Vincenzo Mazzaferro

Background: Hepatobiliary oncology is at an inflection point. Parallel advances in surgical technique, locoregional therapy, systemic treatment, and understanding of tumour biology have expanded the boundaries of curative-intent care yet have also exposed a critical reality that technical resectability is not synonymous with oncologic resectability. Technically successful resection or liver transplantation may be futile when tumour biology is aggressive, leading to early recurrence and limited survival benefit. Modern hepatobiliary surgical and transplant oncology must therefore move beyond anatomy-driven decision-making towards biologically informed strategies that incorporate tumour behaviour, treatment response, and temporal disease stability. Summary: The Asia-Pacific Transplant Oncology Symposium (APTOS) 2024 examined how Eastern and Western paradigms intersect across hepatocellular carcinoma, cholangiocarcinoma, and colorectal liver metastases, identifying pathways towards integration. Eastern and Western programmes have historically approached hepatobiliary oncology through distinct and longstanding philosophies. Eastern centres, frequently operating within living donor liver transplantation-dominant systems characterized by organ scarcity and the ethical principle of double equipoise, have traditionally leveraged high operative volume and technical expertise in complex resections. These environments have favoured surgery-first approaches when resection appears technically feasible, alongside response-driven conversion strategies aimed at expanding operability. Western centres, shaped by deceased-donor allocation frameworks and trial-oriented oncology models, have more consistently prioritized biological selection and longitudinal validation of disease control before proceeding to curative-intent intervention, particularly in borderline-resectable disease. These differences are driven by infrastructural and ethical factors, including donor availability, transplant systems, and biomarker integration, rather than surgical capability. This article is an expert statement reflecting the opinion of an international multidisciplinary faculty of hepatobiliary surgeons, transplant surgeons, hepatologists, and medical and clinical oncologists from Eastern and Western centres. It is a narrative expert perspective and not a formal consensus or guideline. Key Messages: This expert statement proposes that the next phase of hepatobiliary oncology requires harmonized, biology-driven definitions of resectability, transplantability, and futility. Comparative evaluation of regional strategies is essential to clarify how treatment sequencing affects recurrence and survival, an effort that is time-sensitive as advances in systemic therapy may soon obscure strategy-specific effects. Rather than competing models, Eastern procedural expertise and Western biology-centred frameworks should be viewed as complementary, supporting context-dependent or sequential approaches that integrate surgery with biology-guided systemic or locoregional therapy. Aligning these paradigms within ethical stewardship of donor organs can establish globally coherent, biology-driven standards that maximize durable survival while minimizing futile surgery and transplantation.

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.

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms with increasing incidence, particularly within the gastroenteropancreatic (GEP) system. The liver represents the most common site of metastasis, and neuroendocrine liver metastases (NELMs) significantly impact prognosis, symptom burden, and therapeutic decision-making. Surgical management remains a cornerstone in the treatment of NELMs and encompasses a spectrum of strategies, including curative liver resection, cytoreductive surgery, and, in selected cases, liver transplantation (LT). Hepatic resection, although potentially curative when technically feasible, is applicable only to a highly selected subset of patients, and its benefits in terms of long-term survival and symptom control remain limited by recurrence rates and patient-related factors. Cytoreductive surgery has emerged as a valuable alternative in patients with unresectable disease, with increasing evidence supporting a ≥70% debulking threshold as sufficient to achieve meaningful clinical benefit. This approach may improve survival and quality of life, notably in symptomatic patients, and can be combined with parenchymal-sparing techniques and locoregional therapies. Liver transplantation represents a radical but potentially curative strategy for highly selected patients with liver-only disease, favorable tumor biology, and stable disease. Outcomes are strongly dependent on strict selection criteria, and appropriate patient selection remains critical. The incorporation of systemic treatments, such as somatostatin analogues, targeted therapies, and peptide receptor radionuclide therapy (PRRT), has broadened the available therapeutic options and contributed to redefining current treatment strategies. Overall, the management of NELMs requires a multidisciplinary, individualized approach guided by tumor biology, disease distribution, and patient-specific factors, with the goal of optimizing survival outcomes and preserving quality of life.

