The Italian experience on liver transplantation for unresectable peri-hilar cholangiocarcinoma: a national survey and future perspectives.

Liver transplantation (LT) was considered an ineffective treatment for perihilar cholangiocarcinoma (pCCA) until the successful experience of the Mayo Clinic, proposing a protocol with strict inclusion criteria and neoadjuvant radio-chemotherapy. Since 2015, pCCA is considered an indication for LT in Italy only in the context of controlled prospective studies. We performed a survey among the 22 Italian Liver Transplant Centers to assess the results of LT for pCCA. Eight centers reported 53 cases from 1986 to 2021 (Bologna 12, Padova 10, Niguarda 10, Milano Tumori 8, Torino 5, Pisa 4, Ancona 2, Modena 2). Patients were divided according to whether they recieved neoadjuvant radio-chemotherapy (Group 1, 25 cases) or not (Group 2, 28 cases). Eleven patients were transplanted without neoadjuvant treatment after 2015. Overall survival at 1, 3 and 5 years was 83.8%, 56.6% and 50.6% in Group 1 and 72.4%, 41.4% and 35.5% in Gropu 2 (p = 0.13). Recurrence-free survival at 1, 3, and 5 years was 91.2%, 61.1% and 47.2% in Group 1 and 58.2%, 42.2%, and 36.1% in Group 2 (p = 0.16). A competing risk regression analysis showed a 5-year risk of cancer-related death of 19% for patients in Group 1 against 62.3% in Group 2, with a hazard ratio of 0.31 (95%CI [0.10-0.98], p 0.047). This survey promoted a discussion about the limitations of the Mayo protocol and set the basis for the adoption of a new nationwide protocol (LITHALICA-NCT06125769), having the same inclusion criteria but proposing standard of care chemotherapy as neoadjuvant regimen.

Cure after surgery for hepato-pancreato-biliary cancers: A systematic review.

BACKGROUND: Patients undergoing curative-intent surgery for hepato-pancreato-biliary (HPB) malignancies may achieve statistical cure i.e., a mortality risk which aligns with the general population. AIMS: To summarize the results of different cure models in HPB malignancies. METHODS: We conducted a systematic literature search and selected studies on curative-intent surgery (hepatic resection, HR, or liver transplantation, LT) for HPB malignancies including a cure model in their analysis. The review protocol was registered in PROSPERO (CRD42024528694). RESULTS: Eleven studies reporting a cure model after HPB surgery for malignancy were included: 6 on hepatocellular carcinoma (HCC) two on biliary tract cancers (BTC), one on pancreatic neuroendocrine tumors (pNET), one on pancreatic ductal adenocarcinoma (PDAC), and one on colorectal liver metastases (CRLM). In terms of OS, the cure fraction of HCC is 63.4 %-75.8 % with LT and 31.8 %-40.5 % with HR, achieved within 7.2-10 years and 7-14.4 years respectively. The cure fraction of intrahepatic cholangiocarcinoma is 9.7 % in terms of DFS, but largely depends on tumor stage. PDAC and pNET display a cure fraction of 20.4 % and 57.1 % respectively in terms of DFS, confirming the impact of histotype on DFS. CONCLUSION: Statistical cure for hepato-pancreato-biliary cancers can be achieved with surgery. The probability of cure depends on the interplay between tumor stage and aggressiveness, effectiveness of the surgical treatment and persistence of chronic conditions after surgery.

Recurrence and tumor-related death after resection of hepatocellular carcinoma in patients with metabolic syndrome.

Background & Aims: Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed. Methods: Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events. Results: In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1-157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7-174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977-0.995; p = 0.002). Conclusions: Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors. Impact and implications: Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.

A snapshot on current approaches to lymphadenectomy in liver resection for intrahepatic cholangiocarcinoma: results from an international survey.

The use of lymphadenectomy (LND) during resection of intrahepatic cholangiocarcinoma (ICC) is still debated, leading to differing practices in different centers and countries. The aim of this study was to assess such differences. A survey on LND for ICC was distributed to the members of the International Hepato-PancreatoBiliary Association (IHPBA) and the Italian Chapter of IHPBA (AICEP). Two-hundred thirty-four surgeons completed the survey (88% males; median age 46 years). Preoperative nodal staging was deemed mandatory/very important by 65%. Adequate LND was defined as hepatoduodenal ligament LND by 33%, LND at specific nodal stations by 28% and retrieval of > 5 nodes by 28%. The decision to perform LND was influenced by comorbidities (48%), chronic liver disease (38%) and satellitosis (32%). Most participants modify perioperative management in case of clinically positive nodes, 50% stating they would give neoadjuvant therapy. The role of LND in clinically node negative disease was adequate staging for 88%, survival benefit for 50.5% and clinical trials eligibility for 18.5%. Our survey confirms heterogeneity in the evaluation of role and extent of LND for ICC, how this relates to subjective perception of importance of LND, and need of a systematic approach in this area.

