2026-07-03 | Glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors after liver resection for hepatocellular carcinoma in patients with type 2 diabetes: a target trial emulation study
BACKGROUND: Recurrence after curative-intent resection remains common in hepatocellular carcinoma (HCC), and whether postoperative incretin-based treatment choice influences outcomes in patients with type 2 diabetes (T2D) is unclear. OBJECTIVE: To determine whether postoperative initiation of glucagon-like peptide-1 receptor agonists (GLP-1RAs), compared with dipeptidyl peptidase-4 inhibitors (DPP-4is), is associated with improved recurrence-free and overall survival after curative-intent resection for HCC. DESIGN: Active-comparator, new-user target trial emulation using electronic medical records from 36 hospitals across China from 2014 to 2023, with follow-up through 1 October 2025. Eligible adults had histologically confirmed HCC and T2D, underwent R0 resection and initiated a GLP-1RA or DPP-4i within postoperative days 0 to 90. Time zero was the first qualifying prescription or order date. The primary estimand was intention-to-treat; a prespecified per-protocol analysis assessed sustained adherence. The primary outcome was recurrence-free survival (RFS), treating death without recurrence as a competing event; overall survival (OS) was secondary. The study was registered with the Chinese Clinical Trial Registry (ChiCTR2600118495). RESULTS: Among 42 855 patients with HCC and T2D who underwent liver resection, 1249 were included in the final analytical cohort, including 723 DPP-4i initiators and 526 GLP-1RA initiators; median follow-up was 50.8 months. In weighted intention-to-treat analyses, GLP-1RA versus DPP-4i initiation was associated with longer RFS (cause-specific HR 0.80, 95% CI 0.67 to 0.96; p=0.016) and OS (HR 0.58, 95% CI 0.47 to 0.71; p<0.001). Per-protocol analyses were directionally consistent. CONCLUSION: Postoperative GLP-1RA initiation, compared with DPP-4i initiation, was associated with delayed recurrence and longer OS; prospective confirmation is warranted. TRIAL REGISTRATION NUMBER: ChiCTR2600118495.
Open article ↗
2026-05-27 | CheckMate-9DW 4-year follow-up: Overall survival by depth of response and outcomes in long-term survivors.
4104 Background: Nivolumab plus ipilimumab (NIVO + IPI) was globally approved as a first-line (1L) treatment for unresectable hepatocellular carcinoma (HCC) based on the phase 3 CheckMate 9DW trial (NCT04039607). We report 4-year follow-up results and overall survival (OS) by depth of response (DpR). Methods: Methods were reported previously (Yau T. Lancet 2025). Briefly, adults with previously untreated unresectable HCC were randomized 1:1 to receive NIVO + IPI (then NIVO for ≤ 2 years) or lenvatinib/sorafenib (LEN/SOR). OS analyses were done by best percentage change in tumor burden from baseline. We also present exploratory analyses on long-term survivors (survival ≥ 4 years after randomization). Results: A total of 668 patients (pts) were randomized to NIVO + IPI (n = 335) or LEN/SOR (n = 333); among 325 pts treated with LEN/SOR, 275 (85%) received LEN. At a median (range) follow-up of 52.5 (44.0–66.1) mo, NIVO + IPI continued to show OS benefit (95% CI) vs LEN/SOR (HR 0.78 [0.65–0.93]) with higher objective response rate (ORR; 95% CI) by blinded independent central review (BICR; 36% [31–42] vs 13% [10–17]) and more durable responses. Pts with deeper tumor reduction had numerically improved median OS on both NIVO + IPI and LEN/SOR; the trend was more pronounced with NIVO + IPI specifically in pts with tumor shrinkage ≥ 30% (Table). More pts treated with NIVO + IPI (n = 62) were long-term survivors vs pts treated with LEN/SOR (n = 33). In long-term survivors, ORR by BICR was higher with NIVO + IPI vs LEN/SOR (76% vs 24%), with higher rates of complete