Laparoscopic versus open liver resection for colorectal liver metastasis: an umbrella review.

Introduction: This study comprehensively compared laparoscopic liver resection (LLR) to open liver resection (OLR) in treating colorectal cancer liver metastasis (CRLM). Methods: A systematic review of relevant literature was conducted to assess a range of crucial surgical and oncological outcomes. Results: Findings indicate that minimally invasive surgery (MIS) did not significantly prolong the duration of surgery compared to open liver resection and notably demonstrated lower blood transfusion rates and reduced intraoperative blood loss. While some studies favored MIS for its lower complication rates, others did not establish a statistically significant difference. One study identified a lower post-operative mortality rate in the MIS group. Furthermore, MIS consistently correlated with shorter hospital stays, indicative of expedited post-operative recovery. Concerning oncological outcomes, while certain meta-analyses reported a lower rate of cancer recurrence in the MIS group, others found no significant disparity. Overall survival and disease-free survival remained comparable between the MIS and open liver resection groups. Conclusion: The analysis emphasizes the potential advantages of LLR in terms of surgical outcomes and aligns with existing literature findings in this field. Systematic review registration: [website], identifier [registration number].

Surgical Resection in Colorectal Liver Metastasis: An Umbrella Review.

Surgical resection is the gold standard for treating synchronous colorectal liver metastases (CRLM). The resection of the primary tumor and metastatic lesions can follow different sequences: "simultaneous", "bowel-first", and "liver-first". Conservative approaches, such as parenchymal-sparing surgery and segmentectomy, may serve as alternatives to major hepatectomy. A comprehensive search of Medline, Epistemonikos, Scopus, and the Cochrane Library was conducted. Studies evaluating patients who underwent surgery for CRLM and reported survival results were included. Other secondary outcomes were analyzed, including disease-free survival, perioperative complications and mortality, and recurrence rates. Quality assessment was performed using the AMSTAR-2 method. No significant differences in overall survival, disease-free survival, and secondary outcomes were observed when comparing simultaneous to "bowel-first" resections, despite a higher rate of perioperative mortality in the former group. The 5-year OS was significantly higher for simultaneous resection compared to "liver-first" resection. No significant differences in OS and DFS were noted when comparing "liver-first" to "bowel-first" resection, or anatomic to non-anatomic resection. Our umbrella review validates simultaneous surgery as an effective oncological approach for treating SCRLM, though the increased risk of perioperative morbidity highlights the importance of selecting suitable patients. Non-anatomic resections might be favored to preserve liver function and enable future surgical interventions.

Indocyanine green clearance tests to assess liver transplantation outcomes: a systematic review.

BACKGROUND: Liver transplantation (LT) is the gold standard for end-stage liver disease, yet postoperative complications challenge patients and physicians. Indocyanine green (ICG) clearance, a quantitative dynamic test of liver function, is a rapid, reproducible, and reliable test of liver function. This study aimed to systematically review and summarize current literature analyzing the association between ICG tests and post-LT outcomes. METHODS: This systematic review was conducted according to PRISMA guidelines. MEDLINE and Cochrane Library, as main databases, and other sources were searched until August 2022 to identify articles reporting the prognostic value of postoperative ICG tests associated with outcomes of adult LT recipients.Risk of bias of included articles was assessed using Quality In Prognosis Studies tool. Methodological quality varied from low to high across risk of bias domains. RESULTS: Six studies conducted between 1994 and 2018 in Europe, America, and Asia were included. The study population ranged from 50 to 332 participants. ICG clearance on the first postoperative day was associated with early allograft dysfunction, graft loss, 1-month and 3-month patient survival probability, prolonged ICU, and hospital stay. The dichotomized ICG plasma disappearance rate (PDR) provided a strong association with medium-term and long-term outcomes: PDR less than 10%/min with 1-month mortality or re-transplantation (odds ratio: 7.89, 95% CI 3.59-17.34, P <0.001) and PDR less than 16.0%/min with 3-month patient survival probability (hazard ratio: 13.90, 95% CI 4.67-41.35, P <0.01). The preoperative model for end-stage liver disease and body mass index were independent prognostic factors for early allograft dysfunction, early complications, and prolonged ICU stay; post-LT prothrombin time and INR were independently associated with graft loss and bilirubin with a prolonged hospital stay. CONCLUSION: This review shows that ICG clearance tests are associated with graft function recovery, suggesting that a potential prognostic role of ICG test, as an aid in predicting the post-LT course, could be considered.

