Factors associated with the response to atezolizumab/bevacizumab combination therapy for hepatocellular carcinoma.

Background and Aim: The purpose of this study was to analyze factors associated with the overall survival (OS) of atezolizumab/bevacizumab combination therapy for advanced hepatocellular carcinoma (aHCC). We also assessed the OS of patients with ineffective therapy and those who discontinued treatment owing to adverse events (AEs). Methods: This retrospective multicenter study involved 139 patients with aHCC who received atezolizumab/bevacizumab combination therapy between November 2020 and September 2022. Results: The median duration of treatment was 136.5 days, and the median observation period was 316 days. The overall response rate was 40%, and the disease control rate was 78% according to mRECIST criteria. Grade ≥2 AEs occurred in 63 patients (43%) and led to treatment discontinuation in 16 patients. Multivariate analysis revealed that treatment response and occurrence of grade ≥2 AEs after therapy, as well as low level of albumin-bilirubin (ALBI) grade and low level of des-gamma carboxy prothrombin (DCP) before therapy, were extracted as factors that contributed to OS. Log-rank tests with the Kaplan-Meier method showed significant differences in OS among these factors. The OS of patients who discontinued owing to AEs was significantly shorter than that of other patients. Conclusion: Not only factors before therapy but also treatment response and the appearance of AEs are involved in OS for atezolizumab/bevacizumab combination therapy. Although the development of AEs also contributed to OS, appropriate management of AEs is important to avoid discontinuing treatment with this combination.

Constitution of mucosa-associated microbiota in the lower digestive tract does not change in early stage of non-alcoholic fatty liver disease with fecal dysbiosis.

Background and Aim: Regarding the gut-liver axis, fecal dysbiosis is implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The significance of mucosa-associated microbiota (MAM, which is present in the mucin layer covering the intestinal mucosa) has not been well explored. We aimed to clarify the characteristics of MAM in patients with NAFLD. Methods: MAM were obtained from seven patients with early-stage NAFLD and seven controls by colonoscopy in five locations (terminal ileum, cecum, ascending and sigmoid colon, and rectum) using mucosal brushes. The microbial 16S rDNA profiles of the MAM and fecal microbiota of patients in the NAFLD and control groups were analyzed. Results: α-diversities of fecal microbiota were decreased in patients with NAFLD (observed species, Shannon index, and Chao1: 174.57 vs 134.86, 5.51 vs 4.65, and 206.34 vs 167.91; P = 0.048, 0.067, and 0.087, respectively), and microbial composition analyses by principal coordinate analysis differed between the fecal microbiota of patients with NAFLD and those of controls (permutational analysis of variance [PERMANOVA] of weighted and unweighted: Pseud-F: 1.4179/P-value: 0.05 and Pseud-F: 2.1497/P-value: 0.049, respectively). However, α-diversities or microbial composition of MAM in most parts of the intestine did not differ significantly between the NAFLD and control groups. Unclassified Rikenellaceae, Oscillospira, Odoribacter, unclassified clostridiales, and Holdemania were decreased in the feces of patients with NAFLD (determined by linear discriminant analysis effect size), but five (except Holdemania) of the six genera were not decreased in the MAM of these patients. Conclusion: In early-stage NAFLD, MAM was uniform and relatively stable throughout the intestine, even when fecal dysbiosis appeared.

Acid-treated high-amylose corn starch suppresses high-fat diet-induced steatosis.

