cell therapies

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.

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2026-01-22 | HCC recurrence in liver transplants treated with hypothermic oxygenated machine perfusion: An international matched cohort study

Background & Aims Liver transplantation (LT) for hepatocellular carcinoma (HCC) is performed worldwide, with 5-year survival rates of approximately 70%. However, post-transplant HCC recurrence occurs in 15-20% of recipients. We aimed to evaluate, for the first time, long-term recurrence-free survival in a large international cohort of patients undergoing LT for HCC using grafts treated with hypothermic oxygenated machine perfusion (HOPE). Methods This observational post hoc analysis of the multicenter European HOPE-REAL study (NCT05520320) included adult recipients with HCC (N = 599) who received a liver from either a donation after brain death (DBD) or donation after circulatory death (DCD) donor, preserved using HOPE, dual-HOPE (DHOPE), or normothermic regional perfusion followed by HOPE (NRP-HOPE) between 2012 and 2022. Propensity score matching was used to compare outcomes between HCC and non-HCC recipients within the HOPE-REAL cohort, and between HOPE-treated HCC recipients and an external control cohort receiving non-perfused livers (n = 484). Results The overall HCC recurrence rate in the HOPE-REAL cohort was 6.9% (41/599), with no significant difference between DBD and DCD liver transplants (7.1% [25/350] vs. 6.4% [16/249]; p = 0.346). One-, 3-, and 5-year overall survival rates were 92%, 86%, and 81%, while recurrence-free survival rates were 90%, 83%, and 78%, respectively. Five-year overall survival was similar between 347 HOPE-treated HCC recipients (82%) and 347 matched non-HCC recipients (84%) ( p = 0.625). In contrast, compared to an external cohort of 312 non-perfused HCC recipients, 5-year overall survival was significantly higher in 312 matched HOPE-treated HCC recipients (74% vs. 84%; p = 0.034). Conclusions HCC recurrence was rare after transplantation of livers treated with HOPE. Long-term survival in HOPE-treated HCC recipients was significantly better than in those receiving non-perfused livers, and comparable to outcomes in non-HCC recipients. These findings warrant validation in a randomized clinical trial. Impact and implications This post hoc analysis of the HOPE REAL study demonstrates, for the first time, low hepatocellular carcinoma (HCC) recurrence rates in a large cohort of hypothermic oxygenated machine perfusion-treated liver transplant recipients with HCC, and significantly better survival outcomes compared to matched recipients of non-perfused grafts. These findings may have important implications, particularly as tumor-related indications for liver transplantation continue to rise. Machine liver perfusion could emerge as a novel strategy to improve oncological outcomes in high-risk cancer conditions after transplantation, potentially via mitigation of inflammation and reduced tumor cell seeding. Clinical trial number NCT05520320

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2025-09-26 | Hypothermic oxygenated perfusion (HOPE) against cancer recurrence after liver transplantation for hepatocellular carcinoma—study protocol for an international multicenter randomized controlled trial (HOPE4Cancer)

BACKGROUND: A frequent and increasing indication for liver transplantation (LT) is hepatocellular carcinoma (HCC). However, despite strict selection criteria, HCC recurrence after LT occurs in a relevant proportion of patients and is associated with an unfavorable prognosis. Hypothermic oxygenated perfusion (HOPE) is a novel machine liver perfusion approach to optimize liver grafts before implantation and has been suggested to decrease graft inflammation with potential anti-cancer effects. METHODS: HOPE4Cancer is an international, multicentric, parallel group, randomized controlled trial comparing HOPE performed after initial cold storage (intervention) with conventional cold storage alone (control) in a 1:1 allocation ratio. Adult recipients with proven HCC will be included for transplantation of a DBD (donation after brain death) Liver graft. The minimum perfusion duration is defined at 2 h and perfusion is generally continued until the recipient hepatectomy is completed. The conventional cold storage at 4 °C will be performed with a precooled preservation solution according to the local standard of care. The primary endpoint is defined as post-transplant HCC recurrence-free survival, i.e., the time interval a patient is alive without HCC recurrence after transplantation. Secondary endpoints are the single components of the events considered for the primary outcome (i.e., HCC recurrence, HCC-related death, death from any other causes than HCC), circulating tumor DNA, high-mobility-group-protein B1 in the blood, the Rejection Activity index, and the number of liver-related complications experienced by the patient. DISCUSSION: HOPE4Cancer investigates if cold storage plus end-ischemically applied HOPE in DBD LT is superior to conventional cold storage of liver grafts in terms of post-transplant HCC recurrence-free survival. The results will indicate for the first time whether ex situ HOPE before transplant has an anti-cancer potential compared to transplantation of un-perfused livers. TRIAL REGISTRATION: ClinicalTrials.gov NCT06717919. Registered on December 5, 2024.