Therapeutic Approach to Post-Transplant Recurrence of Hepatocellular Carcinoma: Certainties and Open Issues.

Hepatocellular carcinoma (HCC) is a growing indication for liver transplantation (LT). Careful candidate selection is a prerequisite to keep post-LT recurrence rates within acceptable percentages. In the pre-LT period, various types of locoregional treatments and/or systemic therapies can be used for bridging or downstaging purposes. In this context, one of the factors limiting the possibility of treatment is the degree of functional liver impairment. In the LT subject, no widely accepted indications are available to guide treatment of disease recurrence and heterogeneity exists between transplant centers. Improved liver function post LT makes multiple therapeutic strategies theoretically feasible, but patient management is complicated by the need to adjust immunosuppressive therapy and to assess potential toxicities and drug-drug interactions. Finally, there is controversy and uncertainty about the use of recently introduced immunotherapeutic drugs, mainly due to the risk of organ rejection. In this paper, we will review the most recent available literature on the management of post-transplant HCC recurrence, discussing evidence and controversies.

Outcome of liver transplantation in elderly patients: an Italian multicenter case-control study.

Despite the controversial results of liver transplantation (LT) in elderly recipients, the proportion of patients continues to increase. This study investigated the outcome of LT in elderly patients (≥ 65 years) in an Italian, multicenter cohort. Between January 2014 and December 2019, 693 eligible patients were transplanted, and two groups were compared: recipients ≥ 65 years (n = 174, 25.1%) versus 50-59 years (n = 519, 74.9%). Confounders were balanced using a stabilized inverse probability therapy weighting (IPTW). Elderly patients showed more frequent early allograft dysfunction (23.9 versus 16.8%, p = 0.04). Control patients had longer posttransplant hospital stays (median: 14 versus 13 days; p = 0.02), while no difference was observed for posttransplant complications (p = 0.20). At multivariable analysis, recipient age ≥ 65 years was an independent risk factor for patient death (HR 1.76; p = 0.002) and graft loss (HR 1.63; p = 0.005). The 3-month, 1-year, and 5-year patient survival rates were 82.6, 79.8, and 66.4% versus 91.1, 88.5, and 82.0% in the elderly and control group, respectively (log-rank p = 0.001). The 3-month, 1-year, and 5-year graft survival rates were 81.5, 78.7, and 66.0% versus 90.2, 87.2, and 79.9% in the elderly and control group, respectively (log-rank p = 0.003). Elderly patients with CIT > 420 min showed 3-month, 1-year, and 5-year patient survival rates of 75.7%, 72.8%, and 58.5% versus 90.4%, 86.5%, and 79.4% for controls (log-rank p = 0.001). LT in elderly (≥ 65 years) recipients provides favorable results, but inferior to those achieved in younger patients (50-59), especially when CIT > 7 h. Containment of cold ischemia time seems pivotal for favorable outcomes in this class of patients.

The liver transplant surgeon Mondays blues: an Italian perspective.

