Direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection patients (CH) results in a sustained viral response (SVR) in over 95% of patients. However, hepatocellular carcinoma (HCC) occurs in 1–5% of patients who achieved an SVR after treatment with interferon. We attempted to develop a minimally invasive and highly reliable method of predicting the occurrence and recurrence of HCC in patients who achieved an SVR with DAA therapy. The exosomal miRNA expression patterns of 69 CH patients who underwent HCC curative treatment and 70 CH patients were assessed using microarray analysis. We identified a miRNA expression pattern characteristic of SVR-HCC by using machine learning. Twenty-five of 69 patients had HCC recurrence. The expression of four exosomal miRNAs predicted HCC recurrence with 85.3% accuracy. Fifteen of 70 patients had HCC occurrence. The expression of four exosomal miRNAs predicted the onset of HCC with 85.5% accuracy. The expression patterns of miR-4718, 642a-5p, 6826-3p, and 762 in exosomes were positively correlated with those in the liver, and downregulation of these miRNAs induced cell proliferation and prevented apoptosis in vitro. Aberrant expression of four miRNAs, which was used for prediction, was associated with HCC onset after HCV eradication. Expression patterns of exosomal miRNAs are a promising tool to predict SVR-HCC.

Notch signaling receptors, ligands, and their downstream target genes are dysregulated in pancreatic ductal adenocarcinoma (PDAC), suggesting a role of Notch signaling in pancreatic tumor development and progression. However, dysregulation of Notch signaling by post-translational modification of Notch receptors remains poorly understood. Here, we analyzed the Notch-modifying glycosyltransferase involved in the regulation of the ligand-dependent Notch signaling pathway. Bioinformatic analysis revealed that the expression of epidermal growth factor (EGF) domain-specific O-linked N-acetylglucosamine (EOGT) and Lunatic fringe (LFNG) positively correlates with a subset of Notch signaling genes in PDAC. The lack of EOGT or LFNG expression inhibited the proliferation and migration of Panc-1 cells, as observed by the inhibition of Notch activation. EOGT expression is significantly increased in the basal subtype, and low expression of both EOGT and LFNG predicts better overall survival in PDAC patients. These results imply potential roles for EOGT- and LFNG-dependent Notch signaling in PDAC.

Steatotic liver disease (SLD) is often detected in health examinations. However, although individuals with metabolic dysfunction-associated SLD (MASLD) may have decreased bone mineral density (BMD), the specific risk factors remain unclarified. The objective of this study was to identify the factors associated with decreased BMD in patients with MASLD. Individuals who underwent abdominal ultrasonography and BMD measurements at our healthcare center were included. The BMD of the calcaneus was assessed using an AOS-10SA bone densitometer. Decreased BMD was defined as a T-score below -1.0 SD or the administration of osteoporosis treatment. SLD was diagnosed based on specific ultrasonographic criteria. A total of 1410 patients were diagnosed with MASLD. The median age was 52 years. Multivariate analysis using a logistic regression model revealed that the independent predictors of decreased BMD were a low body mass index (BMI) or a small waist circumference (odds ratio (OR): 0.48, 95% confidence interval (CI): 0.34-0.67), hypertriglyceridemia (OR: 1.29, 95% CI: 1.00-1.65), and a weak grip strength (OR: 0.98, 95% CI: 0.97-1.00). Subgroup analyses of individuals aged 50 years or older, men, and individuals with a FIB-4 index of 1.3 or greater revealed that the absence of a high BMI or a large waist circumference was associated with decreased BMD. The subgroup analysis of men revealed that a weaker grip strength was associated with decreased BMD. The present study suggested several potential risk factors for decreased BMD in patients with MASLD. Individuals with the abovementioned risk factors should be encouraged to undergo BMD measurement from the perspective of preventive medicine.