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2025-09-01 | REPRIORITIZING THE LIVER TRANSPLANT WAITING LIST: IMPACT OF AUTOMATIC MELD-NA 29 FOR REFRACTORY ASCITES

In Brazil, liver allocation follows the MELD-Na score. To address high-risk conditions not reflected by high scores, special situations are evaluated individually. Refractory ascites and hepatocellular carcinoma (HCC) account for ∼80% of such cases. In 2021, Technical Note No. 32/2021 granted 29 MELD-Na points to patients with refractory ascites to improve access to liver transplant (LT). Primary, to compare the time from special situation approval to LT in cases of refractory ascites and HCC, before and after the new policy. Secondary, assess transplant volume and waiting list mortality in both groups. Retrospective, single-center study including adult patients granted special situation for refractory ascites or HCC in 2018–2020 (pre-policy) and 2022–2024 (post-policy). Cases from 2021 were excluded. Outcomes were time to LT, mortality on the waiting list, and transplant numbers. In refractory ascites, median time to LT decreased by 95 days (186 to 91; −51.1%). In HCC, waiting time increased by 36 days (197 to 233; +18.3%). Waiting list mortality dropped in both groups: from 16% to 7% for refractory ascites and from 11% to 6% for HCC. The absolute number of transplants remained stable across periods. Technical Note 32/2021 had a direct positive impact on patients with refractory ascites. However, it was associated with increased waiting time for HCC patients, although without increased mortality. These findings highlight the need for continuous monitoring of allocation policies and broader multicenter evaluation.

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2025-07-10 | Liver transplantation for HCC within and beyond Milan Criteria: single center experience with literature review

The Milan Criteria (MC) are widely accepted as the standard patient selection criteria for liver transplantation (LT). However, patients who exceed these criteria may still benefit from transplantation. Various extended criteria have been published. This study aimed to evaluate survival outcomes in hepatocellular carcinoma (HCC) patients undergoing LT, comparing those within and beyond MC, and to review the role of extended criteria in LT. This retrospective, single-center study included adult patients who underwent LT at Koç University between 2018 and 2024. Pathological data were used to categorize patients into two groups: those within MC and beyond MC. Preoperative data and postoperative overall and disease-free survival rates were compared between these groups. Additionally, a comprehensive literature review of studies evaluating extended criteria for LT in HCC patients was conducted. A total of 45 adult patients were included in the analysis. There were 23(51.1%) patients within MC, and 22(48.9%) patients in the beyond MC group. Demographics, donor types, graft types, tumor differentiations, Child scores, MELD scores, ischemia times, length of intensive care unit stays, length of hospital stays, and mortality rates were similar (p > 0.05). Tumor count, total tumor diameter, and microvascular invasion rates were statistically higher in patients beyond MC (p < 0.05). Survival analyses revealed no statistically significant differences in 1-year, 3-year, and 5-year survival rates of the patients (p > 0.05). This study highlights the potential for liver transplantation in HCC patients exceeding the Milan Criteria, with survival outcomes comparable to those within the Milan Criteria in certain cases. Despite numerous studies in the literature, optimal criteria for LT patient selection in beyond MC HCC have not been established. An optimal guideline that will help to better understand tumor behavior, guide the decision-making and timing of liver transplantation (LT), and ultimately improve post-transplant outcomes remains a key objective for future research.

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proteins

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.

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2025-12-28 | Impact of Glucagon-Like Peptide-1 Agonists on Hepatocellular Carcinoma Risk and Management in Type 2 Diabetes Mellitus: A Scoping Review

