JHEP Reports最新文献

Background & aims: Irreversible electroporation (IRE) and stereotactic body radiotherapy (SBRT) are important therapeutic alternatives for hepatocellular carcinoma (HCC) unsuitable for thermal ablation, but comparative outcome data remain limited. We compared the efficacy and safety of IRE versus SBRT for solitary HCC ≤5.0 cm.

Methods: Between January 2019 and December 2024, this multicenter retrospective cohort study at five centers included 315 patients with solitary HCC ≤5.0 cm (IRE, n=180; SBRT, n=135). To reduce confounding, propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and restricted cubic splines (RCS) were applied. The primary endpoint was cumulative recurrence rate (CRR), comprising cumulative local recurrence (CLRR) and cumulative distant recurrence (CDRR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs).

Results: After a median follow-up of 36 months, matched cohorts showed no significant differences in CRR (HR, 0.83; P=.332), PFS (HR, 0.77; P=.171), or OS (HR, 0.76; P=.529). However, in the matched cohort, IRE achieved superior local control, with a lower 3-year CLRR (14.2% vs 30.5%; HR, 0.31; P=.001). SBRT local control was lower than in some prior studies, possibly reflecting anatomically complex tumors requiring risk-adapted planning. This CLRR benefit was consistent across tumor sizes and in perivascular HCC. CDRR was comparable (HR, 0.92; P=.685). Overall AE rates were similar (33.3% vs. 38.5%; P = .266), though profiles differed (transaminase elevations with IRE vs. gastrointestinal disturbances with SBRT).

Conclusions: IRE and SBRT yielded comparable OS and PFS for solitary HCC ≤ 5.0 cm. However, IRE offered significantly superior local tumor control, especially for tumors adjacent to major vessels.

Impact and implications: This multicenter study addresses the limited comparative evidence between irreversible electroporation (IRE) and stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma unsuitable for thermal ablation. The findings indicate that while survival outcomes were comparable, IRE demonstrated superior local tumor control, particularly for perivascular lesions. These results support IRE as a strategic therapeutic option for anatomically complex tumors, aiding clinicians in optimizing treatment selection based on specific tumor location and vascular proximity. Future prospective trials are warranted to validate these findings and refine patient selection.

Background and aims: Unresectable intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis, with limited curative options. Chemotherapy combined with selective internal radiation therapy (SIRT) has shown promising results in tumors response and survival. We evaluated liver transplantation (LT) outcomes following this neoadjuvant approach in patients with liver-limited iCCA in our center.

Method: We retrospectively included all patients who underwent LT in the Rennes University Hospital for unresectable, locally advanced iCCA following neoadjuvant treatment with a combination of chemotherapy and SIRT.

Results: 6 patients were transplanted between 2010 to 2024. The median timeframe from diagnosis to listing was 351 days (IQR 250-558 days). The median time from listing to LT was 114 days (44-192 days). Age was 50.7 years (39.9-59.3) with a sex ratio of 1/1. The initial total tumor size was 100 mm (65-115 mm), with one tumoral lesion (1-1). Neoadjuvant treatment consisted of a gemcitabine-cisplatin regimen in 4 of 6 patients (66.7%), while one patient received cisplatin combined with 5-fluorouracil. The median follow-up was 4.9 years (1.8-8.8). The median length of hospitalization following LT was 12 days (10-20 days). Five-year overall survival was 100%, while five-year progression-free survival was 44.4% (95% CI: 8.9-88.0) with 3 patients experienced iCCA recurrence on days 573, 577, and 1180 after LT. No patient has yet died from tumor progression.

Conclusion: this study presents one of the first series of unresectable iCCA cases treated with a neoadjuvant combination of SIRT and chemotherapy. Very selected patients (6 patients over 15 years) who underwent LT demonstrated high long-term survival rates and an acceptable recurrence rate, even in the presence of large tumor sizes. Prospective trials evaluating this neoadjuvant combination are awaited.

Impact and implications: Liver transplantation is not currently considered a standard therapeutic option for patients with unresectable, liver-limited intrahepatic cholangiocarcinoma due to historically poor outcomes. This study provides a scientific rationale for reconsidering transplantation in a highly selected subgroup of patients who achieve sustained disease control after neoadjuvant chemotherapy combined with selective internal radiation therapy. The results are particularly relevant for transplant hepatologists, oncologists, and surgeons, as they suggest that treatment response and prolonged disease stability may better predict post-transplant outcomes than tumor size alone. Clinically, these findings support a multidisciplinary, response-based selection strategy with a "test-of-time" approach, while acknowledging the small sample size and retrospective design, and highlight the need for prospective studies and structured allocation frameworks to safely expand this approach.

Background and aims: Biliary atresia (BA) is a progressive neonatal cholangiopathy characterized by unresolved inflammation and neutrophil extracellular traps (NET) formation. Although neutrophils contribute to bile duct injury, the upstream mechanisms driving their activation remain poorly defined. This study investigated whether platelet (PLT) hyperactivation promotes NET-mediated inflammation in BA and evaluated the therapeutic potential of targeting S100A8/A9.

Methods: The role of PLT hyperactivation in neutrophil-mediated inflammation in BA was evaluated through retrospective clinical review, single-cell RNA sequencing, and cell coculture experiments. The therapeutic potential of paquinimod, a small-molecule inhibitor that blocks S100A8/A9 binding to Toll-like receptor 4 on PLT and thereby suppresses PLT activation, was evaluated in a murine model of BA.