Hemodialysis and imatinib: Plasma levels, efficacy and tolerability in a patient with metastatic GIST - Case report.

Purpose: To study plasma levels, efficacy and tolerability of imatinib in a patient affected by metastatic GIST treated with oral Imatinib and undergoing hemodialysis. Patients and methods: The patient suffered from metastatic GIST to the liver having a mutation of exon 9 of KIT. He was on hemodialysis and received first-line treatment with imatinib 400 mg/day. Results: The overall mean plasma level of imatinib was 1875,4 ng/ml pre-dialysis, 1553,0 ng/ml post-dialysis and 1998,1 ng/ml post-24h. In red blood cells the overall mean level of imatinib was 619,5 ng/ml pre-dialysis, 484,9 ng/ml post-dialysis and 663,1 ng/ml post-24h. The plasma level of nor-imatinib/imatinib was 16,2% pre-dialysis, 15,6% post-dialysis and 16,4% post-24h. Comparing our findings regarding levels of imatinib in plasma and RBC, we found a statistically significant difference between pre-dialysis and post-dialysis (respectively p < 0,001 and p = 0,002), post-dialysis and post-24h (both p < 0,001), pre-dialysis and post-24h (respectively p = 0.035 and p = 0,042). Ultimately, regarding nor-imatinib/imatinib in plasma, we did not find any statistically significant difference between pre-dialysis and post-dialysis (p = 0,091), post-dialysis and post-24h (p = 0,091), pre-dialysis and post-24h (p = 0.903). Currently the patient is receiving oral imatinib 400 mg/day with radiological evidence of response. Conclusion: In this case, hemodialysis did not affect significantly imatinib plasma levels. The statistically significant difference between pre- and post-dialysis can be explained by the fact that dialysis may likely contribute to a small portion of the normal metabolism of imatinib. The evaluation of imatinib levels in RBC and of its main metabolite in plasma also suggests that hemodialysis did not affect other aspects of the elimination of the drug.

A phase II/III randomized clinical trial of CisPlatin plUs Gemcitabine and Nabpaclitaxel (GAP) as pReoperative chemotherapy versus immediate resection in patIents with resecTable BiliarY Tract Cancers (BTC) at high risk for recurrence: PURITY study.

BACKGROUND: Biliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1-3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20-40% and recurrence rates are up to ~ 75%(4-6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4-6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8). METHODS: PURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study. Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: Considering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients' outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery. TRIAL REGISTRATION: PURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023-503295-25-00).

NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Importance: The NAPOLI 3 trial showed the superiority of fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin (NALIRIFOX) over the combination of gemcitabine and nab-paclitaxel (GEM-NABP) as first-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). Analyses comparing NALIRIFOX and GEM-NABP with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) have not yet been reported. Objective: To derive survival, response, and toxic effects data from phase 3 clinical trials and compare NALIRIFOX, FOLFIRINOX, and GEM-NABP. Data Sources: After a systematic search of PubMed, Scopus, Embase, and American Society of Clinical Oncology and European Society for Medical Oncology meetings' libraries, Kaplan-Meier curves were extracted from phase 3 clinical trials conducted from January 1, 2011, until September 12, 2023. Study Selection: Phase 3 clinical trials that tested NALIRIFOX, FOLFIRINOX, or GEM-NABP as first-line treatment of metastatic PDAC and reported overall survival (OS) and progression-free survival (PFS) curves were selected. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses of Individual Participant Data reporting guidelines. Data Extraction And Synthesis: Individual patient OS and PFS data were extracted from Kaplan-Meier plots of original trials via a graphic reconstructive algorithm. Overall response rates (ORRs) and grade 3 or higher toxic effects rates were also collected. A pooled analysis was conducted, and results were validated via a network meta-analysis. Main Outcomes and Measures: The primary end point was OS. Secondary outcomes included PFS, ORR, and toxic effects rates. Results: A total of 7 trials with data on 2581 patients were analyzed, including 383 patients treated with NALIRIFOX, 433 patients treated with FOLFIRINOX, and 1756 patients treated with GEM-NABP. Median PFS was longer in patients treated with NALIRIFOX (7.4 [95% CI, 6.1-7.7] months) or FOLFIRINOX (7.3 [95% CI, 6.5-7.9] months; [HR], 1.21 [95% CI, 0.86-1.70]; P = .28) compared with patients treated with GEM-NABP (5.7 [95% CI, 5.6-6.1] months; HR vs NALIRIFOX, 1.45 [95% CI, 1.22-1.73]; P < .001). Similarly, GEM-NABP was associated with poorer OS (10.4 [95% CI, 9.8-10.8]; months) compared with NALIRIFOX (HR, 1.18 [95% CI, 1.00-1.39]; P = .05], while no difference was observed between FOLFIRINOX (11.7 [95% CI, 10.4-13.0] months) and NALIRIFOX (11.1 [95% CI, 10.1-12.3] months; HR, 1.06 [95% CI, 0.81-1.39]; P = .65). There were no statistically significant differences in ORR among NALIRIFOX (41.8%), FOLFIRINOX (31.6%), and GEM-NABP (35.0%). NALIRIFOX was associated with lower incidence of grade 3 or higher hematological toxic effects (eg, platelet count decreased 1.6% vs 11.8% with FOLFIRINOX and 10.8% with GEM-NABP), but higher rates of severe diarrhea compared with GEM-NABP (20.3% vs 15.7%). Conclusions and Relevance: In this systematic review and meta-analysis, NALIRIFOX and FOLFIRINOX were associated with similar PFS and OS as first-line treatment of advanced PDAC, although NALIRIFOX was associated with a different toxicity profile. Careful patient selection, financial toxic effects consideration, and direct comparison between FOLFIRINOX and NALIRIFOX are warranted.

The Role of Liver Transplantation in the Treatment of Liver Metastases from Neuroendocrine Tumors.

OPINION STATEMENT: Transplant oncology is a new field of medicine referred to the use of solid organ transplantation, particularly the liver, to improve prognosis and quality of life in cancer patients. In unresectable, liver-only metastases from neuroendocrine tumors (NETs) of the digestive tract, liver transplantation represents a competitive chance of cure. Due to the limited resource of donated organs, accurate patients' selection is crucial in order to maximize transplant benefit. Several tumor- and patient-related factors should be considered. Among them, primary tumors with a low grade of differentiation (G1-G2 or Ki67 < 10%), located in a region drained by the portal system and removed before transplantation with at least 3-6 months period of disease stability observed before transplant listing, can be considered for transplantation. In case of NET located in the pancreas, extended lymphadenectomy should complement curative pancreatic resection. A number of other features are described in this review of liver transplantation for NET metastases. Comprehensive approach including various forms of non-surgical treatment and detailed planning and timing of total hepatectomy are discussed. Open issues remain on possible expansion of current criteria while maintaining the same long-term benefit demonstrated with the Milan NET criteria with respect to other non-transplant options, with particular reference to liver resection, peptide receptor radionuclide therapy, and locoregional and systemic treatments.

Impact of Indocyanine Green Fluorescence Imaging on Lymphadenectomy Quality During Laparoscopic Distal Gastrectomy for Gastric Cancer (Greeneye): An Adaptative, Phase 2, Clinical Trial.

BACKGROUND: Indocyanine green (ICG)-guided lymphadenectomy using near-infrared visualization (NIR) may increase nodal yield during gastrectomy. The purpose of this study was to evaluate the clinical benefit of NIR visualization on the quality of D2 lymphadenectomy during laparoscopic distal gastrectomy. METHODS: This single-arm, open-label, Simon's two-stage, adaptive, phase 2 trial included patients who underwent laparoscopic distal gastrectomy for gastric adenocarcinoma. Endoscopic peritumoral injection of ICG was performed 24 ± 6 h before surgery. Intraoperatively, after standard D2 lymphadenectomy and specimen extraction, NIR was used for eventual completion lymphadenectomy. The primary endpoint was clinical benefit of NIR (i.e., at least one additional harvested station containing lymph nodes, with negative points for every harvested station with no lymph nodes at final pathology). RESULTS: We enrolled 18 patients (61% female, median age 69 years). With NIR, an extra 23 stations were harvested: 9 contained no lymph nodes, 12 contained nonmetastatic lymph nodes, and 2 contained metastatic lymph nodes. The most commonly visualized station with NIR were station 6 (8 patients) and 1 (4 patients). The total number of harvested nodes per patient was 32 (interquartile range [IQR] 26-41), with a median of 1 (IQR 0-1) additional lymph node after NIR. Overall, seven (39%) patients had a clinical benefit from NIR, of which two (11%) had one metastatic lymph node harvested with NIR. CONCLUSIONS: NIR visualization improves the quality of D2 lymphadenectomy in distal gastrectomy for gastric cancer. Considering the limited improve in the number of harvested lymph nodes, its real oncological benefit is still questionable.