Type 2 diabetes mellitus (T2DM) is a global health burden associated with an increased risk of severe complications, including hepatocellular carcinoma (HCC). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained prominence in the management of T2DM due to their glucose-lowering and weight-reduction effects. Emerging evidence further suggests that GLP-1RAs may mitigate liver-related conditions such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, both of which are major risk factors for HCC development. This scoping review aimed to summarize and map the existing evidence on the impact of GLP-1RA therapy on the risk and management of HCC in adults with T2DM. A comprehensive, systematized search was conducted across EMBASE, Ovid MEDLINE, and Web of Science using terms related to "GLP-1 receptor agonists," "type 2 diabetes mellitus," and "hepatocellular carcinoma." Eligible studies included adult populations (≥18 years) with T2DM prescribed GLP-1RAs and reported outcomes specific to HCC incidence or progression. Six studies met the inclusion criteria, and most demonstrated a significantly reduced risk of HCC among patients with T2DM treated with GLP-1RAs compared with those using insulin or sulfonylureas. GLP-1RA monotherapy was generally more protective than combination therapy with insulin, whereas comparisons with metformin were inconclusive. The observed reduction in HCC risk is likely attributable to the anti-inflammatory, metabolic, and immunomodulatory effects of GLP-1RAs. Current evidence suggests that GLP-1RAs may play a protective role in reducing HCC risk among individuals with T2DM, particularly when compared with insulin-based regimens. Further longitudinal and randomized controlled trials are needed to elucidate the causal mechanisms and quantify the potential role of GLP-1RAs in reducing hepatocarcinogenesis. To our knowledge, this is the first scoping review to systematically map the literature examining GLP-1RA use and HCC risk in populations with T2DM.

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2024-12-19 | Enhancement of adult liver regeneration in mice through the hepsin-mediated epidermal growth factor receptor signaling pathway

Given the widespread use of partial hepatectomy for treating various liver pathologies, understanding the mechanisms of liver regeneration is vital for enhancing liver resection and transplantation therapies. Here, we demonstrate the critical role of the serine protease Hepsin in promoting hepatocyte hypertrophy and proliferation. Under steady-state conditions, liver-specific overexpression of Hepsin in adult wild-type mice triggers hepatocyte hypertrophy and proliferation, significantly increasing liver size. This effect is predominantly driven by the catalytic activity of Hepsin, engaging the EGFR-Raf-MEK-ERK signaling pathway. Significantly, administering Hepsin substantially enhances hepatocyte proliferation and facilitates liver regeneration following a 70% partial hepatectomy. Crucially, the proliferation induced by Hepsin is a transient event, without leading to long-term adverse effects such as liver fibrosis or hepatocellular carcinoma, as evidenced by extensive observation. These results offer substantial potential for future clinical applications and translational research endeavors in the field of liver regeneration post-hepatectomy.

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2019-12-06 | A tumor suppressor enhancing module orchestrated by GATA4 denotes a therapeutic opportunity for GATA4 deficient HCC patients

Rationale: Effective targeting therapies are limited in Hepatocellular carcinoma (HCC) clinic. Characterization of tumor suppressor genes (TSGs) and elucidation their signaling cascades could shed light on new strategies for developing targeting therapies for HCC. Methods: We checked genome-wide DNA copy number variation (CNV) of HCC samples, focusing on deleted genes for TSG candidates. Clinical data, in vitro and in vivo data were collected to validate the tumor suppressor functions. Results: Focal deletion of GATA4 gene locus was the most prominent feature across all liver cancer samples. Ectopic expression of GATA4 resulted in senescence of HCC cell lines. Mechanistically, GATA4 exerted tumor suppressive role by orchestrating the assembly of a tumor suppressor enhancing module: GATA4 directly bound and potently inhibited the mRNA transcription activity of β-catenin; meanwhile, β-catenin was recruited by GATA4 to promoter regions and facilitated transcription of GATA4 target genes, which were TSGs per se. Expression of GATA4 was effective to shrink GATA4-deficient HCC tumors in vivo. We also showed that β-catenin inhibitor was capable of shrinking GATA4-deficient tumors. Conclusions: Our study unveiled a previously unnoticed tumor suppressor enhancing module assembled by ectopically expressed GATA4 in HCC cells and denoted a therapeutic opportunity for GATA4 deficient HCC patients. Our study also presented an interesting case that an oncogenic transcription factor conditionally functioned as a tumor suppressor when recruited by a TSG transcription factor.