Results: Elevated PLT counts were observed in 54.2% (236/435) of patients with BA, and PLT hyperactivation (CD62p⁺) was increased in both patients and RRV-injected mice (P<0.0001). Single-cell analysis identified an expanded hyperactivated PLT subset enriched in proinflammatory pathways. Mechanistically, PLTs from patients with BA exhibited mitochondrial dysfunction and released oxidized mitochondrial DNA (ox-mtDNA), thereby promoting NET formation. An expanded population of S100⁺ neutrophils (47.0% vs. 14.3%, P<0.0001) expressing S100A8/A9 established a self-perpetuating inflammatory circuit that amplified PLTs activation and enhanced proinflammatory cytokine production (IL-1β, IL-6, TNF-α, P<0.001). In the murine model, treatment with paquinimod suppressed platelet activation, reduced hepatic NET formation, and significantly improved survival (83.3% vs. 0.0%, P<0.0001).

Conclusions: PLT hyperactivation drives ox-mtDNA-dependent NET formation and amplifies inflammatory signaling in BA. Pharmacological inhibition of S100A8/A9 with paquinimod attenuates disease progression in mice.

Impact and implications: Biliary atresia is a serious neonatal liver disease featuring bile duct inflammation and obstruction. Here, hyperactivated PLTs in biliary atresia patients released ox-mtDNA, triggering NET formation and exacerbating liver injury. Blocking the key inflammatory mediator S100A8/A9 with paquinimod reduced PLT activation and liver inflammation and improved survival in mice. These findings reveal a vicious immune cycle between PLTs and neutrophils and highlight novel treatment options for attenuating disease progression.

Background and aims: Evidence on atezolizumab plus bevacizumab (AtezoBev) in very elderly with hepatocellular carcinoma (HCC) remains rare in European ancestry population. We compared outcomes in patients aged ≥75 years with younger patients.

Methods: This multicenter retrospective study included patients treated with first-line AtezoBev for advanced HCC. Patients aged ≥75 years were matched 1:1 with those <75 years using propensity scores. Overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs) were analyzed.

Results: Among 814 patients, 566 (69.5%) were <75 (median age 64, 84% male) and 248 (30.5%) ≥75 (median age 78, 86% male). After matching, 484 were analyzed. After a median follow-up of 28.0 months, OS and PFS were similar in ≥75 and <75 (15.4 vs 16.07 months; p=0.936), (7.2 vs 6.5 months; p=0.706) respectively. Age ≥ 75 years was not associated with PFS nor OS. In patients aged ≥ 75 years, modified Albumin-Bilirubin grade 3 (mALBI) was the only factor associated with disease progression (HR 4.37, 95% CI 2.04,9.37; p<0.001) and mortality (HR 5.62, 95% CI 2.47,12.8; p<0.001). In mALBI 3 median OS and PFS were 5.43 (2.93-) and 2.3 months (1.63-) respectively. Immune-related AEs (IRAEs) were less frequent in ≥ 75 including (22.1% vs 36.9%; p<0.001) or excluding dysthyroidism (15.9% vs 25.9%; p=0.01). In univariate analysis, OS and PFS were longer in patients ≥ 75 years who developed hypertension (p=0.04 and p=0.09), proteinuria (p<0.0001 and p=0.015) and IRAEs (p=0.02 and p=0.007). Hypertension during treatment was associated with proteinuria (odds ratio=13.1; 95% CI 4.1-42.4), without difference at baseline (p=0.35).

Conclusion: Atezolizumab-Bevacizumab is effective and safe in patients ≥ 75 years but mALBI 3 warrants particular caution.

Clinical number: NCT06416683.

Background and aims: Immune checkpoint inhibition (ICI) and anti-angiogenic therapies are active in hepatocellular carcinoma (HCC), although patients with impaired hepatic function have worse outcomes.

Methods: We conducted an open-label phase II clinical trial to assess the safety and efficacy of the multikinase inhibitor, sorafenib, combined with nivolumab, in patients with advanced HCC and varying liver function. In a Part 1 safety lead-in, we investigated the maximum-tolerated dose (MTD) of the combination in patients with Child-Pugh A or B7. In Part 2, we enrolled patients with Child-Pugh B7-9 HCC with the primary endpoint of grade >/=3 treatment-related adverse events (TRAE) incidence. Exploratory endpoints included immunologic biomarkers.

Results: Overall, 25 patients were consented and 16 eligible patients enrolled. In Part 1, dose-limiting toxicity occurred in 1 of 6 patients in Dose Level -1, and 2 of 5 patients in Dose Level 1; Dose Level -1 was determined to be the MTD. In total, 69% of patients experienced a Grade >/=3 TRAE, with similar distribution for patients with Child-Pugh A and B (70%, 95% CI: 0.35, 0.93 vs 66.7%, 95% CI: 0.22, 0.96). The objective response rate was 6%; median overall survival was 12.99 months (Child-Pugh A: 15.26 and Child-Pugh B: 10.41). We found that patients with Child-Pugh B liver disease harbored more circulating suppressive CD14⁺ monocytes at baseline.

Conclusions: While combination sorafenib and nivolumab demonstrated acceptable safety at the MTD in both Child-Pugh subgroups, the objective response rate was below the pre-specified threshold to be declared worthy of further exploration. A distinct immune cell profile in Child-Pugh B patients may define mechanisms of resistance and potential therapeutic targets in this population with unmet clinical need.

Impact and implications: This study addresses the critical need for effective therapies for patients with advanced hepatocellular carcinoma (HCC) and compromised liver function, a population historically excluded from many clinical trials. The findings suggest that while the combination of sorafenib and nivolumab demonstrated acceptable safety across different liver function subgroups, there was a low response rate overall. Importantly, the discovery of distinct immune profiles, particularly an increase in suppressive immune cells in patients with worse liver function, provides insights into potential mechanisms of resistance to immunotherapy. These results are crucial for understanding how we can improve the treatment of advanced HCC, especially in patients with impaired liver function.

Clinicaltrials:

Gov identifier: NCT03439891.