.46). Discussion: This retrospective study found no significant differences regarding PFS or OS between CP-B patients given Atez/Bev or LEN as initial systemic treatment for uHCC. [ABSTRACT FROM AUTHOR]

Key Clinical Message: SARS‐CoV‐2 infection has been associated with a prolonged course and a poor prognosis in patients who receive anti‐CD20 antibodies. However, there are no established treatments for such patients. Serial changes in the SARS‐CoV‐2 antigen titer during the clinical course and treatment strategies for immunosuppressed patients are discussed. We report a case of prolonged SARS‐CoV‐2 infection during obinutuzumab and bendamustine treatment for follicular lymphoma. Four years previously, the patient had been diagnosed with follicular lymphoma (Stage IIIA, Grade 2). She received several chemotherapy regimens, including rituximab and radiation therapy. Although these therapies achieved complete response temporally, they did not continue and recurred at 8 months before. Obinutuzumab and bendamustine therapy was selected, and she received five courses of obinutuzumab and bendamustine. She also received a SARS‐CoV‐2 mRNA vaccine two times. Although she did not have any symptoms, a routine check‐up just before the 6th course of obinutuzumab and bendamustine revealed SARS‐CoV‐2 infection. Because she was immunosuppressed and was considered to be at high risk for the exacerbation of her disease, molnupiravir was immediately administered, and her SARS‐CoV‐2 antigen decreased. However, it was not completely cleared and flared‐up at 6 weeks, with symptoms of COVID‐19 appearing. Despite intensive treatment for SARS‐CoV‐2 infection, including remdesivir, baricitinib, tocilizumab and intravenous immunoglobulin, her SARS‐CoV‐2 antigen titer never became negative, and she finally died of respiratory failure caused by prolonged SARS‐CoV‐2 infection. Serial changes in the SARS‐CoV‐2 antigen titer during the clinical course and treatment strategies for immunosuppressed patients are discussed. [ABSTRACT FROM AUTHOR]

Aim: Multiple studies have revealed the correlation between gut microbiome and the response to checkpoint inhibitors (CPIs) in patients with cancer, and oral administration of butyrate‐producing enterobacteria has been reported to enhance the efficacy of CPIs. However, the effects of enterobacteria on patients with hepatocellular carcinoma (HCC) are not well understood. Methods: In this retrospective multicenter study, we enrolled 747 patients with advanced HCC, treated with atezolizumab and bevacizumab combination therapy. Tumor response, survival, and adverse effects were compared between 99 patients who ingested drugs containing butyric acid‐producing enterobacteria (butyric acid group) and the remaining patients (control group). Results: Objective response and disease control rates in butyric acid group (29.7% and 77.8%, respectively) were higher than those in the control group (26.4% and 72.7%, respectively). However, the differences were not statistically significant (p = 0.543 and p = 0.222, respectively). No difference in median survival time was observed between the two groups (20.0 months and 21.4 months, respectively; p = 0.789), even after matching the backgrounds of the patients with propensity scores (p = 0.714). No adverse effects occurred upon the administration of butyrate‐producing bacteria. However, proteinuria (41.4% vs. 30.9%; p = 0.041), fever (17.2% vs. 10.2%, p = 0.036), and diarrhea (15.2% vs. 6.2%; p = 0.001) occurred more frequently in the butyric acid group. Conclusion: Butyrate‐producing bacteria does not enhance the efficacy of atezolizumab–bevacizumab combination therapy in patients with HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Atezolizumab plus bevacizumab (Atez/Bev) is the first-line treatment for unresectable advanced hepatocellular carcinoma (HCC). The tumor markers (TMs) for HCC include alpha-fetoprotein (AFP), fucosylated alpha-fetoprotein (AFP-L3), and des-gamma carboxyprothrombin (DCP). A TM score combining these markers has been reported to be useful in predicting HCC prognosis. This retrospective study aimed to evaluate the ability of this previously reported TM score involving AFP, AFP-L3, and DCP as TMs in predicting prognosis and therapeutic efficacy in HCC patients administered Atez/Bev as first-line treatment. The TM score was found to be effective in stratifying overall survival and progression-free survival in 371 patients with unresectable advanced HCC treated with Atez/Bev. The TM score proved to be a simple and useful prognostic marker and therapeutic efficacy indicator for advanced HCC patients administered Atez/Bev as first-line treatment. Aim: This study aimed to evaluate the ability of a previously reported tumor marker (TM) score involving alpha-fetoprotein (AFP), fucosylated AFP (AFP-L3), and des gamma-carboxy prothrombin (DCP) as TMs in predicting the prognosis and therapeutic efficacy in hepatocellular carcinoma (HCC) patients administered atezolizumab plus bevacizumab (Atez/Bev) as first-line treatment. Materials/Methods: The study period covered September 2020 to December 2022 and involved 371 HCC patients treated with Atez/Bev. The values of the TMs AFP, AFP-L3, and DCP were measured upon introducing Atez/Bev. Elevations in the values of AFP (≥100 ng/mL), AFP-L3 (≥10%), and DCP (≥100 mAU/mL) were considered to indicate a positive TM. The number of positive TMs was summed up and used as the TM score, as previously proposed. Hepatic reserve function was assessed using the modified albumin–bilirubin grade (mALBI). Predictive values for prognosis were evaluated retrospectively. Results: A TM score of 0 was shown in 81 HCC patients (21.8%), 1 in 110 (29.6%), 2 in 112 (29.9%), and 3 in 68 (18.3%). The median overall survival (OS) times for TM scores 0, 1, 2, and 3 were not applicable [NA] (95% CI NA-NA), 24.0 months (95% CI 17.8-NA), 16.7 months (95% CI 17.8-NA), and NA (95% CI 8.3-NA), respectively (p < 0.001). The median progression-free survival (PFS) times for TM scores 0, 1, 2, and 3 were 16.5 months (95% CI 8.0-not applicable [NA]), 13.8 months (95% CI 10.6–21.3), 7.7 months (95% CI 5.3–8.9), and 5.8 months (95% CI 3.0–7.6), respectively (p < 0.001). OS was well stratified in mALBI 1/2a and mALBI 2a/2b. PFS was well stratified in mALBI 2a/2b, but not in mALBI 1/2a. Conclusions: The TM score involving AFP, AFP-L3, and DCP as TMs was useful in predicting the prognosis and therapeutic efficacy in terms of OS and PFS in HCC patients administered Atez/Bev as first-line treatment. [ABSTRACT FROM AUTHOR]

