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Background & Aims: Complex portal vein thrombosis (PVT) is a challenge in liver transplantation (LT). Extra-anatomical approaches to portal revascularization, including renoportal (RPA), left gastric vein (LGA), pericholedochal vein (PCA), and cavoportal (CPA) anastomoses, have been described in case reports and series. The RP4LT Collaborative was created to record cases of alternative portal revascularization performed for complex PVT. Methods: An international, observational web registry was launched in 2020. Cases of complex PVT undergoing first LT performed with RPA, LGA, PCA, or CPA were recorded and updated through 12/2021. Results: A total of 140 cases were available for analysis: 74 RPA, 18 LGA, 20 PCA, and 28 CPA. Transplants were primarily performed with whole livers (98%) in recipients with median (IQR) age 58 (49-63) years, model for end-stage liver disease score 17 (14–24), and cold ischemia 431 (360-505) minutes. Post-operatively, 49% of recipients developed acute kidney injury, 16% diuretic-responsive ascites, 9% refractory ascites (29% with CPA, p

The use of hemadsorption has been purposed to reduce cytokine levels during the reperfusion phase during donation after circulatory death (DCD) programs. This paper aims to describe a cases series of the inflammatory cytokine levels before and after hemadsorption during normothermic reperfusion in DCD donors of liver and kidneys. In this observational pilot paper, we describe 8 DCD donors of liver or kidneys in our center from the year 2018 to 2019. All DCD donor subjects had similar age, were younger than 60 years, without evident critical conditions, no liver or kidney dysfunction known, and they presented with poor neurological outcomes instrumentally and clinically documented. We observed in our patients an interesting reduction of IL-10 and TNF-α levels during the normothermic reperfusion with hemadsorption. We transplanted all livers and kidneys from DCD donors without significant compliances.

The impact of obesity on surgical outcomes in elderly patients candidate for liver surgery is still debated. BACKGROUND The impact of obesity on surgical outcomes in elderly patients candidate for liver surgery is still debated. AIM To evaluate the impact of high body mass index (BMI) on perioperative and oncological outcome in elderly patients (> 70 years old) treated with laparoscopic liver resection for hepatocellular carcinoma (HCC). METHODS Retrospective multicenter study including 224 elderly patients (> 70 years old) operated by laparoscopy for HCC (196 with a BMI < 30 and 28 with BMI ≥ 30), observed from January 2009 to January 2019. RESULTS After propensity score matching, patients in two groups presented comparable results, in terms of operative time (median range: 200 min vs 205 min, P = 0.7 respectively in non-obese and obese patients), complications rate (22% vs 26%, P = 1.0), length of hospital stay (median range: 4.5 d vs 6.0 d, P = 0.1). There are no significant differences in terms of short- and long-term postoperative results. CONCLUSION The present study showed that BMI did not impact perioperative and oncologic outcomes in elderly patients treated by laparoscopic resection for HCC. journal article 2023 Jan 27 imported

Introduction: Currently, the impact of body mass index (BMI) on the outcomes of laparoscopic liver resections (LLR) is poorly defined. This study attempts to evaluate the impact of BMI on the peri-operative outcomes following laparoscopic left lateral sectionectomy (L-LLS). Methods: A retrospective analysis of 2183 patients who underwent pure L-LLS at 59 international centers between 2004 and 2021 was performed. Associations between BMI and selected peri-operative outcomes were analyzed using restricted cubic splines. Results: A BMI of >27kg/m2 was associated with increased in blood loss (Mean difference (MD) 21 mls, 95% CI 5–36), open conversions (Relative risk (RR) 1.13, 95% CI 1.03–1.25), operative time (MD 11 min, 95% CI 6–16), use of Pringles maneuver (RR 1.15, 95% CI 1.06–1.26) and reductions in length of stay (MD -0.2 days, 95% CI -0.3 to −0.1). The magnitude of these differences increased with each unit increase in BMI. However, there was a “U” shaped association between BMI and morbidity with the highest complication rates observed in underweight and obese patients. Conclusion: Increasing BMI resulted in increasing difficulty of L-LLS. Consideration should be given to its incorporation in future difficulty scoring systems in laparoscopic liver resections.