Resistant starch (RS) has been reported to improve steatosis as well as obesity. Type 4 resistant starch (RS4), a chemically modified starch, is particularly hard to digest and suggesting higher efficacy. However, because the effects of RS4 on steatosis are not yet fully understood, the effects of RS4 on steatosis were examined using a murine high-fat diet model. Seven-week-old male mice were divided into three groups and fed a normal diet, a high-fat diet (HFD), or a high-fat diet with added RS (HFD + RS). Amylofiber SH® produced from acid-treated corn starch was used as the dietary RS. At 22 weeks old, hepatic steatosis and short chain fatty acid (SCFA) content and gut microbiota in cecum stool samples were analyzed. The ratio of body weight to 7 weeks was significantly suppressed in the HFD + RS group compared to the HFD group (132.2 ± 1.4% vs. 167.2 ± 3.9%, p = 0.0076). Macroscopic and microscopic steatosis was also suppressed in the HFD + RS group. Analysis of cecum stool samples revealed elevated SCFA levels in the HFD + RS group compared with the HFD group. Metagenome analysis revealed that Bifidobacterium (17.9 ± 1.9% vs. 3.6 ± 0.7%, p = 0.0019) and Lactobacillus (14.8 ± 3.4% vs. 0.72 ± 0.23%, p = 0.0045), which degrade RS to SCFA, were more prevalent in the HFD + RS group than the HFD group. In conclusion, RS4 suppressed steatosis, and increased Bifidobacterium and Lactobacillus, and SCFAs. RS4 may prevent steatosis by modulating the intestinal environment.

Liver abscess caused by Cutibacterium namnetense after transarterial chemoembolization for hepatocellular carcinoma.

A 72-year-old man underwent transarterial chemoembolization (TACE) for solitary hepatocellular carcinoma (HCC) located on the S6 segment. He had a history of anti-viral therapy for hepatitis C virus and was being treated for diabetes mellitus with inadequate control. On day 28 after TACE, he visited our hospital again, with complaints of fever and abdominal pain in the right upper quadrant. Blood examination showed elevated levels of white blood cells and C-reactive protein. Computed tomography showed a poorly marginated, low-density lesion measuring 9.5 × 8.0 × 4.0 cm, forming multiple small gas bubbles, located superiorly, and in contact with HCC treated by TACE. Ultrasound-guided puncture revealed whiffy and muddy pus. Gram staining of the pus showed the presence of numerous gram-positive rods, which were identified as Cutibacterium namnetense. He underwent percutaneous trans-hepatic abscess drainage and received antibiotics treatment. The abscess was successfully treated, and he was discharged on day 19. The incidence of liver abscess after TACE is rare, and intestinal microbiota have been reported to be the common pathogens. To the best of our knowledge, this is the first case of liver abscess caused by Cutibacterium namnetense.

Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers.

PURPOSE: The risk factors and clinical characteristics of ICI-induced immune-mediated hepatotoxicity (IMH) are not fully understood. Thus, the present study sought to clarify the clinical features of IMH. METHODS: All patients treated with ICIs between September 2014 and April 2019 at our institution were included. Clinical data were retrospectively collected from medical records. The frequency of grade ≥ 2 liver damage, clinical characteristics, and risk factors for developing IMH were examined. RESULTS: Overall, 250 patients (median age 71 years; range 30-87 years; 202 males and 48 females) were included in the analyses. Forty-five patients had elevated transaminase levels (> threefold the upper limit of normal). Of these, 21 were considered to have IMH. The remaining 24 patients had other causes of elevated transaminase levels. Steroids were administered to 13/21 patients with IMH. Although all patients exhibited improvement, IMH was not associated with the anticancer efficacy of the ICIs or OS. A multivariable analysis revealed that IMH was significantly associated with malignant melanoma (odds ratio [OR] 11.6; 95% confidence interval [CI] 3.5-38.0; P = 0.0002) and ipilimumab-nivolumab combination therapy (OR 61.2; 95% CI 7.9-1275.3; P < 0.0001). CONCLUSION: Immune-mediated hepatotoxicity occurred in 9.5% of patients treated with ICIs. Appropriate therapeutic interventions are important to avoid affecting the patient's prognosis, and accurate diagnosis of IMH is essential for this purpose. The frequency of IMH varied according to the type of cancer and the drug used, and was significantly higher in patients with malignant melanoma and in patients given ipilimumab-nivolumab combination therapy.