Background and Aim: The study goal was to compare the outcomes of patients with unresectable hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) as either first‐ or later‐line systemic therapy. Methods: A total of 430 patients with HCC treated with Atezo/Bev at 22 institutions in Japan were included. Patients treated with Atezo/Bev as first‐line therapy for HCC were defined as the first‐line group (n = 268) while those treated with Atezo/Bev as second‐ or later‐line therapy were defined as the later‐line group (n = 162). Results: The median progression‐free survival times in the first‐ and later‐line groups were 7.7 months (95% confidence interval [CI], 6.7–9.2) and 6.2 months (95% CI, 5.0–7.7) (P = 0.021). Regarding treatment‐related adverse events, hypertension of any grade was more common in the first‐line group than in the later‐line group (P = 0.025). Analysis adjusted by inverse probability weighting, including patient and HCC characteristics, showed that the later‐line group (hazard ratio, 1.304; 95% CI, 1.006–1.690; P = 0.045) was significantly associated with progression‐free survival. In patients with Barcelona Clinic Liver Cancer stage B, the median progression‐free survival times in the first‐ and later‐line groups were 10.5 months (95% CI, 6.8–13.8) and 6.8 months (95% CI, 5.0–9.4) (P = 0.021). Among patients with a history of lenvatinib therapy, the median progression‐free survival times in the first‐ and later‐line groups were 7.7 months (95% CI, 6.3–9.2) and 6.2 months (95% CI, 5.0–7.7) (P = 0.022). Conclusion: The use of Atezo/Bev as first‐line systemic therapy in patients with HCC is expected to prolong survival. [ABSTRACT FROM AUTHOR]

Investigates the link between human leukocyte antigen (HLA)-A2 and the autoimmune thyroid disorders induced by interferon (IFN)-alpha therapy in patients with chronic hepatitis in Japan. Presence of autoimmune thyroid disorders not induced by IFN-alpha; Developments in HLA-A2 antigen genotyping by DNA-based methods; Classification of HLA-A2 alleles into subtypes.