Perihilar cholangiocarcinoma (pCCA) is one of the most complex challenges for hepatobiliary surgeons. Poor results and high incidence of morbidity after Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) for pCCA discouraged this indication. It has been proposed that minimally invasive approach for ALPPS first stage, as well as combination of surgical liver partition and radiologic portal vein embolization (PVE), may improve outcomes reducing interstage morbidity. We report a case of right trisectionectomy with enbloc caudatectomy ALPPS scheduled for pCCA with robotic approach at stage-1, the full video is provided as supplementary material. Due to intraoperative presence of portal vein tumor infiltration during hilar dissection (no evidence in the pre-operative work-up), a radiologic right PVE was performed after stage-1 instead of portal vein ligation, followed by portal vein resection and biductal hepatico-jejunostomy at stage-2 with open approach. The patient was a 74-year-old female diagnosed with 3-cm mass-forming pCCA. The total clean liver volume was 1231 cc, with future liver remnant (FLR) volume of 25.1% (segments II and III). She was discharged in the interstage interval on postoperative day (POD) 4; CT scan on POD 12 showed that FLR increased up to 33% (369 cc) (Fig. 1). ALPPS was completed on POD 17, the postoperative course was uneventful, and the patient was discharged in good general condition on POD 19 after stage-2. Besides the already demonstrated advantages in terms of reduced interstage morbidity, robotic ALPPS represents a promising strategy to expand surgical indication in patients with pCCA. The combination of liver partition and PVE may increase the opportunities to perform radical resections in selected patients with pCCA and portal vein infiltration. Supplementary Information The online version contains supplementary material available at 10.1007/s13304-021-01209-x.

Background Although laparoscopic liver resection has become the standard for minor resections, evidence is lacking for more complex resections such as the right posterior sectionectomy (RPS). We aimed to compare surgical outcomes between laparoscopic (LRPS) and open right posterior sectionectomy (ORPS). Methods An international multicenter retrospective study comparing patients undergoing LRPS or ORPS (January 2007—December 2018) was performed. Patients were matched based on propensity scores in a 1:1 ratio. Primary endpoint was major complication rate defined as Accordion ≥ 3 grade. Secondary endpoints included blood loss, length of hospital stay (LOS) and resection status. A sensitivity analysis was done excluding the first 10 LRPS patients of each center to correct for the learning curve. Additionally, possible risk factors were explored for operative time, blood loss and LOS. Results Overall, 399 patients were included from 9 centers from 6 European countries of which 150 LRPS could be matched to 150 ORPS. LRPS was associated with a shorter operative time [235 (195–285) vs. 247 min (195–315) p = 0.004], less blood loss [260 (188–400) vs. 400 mL (280–550) p = 0.009] and a shorter LOS [5 (4–7) vs. 8 days (6–10), p = 0.002]. Major complication rate [n = 8 (5.3%) vs. n = 9 (6.0%) p = 1.00] and R0 resection rate [144 (96.0%) vs. 141 (94.0%), p = 0.607] did not differ between LRPS and ORPS, respectively. The sensitivity analysis showed similar findings in the previous mentioned outcomes. In multivariable regression analysis blood loss was significantly associated with the open approach, higher ASA classification and malignancy as diagnosis. For LOS this was the open approach and a malignancy. Conclusion This international multicenter propensity score-matched study showed an advantage in favor of LRPS in selected patients as compared to ORPS in terms of operative time, blood loss and LOS without differences in major complications and R0 resection rate.

BACKGROUND Surgical resection and radiofrequency ablation (RFA) represent two possible strategy in treatment of hepatocellular carcinoma (HCC) in Milan criteria. AIM To evaluate short- A nd long-term outcome in elderly patients (70 years) with HCC in Milan criteria, which underwent liver resection (LR) or RFA. METHODS The study included 594 patients with HCC in Milan criteria (429 in LR group and 165 in RFA group) managed in 10 European centers. Statistical analysis was performed using the Kaplan-Meier method before and after propensity score matching (PSM) and Cox regression. RESULTS After PSM, we compared 136 patients in the LR group with 136 patients in the RFA group. Overall survival at 1, 3, and 5 years was 91%, 80%, and 76% in the LR group and 97%, 67%, and 41% in the RFA group respectively (P = 0.001). Diseasefree survival at 1, 3, and 5 years was 84%, 60% and 44% for the LR group, and 63%, 36%, and 25% for the RFA group (P = 0.001).Postoperative Clavien-Dindo IIIIV complications were lower in the RFA group (1% vs 11%, P = 0.001) in association with a shorter length of stay (2 d vs 7 d, P = 0.001).In multivariate analysis, Model for End-stage Liver Disease (MELD) score (10) [odds ratio (OR) = 1.89], increased value of international normalized ratio (1.3) (OR = 1.60), treatment with radiofrequency (OR = 1.46) ,and multiple nodules (OR = 1.19) were independent predictors of a poor overall survival while a high MELD score (10) (OR = 1.51) and radiofrequency (OR = 1.37) were independent factors associated with a higher recurrence rate. CONCLUSION Despite a longer length of stay and a higher rate of severe postoperative complications, surgery provided better results in long-term oncological outcomes as compared to ablation in elderly patients (70 years) with HCC in Milan criteria. © 2021 The Author(s). Published by Baishideng Publishing Group Inc. All rights reserved.