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2012-08-29 | Identification of a novel HLA-A2-restricted mutated Survivin epitope and induction of specific anti-HCC CTLs that could effectively cross-recognize wild-type Survivin antigen

Peptide vaccine based on tumor-associated antigen (TAA), which usually belongs to self-antigen with poor immunogenicity, has been considered as an attractive option for treatment of malignant tumors. The ideal TAA epitopes should have stable affinity to major histocompatibility complex (MHC) molecules and elicit strong anti-tumor immune response. Although point-mutation technology of TAA peptide may increase the binding capability to MHC molecules, some previous studies have revealed that part of the variant peptides results in lymphocyte not to effectively cross-recognize and kill the target tumor expressed wild-type TAA. Here, we designed a novel HLA-A2-restricted mutated TAA Survivin epitope nonapeptide Sur79L2 (KLSSGCAFL) that showed higher binding ability compared to wild-type peptide Sur79 (KHSSGCAFL) in T2-binding assays. To investigate whether Sur79L2 can induce Survivin-specific anti-hepatocellular carcinoma (HCC) response, we stimulated tumor-associated lymphocytes from a HCC patient with Sur79L2 in vitro. IFN-γ release and cytotoxicity assays showed Sur79L2 could effectively cross-recognize and lysis T2 cell plus peptide Sur79 and HCC cell lines (expression of wild-type Survivin antigen) in an HLA-A2-restricted manner. In contrast, peptide Sur95 (ELTLGEFLKL) that has been reported as a very promising anti-tumor epitope in a variety of tumors except HCC were not able to generate detectable cytotoxic immune responses against HCC in this study. Our results suggest that point-mutated peptide Sur79L2 is a new HLA-A2-restricted CTL epitope and may be useful for the immunotherapy for patients with HCC.

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small molecules

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.

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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

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2026-03-23 | Fibrolamellar hepatocellular carcinoma: Case report of a rare tumor and a brief review of literature

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare primary liver malignancy that typically arises in young adults without underlying cirrhosis or other established hepatic risk factors. We present the case of a 24-year-old male with a four-month history of progressive right upper quadrant abdominal pain, unintentional weight loss, and early satiety. Laboratory evaluation demonstrated mildly elevated liver transaminases and a markedly elevated serum vitamin B12 level of 3,240 pg/mL. Alpha-fetoprotein (AFP) levels were within normal limits. Cross-sectional imaging revealed a 12 cm hypervascular mass within the left hepatic lobe, with a central fibrotic scar and areas of calcification. Core needle biopsy followed by molecular analysis confirmed the diagnosis of fibrolamellar carcinoma through identification of the pathognomonic DNAJB1–PRKACA gene fusion. The patient underwent an extended left hepatectomy (R0 resection) and achieved a disease-free interval of 20 months. Twenty-six months after the initial diagnosis, routine surveillance imaging detected metastatic recurrence involving the lungs and L3 vertebral body. The patient was managed with a multidisciplinary approach that included pulmonary metastasectomy, platinum-based chemotherapy, and participation in a clinical trial evaluating a PRKACA inhibitor. This case underscores the importance of vigilant long-term surveillance in patients with FL-HCC and highlights the emerging role of targeted molecular therapies in addressing recurrent diseases.

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2026-01-10 | Trends in hepatocellular carcinoma (HCC) incidence and impact of hepatitis C antiviral therapy: A population-based subgroup analysis.

519 Background: Hepatitis C is one of the most common causes of hepatocellular cancer (HCC) in the United States. Since their introduction in the last decade, direct-acting antivirals (DAAs) have transformed the treatment of hepatitis C, leading to cure rates of over 90% sustained virologic response (SVR). This study explored recent trends in HCC incidence across the U.S, assessing the impact of HCV therapy and subgroup variations by age, race/ethnicity, and sex. Methods: SEER data from 2014 to 2024 were used to identify adults diagnosed with primary HCC. Inclusion criteria required a confirmed HCC diagnosis and complete demographic information. Patients with metastatic liver cancers or missing key variables were excluded. Age-adjusted incidence rates were calculated per 100,000 person-years. Joinpoint regression was used to estimate the annual percent change (APC) in incidence over time. Subgroup analyses were performed by age group (45–54, 55–64, ≥65), race/ethnicity (White, Black, Hispanic, Asian), and sex. In addition, a real-world cohort of 1,075 patients with hepatitis C virus (HCV) infection who were treated with direct-acting antivirals (DAAs) between 2015 and 2019 was analyzed to assess 5-year post-treatment HCC incidence through 2024. Results: From 2014 to 2024, hepatocellular carcinoma (HCC) incidence declined from 11.5 to 9.4 per 100,000 in the U.S. Sub group analysis revealed, 1) by age: 45–54 years (APC –8.22%), 55–64 years (APC –7.03%); 2) by race: Black (APC –10.64%), Hispanic (APC –8.25%), Asian (APC –8.06%); 3) by sex: male (APC –7.28%), female (APC –2.4%). The sharpest drops were seen in adults aged 45–64 and among Black, Hispanic, and Asian populations. Men had a greater decline than women. While early-stage HCC decreased significantly, advanced-stage cases plateaued or slightly increased in older adults and non-Hispanic Whites. In a real-world cohort of 1,075 hepatitis C patients treated with DAAs (2015–2019), the 5-year HCC incidence was 5.9% through 2024. Highest risk was seen in patients with cirrhosis (2.31/100 PY). Cirrhosis, non-SVR, and baseline liver nodules were significant predictors of HCC. Conclusions: HCC incidence has declined, particularly among middle-aged adults and minority populations, reflecting improved HCV treatment uptake. However, disparities persist, women and older adults saw smaller declines and more advanced-stage disease. Post-SVR HCC risk remains elevated in cirrhotic patients, highlighting the need for ongoing surveillance and targeted screening strategies. Expanding early HCV treatment and addressing demographic gaps are essential to further reduce HCC burden.