Introduction: This study investigated the relationship between nutritional status, as determined by the prognostic nutritional index (PNI), and outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/bev). Methods: The study analyzed 485 HCC patients treated with Atez/bev. Results: There were 342 patients with a low PNI (<47) and 143 patients with a high PNI (≥47). The median follow-up duration was 9.4 (6.0–14.3) months. Multivariate Cox hazards analysis showed that an α-fetoprotein level ≥100 ng/mL (hazard ratio (HR), 2.217; 95% confidence interval (CI), 1.588–3.095; p < 0.001), and PNI ≥47 (HR, 0.333; 95% CI, 0.212–0.525; p < 0.001) were independently associated with overall survival. Multivariate analysis showed that an α-fetoprotein level ≥100 ng/mL (HR, 1.690; 95% CI, 1.316–2.170; p < 0.001) and PNI ≥47 (HR, 0.696; 95% CI, 0.528–0.918; p = 0.010) were independently associated with progression-free survival. Cumulative overall and progression-free survival rates differed significantly by PNI (p < 0.001 and p < 0.002, respectively). In a subgroup analysis using inverse probability weighting adjustment in patients with albumin-bilirubin grade 1 (n = 173), univariate Cox hazards analysis showed that a PNI ≥47 (HR, 0.502; 95% CI, 0.260–0.991; p = 0.047) was significantly associated with overall survival. Spline curve analysis revealed that a PNI of approximately 34–48 is an appropriate cutoff for predicting good overall and progression-free survival. Conclusion: The PNI, a biomarker of nutritional status, can predict prognosis in patients with HCC treated with Atez/bev, even those who are considered to have a good prognosis due to good liver function. [ABSTRACT FROM AUTHOR]

Aim: To investigate the possible correlation between the development of adverse events (AEs) and prognosis in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev). Methods: A total of 286 patients with unresectable HCC treated with Atez/Bev as first‐line systematic therapy were included. Results: Regarding treatment‐related AEs, decreased appetite of any grade, proteinuria of any grade, and fatigue of any grade were found with a frequency of ≥20%. Multivariate analysis adjusted for immune‐related liver injury, immune‐related endocrine dysfunction, proteinuria, fatigue, decreased appetite, hypertension, sex, age, Eastern Cooperative Oncology Group performance status, HCC etiology, HCC stage, Child–Pugh score, and α‐fetoprotein showed that hypertension of any grade (hazard ratio [HR], 0.527; 95% confidence interval [CI], 0.326–0.854; p = 0.009) and α‐fetoprotein ≥100 ng/ml (HR, 1.642; 95% CI, 1.111–2.427; p = 0.013) were independently associated with progression‐free survival. Multivariate analysis adjusted for the same AEs showed that fatigue (HR, 2.354; 95% CI, 1.299–4.510; p = 0.010) was independently associated with overall survival. Median progression‐free survival was 6.5 months (95% CI, 5.2–8.1) in patients without hypertension of any grade and 12.6 months (95% CI, 6.7–not available) in patients with hypertension of any grade (p = 0.035). The overall survival was significantly shorter in patients in whom treatment‐related fatigue of any grade was observed (p < 0.001). Regarding response rates, the disease control rate of patients who developed treatment‐related hypertension (94.2%) was significantly higher than those who did not (79.1%) (p = 0.009). Conclusions: Treatment‐related hypertension is associated with good outcomes in patients with HCC treated with Atez/Bev. [ABSTRACT FROM AUTHOR]

Aim: Recently, the neo‐Glasgow prognostic score (GPS), a composite biomarker determined by the C‐reactive protein level and albumin–bilirubin grade, was developed to predict outcomes in hepatocellular carcinoma (HCC) patients who undergo hepatic resection. The present research investigated whether the neo‐GPS could predict prognosis in HCC patients treated with atezolizumab plus bevacizumab (Atez/Bev). Methods: A total of 421 patients with HCC who were treated with Atez/Bev were investigated. Results: Multivariate Cox hazards analysis showed that a GPS of 1 (hazard ratio (HR), 1.711; 95% confidence interval (CI), 1.106–2.646) and a GPS of 2 (HR, 4.643; 95% CI, 2.778–7.762) were independently associated with overall survival. Conversely, multivariate Cox hazards analysis showed that a neo‐GPS of 1 (HR, 3.038; 95% CI, 1.715–5.383) and a neo‐GPS of 2 (HR, 5.312; 95% CI, 2.853–9.890) were also independently associated with overall survival in this cohort. Additionally, cumulative overall survival rates differed significantly by GPS and neo‐GPS (p < 0.001). The neo‐GPS, compared with the GPS, had a lower Akaike information criterion (1207 vs. 1,211, respectively) and a higher c‐index (0.677 vs. 0.652, respectively) regarding to overall survival. In a subgroup analysis of patients considered to have a good prognosis as confirmed using a Child–Pugh score of 5 (p = 0.001), a neutrophil‐to‐lymphocyte ratio <3 (p = 0.001), or an α‐fetoprotein level < 100 ng/mL (p < 0.001), those with a high neo‐GPS (≥1) had a statistically poorer overall survival than those with a low neo‐GPS. Conclusions: The neo‐GPS can predict prognosis in advanced unresectable HCC patients treated with Atez/Bev. [ABSTRACT FROM AUTHOR]