Pancreatic ductal adenocarcinoma (PDAC) is a relatively uncommon malignancy; however, its incidence is rising worldwide, and it is expected to become the second-leading cause of cancer-related death by 2030. From a histological point of view, PDAC is characterized by a prominent desmoplastic reaction that compresses blood vessels, limiting oxygen and nutrient availability in the tumor microenvironment. Despite that, PDAC cells are capable to adapt dynamically to these stress conditions, adopting different strategies that includes the strict regulation of the autophagic flux. Thus, studying these adaptive mechanisms is crucial to understand PDAC progression and to establish new therapeutic modalities to tackle it. Here, we explore the role of the tumor suppressor miR-15a in the regulation of its putative target Fra-2, a transcription factor, commonly activated by cell stress. By employing IPA on PDAC tumors from TCGA dataset, we found that both miR-15a and its target Fra-2 are predicted to regulate the IGF-1 signaling pathway. In an independent cohort of 44 PDAC samples, miR-15a levels inversely correlated with both Fra-2 and IGF1R expression; conversely, Fra-2 significantly correlated with IGF1R. By chromatin immunoprecipitation and luciferase assay, we assessed that miR-15a directly targeted Fra-2 and IGF1R that, in turn, is transcriptionally regulated by Fra-2 activity. Then, we investigated the role of miR-15a/Fra-2 regulation of IGF1R in the response to starvation-induced cell stress. In starved PDAC cell lines, Fra-2 transcriptional activity triggered IGF1R promoter, causing IGF1R overexpression in control cells but not in miR-15a-overexpressing cells. Consistently, the IGF1 release after starvation induced phosphorylation of IGF1R and activation of the downstream mTOR pathway in control cells but not in miR-15a-overexpressing cells. Therefore, TEM and western blot analysis demonstrated that activation of mTOR via IGF1 release reduced the autophagic flux of PDAC control cell lines compared to miR-15a overexpressing cells under starvation. To assess our results in vivo, we injected PDAC cells wild type or Fra-2 knockout into the flank of nude mice. At tumor onset, mice were randomly divided in two groups and fed with control or hypoproteic diet for three weeks. Hypoproteic diet did not interfere with the growth of wild-type tumors, by contrast, significantly impaired Fra-2KO tumors growth rate. Tumor analysis revealed that hypoproteic diet potently induced IGF1R overexpression and mTOR pathway activation in wild-type tumors but not in Fra-2KO tumors. Our findings demonstrate that IGF1R expression is regulated by miR-15a directly and indirectly via Fra-2 in PDAC. This novel miR-15a/Fra-2/IGF1R axis, triggered by starvation, regulates the autophagic flux and growth of PDAC cells in stress condition, and could be targeted by specific small inhibitors. Citation Format: Gian Luca Rampioni Vinciguerra, Marina Capece, Luca Reggiani Bonetti, Paolo Magistri, Federica Calore, Giovanni Nigita, Rosario Distefano, Roberto Ballarin, Fabrizio Di Benedetto, Andrea Vecchione, Barbara Belletti, Gustavo Baldassarre, Francesca Lovat, Carlo M. Croce. The novel miR-15a/Fra-2/IGF1R axis drives response to starvation-induced cell stress in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4823.

Robotic approach to the liver may allow to perform difficult resections with a minimally invasive strategy in an easier way as compared to standard laparoscopy. The aim of this study is to review our experience with robotic major hepatectomies, reporting technical considerations, and describing the outcomes of patients that underwent either left (LRH) or right robotic hepatectomy (RRH). Our prospectively maintained database was screened to identify all patients that received a major liver resection for benign or malignant disease. Preoperative data and postoperative short-term and long-term outcomes were reported. 261 robotic procedures were performed in our Center between May 2014 and October 2020. 12 patients underwent robotic left hepatectomy (RLH) and 10 patients were treated by robotic right hepatectomy (RRH). In the RLH group, median operative time (OT) was 383 min, median estimated blood loss (EBL) was 300 ml, and median in-hospital stay was of 3 days. In the RRH group, median OT was 490 min, median EBL 725 ml, and median hospital stay was 5 days. Although one of the advantages of minimally invasive surgery is to obtain radical resections with parenchyma sparing strategies, patients that need a major hepatectomy may benefit of a robotic resection with good postoperative outcomes. Team learning curve and growth instead of personal progression is crucial to expand the limits of novel surgical techniques.

Background Intraductal papillary neoplasm of the bile duct (IPNB) is a rare variant of bile duct tumors, characterized by an exophytic growth exhibiting a papillary mass within the bile duct lumen and it can be localized anywhere along the biliary tree, with morphological variations and occasional invasion. Case summary We present a patient with obstructive jaundice who was diagnosed with IPNB using cholangioscopy during endoscopic retrograde cholangio-pancreatography. Using the SpyGlass DS II technology, we were able to define tumor extension and obtain targeted Spy-byte biopsies. After multidisciplinary evaluation, the patient was scheduled for surgical resection of the tumor, which was radically removed. Conclusion Cholangioscopy appears to be crucial for the rapid and clear diagnosis of lesions in the bile duct to achieve radical surgical resection.