Macrophage morphology and distribution are strong predictors of prognosis in resected colorectal liver metastases: results from an external retrospective observational study.

INTRODUCTION: Tumor-associated macrophages (TAMs) are key components of a tumoral microenvironment and have been shown to impact prognosis in different cancers. Previously reported data showed that TAM morphology correlates with prognosis in colorectal liver metastases (CLMs) after hepatectomy, with smaller TAMs (S-TAMs) conferring a more favorable prognosis than larger ones (L-TAMs). This study aims to externally validate this finding. MATERIAL AND METHODS: The external cohort consisted of 84 formalin-fixed and paraffin-embedded surgical samples of CLMs and peritumoral tissue. Two-micrometer-section slides were obtained; the area and perimeter of 21 macrophages in each slide were recorded. The endpoints were TAMs morphometrics and their prognostic significance in relation to disease-free survival (DFS). RESULTS: The average macrophage perimeter was 71.5±14.1 µm whilst the average area was 217.7±67.8 µm 2 . At univariate analysis, the TAM area demonstrated a statistically significant association with DFS ( P =0.0006). Optimal area cutoff value was obtained, showing a sensitivity and specificity of 92 and 56%, respectively. S-TAMs and L-TAMs were associated with 3-year DFS rates of 60 and 8.5%, respectively ( P <0.001). Multivariate analysis confirmed the predictive role of TAM area for DFS [hazard ratio (HR)=5.03; 95% CI=1.70-14.94; P =0.003]. Moreover, in a subset of patients ( n =12) characterized by unfavorable ( n =6, recurrence within 3 months) or favorable ( n =6, no recurrence after 48 months) prognosis, TAMs showed a different distribution: L-TAMs were more abundant and closer to the tumor invasive margin in patients that encountered early recurrence and tended to cluster in foci significantly larger ( P =0.02). CONCLUSIONS: This external validation confirms that morphometric characterization of TAMs can serve as a simple readout of their diversity and allows to reliably stratify patient outcomes and predict disease recurrence after hepatectomy for CLMs.

Surgical Treatment of Hepatocellular Carcinoma: Multicenter Competing-risk Analysis of Tumor-related Death Following Liver Resection and Transplantation Under an Intention-to-treat Perspective.

BACKGROUND: Early-stage hepatocellular carcinoma could benefit from upfront liver resection (LR) or liver transplantation (LT), but the optimal strategy in terms of tumor-related outcomes is still debated. We compared the oncological outcomes of LR and LT for hepatocellular carcinoma, stratifying the study population into a low-, intermediate-, and high-risk class according to the risk of death at 5-y predicted by a previously developed prognostic model. The impact of tumor pathology on oncological outcomes of low- and intermediate-risk patients undergoing LR was investigated as a secondary outcome. METHODS: We performed a retrospective multicentric cohort study involving 2640 patients consecutively treated by LR or LT from 4 tertiary hepatobiliary and transplant centers between 2005 and 2015, focusing on patients amenable to both treatments upfront. Tumor-related survival and overall survival were compared under an intention-to-treat perspective. RESULTS: We identified 468 LR and 579 LT candidates: 512 LT candidates underwent LT, whereas 68 (11.7%) dropped-out for tumor progression. Ninety-nine high-risk patients were selected from each treatment cohort after propensity score matching. Three and 5-y cumulative incidence of tumor-related death were 29.7% and 39.5% versus 17.2% and 18.3% for LR and LT group ( P = 0.039), respectively. Low-risk and intermediate-risk patients treated by LR and presenting satellite nodules and microvascular invasion had a significantly higher 5-y incidence of tumor-related death (29.2% versus 12.5%; P < 0.001). CONCLUSIONS: High-risk patients showed significantly better intention-to-treat tumor-related survival after upfront LT rather than LR. Cancer-specific survival of low- and intermediate-risk LR patients was significantly impaired by unfavorable pathology, suggesting the application of ab-initio salvage LT in such scenarios.