Poor data exist on the influence of holidays and weekdays on the number and the results of liver transplantation (LT) in Italy. The study's main objective is to investigate the impact of holidays and the different days of the week on the LT number and early graft survival rates in a multi-centric Italian series. We performed a retrospective analysis on 1,026 adult patients undergoing first deceased-donor transplantation between January 2004 and December 2018 in the three university centers in Rome. During the 4,504 workdays, 881 LTs were performed (85.9%; one every 5.1 days on average). On the opposite, 145 LTs were done during the 975 holidays (14.1%; one every 7.1 days on average). Fewer LTs were performed on holidays (P = 0.004). There were no substantial differences in donor-, recipient- and transplant-related characteristics in LTs performed on weekdays or holidays. On Monday, fewer transplants were performed (vs. other weekdays: P < 0.0001; vs. Sunday: P = 0.03). At multivariable Cox regression analysis, LTs performed during the holiday or during the different days of the week were not found to be independent risk factors for the risk of 3- and 12-month graft loss. At three-month survival curves, no differences were observed among the transplants performed during the holidays versus the workdays (86.2 vs. 85.0%; P-0.70). The range of graft survival rates based on the day of the week was 81.6-86.9%, without showing any significant differences (P = 0.57). Fewer transplants are performed on holidays and Mondays. Survivals are not affected by holidays or the day the transplant is performed.

Tissue-Specific Human Extracellular Matrix Scaffolds Promote Pancreatic Tumour Progression and Chemotherapy Resistance.

Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed at a late stage and are locally advanced or with concurrent metastases. The aggressive phenotype and relative chemo- and radiotherapeutic resistance of PDAC is thought to be mediated largely by its prominent stroma, which is supported by an extracellular matrix (ECM). Therefore, we investigated the impact of tissue-matched human ECM in driving PDAC and the role of the ECM in promoting chemotherapy resistance. Decellularized human pancreata and livers were recellularized with PANC-1 and MIA PaCa-2 (PDAC cell lines), as well as PK-1 cells (liver-derived metastatic PDAC cell line). PANC-1 cells migrated into the pancreatic scaffolds, MIA PaCa-2 cells were able to migrate into both scaffolds, whereas PK-1 cells were able to migrate into the liver scaffolds only. These differences were supported by significant deregulations in gene and protein expression between the pancreas scaffolds, liver scaffolds, and 2D culture. Moreover, these cell lines were significantly more resistant to gemcitabine and doxorubicin chemotherapy treatments in the 3D models compared to 2D cultures, even after confirmed uptake by confocal microscopy. These results suggest that tissue-specific ECM provides the preserved native cues for primary and metastatic PDAC cells necessary for a more reliable in vitro cell culture.

Indocyanine green clearance test in liver transplantation: defining cut-off levels for graft viability assessment during organ retrieval and for the prediction of post-transplant graft function recovery - the Liver Indocyanine Green (LivInG) Trial Study Protocol.

INTRODUCTION: Viability assessment of the graft is essential to lower the risk of liver transplantation (LT) failure and need for emergency retransplantation, however, this still relies mainly on surgeon's experience. Post-LT graft function recovery assessment is also essential to aid physicians in the management of LT recipients and guide them through challenging decision making.This study aims to trial the use of indocyanine green clearance test (IGT) in the donor as an objective tool to assess graft viability and in the recipient to assess graft function recovery after LT. METHODS AND ANALYSIS: This is an observational prospective single-centre study on consecutive liver transplant donors and recipients. PRIMARY OBJECTIVE: To determine the capability of IGT of predicting graft viability at the time of organ retrieval. Indocyanine green will be administered to the donor and the plasma disappearance rate (PDR) measured using the pulsidensitometric method. Some 162 IGT donor procedures will be required (α, 5%; ß, 20%) using an IGT-PDR cut-off value of 13% to achieve a significant discrimination between viable and non-viable grafts. SECONDARY OBJECTIVE: IGT-PDR will be measured at different time-points in the LT recipient: during the anhepatic phase, after graft reperfusion, at 24 hours, on day 3 and day 7 after LT. The slope of IGT values from the donor to the recipient will be evaluated for correlation with the development of early allograft dysfunction. ETHICS AND DISSEMINATION: This research protocol was approved by Fondazione Policlinico Universitario Agostino Gemelli IRCCS Ethics Committee (reference number: 0048466/20, study ID: 3656) and by the Italian National Transplant Center (CNT) (reference number: Prot.11/CNT2021). Liver recipients will be required to provide written informed consent. Results will be published in international peer-reviewed scientific journals and presented in congresses. TRIAL REGISTRATION NUMBER: NCT05228587.