Liver resection (LR) and radiofrequency ablation (RFA) are considered curative options for hepatocellular carcinoma (HCC). The aim of this study was to compare outcomes after LR and RFA in octogenarian patients with HCC.This multicenter retrospective study included 102 elderly patients ( 80 years old) treated between January 2009 and January 2019, who underwent LR or RFA for HCC (65 and 37 with, respectively).After Propensity Score Matching, the postoperative course of LR was burdened by a higher rate of complications than RFA group (64% vs 14%, respectively, p: 0.001). The LR group had also significantly longer operative time (207 ± 85 min vs 33 ± 49 min, p 0.001) and postoperative hospital stays than the RFA group (7 d vs 2 d, p = 0.019). Overall survival at 1-, 2-, and 3-year were 86%, 86%, and 70% for the LR group and 82%, 64%, and 52% for the RFA group (p = 0.380). Disease-free survival at 1-, 2-, and 3-year were 89%, 74%, and 56% for the LR group, and 51%, 40%, and 40% for the RFA group (p = 0.037).Despite a higher rate of Dindo-Clavien I-II post-operative complications, a longer operative time and length of hospital stay, LR in octogenarian patients can provide comparable 90d mortality than RFA and better long-term outcomes.

(1) Background: Primary liver transplantation (PLT) for HCC represents the ideal treatment. However, since organ shortage increases the risk of drop-out from the waiting list for tumor progression, a new surgical strategy has been developed: Salvage Liver Transplantation (SLT) can be offered as an additional curative strategy for HCC recurrence after liver resection. The aim of this updated meta-analysis is to compare surgical and long-term outcomes of SLT versus PLT for HCC. (2) Materials and Methods: A systematic review and meta-analysis was conducted using the published papers comparing SLT and PLT up to January 2022. (3) Results: 25 studies describing 11,275 patients met the inclusion criteria. The meta-analysis revealed no statistical difference in intraoperative blood loss, overall vascular complications, retransplantation rate, and hospital stay in the SLT group compared with the PLT group. However, the SLT group showed a slightly significant lower 5-year OS rate and 5-year disease-free survival rate. (4) Conclusion: meta-analysis advocates the relative safety and feasibility of both Salvage LT and Primary LT strategies. Specifically, SLT seems to have comparable surgical outcomes but slightly poorer long-term survival than PLT.

The use of machine perfusion (MP) in liver transplantation (LT) is spreading worldwide. However, its efficacy has not been demonstrated, and its proper clinical use has far to go to be widely implemented. The Società Italiana Trapianti d’Organo (SITO) promoted the development of an evidence-based position paper. A 3-step approach has been adopted to develop this position paper. First, SITO appointed a chair and a cochair who then assembled a working group with specific experience of MP in LT. The Guideline Development Group framed the clinical questions into a patient, intervention, control, and outcome (PICO) format, extracted and analyzed the available literature, ranked the quality of the evidence, and prepared and graded the recommendations. Recommendations were then discussed by all the members of the SITO and were voted on via the Delphi method by an institutional review board. Finally, they were evaluated and scored by a panel of external reviewers. All available literature was analyzed, and its quality was ranked. A total of 18 recommendations regarding the use and the efficacy of ex situ hypothermic and normothermic machine perfusion and sequential normothermic regional perfusion and ex situ MP were prepared and graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. A critical and scientific approach is required for the safe implementation of this new technology.

Background The use of liver grafts from donors after circulatory death (DCD) is associated with an increased risk of developing severe transplant-related complications. However, a balanced evaluation of risks calculated on both donor's and recipient's specific medical history, may reduce the incidence of post-operative complications avoiding a futile transplant. Methods We report a case wherein we transplanted a patient with hepatocellular carcinoma (HCC) outside Milan criteria using a borderline DCD graft. The decision to accept the offered DCD liver was difficult given the extent of injury from severe abdominal trauma, initial blood tests (AST 1782 U/I, ALT 1803 U/I, CPK 12931 mg/dl on procurement day) and technical complexity of Normothermic Regional Perfusion (NRP) due to the amputation of the left lower limb and multiple pelvic fractures. Liver biopsy showed 0% of macro-steatosis and 30% necrosis. We applied our standardized protocol of sequential NRP during graft procurement followed by D-HOPE machine perfusion prior implantation. Results The graft underwent 130 minutes of cold storage and 192 minutes of D-HOPE machine perfusion before being transplanted and total ischemia time was of 261 minutes. After eleven months, the patient is in good general conditions, no signs of HCC recurrence, AFP 2,7 ng/ml. Conclusions The evaluation of the donor should always be based on both pre- and intra-procurement data, taking into-account lactate and transaminase trend during ECMO, liver perfusion and macroscopic appearance of the organ. The use of this grafts may result in a curative chance for patients that demonstrated a favorable HCC biology by pushing the limits of both organ and recipient selection.