Minimally Invasive Versus Open Liver Resections for Hepatocellular Carcinoma in Patients With Metabolic Syndrome.

OBJECTIVE: To compare minimally invasive (MILR) and open liver resections (OLRs) for hepatocellular carcinoma (HCC) in patients with metabolic syndrome (MS). BACKGROUND: Liver resections for HCC on MS are associated with high perioperative morbidity and mortality. No data on the minimally invasive approach in this setting exist. MATERIAL AND METHODS: A multicenter study involving 24 institutions was conducted. Propensity scores were calculated, and inverse probability weighting was used to weight comparisons. Short-term and long-term outcomes were investigated. RESULTS: A total of 996 patients were included: 580 in OLR and 416 in MILR. After weighing, groups were well matched. Blood loss was similar between groups (OLR 275.9±3.1 vs MILR 226±4.0, P =0.146). There were no significant differences in 90-day morbidity (38.9% vs 31.9% OLRs and MILRs, P =0.08) and mortality (2.4% vs 2.2% OLRs and MILRs, P =0.84). MILRs were associated with lower rates of major complications (9.3% vs 15.3%, P =0.015), posthepatectomy liver failure (0.6% vs 4.3%, P =0.008), and bile leaks (2.2% vs 6.4%, P =0.003); ascites was significantly lower at postoperative day 1 (2.7% vs 8.1%, P =0.002) and day 3 (3.1% vs 11.4%, P <0.001); hospital stay was significantly shorter (5.8±1.9 vs 7.5±1.7, P <0.001). There was no significant difference in overall survival and disease-free survival. CONCLUSIONS: MILR for HCC on MS is associated with equivalent perioperative and oncological outcomes to OLRs. Fewer major complications, posthepatectomy liver failures, ascites, and bile leaks can be obtained, with a shorter hospital stay. The combination of lower short-term severe morbidity and equivalent oncologic outcomes favor MILR for MS when feasible.

Improving Outcome of Selected Patients With Non-Resectable Hepatic Metastases From Colorectal Cancer With Liver Transplantation: A Prospective Parallel Trial (COLT trial).

BACKGROUND: Patients with unresectable Colorectal Liver Metastases (CLM) receiving palliative chemotherapy have a 5-year overall survival (OS) of less than 30%. Liver transplantation (LT) can improve OS up to 60%-83% (SECA-I and SECA-II trials). The aim of the study is to assess the efficacy of LT in liver-only metastatic CRC compared with a matched cohort of patients included in a phase III trial on triplet chemotherapy + antiEGFR. PATIENTS AND METHODS: The COLT trial is an investigator-driven, multicenter, non-randomized, open-label, controlled, prospective, parallel trial (ClinicalTrials.gov NCT03803436). Hyperselected patients with liver-limited unresectable CLM, RAS and BRAF wild-type and curatively removed primary colon cancer are included. The observed post-transplant outcomes will be prospectively compared 1:5 with those obtained in a matched cohort from the TRIPLETE trial (NCT03231722). RESULTS: Primary endpoint is to compare the 3 and 5-years OS of patients enrolled in the COLT trial with COLT-eligible population enrolled in the TRIPLETE trial. An expected gain in OS of 40% at 5-years is predicted for the COLT population (the expected OS at 5-years in COLT vs. TRIPLETE is 70% vs. 30%). Secondary endpoints are to compare the 5-years disease-free survival and to assess the safety of LT (Dindo-Clavien Classification and the Comprehensive Complication Index). CONCLUSION: LT offers the longest OS reported in selected patients with CLM. Improving the selection strategies can give patients a 5-year OS similar to other indications for LT and a better outcome than those undergoing chemotherapy alone.

Liver Transplantation for Hepatic Metastases from Colorectal Cancer: Current Knowledge and Open Issues.

More than 40% of patients with colorectal cancer present liver metastases (CRLM) during the course of their disease and up to 50% present with unresectable disease. Without surgical interventions, survival for patients treated with systemic therapies alone is dismal. In the past, liver transplantation (LT) for patients with unresectable CRLM failed to show any survival benefit due to poor selection, ineffective chemotherapeutic regimens, unbalanced immunosuppression and high perioperative mortality. Since then and for many years LT for CRLM was abandoned. The turning point occurred in 2013, when the results from the Secondary Cancer (SECA I) pilot study performed at Oslo University were published reporting a 60% 5-year overall survival after LT in patients with unresectable CRLM. These results effectively reignited the interest in LT as a potential therapy for CRLM, and several trials are undergoing. The aims of this article are to give a comprehensive overview of the available evidence on LT for CRLM, discuss the open issues in this rapidly evolving field, and highlight possible ways to address the future of this fascinating therapeutic alternative for selected patients with CRLM.