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2026-01-09 | The gut microbiome in diabetic patients with hepatocellular carcinoma: distinct bacterial compositional shifts after hepatitis C virus eradication

Background Hepatocellular carcinoma (HCC) poses a major global health burden, and diabetic patients remain at high risk even after achieving a sustained virological response (SVR) to hepatitis C virus (HCV) with direct-acting antivirals (DAAs). Gut microbiome dysbiosis is implicated in this heightened risk, but the microbial characteristics and underlying mechanisms remain poorly understood. Methods We conducted a cross-sectional study of 81 adults divided into three groups ( n = 27 each): (1) diabetic patients with HCC after SVR (DHCC), (2) diabetic patients without HCC after SVR, and (3) healthy controls. Stool samples and clinical data were collected approximately 3 years post-SVR. Microbial diversity, taxonomic composition, and predicted metabolic functions were analyzed and correlated with clinical markers of liver disease. Results DHCC patients exhibited marked microbial dysbiosis, including reduced alpha diversity (Chao1, p = 0.003) and significant ecological disruption (Kruskal–Wallis, p &lt; 0.001). The key features included enrichment of Treponema_2 (log₂FC = 7.71, padj &lt; 0.001) and Klebsiella (AUC = 0.88) and depletion of the butyrate-producing genus Faecalibacterium (2.08% vs. 9.99% in controls, p = 0.006). Functional analysis revealed a 56% reduction in butyrate synthesis and a 3.2-fold increase in lipopolysaccharide biosynthesis. These shifts correlated with clinical severity: Treponema_2 abundance was associated with hepatic encephalopathy and AST levels, whereas reduced butyrate inversely correlated with FIB-4 scores. Random forest modeling identified Klebsiella , Enterobacter , and Megasphaera as the top predictors of DHCC. Conclusion Diabetic patients with HCC after HCV eradication exhibit a persistent gut microbiome signature characterized by proinflammatory and carcinogenic features. These findings highlight potential targets for microbiome-based risk stratification and therapeutic interventions in this high-risk population.

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antibodies

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.

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2026-02-23 | Impact of Age on Patient-Reported Outcomes with First-Line Camrelizumab plus Rivoceranib versus Sorafenib in Adults with Unresectable Hepatocellular Carcinoma: Post Hoc Analyses of the CARES-310 Open-Label, Randomized, Phase 3 Trial

Introduction: The CARES-310 randomized, open-label, international phase 3 trial reported improved overall survival and progression-free survival with camrelizumab-rivoceranib compared with sorafenib in adults with unresectable hepatocellular carcinoma (uHCC). Methods: We performed a post hoc analysis of data from CARES-310 to evaluate patient-reported outcomes (PROs), survival, and safety in adults <65 years and ≥65 years. PRO endpoints included time to deterioration with a ≥10-point decrease from baseline of health-related quality of life (HRQoL), physical functioning, role functioning, and symptoms. Results: PRO data for these age cohorts demonstrated clinically meaningful benefits with camrelizumab-rivoceranib versus sorafenib in key aspects of the patient experience such as HRQoL, functioning, pain, and fatigue. Similarly, both age groups had a significant survival outcome advantage on camrelizumab-rivoceranib versus sorafenib. Although patients treated with camrelizumab-rivoceranib had higher rates of treatment-related adverse events versus sorafenib, this did not adversely affect HRQoL as assessed by PROs. The most common ≥20% grade ≥3 treatment-related adverse events in the camrelizumab-rivoceranib arm were hypertension and increased AST versus palmar-plantar erythrodysesthesia syndrome in the sorafenib arm. Conclusion: These results support the favorable benefit-risk profile of camrelizumab-rivoceranib in patients <65 years and ≥65 years as a first-line therapy in patients with uHCC who have not received prior systemic therapy.