Background: Despite the rapid advances that minimally invasive liver resection has gained in recent decades, open conversion is still inevitable in some circumstances. In this study, we aimed to determine the risk factors for open conversion after minimally invasive left lateral sectionectomy, and its impact on perioperative outcomes. Methods: This is a post hoc analysis of 2,445 of 2,678 patients who underwent minimally invasive left lateral sectionectomy at 45 international centers between 2004 and 2020. Factors related to open conversion were analyzed via univariate and multivariate analyses. One-to-one propensity score matching was used to analyze outcomes after open conversion versus non-converted cases. Results: The open conversion rate was 69/2,445 (2.8%). On multivariate analyses, male gender (3.6% vs 1.8%, P = .011), presence of clinically significant portal hypertension (6.1% vs 2.6%, P = .009), and larger tumor size (50 mm vs 32 mm, P < .001) were identified as independent factors associated with open conversion. The most common reason for conversion was bleeding in 27/69 (39.1%) of cases. After propensity score matching (65 open conversion vs 65 completed via minimally invasive liver resection), the open conversion group was associated with increased operation time, blood transfusion rate, blood loss, and postoperative stay compared with cases completed via the minimally invasive approach. Conclusion: Male sex, portal hypertension, and larger tumor size were predictive factors of open conversion after minimally invasive left lateral sectionectomy. Open conversion was associated with inferior perioperative outcomes compared with non-converted cases.

Background Laparoscopic liver resection (LLR) and radiofrequency ablation (RFA) represented potential treatments for patients with a single hepatocellular carcinoma (HCC) smaller than 3 cm. As the aging population soared, our study aimed to examine the advantage/drawback balance for these treatments, which should be reassessed in elderly patients. Methods A multicentric retrospective study compared 184 elderly patients (aged >70 years) (86 patients underwent LLR and 98 had RFA) with single ≤3 cm HCC, observed from January 2009 to January 2019. Results After propensity score matching (PSM), the estimated 1- and 3-year overall survival rates were 96.5 and 87.9% for the LLR group, and 94.6 and 68.1% for the RFA group (p = 0.001) respectively. The estimated 1- and 3-year disease-free survival rates were 92.5 and 67.4% for the LLR group, and 68.5 and 36.9% for the RFA group (p = 0.001). Patients with HCC of anterolateral segments were more often treated with laparoscopic resection (47 vs. 36, p = 0.04). The median operative time in the resection group was 205 min and 25 min in the RFA group (p = 0.01). Length of hospital stay was 5 days in the resection group and 3 days in the RFA group (p = 0.03). Conclusion Despite a longer length of hospital stay and operative time, LLR guarantees a comparable postoperative course and a better overall and disease-free survival in elderly patients with single HCC (≤3 cm), located in anterolateral segments.

OBJECTIVE: To investigate the effect of low-dose aspirin in primary adult liver transplantation LT on acute cellular rejection ACR as well as arterial patency rates. BACKGROUND: The use of low-dose aspirin after LT is practiced by many transplant centers to minimize the risk of hepatic artery thrombosis HAT, although solid recommendations do not exist. However, aspirin also possesses potent anti-inflammatory properties and might mitigate inflammatory processes after LT, such as rejection. Therefore, we hypothesized that the use of aspirin after liver transplantation has a protective effect against ACR. METHODS: This is an international, multicenter cohort study of primary adult deceased donor LT. The study included 17 high-volume LT centers and covered the 3-year period from 2013 to 2015 to allow a minimum 5-year follow-up. RESULTS: In this cohort of 2,365 patients, prophylactic antiplatelet therapy with low-dose aspirin was administered in 1,436 recipients 61%. One-year rejection-free survival rate was 89% in the aspirin group versus 82% in the no-aspirin group HR 0.77, 95% CI 0.63-0.94, p=0.01. One-year primary arterial patency rates were 99% in the aspirin and 96% in the no-aspirin group with a HR of 0.23 95% CI: 0.13-0.40; p

ImportanceLong-term oncologic outcomes of robotic surgery remain a hotly debated topic in surgical oncology, but sparse data have been published thus far.ObjectiveTo 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 ParticipantsThis 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 MeasuresA 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 ResultsThe 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 P 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 RelevanceThis 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.