Background & 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 intra-hepatic and perihilar cholangiocarcinoma. Emphasis is placed on strategies to broaden eligibility, optimize donor organ use, and improve oncologic outcomes. Approach & 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. Additionally, 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. Export

Liver transplantation (LT) for unresectable colorectal liver metastases (CRLM) has regained interest after the TransMet trial, which reported 5-year survival exceeding 70%. However, estimates of transplant benefit (TB) are lacking. This study provides a first external validity assessment of the TransMet criteria and estimates the 5-year TB using a real-world international cohort. A retrospective multicenter study included 61 TransMet-eligible patients with unresectable CRLM who underwent LT between 2006 and 2020 across seven centers. Matching-adjusted indirect comparisons were used to improve comparability, with sensitivity analyses on effective sample size. Survival was analyzed using Kaplan-Meier curves and restricted mean survival time up to 5 years. Weighted multivariable Cox regressions were employed to assess prognostic factors after transplantation. The 5-year restricted mean survival time was identical in the weighted cohort (effective sample size=19) and the TransMet LT arm (51.0 mo). Sensitivity analysis yielded a 5-year restricted mean survival time consistent with residual imbalance (48.2 mo, ESS=35). KRAS mutation (HR: 5.90, 95% CI: 1.89–18.4), right-sided primary tumor (HR: 4.17, 95% CI: 1.40–12.4), and female sex (HR: 5.73, 95% CI: 1.04–31.6) were associated with poorer survival; CEA≥80 ng/mL emerged as a potential prognostic factor (HR: 6.3, 95% CI: 1.73–22.6) across alternative specifications. The estimated 5-year TB of LT versus chemotherapy was 22.5 months (95% CI: 15.5–29.6). The findings of this first real-world assessment of the TransMet trial criteria and 5-year TB estimation in unresectable CRLM point to reasonable prognostic candidates and support evaluating the inclusion of CRLM in LT allocation models. We advocate expanded multicenter data to reach sufficient prognostic stratification through well-calibrated, highly discriminative studies.

Background/Objectives: Heterogeneity in clinical scenarios of colorectal liver metastases (CRLM) leads to the possible application of different surgical strategies. Specifically, the possibility of performing combined colorectal and liver resections for synchronous CRLM has been proposed in specific settings but its feasibility, safety and impact in minimally invasive settings remain underexplored. This study examines a multicenter Italian experience, comparing perioperative outcomes of combined (CR) versus non-combined (NCR) minimally invasive liver resections (MILR) for CRLM. Methods: Patients from the prospective multicenter registry of the Italian Group of Minimally Invasive Liver Surgery (I Go MILS) who underwent MILR for CRLM between 2016 and 2024 were included. Perioperative outcomes were compared between CR and NCR using Nearest Neighbor Matching. Results: In total, 2286 patients were analyzed, including 1879 NCR and 407 CR. CR was associated with less challenging resections (technical difficulty Kawaguchi grade III: 7.13% vs. 14.53%, p < 0.001), longer operative time (385 vs. 270 min, p < 0.001) and higher major complication rate (11.55% vs. 5.11%, p < 0.001) compared to NCR. The conversion rate was similar between the two groups (9.09% vs. 7.91%, p = 0.479). Technical complexity, operative time, conversion, low-volume hospital, and CR was an independent predictor of major complications after matching. Conclusions: CR is associated with a higher risk of postoperative complications, despite being selected for minor liver resections, confirming the impact of associated colorectal surgery in determining the postoperative risk and hence highlighting the concept that accurate preoperative patient selection is a key step in guiding treatment allocation for CRLM. Therefore, MILR does not yet justify broadening indications for combined resection beyond carefully selected patients.