From endoscopic resection to pancreatoduodenectomy: a narrative review of treatment modalities for the tumors of the ampulla of Vater.

BACKGROUND AND OBJECTIVE: Tumors of the ampulla of Vater are a rare set of lesions that arise at the confluence of the common bile duct (CBD) and the pancreatic duct. They can be benign or malignant, often not easy to discriminate before treatment. Malignant tumors have low chances of survival (overall 5-year survival between 0% and 60%) and surgery is still the only curative option. Prognostic factors are being investigated to tailor therapeutic approach and improve outcomes. Due to their location in a complex anatomical region, all treatment options are challenging and associated with relevant morbidity. In this review we discuss different excisional techniques for the treatment of ampullary tumors (AT). METHODS: A review of medical databases (PubMed and Google Scholar) was conducted selecting most relevant articles in English language without a specific timeframe. After first selection, most relevant citations were identified through snowballing. KEY CONTENT AND FINDINGS: Pancreatoduodenectomy (PD) is the gold standard in malignant tumors, achieving the most radical treatment, at the price of worse perioperative morbidity/mortality and quality of life. Trans-duodenal ampullectomy (TDA) was developed before endoscopic resection (ER) and maintains a role only in selected patients. ER is now the first choice for benign lesions and expanding towards early stages malignant AT. CONCLUSIONS: Pancreatodudenectomy remains the best option for the radical excision of malignant AT, recently being offered also via minimally invasive approach. However, in early-stage malignant tumors, ER is gaining importance with foreseeable further expansion. Transduodenal ampullectomy still has a role in selected patients, such as unfit for PD when ER is not possible mainly due to anatomical abnormalities.

Prognostic Factors for 10-Year Survival in Patients With Hepatocellular Cancer Receiving Liver Transplantation.

Background: Long-term survival after liver transplantation (LT) for hepatocellular cancer (HCC) continues to increase along with the modification of inclusion criteria. This study aimed at identifying risk factors for 5- and 10-year overall and HCC-specific death after LT. Methods: A total of 1,854 HCC transplant recipients from 10 European centers during the period 1987-2015 were analyzed. The population was divided in three eras, defined by landmark changes in HCC transplantability indications. Multivariable logistic regression analyses were used to evaluate the significance of independent risk factors for survival. Results: Five- and 10-year overall survival (OS) rates were 68.1% and 54.4%, respectively. Two-hundred forty-two patients (13.1%) had HCC recurrence. Five- and 10-year recurrence rates were 16.2% and 20.3%. HCC-related deaths peaked at 2 years after LT (51.1% of all HCC-related deaths) and decreased to a high 30.8% in the interval of 6 to 10 years after LT. The risk factors for 10-year OS were macrovascular invasion (OR = 2.71; P = 0.001), poor grading (OR = 1.56; P = 0.001), HCV status (OR = 1.39; P = 0.001), diameter of the target lesion (OR = 1.09; P = 0.001), AFP slope (OR = 1.63; P = 0.006), and patient age (OR = 0.99; P = 0.01). The risk factor for 10-year HCC-related death were AFP slope (OR = 4.95; P < 0.0001), microvascular (OR = 2.13; P < 0.0001) and macrovascular invasion (OR = 2.32; P = 0.01), poor tumor grading (OR = 1.95; P = 0.001), total number of neo-adjuvant therapies (OR = 1.11; P = 0.001), diameter of the target lesion (OR = 1.11; P = 0.002), and patient age (OR = 0.97; P = 0.001). When analyzing survival rates in function of LT era, a progressive improvement of the results was observed, with patients transplanted during the period 2007-2015 showing 5- and 10-year death rates of 26.8% and 38.9% (vs. 1987-1996, P < 0.0001; vs. 1997-2006, P = 0.005). Conclusions: LT generates long-term overall and disease-free survival rates superior to all other oncologic treatments of HCC. The role of LT in the modern treatment of HCC becomes even more valued when the follow-up period reaches at least 10 years. The results of LT continue to improve even when prudently widening the inclusion criteria for transplantation. Despite the incidence of HCC recurrence is highest during the first 5 years post-transplant, one-third of them occur later, indicating the importance of a life-long follow-up of these patients.