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2025-12-30 | Treatment Patterns and Survival Outcomes Among Patients With Hepatocellular Carcinoma

Importance: The treatment landscape for hepatocellular carcinoma (HCC) is rapidly evolving, with the approval of multiple systemic therapies for patients with advanced disease since 2017. However, ideal treatment sequencing approaches remain unknown, and data on clinical practice patterns are limited. Objective: To evaluate current treatment patterns, sequencing, and survival outcomes among patients receiving systemic therapy for HCC. Design, Setting, and Participants: This retrospective cohort study used data from a nationwide electronic health record (EHR)-derived database of more than 280 oncology practices at more than 800 US cancer clinics to assess adult patients who were treated with systemic therapy for HCC from January 1, 2011, to December 31, 2023. Exposure: First-line systemic therapy type. Main Outcomes and Measures: Overall survival (OS) was defined as the time from first-line systemic therapy initiation to death, last clinical activity, or the censor date of December 31, 2023. Progression-free survival (PFS) was defined as the time from first-line systemic therapy initiation to the earliest of EHR-documented disease progression, death, last clinical encounter, or the censor date. Results: Among 4198 patients (median [IQR] age, 67 [61-74] years; 3353 [79.9%] male), sorafenib was the most common first-line systemic therapy until it was overtaken by atezolizumab-bevacizumab in 2020; durvalumab-tremelimumab also became a common first-line therapy in 2023. Of the full study cohort, 871 (20.7%) received second-line therapy. Median OS was 8.1 months (95% CI, 7.7-8.6 months) but was not significantly associated with first-line systemic therapy type. Median PFS was 3.9 months (95% CI, 3.7-4.0 months); first-line atezolizumab-bevacizumab (hazard ratio, 0.84; 95% CI, 0.71-0.99) was associated with improved PFS compared with sorafenib. Conclusions and relevance: In this cohort study of patients treated with systemic therapy for HCC between 2011 and 2023, atezolizumab-bevacizumab and durvalumab-tremelimumab emerged as the most common first-line systemic therapies administered for HCC, but relatively few patients received second-line therapy. Additional research is needed to determine optimal treatment sequencing and increase the likelihood that patients may benefit from second-line systemic therapy options.

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2025-08-01 | Effective and efficient large‐scale lung cancer screening

This news section offers Cancer readers timely information on events, public policy analysis, topical issues, and personalities. In this issue, low‐dose computed tomography screening for lung cancer enables early diagnosis in asymptomatic, high‐risk individuals and has been shown to reduce lung cancer‐related mortality. In addition, the FDA recently approved the combination of nivolumab and ipilimumab as a frontline treatment for adults with unresectable or metastatic hepatocellular carcinoma, and a trial suggests that transperineal prostate biopsy under local anesthesia offers superior prostate cancer detection over the conventional approach using transrectal ultrasound.

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2025-07-24 | Real-world treatment patterns and outcomes in patients with early-stage HCC in the US treated with resection or ablation

AIM: Real-world outcomes in early-stage hepatocellular carcinoma (eHCC) are not well characterized. We aimed to evaluate treatment patterns and long-term outcomes in patients with eHCC treated with resection or ablation in the United States. MATERIALS AND METHODS: We conducted a retrospective study with Optum's de-identified Market Clarity Data. Patient characteristics, treatment patterns, and overall survival (OS) were assessed in adults with eHCC treated with resection or ablation between July 2016 and March 2021. RESULTS: Of 649 patients who met inclusion criteria, 59.3%, 37.3%, and 3.4% underwent ablation only, resection only, or both, as their initial treatment, respectively. Median age was 64.0 years; most patients were male (72.9%) and White (65.5%). Subsequent treatment was received in 47.1% of patients. The median (quartile 1-3) time to first subsequent treatment was 216 (89.3-414.3) days. The most common subsequent treatments included embolization (22.7%) and ablation (15.6%). In total, 35.7% of patients died post-index. Median OS was 67.7 (95% CI: 56.4-not estimable) months. Estimated 24-month OS was 79.0% (95% CI: 75.0-82.0). CONCLUSIONS: Our results highlight the need for post-treatment surveillance and the potential role for neoadjuvant and/or adjuvant treatments to improve outcomes in patients with eHCC treated with resection or ablation.