response (CR; 21% vs 6%; Table); median duration of response was not reached in either group. Among long-term survivors, median (range) treatment-free interval was 23.3 (0.1–56.6) mo with NIVO + IPI and 0.5 (0.1–54.0) mo with LEN/SOR; 26 of 62 (42%) and 2 of 33 (6%) patients, respectively, were off study treatment and remained free from subsequent treatment. Baseline characteristics and incidence of TRAEs in long-term survivors were consistent with all randomized pts. Conclusions: 1L NIVO + IPI continued to show sustained efficacy benefit vs LEN/SOR in unresectable HCC with no new safety concerns at the 4-year follow-up. These analyses suggest deeper responses with NIVO + IPI may be associated with improved survival outcomes. Long-term survivors treated with NIVO + IPI had higher ORR and CR rates vs LEN/SOR, and were more likely to remain free of subsequent treatment. These results reinforce NIVO + IPI as a 1L treatment for unresectable HCC. Clinical trial information: NCT04039607 . DpR, a % NIVO + IPI(n = 290) b LEN/SOR(n = 286) b Median OS (95% CI), mo Median OS (95% CI), mo −100 to ≤−60 NR (NE) NR (28.3–NE) −60 to ≤−30 31.1 (19.9–40.4) 20.9 (15.1–30.9) −30 to 20 17.0 (14.8–22.0) 20.5 (17.1–22.9) ≥20 14.3 (6.0–17.5) 7.8 (4.8–19.3) Best overall response in long-term survivors a NIVO + IPI (n = 62) LEN/SOR (n = 33) ORR (95% CI), % 76 (63–86) 24 (11–42) CR, % 21 6 a By BICR. b Response evaluable pts. NE, not estimable; NR, not reached.
Open article ↗
2026-05-21 | Association Between SGLT2 Inhibitor Use and Hepatocellular Carcinoma Risk in Type 2 Diabetes: A Systematic Review and Meta-Analysis
Background and Aims: Type 2 diabetes mellitus is a recognized risk factor for hepatocellular carcinoma (HCC), particularly in the setting of metabolic dysfunction-associated steatotic liver disease (MASLD), chronic viral hepatitis, advanced fibrosis, and cirrhosis. Beyond hyperglycemia and insulin resistance, diabetic hepatocarcinogenesis is shaped by metabolic inflammation, lipotoxicity, oxidative stress, fibrogenic remodeling, and the cirrhosis-dysplasia-HCC continuum. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) may influence several hepatometabolic pathways, but the epidemiologic evidence linking SGLT2i use to HCC risk remains heterogeneous. Methods: We conducted a systematic review and meta-analysis of observational studies evaluating SGLT2i exposure and incident HCC in adults with type 2 diabetes. PubMed, Embase, and the Cochrane Library were searched up to 15 March 2026. Adjusted time-to-event estimates were pooled using a restricted maximum likelihood (REML) random-effects model. The certainty of evidence was assessed using the GRADE framework and judged to be very low. Results: Six observational studies including 526,446 participants were included. SGLT2i exposure was associated with a lower observed risk of incident HCC (pooled HR 0.59, 95% CI 0.45–0.77), but between-study heterogeneity was substantial (I2 = 75.2%, τ2 = 0.074). The association remained directionally similar after exclusion of Huynh et al. (HR 0.61, 95% CI 0.45–0.81) and in a DPP-4 inhibitor-restricted active-comparator analysis (HR 0.60, 95% CI 0.39–0.92). However, the 95% prediction interval crossed the null (0.25–1.37), indicating that future comparable studies may plausibly show no protective association. Conclusions: SGLT2i exposure was associated with a lower observed risk of incident HCC across available observational studies. However, the certainty of evidence was judged to be very low, and substantial heterogeneity, comparator variation, mixed time-to-event estimands, residual confounding, and a prediction interval crossing the null preclude causal interpretation. These findings should be considered hypothesis-generating rather than practice-changing evidence and support further hepatology-oriented validation.