Background: Many patients with Hepatocellular Carcinoma (HCC) present at diagnosis a tumor stage suitable for both Liver Resection (LR) and Liver Transplantation (LT). LR is generally safer, available for all, schedulable at the best timing, but less radical and not able to cure the underlying cirrhosis. Contrarily, LT is much more invasive, unavailable for all the candidates, performed at unpredictable time, but with more extended radicality and able also to cure the underlying cirrhosis. Until now, what is the best candidate for LR or LT upfront is extremely unclear. The aim of the study was to validate a model to predict tumor results after LR or LT for patients eligible for both. Methods: All the 2640 consecutive cases of LR or LT for HCC at the 4 centers involved into the study were collected. After a propensity score matching (PSM), an homogeneous patient’s cohort was selected and compared between LR and LT groups. An intention-to-treat (ITT) analysis with a competing risk model was applied comparing the tumor related deaths of patient groups. Results: Between 2005 and 2015, 551 LRs and 580 LT candidates (LTc) were selected for the study. Of the 580 LTc, 512 were effectively transplanted, whereas 68 (11.7%) were dropped due to tumor progression. After a PSM, 101 high risk patients were, respectively, selected for each groups: LR and LT. Variables considered for the risk assignment were: alfafetoprotein, tumor size, tumor number, AST, MELD, and age at tumor diagnosis. The 3- and 5-years cumulative incidence of tumor related death was, respectively, 23% and 31% vs 5% and 9% for LR and LT group (Pvalue = .002). Conclusions: The high risk patients’ cohort has significantly better ITT tumor-related survival with a LT rather than a LR upfront. The microvascular invasion or HCC satellitosis may significantly increase the risk of tumor related death even in low and intermediate risk patients who have received LR. The ab-initio LT should be considered in these reconverted risk patients.

September 2020 signed the beginning of the second wave of COVID-19 outbreak in Italy (Supplementary Material-1) (1). Since the dramatic experience learned during the first epidemic wave, a significant decline of liver transplantations (LT) will be expected. Every year, approximatively 1,200 LTs are performed in Italy (2). The majority of these are concentrated within four northern regions (Lombardia, Veneto, Piemonte, Emilia-Romagna, LoVePiER), accounting about more than the half of the overall LT performed per year (749/1,277 LT, 58.6%, in 2019). Nowadays, LoVePiER was the most involved areas by the Covid-19-outbreak, with a total of 75,738 (71.5%) documented cases until March 31st and 10,174 (81.8%) deaths (Supplementary Material-2) (1).

Recurrent hepatocellular carcinoma (HCC-R) after Liver Transplant (LT) is difficult to manage and often characterized by relevant aggressiveness and extrahepatic localizations. Currently TKIs are the only therapeutic option, but results in term of overall survival (OS) and progression-free survival are disappointing. Immune checkpoint inhibitors in association with recombinant humanized monoclonal antibody to VEGF were to be proved effective in non-LT patients with metastatic hepatocellular carcinoma in determining tumor stabilization and improved survival. However, as in LT patients immunotherapy may increase the risk of acute liver rejection, such combination therapy has not been used so far. We designed a proof-of-concept study to analyze safety and efficacy of Nivolumab and Bevacizumab in LT patients as treatment for HCC-R after LT. Combination therapy received nominal authorization from the Provincial Medicines Commission. Candidate patients underwent routine blood test (hepatic, renal, and cardiac function), echocardiogram and a total body CT as baseline assessment. Patients with creatinine higher than 1.5 ULN or with ejection fraction lower than 45% were excluded. Five patients who experienced HCC-R 2 to 8 years after LT with pulmonary, lymph node, adrenal, bones, and hepatic localization and were either intolerant to TKIs or had had progression on TKIs, were included. All recurrent tumors and extra-hepatic localizations were characterized by high biologic aggressiveness. Patients received Nivolumab infusion every 14 days at a dose of 240 mg. Total body CT scan was performed every 8 weeks. When progression disease (PD) was detected at CT scan, Bevacizumab was added at a dose of 5 mg/kg every 14 days. One patient received a single Nivolumab infusion but was withdrawn because of rapid tumor progression, eventually followed by death. Another patient experienced moderate/severe rejection, which resolved with 1g/day Methylprednisolone e.v. for 3[EV1] days followed by Prednisone 50mg/day for 1 week then tapered and stopped. This patient was maintained on double therapy without residual problems. The 4 alive patients are still on double therapy after a mean period of treatment of 36±21 weeks. Disease stability with the combination of Nivolumab/Bevacizumab has been achieved in all patients at hepatic and all extra-hepatic HCC localization but bone, where 2/2 patients experienced progression. It should be underlined, however, that progression was very slow and mean survival of these two patients on combination therapy is 54±2 weeks. Combination therapy was very well tolerated, with few side effects throughout treatment period. These results indicate that the combination Nivolumab/Bevacizumab can be safely used in liver transplant patients. The risk of acute allograft rejection is minimal and manageable. Bone metastases remain an unsolved issue and need further alternative therapeutic approach. For patients with hepatic or other extra-hepatic localization, this combination obtained a relevant and protracted stabilization of disease. Citation Format: Lorenza Di Marco, Alessandra Pivetti, Nicola De Maria, Francesco Giuseppe Foschi, Dante Romagnoli, Federico Casari, Cristian Caporali, Paolo Magistri, Barbara Catellani, Fabrizio Di Benedetto, Erica Villa. Combination therapy with Nivolumab/Bevacizumab is safe and effective in patients with recurrent hepatocellular carcinoma after liver transplant [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO003.

