BACKGROUND & AIMS:Liver transplantation (LT) is a curative treatment option in early and intermediate hepatocellular carcinoma (HCC) following downstaging with locoregional therapies (LRT). Tumor response to immune checkpoint inhibitors may extend LT eligibility to intermediate and advanced stages. METHODS:In this prospective phase II study, patients with intermediate and advanced HCCs beyond extended transplant criteria, not amenable to further LRTs, were downstaged with atezolizumab-bevacizumab (Atezo-Bev) prior to LT. The primary endpoint was recurrence-free survival with safety and efficacy as additional outcomes. Spectral quantitative pathology and immune signatures in tumor tissue and peripheral blood were studied longitudinally. RESULTS:Sixteen patients with HCC beyond expanded transplant criteria (median tumor size 6.5 cm [IQR 3-8], median AFP 283 ng/ml [IQR 6-1,080], portal vein thrombosis 50%) were downstaged to LT after a median of 4.7 months (IQR 2.4-7.6). Prior LRTs were used in 15 (94%) patients. The washout period from the last Atezo-Bev dose to transplant was 57.5 (IQR 29-87) days. Median follow-up was 16 months (95% CI 4-22). Pre-transplant immune-related adverse events occurred in 3 (19%) patients and post-transplant acute rejection in 4 (25%). Post-LT 90-day morbidity and mortality were 62.5% (95% CI 35-85%) and 6.3% (95% CI 0.2-30%) respectively. Explant pathology revealed 10 complete and 6 partial responses. Responding patients harboured a tumor microenvironment with features suggestive of immune activation/extinguishment, correlated with duration of Atezo-Bev treatment and length of pre-LT washout. One (6.2%) HCC post-LT recurrence occurred during follow-up. Recurrence-free and post-transplant overall survival were 90% and 94% after 2 years, respectively. CONCLUSIONS:LT following Atezo-Bev downstaging achieves promising recurrence-free survival in intermediate and advanced HCC beyond conventional transplant criteria. Acute rejection seemed to be increased but was clinically manageable. LT should be considered in patients with HCC who respond to immunotherapy. IMPACT AND IMPLICATIONS:Immune checkpoint inhibitors are now standard treatment for advanced hepatocellular carcinoma (HCC) and some intermediate-stage cases. Emerging evidence suggests that immunotherapy may also have a role in the neoadjuvant setting before liver resection or transplantation. By inducing tumor responses, immunotherapy may downstage patients initially ineligible for curative therapies, enabling liver transplantation (LT) and favorable post-transplant outcomes. However, treatment-related adverse events, particularly graft rejection, must be balanced against potential survival benefits. In this first prospective study evaluating LT after atezolizumab-bevacizumab (Atezo-Bev) in patients with intermediate or advanced HCC not amenable to other therapies, 26% achieved transplant eligibility. Two-year post-LT outcomes were comparable to those observed with conventional transplant criteria. Immune monitoring indicated that tumor response and graft rejection are closely linked through the PD-1/PD-L1 pathway. Although rejection risk appeared increased, it was manageable with standard steroids and intensified early immunosuppression. These findings support considering expanded transplant criteria in selected patients with sustained responses to immunotherapy. REGISTRATION NUMBER:NCT05879328.

BACKGROUND AND AIMS:Hepatocellular carcinoma (HCC) with tumoral portal vein thrombosis (PVTT) is considered a contraindication to liver transplantation (LT). Transarterial radioembolization (TARE) may induce sustained regression of PVTT and achieve downstaging in selected patients, potentially enabling LT. The aim of this study is to assess post-LT oncological and survival outcomes in patients with HCC and PVTT who were successfully downstaged with TARE. APPROACH AND RESULTS:Consecutive patients with HCC and PVTT treated with TARE (2010-2023) at 5 Italian transplant centers were included. Successful downstaging required a sustained radiological response for at least 6 months with a complete or partial response of the PVTT component, together with fulfillment of center-specific morphological criteria and AFP thresholds. Survival analyses were conducted for the overall cohort from TARE and the transplanted patients. Among downstaged patients, cancer-related death according to transplant status was assessed using competing-risk analysis. Among 240 patients, 61 (25.4%) achieved sustained downstaging after TARE, and 37 patients (15.4%) eventually underwent LT. In competing-risk analysis, LT was associated with a lower risk of cancer-related death (60-month cumulative incidence: 15.8% vs. 45.2%; sHR 0.221, 95% CI 0.071-0.683; p =0.0087). The median time from TARE to LT was 17 months. In the 37 transplanted patients, post-LT 3-year and 5-year OS and RFS were 67.2%/61.6% and 79.3%/79.3%, respectively. Pathology showed complete tumor necrosis in 56.7% explants. CONCLUSIONS:Radioembolization downstaged ~1 in 4 PVTT patients to transplant eligibility. After downstaging, LT conferred markedly superior oncological outcomes. TARE in PVTT associated with HCC represents a valid, transplant-oriented option with a distinct efficacy profile.