Pediatric T-tube in adult liver transplantation: Technical refinements of insertion and removal.

BACKGROUND: With the increasing use of extended-criteria donor organs, the interest around T-tubes in liver transplantation (LT) was restored whilst concerns regarding T-tube-related complications persist. AIM: To describe insertion and removal protocols implemented at our institution to safely use pediatric rubber 5-French T-tubes and subsequent outcomes in a consecutive series of adult patients. METHODS: Data of consecutive adult LT patients from brain-dead donors, treated from March 2017 to December 2019, were collected (i.e., biliary complications, adverse events, treatment after T-Tube removal). Patients with upfront hepatico-jejunostomy, endoscopically removed T-tubes, those who died or received retransplantation before T-tube removal were excluded. RESULTS: Seventy-two patients were included in this study; T-tubes were removed 158 d (median; IQR 128-206 d) after LT. In four (5.6%) patients accidental T-tube removal occurred requiring monitoring only; in 68 (94.4%) patients Nelaton drain insertion was performed according to our protocol, resulting in 18 (25%) patients with a biliary output, subsequently removed after 2 d (median; IQR 1-4 d). Three (4%) patients required endoscopic retrograde cholangiopancreatography (ERCP) due to persistent Nelaton drain output. Three (4%) patients developed suspected biliary peritonitis, requiring ERCP with sphincterotomy and nasobiliary drain insertion (only one revealing contrast extravasation); no patient required percutaneous drainage or emergency surgery. CONCLUSION: The use of pediatric rubber 5-French T-tubes in LT proved safe in our series after insertion and removal procedure refinements.

Prognostic role of artificial intelligence among patients with hepatocellular cancer: A systematic review.

BACKGROUND: Prediction of survival after the treatment of hepatocellular carcinoma (HCC) has been widely investigated, yet remains inadequate. The application of artificial intelligence (AI) is emerging as a valid adjunct to traditional statistics due to the ability to process vast amounts of data and find hidden interconnections between variables. AI and deep learning are increasingly employed in several topics of liver cancer research, including diagnosis, pathology, and prognosis. AIM: To assess the role of AI in the prediction of survival following HCC treatment. METHODS: A web-based literature search was performed according to the Preferred Reporting Items for Systemic Reviews and Meta-Analysis guidelines using the keywords "artificial intelligence", "deep learning" and "hepatocellular carcinoma" (and synonyms). The specific research question was formulated following the patient (patients with HCC), intervention (evaluation of HCC treatment using AI), comparison (evaluation without using AI), and outcome (patient death and/or tumor recurrence) structure. English language articles were retrieved, screened, and reviewed by the authors. The quality of the papers was assessed using the Risk of Bias In Non-randomized Studies of Interventions tool. Data were extracted and collected in a database. RESULTS: Among the 598 articles screened, nine papers met the inclusion criteria, six of which had low-risk rates of bias. Eight articles were published in the last decade; all came from eastern countries. Patient sample size was extremely heterogenous (n = 11-22926). AI methodologies employed included artificial neural networks (ANN) in six studies, as well as support vector machine, artificial plant optimization, and peritumoral radiomics in the remaining three studies. All the studies testing the role of ANN compared the performance of ANN with traditional statistics. Training cohorts were used to train the neural networks that were then applied to validation cohorts. In all cases, the AI models demonstrated superior predictive performance compared with traditional statistics with significantly improved areas under the curve. CONCLUSION: AI applied to survival prediction after HCC treatment provided enhanced accuracy compared with conventional linear systems of analysis. Improved transferability and reproducibility will facilitate the widespread use of AI methodologies.

Development and Validation of a Comprehensive Model to Estimate Early Allograft Failure Among Patients Requiring Early Liver Retransplant.