Simple Summary HCC are now emerging as leading causes of morbidity in HIV-infected patients since HAART has made it possible to achieve long life expectation by reducing AIDS-related complications. The results of liver transplantation for HCC in HIV-infected patients are still contradictory. In this paper we demonstrated in a cohort of 32 HIV-infected patients undergoing LT for HCC that the post-LT outcomes are comparable to the controlled cohort of uninfected recipients. Long survival rates were observed for HIV-infected LT patients with HCC. Abstract Background: HIV-infected patients now have long life expectation since the introduction of the highly active antiretroviral therapy (HAART). Liver diseases, especially cirrhosis and hepatocellular carcinoma (HCC), currently represent a leading cause of death in this setting of patients. Aim: To address the results of liver transplantation (LT) for HCC in HIV-infected patients. Methods: All patients with and without HIV infection who underwent LT for HCC (n = 420) between 2001 and 2021 in our center were analyzed with the intent of comparing graft and patient survival. Cox regression analysis was used to determine prognostic survival factors and logistic regression to determine the predictor factors of post-LT recurrence. Results: Among 1010 LT, 32 were HIV-infected recipients. With an average follow-up of 62 ± 51 months, 5-year overall survival in LT recipients with and without HIV-infection was 71.6% and 69.9%, respectively (p = ns), whereas 5-year graft survival in HIV-infected and HIV-non infected was 68.3% and 68.2%, respectively (p = ns). The independent predictive factor of survival in the study group was: HCV infection (HR 1.83, p = 0.024). There were no significant differences in the pathological characteristics of HCC between the two groups. The logistic regression analysis of the study population demonstrated that microvascular invasion (HR 5.18, p< 0.001), HCC diameter (HR 1.16, p = 0.028), and number of HCC nodules (HR 1.26, p = 0.003) were predictors of recurrence post-LT. Conclusion: Our study shows that HIV patients undergoing LT for HCC have comparable results in terms of post-LT survival. Excellent results can be achieved for HIV-infected patients with HCC, as long as a strategy of close surveillance and precise treatment of the tumor is adopted while on the waiting list.

Background. While laparoscopy is currently adopted for hepatic resections, robotic approaches to the liver have not gained wide acceptance. We decided to analyze the learning curve in the field of robotic liver surgery comparing short-term outcomes between the first and the second half of our series. Methods. We retrospectively reviewed demographics and clinical data of patients who underwent robotic liver resection at our institution from July 2014 through September 2017. 60 patients diagnosed with primary or secondary liver neoplasms or hydatid disease were included in this study. ASA PS >3, heart failure, respiratory insufficiency, and general contraindication to pneumoperitoneum were exclusion criteria. Results. 60 patients were included. We observed a statistically significant decrease in operative time (p Discussion. This is the first European analysis of the learning curve for robotic liver resection in an HPB and liver transplant referral center. However, more studies are needed to confirm such results outside a HPB referral center. This is crucial to develop formal credentialing protocols for both junior and senior surgeons.

This study assesses the expression of all TNF-related apoptosis-inducing ligand (TRAIL) receptors in pancreatic ductal adenocarcinoma (PDAC) tumor tissue. We aimed to include TRAIL receptor expression as an inclusion parameter in a future clinical study using a TRAIL-based therapy approach for PDAC patients. Considering the emerging influence of PDAC desmoplastic stroma on the efficacy of anti-PDAC therapies, this analysis was extended to tumor stromal cells. Additionally, we performed PDAC stroma characterization. Our retrospective cohort study (N=50) included patients with histologically confirmed PDAC who underwent surgery. The expression of TRAIL receptors (DR4, DR5, DcR1, DcR2, and OPG) in tumor and stromal cells was evaluated by immunohistochemistry (IHC). The amount of tumor stroma was assessed by anti-vimentin IHC and Mallory’s trichrome staining. The prognostic impact was determined by the univariate Cox proportional hazards regression model. An extensive expression of functional receptors DR4 and DR5 and a variable expression of decoy receptors were detected in PDAC tumor and stromal cells. Functional receptors were detected also in metastatic tumor and stromal cells. A poor prognosis was associated with low or absent expression of decoy receptors in tumor cells of primary PDAC. After assessing that almost 80% of tumor mass was composed of stroma, we correlated a cellular-dense stroma in primary PDAC with reduced relapse-free survival. We demonstrated that TRAIL functional receptors are widely expressed in PDAC, representing a promising target for TRAIL-based therapies. Further, we demonstrated that a low expression of DcR1 and the absence of OPG in tumor cells, as well as a cellular-dense tumor stroma, could negatively impact the prognosis of PDAC patients.