Immune checkpoint inhibitors (ICPIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) pathways have transformed systemic therapy for advanced hepatocellular carcinoma (HCC), prompting exploration of their neoadjuvant role in downstaging tumors to meet the liver transplantation (LT) criteria. While ICPIs have demonstrated impressive tumor responses and survival benefits in non-transplant settings, their peri-transplant application is limited by the substantial risk of acute graft rejection due to immune activation against the allograft. Retrospective data indicate rejection rates of approximately 18%–26% pre-LT and 28%–37% post-LT, with fatal outcomes in a subset of cases. Optimal washout periods (typically ≥50–90 days, ideally ~3 months), PD-L1 graft expression, and intensified immunosuppression appear to mitigate but not eliminate the risk. Living donor LT offers scheduling advantages for precise timing. Post-transplant ICPI use remains high-risk and requires individualized decision-making. Emerging biomarkers (e.g., graft PD-L1, ctDNA, and tumor mutational burden) and surveillance strategies hold promise for risk stratification. This review examines the safety profile, timing considerations, class-specific differences, post-LT palliative applications, and innovations needed for the safe incorporation of ICPIs into the transplant oncology protocols for HCC.

The management of hepatocellular carcinoma (HCC) has undergone radical change over the past decade. Immunotherapies now dominate the treatment of advanced-stage disease and are increasingly being evaluated in perioperative and intermediate-stage settings. However, in some instances, positive phase III trials have not translated into adoption by guidelines or regulatory agencies, highlighting the need to harmonize and update the current standards for trial design and end points. In response to these challenges, four scientific societies - the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), the International Liver Cancer Association (ILCA) and the American Society of Clinical Oncology (ASCO) - appointed representatives to develop a consensus recommendations document addressing current unmet needs and future challenges in HCC trial design and end points. Through a modified Delphi process, 102 consensus statements were developed across several distinct domains: surveillance; early-stage, intermediate-stage and advanced-stage disease; transplant-related contexts; regulatory considerations; and emerging topics. The document rigorously defines target populations, stratification factors, control arms and benchmarks for expected clinical benefit. Collectively, this consensus is intended to provide a dynamic, evidence-based, multisociety roadmap for optimizing trial design, accelerating therapeutic development and improving clinically meaningful outcomes in patients with HCC.

Background: The adoption of robotic surgery in minimally invasive liver surgery has accelerated globally in the last decade, yet its impact on clinical outcomes and the associated benefits remain to be explored. Methods: The study analyzed 8928 minimally invasive liver resections recorded in the I Go MILS registry between 2015 and 2025. Temporal trends in surgical approach, Pringle maneuver utilization, conversion to open surgery, and postoperative morbidity were assessed using Cochran-Armitage and Spearman tests. Case-mix evolution was quantified by the Kawaguchi-Gayet difficulty score. Results: Robotic utilization increased monotonically from 10.4% to 42.2%, while fully laparoscopic procedures declined from 89.6% to 57.8%. Despite this transition, aggregate conversion and morbidity showed no significant temporal trends. Stratified analysis demonstrated lower observed conversion rates in the robotic group and a progressively narrowing difference in morbidity. Overall case-mix complexity increased significantly, driven exclusively by the laparoscopic arm, while the robotic case mix remained structurally stable. Conclusions: Aggregate outcome stability during the robotic transition suggests progressive case-mix complexification rather than technological stagnation. The robotic platform seems to be associated with an apparent conversion advantage; its higher observed morbidity may be attributable to structural differences in operative difficulty. Robotics act not as a substitute for laparoscopy but as a complementary approach applied to more complex resections.