Importance: Expansion of donor acceptance criteria for liver transplant increased the risk for early allograft failure (EAF), and although EAF prediction is pivotal to optimize transplant outcomes, there is no consensus on specific EAF indicators or timing to evaluate EAF. Recently, the Liver Graft Assessment Following Transplantation (L-GrAFT) algorithm, based on aspartate transaminase, bilirubin, platelet, and international normalized ratio kinetics, was developed from a single-center database gathered from 2002 to 2015. Objective: To develop and validate a simplified comprehensive model estimating at day 10 after liver transplant the EAF risk at day 90 (the Early Allograft Failure Simplified Estimation [EASE] score) and, secondarily, to identify early those patients with unsustainable EAF risk who are suitable for retransplant. Design, Setting, and Participants: This multicenter cohort study was designed to develop a score capturing a continuum from normal graft function to nonfunction after transplant. Both parenchymal and vascular factors, which provide an indication to list for retransplant, were included among the EAF determinants. The L-GrAFT kinetic approach was adopted and modified with fewer data entries and novel variables. The population included 1609 patients in Italy for the derivation set and 538 patients in the UK for the validation set; all were patients who underwent transplant in 2016 and 2017. Main Outcomes and Measures: Early allograft failure was defined as graft failure (codified by retransplant or death) for any reason within 90 days after transplant. Results: At day 90 after transplant, the incidence of EAF was 110 of 1609 patients (6.8%) in the derivation set and 41 of 538 patients (7.6%) in the external validation set. Median (interquartile range) ages were 57 (51-62) years in the derivation data set and 56 (49-62) years in the validation data set. The EASE score was developed through 17 entries derived from 8 variables, including the Model for End-stage Liver Disease score, blood transfusion, early thrombosis of hepatic vessels, and kinetic parameters of transaminases, platelet count, and bilirubin. Donor parameters (age, donation after cardiac death, and machine perfusion) were not associated with EAF risk. Results were adjusted for transplant center volume. In receiver operating characteristic curve analyses, the EASE score outperformed L-GrAFT, Model for Early Allograft Function, Early Allograft Dysfunction, Eurotransplant Donor Risk Index, donor age × Model for End-stage Liver Disease, and Donor Risk Index scores, estimating day 90 EAF in 87% (95% CI, 83%-91%) of cases in both the derivation data set and the internal validation data set. Patients could be stratified in 5 classes, with those in the highest class exhibiting unsustainable EAF risk. Conclusions and Relevance: This study found that the developed EASE score reliably estimated EAF risk. Knowledge of contributing factors may help clinicians to mitigate risk factors and guide them through the challenging clinical decision to allocate patients to early liver retransplant. The EASE score may be used in translational research across transplant centers.

Transplantation during the COVID-19 pandemic: nothing noble is accomplished without danger.

The global health crisis due to the fast spread of coronavirus disease (COVID-19) has caused major disruption in all aspects of healthcare. Transplantation is one of the most affected sectors, as it relies on a variety of services that have been drastically occupied to treat patients affected by COVID-19. With this report from two transplant centers in Italy, we aim to reflect on resource organization, organ allocation, virus testing and transplant service provision during the course of the pandemic and to provide actionable information highlighting advantages and drawbacks.To what extent can we preserve the noble purpose of transplantation in times of increased danger? Strategies to minimize risk exposure to the transplant population and health- workers include systematic virus screening, protection devices, social distancing and reduction of patients visits to the transplant center. While resources for the transplant activity are inevitably reduced, new dilemmas arise to the transplant community: further optimization of time constraints during organ retrievals and implantation, less organs and blood products donated, limited space in the intensive care unit and the duty to maintain safety and outcomes.

A Bioreactor Technology for Modeling Fibrosis in Human and Rodent Precision-Cut Liver Slices.