Model to predict major complications following liver resection for HCC in patients with metabolic syndrome.

BACKGROUND: Metabolic syndrome (MS) is rapidly growing as risk factor for HCC. Liver resection for HCC in patients with MS is associated with increased postoperative risks. There are no data on factors associated with postoperative complications. AIMS: The aim was to identify risk factors and develop and validate a model for postoperative major morbidity after liver resection for HCC in patients with MS, using a large multicentric Western cohort. MATERIALS AND METHODS: The univariable logistic regression analysis was applied to select predictive factors for 90 days major morbidity. The model was built on the multivariable regression and presented as a nomogram. Performance was evaluated by internal validation through the bootstrap method. The predictive discrimination was assessed through the concordance index. RESULTS: A total of 1087 patients were gathered from 24 centers between 2001 and 2021. Four hundred and eighty-four patients (45.2%) were obese. Most liver resections were performed using an open approach (59.1%), and 743 (68.3%) underwent minor hepatectomies. Three hundred and seventy-six patients (34.6%) developed postoperative complications, with 13.8% major morbidity and 2.9% mortality rates. Seven hundred and thirteen patients had complete data and were included in the prediction model. The model identified obesity, diabetes, ischemic heart disease, portal hypertension, open approach, major hepatectomy, and changes in the nontumoral parenchyma as risk factors for major morbidity. The model demonstrated an AUC of 72.8% (95% CI: 67.2%-78.2%) ( https://childb.shinyapps.io/NomogramMajorMorbidity90days/ ). CONCLUSIONS: Patients undergoing liver resection for HCC and MS are at high risk of postoperative major complications and death. Careful patient selection, considering baseline characteristics, liver function, and type of surgery, is key to achieving optimal outcomes.

Safety and Efficacy of Robotic vs Open Liver Resection for Hepatocellular Carcinoma.

Importance: Long-term oncologic outcomes of robotic surgery remain a hotly debated topic in surgical oncology, but sparse data have been published thus far. Objective: To analyze short- and long-term outcomes of robotic liver resection (RLR) for hepatocellular carcinoma (HCC) from Western high-volume centers to assess the safety, reproducibility, and oncologic efficacy of this technique. Design, Setting, and Participants: This cohort study evaluated the outcomes of patients receiving RLR vs open liver resection (OLR) for HCC between 2010 and 2020 in 5 high-volume centers. After 1:1 propensity score matching, a group of patients who underwent RLR was compared with a validation cohort of OLR patients from a high-volume center that did not perform RLR. Main Outcomes and Measures: A retrospective analysis was performed of prospectively maintained databases at 2 European and 2 US institutions of patients who underwent RLR for HCC between January 1, 2010, and September 30, 2020. The main outcomes were safety and feasibility of RLR for HCC and its oncologic outcomes compared with a European OLR validation cohort. A 2-sided P < .05 was considered significant. Results: The study included 398 patients (RLR group: 125 men, 33 women, median [IQR] age, 66 [58-71] years; OLR group: 315 men, 83 women; median [IQR] age, 70 [64-74] years), and 106 RLR patients were compared with 106 OLR patients after propensity score matching. The RLR patients had a significantly longer operative time (median [IQR], 295 [190-370] minutes vs 200 [165-255] minutes, including docking; P < .001) but a significantly shorter hospital length of stay (median [IQR], 4 [3-6] days vs 10 [7-13] days; P < .001) and a lower number of admissions to the intensive care unit (7 [6.6%] vs 21 [19.8%]; P = .002). Incidence of posthepatectomy liver failure was significantly lower in the RLR group (8 [7.5%] vs 30 [28.3%]; P = .001), with no cases of grade C failure. The 90-day overall survival rate was comparable between the 2 groups (RLR, 99.1% [95% CI, 93.5%-99.9%]; OLR, 97.1% [95% CI, 91.3%-99.1%]), as was the cumulative incidence of death related to tumor recurrence (RLR, 8.8% [95% CI, 3.1%-18.3%]; OLR, 10.2% [95% CI, 4.9%-17.7%]). Conclusions and Relevance: This study represents the largest Western experience to date of full RLR for HCC. Compared with OLR, RLR performed in tertiary centers represents a safe treatment strategy for patients with HCC and those with compromised liver function while achieving oncologic efficacy.