Immune checkpoint inhibitors (ICIs), which target immune regulatory molecules such as cytotoxic T-lymphocyte–associated protein 4 and programmed death-ligand 1, are widely used as standard treatments for various cancer types. However, by overcoming T-cell suppression, they can also trigger immune-related adverse events (irAEs) that may necessitate treatment discontinuation. Rechallenging with an ICI after irAE resolution remains a clinical dilemma. This review evaluates current evidence on the efficacy and safety of ICI rechallenge. Systematic reviews and meta-analyses have demonstrated notable efficacy, with pooled objective response rates (ORR) ranging from 21.8% to 43.1% and disease control rates from 62.0% to 71.9%. Efficacy appears higher among patients who initially discontinued treatment due to an irAE than among those who stopped because of disease progression. For instance, a recent phase II study of nivolumab rechallenge in non–small cell lung cancer patients who relapsed after an initial response reported a modest ORR of 8.5%. Nonetheless, this potential benefit must be balanced against the risk of toxicity recurrence. The recurrence rate of the same irAE is ~32%, with risk varying by organ systems. Safety comparisons between initial treatment and rechallenge yield mixed results, with some studies reporting higher and others similar rates of severe events. Although major guidelines recommend permanent discontinuation for severe (Grade ≥ 3) irAEs, emerging evidence—including class-switching strategies and organ-specific prophylaxis—suggests that rechallenge may be feasible in selected patients. A personalized risk–benefit assessment remains essential, considering the type and severity of the initial irAE and the reason for discontinuation.

Immune checkpoint inhibitor (ICIs) therapy can cause immune checkpoint inhibitor-related pancreatic injury (ICI-PI). This study aimed to elucidate the clinical characteristics of ICI-PI and explore treatment approaches. We retrospectively analyzed data from patients with malignancies treated with ICIs at Nagoya University Hospital between September 2014 and June 2023. ICI-PI and pancreatitis were identified and classified using the Common terminology Criteria for Adverse Events (CTCAE) ver.5.0, and the patients with ICI-PI with/without pancreatitis were analyzed. This study included data from 930 patients treated with ICIs. Of these, eight (0.85 %) and 10 (1.08 %) patients were diagnosed with ICI-PI without and with pancreatitis, respectively. Five of the 10 patients received standard pancreatitis treatment, while three received additional glucocorticoid therapy. One patient experienced recurrent pancreatitis and developed a pancreatic pseudocyst, which improved after high-dose glucocorticoid treatment. ICI rechallenge was pursued in five patients. Two patients received ICIs without an interval. ICI-PI with pancreatitis is rare but has become more prevalent with the increasing use of ICIs. Future prospective multicenter studies are needed to confirm these findings and develop standardized diagnostic and treatment protocols.

Background: While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, they can trigger severe immune-related adverse events (irAEs). The safety and efficacy of ICI retreatment after severe irAEs remain poorly understood. Methods: We conducted a retrospective analysis of 1271 patients with malignancies treated with ICIs at a university hospital in Japan between September 2014 and June 2023. We evaluated the incidence and characteristics of severe irAEs, defined as grade ≥3, and the safety and efficacy of ICI retreatment. Results: Severe irAEs occurred in 222 patients (17.5%). Patients with single endocrinopathies were excluded, and 46 (28.4%) of the remaining 162 patients underwent ICI retreatment. Upon retreatment, 14 patients (30.4%) experienced recurrent or new grade ≥2 irAEs. One patient who experienced hepatotoxicity (grade 3) at initial ICI treatment developed a recurrence (grade 4). Regarding antitumor response, the objective response rate to retreatment was 28.3% (13/46), with 10.9% achieving complete and 17.4% partial response. The median duration of ICI administration after retreatment was 218 days (95% confidence interval [CI]: 84-399). At 1 year after retreatment, 15.4% (95% CI: 6.8-27.4) of patients discontinued due to irAEs, 44.4% (95% CI: 29.7-58.1) due to disease progression, 6.6% (95% CI: 1.7-16.3) completed planned treatment, and 33.4% (95% CI: 20.3-47.2) continued treatment. Conclusions: ICI retreatment after severe irAEs demonstrated a manageable safety profile and promising efficacy, even in patients with grade ≥3 irAEs. ICI retreatment may be a viable option for patients with limited alternatives, particularly those showing favorable antitumor responses at initial treatment.