Precision cut liver slices (PCLSs) retain the structure and cellular composition of the native liver and represent an improved system to study liver fibrosis compared to two-dimensional mono- or co-cultures. The aim of this study was to develop a bioreactor system to increase the healthy life span of PCLSs and model fibrogenesis. PCLSs were generated from normal rat or human liver, or fibrotic rat liver, and cultured in our bioreactor. PCLS function was quantified by albumin enzyme-linked immunosorbent assay (ELISA). Fibrosis was induced in PCLSs by transforming growth factor beta 1 (TGFß1) and platelet-derived growth factor (PDGFßß) stimulation ± therapy. Fibrosis was assessed by gene expression, picrosirius red, and α-smooth muscle actin staining, hydroxyproline assay, and soluble ELISAs. Bioreactor-cultured PCLSs are viable, maintaining tissue structure, metabolic activity, and stable albumin secretion for up to 6 days under normoxic culture conditions. Conversely, standard static transwell-cultured PCLSs rapidly deteriorate, and albumin secretion is significantly impaired by 48 hours. TGFß1/PDGFßß stimulation of rat or human PCLSs induced fibrogenic gene expression, release of extracellular matrix proteins, activation of hepatic myofibroblasts, and histological fibrosis. Fibrogenesis slowly progresses over 6 days in cultured fibrotic rat PCLSs without exogenous challenge. Activin receptor-like kinase 5 (Alk5) inhibitor (Alk5i), nintedanib, and obeticholic acid therapy limited fibrogenesis in TGFß1/PDGFßß-stimulated PCLSs, and Alk5i blunted progression of fibrosis in fibrotic PCLS. Conclusion: We describe a bioreactor technology that maintains functional PCLS cultures for 6 days. Bioreactor-cultured PCLSs can be successfully used to model fibrogenesis and demonstrate efficacy of antifibrotic therapies.

Cirrhotic Human Liver Extracellular Matrix 3D Scaffolds Promote Smad-Dependent TGF-ß1 Epithelial Mesenchymal Transition.

An altered liver microenvironment characterized by a dysregulated extracellular matrix (ECM) supports the development and progression of hepatocellular carcinoma (HCC). The development of experimental platforms able to reproduce these physio-pathological conditions is essential in order to identify and validate new therapeutic targets for HCC. The aim of this work was to validate a new in vitro model based on engineering three-dimensional (3D) healthy and cirrhotic human liver scaffolds with HCC cells recreating the micro-environmental features favoring HCC. Healthy and cirrhotic human livers ECM scaffolds were developed using a high shear stress oscillation-decellularization procedure. The scaffolds bio-physical/bio-chemical properties were analyzed by qualitative and quantitative approaches. Cirrhotic 3D scaffolds were characterized by biomechanical properties and microarchitecture typical of the native cirrhotic tissue. Proteomic analysis was employed on decellularized 3D scaffolds and showed specific enriched proteins in cirrhotic ECM in comparison to healthy ECM proteins. Cell repopulation of cirrhotic scaffolds highlighted a unique up-regulation in genes related to epithelial to mesenchymal transition (EMT) and TGFß signaling. This was also supported by the presence and release of higher concentration of endogenous TGFß1 in cirrhotic scaffolds in comparison to healthy scaffolds. Fibronectin secretion was significantly upregulated in cells grown in cirrhotic scaffolds in comparison to cells engrafted in healthy scaffolds. TGFß1 induced the phosphorylation of canonical proteins Smad2/3, which was ECM scaffold-dependent. Important, TGFß1-induced phosphorylation of Smad2/3 was significantly reduced and ECM scaffold-independent when pre/simultaneously treated with the TGFß-R1 kinase inhibitor Galunisertib. In conclusion, the inherent features of cirrhotic human liver ECM micro-environment were dissected and characterized for the first time as key pro-carcinogenic components in HCC development.

Laparoscopic liver resection for large HCC: short- and long-term outcomes in relation to tumor size.