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2024-11-01 | 609 A phase 1 clinical trial of GEN2, a personalizing gene vector immunotherapy, in combination with valganciclovir in adult patients with hepatocellular carcinoma or tumors metastatic to liver

GEN2 is a replication-incompetent gene transfer vector, containing an mRNA genome encoding for an optimized prodrug activated enzyme [enhanced mutant herpes simplex thymidine kinase (HSV-eTK)] and an immunostimulatory cytokine (GM-CSF). In the presence of the oral prodrug, valganciclovir (VGCV), HSV-eTK triggers tumor cell killing by releasing the patient’s full complement of unique tumor antigens, including neoantigens, to directly stimulate immune activation facilitated and augmented by the locally secreted immunostimulatory cytokine. GEN2 is off-the shelf without the need for tumor biopsies and genomic sequencing in order to generate personalized neoantigens. GEN2 in combination with VGCV was evaluated in a dose-escalating Phase 1 clinical trial in 61 adult patients with hepatocellular carcinoma (HCC) or advanced solid tumors metastatic to liver (NCT04313868). Three routes of administration were investigated (data from the hepatic artery infusion and intratumoral cohort will be presented elsewhere). For the intravenous cohort (IV; n=48), GEN2 was given on Days 1/2/3 every 3 weeks with VGCV Days 8–12. As of 16 April 2024, median age 59 years; 48% male, median KPS 90, 2 median prior therapies (range 0–9). The most common tumor type was HCC (n=19), followed by colon cancer (n=13) and breast cancer (BC; n=12). Drug exposure was a median of 3.5 cycles (range 1–28), with 13 cohorts tested over an 800-fold range (1.5 x105 – 1.2 x108 TU/kg). Two dose limiting toxicities were observed: drug hypersensitivity (HSR) in Cohort 3 and Grade 3 decreased appetite in Cohort 7. Common drug-related adverse events (AEs) included HSR (15%), abdominal pain, increased total bilirubin (both 10%), elevated AST, and decreased appetite (8%). No dose dependency for AEs was observed. Common Grade 3+ toxicities (all cause): anemia (13%), pneumonia (10%), elevated total bilirubin (10%) and elevated AST (6%). Plasma pharmacokinetics: rapid blood clearance with an elimination half-life of ~24 minutes. Linear relationship between dose:Cmax and dose:AUC0->inf was observed across the dosing range. Preliminary signs of clinical activity was observed in patients with HCC and hormone-receptor positive BC. GEN2 was well tolerated at all dose levels administered. A maximum tolerated dose was not defined. Although HSRs were observed at lower doses, improved manufacturing processes (with removal of animal proteins) led to substantial reduction of this toxicity. Signs of clinical activity (HCC and HR+ BC) were observed. A second phase 1 trial is exploring IV administration on a different schedule (NCT06391918) with expansion cohorts planned at the Recommended Phase 2 Dose. NCT04313868. The study protocol and any accompanying material provided to the patient was reviewed and approved in writing by the following institutional review board/independent ethics committee: • National Kidney Transplant Institute Research Ethics Committee • Makati Medical Center Institutional Review Board • The Medical City Institutional Review Board • St. Luke’s Medical Center Institutional Ethics Review Committee • Manila Doctors Hospital Institutional Review Board The IRB/IECs were appropriately constituted and operated in accordance with the Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice ICH E6(R2). Patients provided written informed consent before any study-specific tests or procedures were performed.

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2024-01-20 | Oncolytic virus CF33-hNIS monotherapy for the treatment of gastrointestinal (GI) malignancies.