Background Jejunal carcinoma is an exceptionally rare malignancy with limited therapeutic options beyond chemotherapy. Polymerase epsilon (POLE) mutations in this tumor type are even rarer, yet they may represent a predictive biomarker for response to immune checkpoint inhibitors in jejunal cancer and agnostically.Case presentation We report a 58-year-old male patient diagnosed with a POLE-mutated jejunal carcinoma. He presented with left-sided abdominal pain and was found to have an extremely large mass in the left upper quadrant. Biopsy confirmed jejunal adenocarcinoma. He was initially treated with two cycles of FOLFOX, and upon detection of the POLE mutation, nivolumab was added. After four cycles of chemo-immunotherapy, imaging demonstrated significant tumor regression. However, radiologic and clinical signs of subocclusion prompted treatment discontinuation and surgical resection. Histopathologic analysis revealed a complete pathological response, with no viable tumor cells. The patient has been disease-free since January 2025.Conclusion This case underscores the role of immunotherapy in POLE-mutated tumors regardless of the site of origin and highlights the potential usefulness of molecular profiling in rare malignancies. In line with the agnostic approach used for microsatellite instability, molecular-driven clinical trials should be prioritized over histology-based studies to optimize treatment strategies for these orphan diseases.

The incorporation of liver-directed surgical procedures into cytoreductive surgery represents a challenge in stage IV epithelial ovarian cancer. Overall, 49 patients undergoing primary or interval debulking surgery with at least one hepatobiliary procedure were retrospectively analyzed. One intraoperative complication occurred and severe postoperative morbidity (grade III or higher according to the Clavien-Dindo classification) was observed in 8 (16.4%) patients. Only one of these complications (biliary leakage requiring endoscopic stenting) was directly attributable to liver surgery. Although limited by the small sample size, these findings suggest that, in carefully selected patients and within a multidisciplinary framework, hepatobiliary surgery can be safely incorporated into cytoreductive strategies to achieve complete tumor removal.

Indocyanine green (ICG) is exclusively uptaken by hepatocytes and rapidly cleared. Hepatocellular carcinoma (HCC) cells may also uptake ICG, but their clearance may be impaired, thus remaining fluorescent for a prolonged period of time. This characteristic may be exploited to visualize not only intrahepatic HCCs, but also extrahepatic HCC implants. We conducted a systematic literature search on Medline, Scopus, Web of Science (WoS) Core Collection and the Cochrane library to identify studies on the use of ICG fluorescence for the intraoperative visualization of extrahepatic HCC until December 2024. Eleven studies were included for a total of 44 patients: seven studies were case reports, two studies were small case series (2 patients), and two studies were larger case series (≥15 patients). The studies reported a total of 119 lesions suspected of extrahepatic localization of HCC with an ICG-detection rate after intravenous ICG infusion of 89.0%; 22 new lesions positive for ICG fluorescence not suspected during pre-operatory planning were identified intraoperatively. Among all removed fluorescent lesions, only 4 were negative for HCC. Sensitivity was 91.9%, specificity 33.3% (based on only 6 HCC-negative lesions), accuracy 89.4% while the positive predictive value 96.9%. Per-site diagnostic accuracy varied substantially, as sensitivity was 89.2% for the lungs, 93.8% for lymph nodes and 100% for peritoneum. Overall, the use of ICG as a guiding tool for intraoperative identification and dissection of extrahepatic localization of HCC appears promising, although further evidence is needed to assess whether ICG can become a standard of care in this setting.