Open article ↗
2026-05-01 | Metastatic Fibrolamellar Hepatocellular Carcinoma in a Young Adult: A Case Report and Narrative Review
Abstract: Fibrolamellar hepatocellular carcinoma (FLC) is a rare and distinct histologic subtype of hepatocellular carcinoma that typically arises in non-cirrhotic livers of adolescents and young adults without underlying viral hepatitis or chronic liver disease. Accounting for less than 1% of all primary liver cancers, FLC is characterized by unique clinical, radiologic, and molecular features, most notably the highly characteristic DNAJB1–PRKACA fusion. Due to its rarity and frequently nonspecific presentation, diagnosis is often delayed or misinterpreted as by benign hepatic lesions such as focal nodular hyperplasia or adenoma. This report presents a rare case of metastatic FLC in a young adult who initially presented with right upper quadrant pain, anemia, and preserved hepatic function. Imaging revealed a large hepatic mass with a central non-enhancing area suggestive of necrosis, and histopathologic evaluation aided in the diagnosis based on characteristic lamellar fibrosis, polygonal eosinophilic cells, and positive CK7 and HepPar-1 staining. Confirmatory molecular testing through DNAJB1–PRKACA fusion was not performed. Planned treatment with a combination regimen of nivolumab and neratinib was scheduled; however, the patient deteriorated rapidly, and systemic therapy could not be initiated before death. Through this case and accompanying review, we aim to highlight the diagnostic complexity, molecular underpinnings, and current therapeutic approaches of FLC. This case was notable for advanced peritoneal carcinomatosis at presentation, severe thrombocytosis, and the diagnostic and therapeutic challenges posed by metastatic fibrolamellar carcinoma without molecular confirmation. Taken together, this underscores the importance of early recognition, molecular testing, and coordinated clinical management in optimizing outcomes for this uncommon malignancy. Keywords: fibrolamellar hepatocellular carcinoma, liver cancer, case report, pathogenesis, diagnosis, treatment, immunotherapy
Open article ↗
2026-04-15 | Liver transplantation for hepatocellular carcinoma arising in non-cirrhotic liver: a national-wide retrospective cohort study with propensity score matching analysis in China.
The majority of liver transplantation (LT) recipients for hepatocellular carcinoma (HCC) present with concomitant liver cirrhosis. However, there is limited research focusing on recipients without cirrhosis. This study aims to investigate the prognosis of non-cirrhotic HCC recipients, with the objective of providing a theoretical basis for improving outcomes in this patient population. This retrospective study analyze outcomes between adult HCC recipients arising in non-cirrhotic and cirrhotic liver based on the China Liver Transplant Registry (CLTR) database from January 2015 to December 2020. Based on important variables, 1:2 propensity score matching (PSM) was performed respectively. A total of 845 non-cirrhotic HCC recipients were enrolled, which were matched with cirrhotic HCC recipients (n=1,690) at a 1:2 ratio from CLTR. Compared with cirrhotic recipients, non-cirrhotic recipients presented lower overall (P=0.003), tumor free (P=0.03) and graft survival rates (P=0.007). Among recipients fulfilling Hangzhou criteria, the above survival rates of non-cirrhotic recipients were lower than those of cirrhotic recipients (P=0.001, P=0.02 and P=0.002, respectively). The HCC recurrence rate was higher in cirrhotic recipients than that in non-cirrhotic recipients (15.3% vs. 11.1%, P=0.005). In non-cirrhosis recipients, multivariate analysis revealed that beyond Hangzhou criteria [hazard ratio (HR) =2.079, P<0.001], Model for End-stage Liver Disease score ≥25 (HR =1.502, P=0.01) and early allograft dysfunction (EAD) (HR =2.139, P<0.001) were independent risk factors for overall survival, while recipient age ≥50 years (HR =1.423, P=0.02), beyond Hangzhou criteria (HR =2.188, P<0.001) and EAD (HR =1.918, P<0.001) for tumor-free survival. LT for non-cirrhotic HCC is associated with a poor prognosis. This finding suggests that non-cirrhotic HCC may exhibit more aggressive characteristics and warrants greater clinical attention.
Open article ↗