749 Background: CF33-hNIS is a novel chimeric DNA vaccinia virus engineered with the human sodium-iodide symporter (hNIS) gene. CF33-hNIS selectively replicates in tumor cells leading to cell lysis and the release of tumor- and virus-associated antigens stimulating antitumor immunity. Here, we report results of patients with GI malignancies enrolled on a first-in-human phase 1 ascending, multiple dose, safety and tolerability study of CF33-hNIS, administered intratumorally (IT) or intravenously (IV) in adult patients with metastatic or advanced solid tumors (MAST). Methods: The MAST study is evaluating the safety of CF33-hNIS administered IT or IV, alone or in combination with pembrolizumab in patients with advanced or metastatic solid tumors with ≥ 2 prior lines of therapy (NCT05346484). CF33-hNIS is administered in 21-day cycles on C1D1 and C1D8, then D1 of each cycle thereafter. Pembrolizumab begins C2D1 for the combination groups and is administered Q3W. The co-primary endpoints are safety and to identify the recommended phase 2 dose. Secondary endpoints include objective response rate according to RECIST v1.1 and iRECIST, and to assess levels of viral replication via Single-Photon Emission Computerized Tomography (SPECT) with technetium-99. Results: As of Aug 2023, we report early results from seven patients with GI malignancies who received CF33-hNIS alone, including: colorectal cancer (3), bile duct (2), pancreatic (1) and hepatocellular carcinoma (1). The disease control rate is 86%. Notably one patient with cholangiocarcinoma, treated IT with 3.0x10 7 PFU, presented with pseudoprogression with a 49% increase in tumor burden after two cycles of therapy. By the 4 th cycle they achieved a complete response (CR) with no known recurrence. A second patient with bile duct cancer, who previously progressed on checkpoint blockade therapy, achieved stable disease for >5 months upon receiving IV-administered CF33-hNIS (3.0x10 7 PFU). Treatment-related adverse events for the CR patient included grade 1 fever and injection site reaction. All other patients experienced no treatment-related adverse events. SPECT analysis of the CR patient reveals intense levels of viral replication within the injected lesion and a concomitant increase in Th1 cytokines in cycle three that coordinated with tumor reduction. In-depth immunological changes in peripheral blood and on-treatment tumor biopsies will be presented. Conclusions: CF33-hNIS can replicate within cholangiocarcinoma lesions, as shown by SPECT imaging, and drive immunological changes known to promote antitumor immunity. CF33-hNIS monotherapy may be an effective and safe treatment option for GI malignancies, including cholangiocarcinoma, a rare disease with an unmet medical need. Treatment with CF33-hNIS monotherapy was well tolerated and the study has advanced to examine combination therapy with pembrolizumab. Clinical trial information: NCT05346484 .

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2023-07-31 | SRSF10 inhibition prevents HCC growth and metastasis and enhances the anti-PD-L1- mediated tumor suppression

Abstract The authors have requested that this preprint be removed from Research Square.

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2020-05-30 | IGF2BP3 and miR191‑5p synergistically increase HCC cell invasiveness by altering ZO‑1 expression

Early studies have indicated that insulin-like growth factor II mRNA binding protein 3 (IGF2BP3/IMP3) may affect the progression of hepatocellular carcinoma (HCC); however, the detailed underlying mechanisms, particularly its linkage to tight junction protein-mediated cell invasion, remain unclear. The present study revealed that IGF2BP3 increased HCC cell invasiveness by suppressing zonula occludens-1 (ZO-1) expression, via direct binding to the 3' untranslated region (3'-UTR). Analysis of the molecular mechanisms demonstrated that IGF2BP3 binds to the overlapping targets of IGF2BP3-RNA cross-linkage and microRNA (miR)191-5p targeting sites, and promotes the formation of an miR191-5p-induced RNA-induced silencing complex. The knockdown of IGF2BP3 or the addition of a miR-191-5p inhibitor decreased cellular invasiveness and increased ZO-1 expression. Analysis of the human HCC database also confirmed the association between IGF2BP3 and HCC progression. Collectively, these preclinical findings suggest that IGF2BP3 increases HCC cell invasiveness by promoting the miR191-5p-induced suppression of ZO-1 signaling. This newly identified signaling effect on small molecule targeting may aid in the development of novel strategies with which to inhibit HCC progression more effectively.

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2017-10-23 | Dysregulated long noncoding RNAs (lncRNAs) in hepatocellular carcinoma: implications for tumorigenesis, disease progression, and liver cancer stem cells

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours with a poor prognosis worldwide. While early stage tumours can be treated with curative approaches such as liver transplantation or surgical resection, these are only suitable for a minority of patients. Those with advanced stage disease are only suitable for supportive approaches and most are resistant to the conventional chemotherapy or radiotherapy. Liver cancer stem cells (LCSCs) are a small subset of cancer cells with unlimited differentiation ability and tumour forming potential. In order to develop novel therapeutic approaches for HCC, we need to understand how the cancer develops and why treatment resistance occurs. Using high-throughput sequencing techniques, a large number of dysregulated long noncoding RNAs (lncRNAs) have been identified, and some of which are closely linked to key aspects of liver cancer pathology, progression, outcomes and for the maintenance of cancer stem cell-like properties. In addition, some lncRNAs are potential biomarkers for HCC diagnosis and may serve as the therapeutic targets. This review summarizes data recently reported lncRNAs that might be critical for the maintenance of the biological properties of LCSCs.

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