Background Hepatocellular carcinoma (HCC) is a common indication for associating liver partition with portal vein ligation for staged hepatectomy (ALPPS). Robotic liver resection has been done for HCC, but robotic ALPPS is a rare procedure. Methods To present three cases of totally robotic ALPPS in cirrhotic patients with HCC. Results Three cirrhotic male patients with HCC underwent ALPPS; the mean age was 54.3 years. MELD score was ≤9 and tumour size between 90 and 140 mm. The mean hypertrophy of the future liver remnant after the first stage was 77.5% and no postoperative liver failure was reported. Mean operative time of stage 1 was 7:30 h and of stage 2 was 4:37 h, without blood transfusion. The mean hospital stay for the first stage was 10 days and for the second stage was 9.3 days. No postoperative complication was recorded. Conclusions Robotic ALPPS in cirrhotic patients with HCC is safe and feasible.

Background: Surgical resection is a first-line curative option for hepatocellular carcinoma, but its role is still unclear in elderly patients. The aim of our study was to compare short- and long-term outcomes of laparoscopic and open liver resection in elderly patients with hepatocellular carcinoma. Methods: The study included 665 consecutive hepatocellular carcinoma liver resection cases in patients with ≥70 years of age treated in eight European hospital centres. Patients were divided into laparoscopic and open liver resection groups. Perioperative and long-term outcomes were compared between these groups. Results: After a 1:1 propensity score matching, 219 patients were included in each group. Clavien-Dindo grades III/IV (6 vs. 20%, p = 0.04) were lower in the laparoscopic than in the open matched group. Hospital stay was shorter in the laparoscopic than in the open matched group (5 vs. 7 days, p < 0.001). There were no significant differences between laparoscopic and open groups regarding overall survival and disease-free survival at 1-, 3- and 5- year periods. Conclusion: Laparoscopic liver resection for hepatocellular carcinoma is associated with good short-term outcomes in patients with ≥70 years of age compared to open liver resection. Laparoscopic liver resection is safe and feasible in elderly patients with hepatocellular carcinoma.

BACKGROUND Surgical resection and radiofrequency ablation (RFA) represent two possible strategy in treatment of hepatocellular carcinoma (HCC) in Milan criteria. AIM To evaluate short- and long-term outcome in elderly patients (> 70 years) with HCC in Milan criteria, which underwent liver resection (LR) or RFA. METHODS The study included 594 patients with HCC in Milan criteria (429 in LR group and 165 in RFA group) managed in 10 European centers. Statistical analysis was performed using the Kaplan-Meier method before and after propensity score matching (PSM) and Cox regression. RESULTS After PSM, we compared 136 patients in the LR group with 136 patients in the RFA group. Overall survival at 1, 3, and 5 years was 91%, 80%, and 76% in the LR group and 97%, 67%, and 41% in the RFA group respectively (P = 0.001). Disease-free survival at 1, 3, and 5 years was 84%, 60% and 44% for the LR group, and 63%, 36%, and 25% for the RFA group (P = 0.001).Postoperative Clavien-Dindo III-IV complications were lower in the RFA group (1% vs 11%, P = 0.001) in association with a shorter length of stay (2 d vs 7 d, P = 0.001).In multivariate analysis, Model for End-stage Liver Disease (MELD) score (> 10) [odds ratio (OR) = 1.89], increased value of international normalized ratio (> 1.3) (OR = 1.60), treatment with radiofrequency (OR = 1.46) ,and multiple nodules (OR = 1.19) were independent predictors of a poor overall survival while a high MELD score (> 10) (OR = 1.51) and radiofrequency (OR = 1.37) were independent factors associated with a higher recurrence rate. CONCLUSION Despite a longer length of stay and a higher rate of severe postoperative complications, surgery provided better results in long-term oncological outcomes as compared to ablation in elderly patients (> 70 years) with HCC in Milan criteria.

Background: The benefits of pure laparoscopic and robot-assisted liver resections (LLR and RALR) are known in comparison to open surgery. The aim of the present retrospective comparative study is to investigate the role of RALR and LLR according to different levels of difficulty. Methods: The institutional databases of six high-volume hepatobiliary centers were retrospectively reviewed. The study population was divided in two groups: LLR and RALR. The procedures were stratified for difficulty levels accordingly to three classifications. A propensity score matching was implemented to mitigate selection bias. Short-term outcomes were the object of comparison. Results: Nine hundred and thirty-six LLR and 403 RALR were collected. RALR exhibited fewer cases of intraoperative blood loss, lower transfusion and conversion rates (especially for oncological radicality) than LLR in the setting of highly difficult operations, whereas LLR had lower postoperative morbidity and fewer low-grade complications. For intermediate and low-difficulty resections, the intraoperative advantages of RALR gradually decreased to nonsignificant results and LLR remained associated with lower postoperative morbidity. Conclusion: Robot-assisted liver resections do not show operative nor clinically significant benefits over LLR for low- and intermediate-difficulty resections. By reducing conversion rates, RALR can favour the operative feasibility of difficult resections possibly extending the indications of minimally invasive approaches for liver resection.