Approximately 25% of patients with colorectal cancer (CRC) are diagnosed with distant metastases, with the liver being the most common site. A simultaneous approach to resections in these patients may lead to higher complication rates. Recent research suggests that minimally invasive surgical (MIS) techniques can help reduce this additional morbidity. This study examines a multicenter Italian experience, comparing perioperative outcomes of robotic (RS) and laparoscopic surgery (LS) in this setting. Patients from the prospective multicentre registry of the Italian Group of Minimally Invasive Liver Surgery (I Go MILS) who underwent MIS simultaneous resection for CRC with colorectal liver metastasis between 2015 and 2025 were included. Perioperative outcomes were compared between RS and LS using nearest neighbor matching with 2:1 ratio and caliper of 0.2 to mitigate the selection bias. A total of 505 patients were analyzed, including 415 undergoing LS and 90 undergoing RS. After matching, demographic characteristics were similar. Operative time, conversion rate (11.71% for LS vs 6.67% for RS, p = 0.224) and length of stay were comparable between the two groups. Robotic surgery enabled more challenging resections compared to laparoscopy and after matching for complexity was associated with lower major complications (21.62% vs 8.89%, p = 0.014). The robotic approach has demonstrated superior feasibility for technically challenging resections while maintaining similar length of stay, rate of conversion and postoperative complications, after matching for complexity RS was associated with a significantly lower rate of major complications. Robotic surgery can be an alternative to open surgery in complex cases in order to maximise the benefits of minimally invasive surgery and to have better short term postoperative outcomes.

BACKGROUND AND AIMS:Liver transplantation has evolved from a treatment restricted to patients with end-stage liver disease to a therapeutic option for selected patients with primary and metastatic liver malignancies. This review explores the rapidly expanding field of transplant oncology, highlighting its role in hepatocellular carcinoma, colorectal liver metastasis, neuroendocrine liver metastasis, and intrahepatic and perihilar cholangiocarcinoma. Emphasis is placed on strategies to broaden eligibility, optimize donor organ use, and improve oncologic outcomes. APPROACH AND RESULTS:We synthesized current evidence from clinical series, registries, and experimental protocols to evaluate patient selection criteria, outcomes, and peri-transplant management. Key topics include downstaging approaches to meet transplant criteria, such as locoregional therapies and systemic regimens, and their prognostic implications. Advances in donor utilization have been analyzed for their capacity to expand the graft pool. In addition, the review addresses the integration of oncologic principles into immunosuppression regimens, balancing graft protection with cancer control. Collectively, the reported studies demonstrate improved survival and reduced recurrence when stringent selection and multimodal therapy were applied. CONCLUSIONS:Transplant oncology reshapes the therapeutic landscape of liver malignancies, with growing evidence supporting liver transplantation in carefully selected patients beyond traditional indications. Optimized downstaging, innovative donor strategies, and tailored immunosuppression are pivotal for safe expansion. Continued collaboration between the transplant and oncology disciplines, along with prospective trials, is essential to further define standardized protocols and solidify transplantation as a cornerstone of multidisciplinary cancer care.

Background: Presently, evidence on the volume-outcome relationship for minimally-invasive liver resections (MILR) remains heterogeneous. This study aimed to investigate the volume-outcome relationships in expert centers which had already mounted the initial learning curve of MILR and had a case volume of >20 MILR/annum. Methods: This was an international multicenter retrospective analysis of 22,210 patients undergoing MILR between 2015 and 2022 at 64 centers. Centers were stratified into medium volume (MV), high volume (HV) and very high volume (VHV) defined as 20-50/51-80 and >80 MLR/annum. Difficulty of resections was graded according to the Iwate score and Institute Mutualiste Montsouris (IMM) system. Results: A total of 19,691 MILR met study criteria and were included. Of the 19,961 patients, 4,747 (2 5.6%), 4,222 (23.8%) and 10,243 (50.7%) were performed in 28 MV, 15 HV and 17 VHV centers, respectively. In the overall IMM I and IMM III cohorts, open conversion rates were consistently significantly higher in MV centers. Significantly, in the subgroup analysis of IMM 3 MILR, the VHV cohort had less blood loss [>500 mL: 443.7 (19.6%) vs. 221.6 (22.1%) (MV) vs. 296.9 (26.0%) (HV), P=0.001], shorter operative times [292 vs. 362.7 (MV) vs. 372.9 (HV) min, P<0.001] and shorter postoperative stay [7.8 vs. 8.3 (MV) and 10 (HV) days, P<0.001]. However, the HV cohort had the lower rates of open conversion [79.4 (7.0%) vs. 174.3(7.7%) (VHV) vs. 103.2 (10.3%) (MV); P=0.03]. Conclusions: Center volume-outcome relationship beyond 20 MILR/annum was not clear and results were heterogenous suggesting that factors other than center volume alone had a more significant impact on perioperative outcomes of MILR in these expert centers.

Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a rare, but deadly biliary tract cancer, increasing in incidence globally. One in five patients harbor a genetic activation of FGFR2 (fibroblast growth factor 2), where gene fusions enhance neoplastic growth. Inhibitors of FGFRs have displayed sub-optimal results—patients with advanced stage iCCA acquire drug resistance. Therefore, novel, alternative therapeutics for FGFR-driven iCCAs are crucial. A major limitation is that current preclinical models do not mimic the immunobiology of human disease. Methods We generated a mouse model harboring the FGFR2-PPHLN1 fusion (or its murine homolog mFgfr2-Pphln1) and activated YAP1 via hydrodynamic tail vein injection, and established cell lines and organoids. Additionally, the V565F resistance mutation was introduced in the FGFR2 fusion gene. We characterized tumors using RNA-sequencing (n = 3 per group) and spectral cytometry (n = 3-7 per group) and performed cross-species analysis using published human datasets [OEP001105, (n = 262); GSE33327, (n = 149)] and molecular characterization by GSEA. In vitro and in vivo drug treatment with reversible and irreversible FGFR inhibitors was performed. Results FGFR2-driven murine tumors were molecularly and immunologically similar to human iCCA carrying FGFR2 alterations, with accumulation of tumor-associated neutrophils (TANs, 60% of all CD45+) and impaired T cell infiltration. Organoids reproduced clinical responses to reversible and irreversible FGFR inhibitors, while also showing a sustained response to the reversible inhibitor derazantinib in the FGFR2V565F-PPHLN1 organoids. Mice exhibited response to derazantinib but no synergy was observed when combined with immune checkpoint inhibitor PD-L1. Conclusion Our mouse model and it’s in vitro derivatives recapitulate the immunobiology and therapeutic sensitivities of human disease. Inter-species and cross-species analyses suggest a critical role of FGFR2 fusions in shaping a cold tumor microenvironment with accumulation of TANs in both humans and mice. Poor sensitivity to ICI in vivo suggests the need for novel therapeutic strategies harnessing the immunosuppressive nature of these tumors.

BACKGROUND:FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) is the standard second-line treatment in patients with biliary tract cancer (BTC) not eligible for targeted therapies. FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) is a frequently adopted alternative combination in clinical practice, especially in patients primarily refractory to platinum-based first-line treatment. However, a real-world direct comparison between the two regimens has not yet been reported. METHODS:We performed a multicenter, retrospective analysis comparing patients with advanced BTC treated with cisplatin-gemcitabine, with or without durvalumab, as first-line and FOLFIRI or FOLFOX as second-line therapy. The primary endpoints were overall survival (OS) and progression free survival (PFS), as evaluated from the start of second-line, according to the chosen regimen. Multivariable models were tested, also considering prior cisplatin sensitivity and BRCAness status according to tumour molecular profiling. Clinical differences between the FOLFOX and FOLFIRI arms were balanced through inverse probability of treatment weighting (IPTW) methodology. RESULTS:A total of 259 patients were included, of whom 109 were treated with FOLFOX and 150 with FOLFIRI. Patient and tumour characteristics were overall balanced between the two arms. No significant difference between FOLFIRI and FOLFOX was observed in terms of PFS (median 3.1 vs. 3.5 months, HR 1.01; IPTW-adjusted median 3.2 vs. 3.5 months, HR 0.86) or OS (median 9.9 vs. 9.0 months, HR 1.09; IPTW-adjusted median 10.0 vs. 8.9 months, HR 1.04), with platinum sensitivity and BRCAness status emerging as independent prognostic factors. CONCLUSIONS:FOLFOX and FOLFIRI showed modest, comparable efficacy as second-line regimens in patients with BTC pretreated with cisplatin-gemcitabine, with platinum-sensitive patients experiencing significantly longer PFS and OS, independently of the chosen second-line regimen.