OBJECTIVE: In this study, we aim to assess the impact of tumor size on clinical and oncological outcomes in patients undergoing laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC). BACKGROUND: LLR has been shown to be feasible, safe, and oncologically efficient. However, it has been slow to develop in patients with HCC who often suffer from chronic liver disease which represents an additional challenge for the surgeon. The experience with large HCCs is even more limited. METHODS: Between 2003 and 2016, 172 patients from two high-volume liver surgery centers underwent LLR for HCC. Prospectively collected data were analyzed after stratification in 3 groups according to tumor major diameter (group 1: < 3 cm; group 2: between 3 and 5 cm; group 3: ≥ 5 cm). Perioperative and long-term outcomes were compared between the three groups and sub-analyses were carried out on the extent and location of the resections. RESULTS: Groups 1, 2, and 3 consisted of 82, 52, and 38 patients, respectively. Minor and major resections were performed in 98.8% and 1.2% in group 1, in 90.4% and 9.6% in group 2, and in 68.4% and 31.6% in group 3, respectively. Postero-superior "technically major" resections were performed in 15.8% patients in group 1, in 19.2% in group 2, and in 15.8% in group 3, respectively. Group 3 had higher conversion rates (p < 0.001), more frequent (p = 0.056) and more prolonged (p = 0,075) pedicle clamping and longer operative time (p < 0.001), higher blood losses (p = 0.025), and longer total hospital and intensive care unit stays. These differences ceased after removing the major resections from the study population, except for the postoperative length of stay. There were no differences in morbidity, mortality, completeness of resection rates, and long-term outcomes between the three groups. CONCLUSION: LLR for HCC appears to be safe and oncologically efficient when performed in high-volume HPB and laparoscopic centers. Tumor size does not appear to impact negatively on the outcomes except for postoperative hospital stay.

Intention-to-treat survival benefit of liver transplantation in patients with hepatocellular cancer.

The debate about the best approach to select patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still ongoing. This study aims to identify the best variables allowing to discriminate between "high-" and "low-benefit" patients. To do so, the concept of intention-to-treat (ITT) survival benefit of LT has been created. Data of 2,103 adult HCC patients consecutively enlisted during the period 1987-2015 were analyzed. Three rigorous statistical steps were used in order to create the ITT survival benefit of LT: the development of an ITT LT and a non-LT survival model, and the individual prediction of the ITT survival benefit of LT defined as the difference between the median ITT survival with (based on the first model) and without LT (based on the second model) calculated for each enrolled patient. Four variables (Model for End-Stage Liver Disease, alpha-fetoprotein, Milan-Criteria status, and radiological response) displayed a high effect in terms of delta benefit. According to these risk factors, four benefit groups were identified. Patients with three to four factors ("no-benefit group"; n = 405 of 2,103; 19.2%) had no benefit of LT compared to alternative treatments. Conversely, patients without any risk factor ("large-benefit group"; n = 108; 5.1%) yielded the highest benefit from LT reaching 60 months. CONCLUSION: The ITT transplant survival benefit presented here allows physicians to better select HCC patients waiting for LT. The obtained stratification may lead to an improved and more equitable method of organ allocation. Patients without benefit should be de-listed, whereas patients with large benefit ratio should be prioritized for LT. (Hepatology 2017;66:1910-1919).

The use of robotic surgery in abdominal organ transplantation: A literature review.

Minimally invasive surgical approaches in transplantation are gaining increasing interest, and many centers are reporting their, mainly laparoscopic, experiences. Robotic surgery (RS) has some hypothetical advantages over traditional laparoscopy and has been successfully applied, although infrequently to organ transplantation. Our goal was to review and critique the publications reporting RS use in organ transplantation. Most of the RS experience has been with living renal donor organ procurement and, to a lesser extent, with RS procedures in the transplant recipient. The available literature suggests that RS appears to be a safe surgical alternative to standard open procedures. RS in living liver donor surgery remains limited, and more experience is required before commenting on RS-related outcomes RS in pancreatic transplantation is exceedingly rare. The enhanced precision and ergonomics of RS may expand its applicability to liver living donation and pancreas transplantation at some point in the future.

Surgical management of neuroendocrine tumors.

During the last decades an increase in the incidence of neuroendocrine tumors (NETs) was observed. Gastroenteropancreatic NETs represent the majority of NETs. Compared with their epithelial counterpart they usually have a more indolent behaviour and surgical resection improves survival. Tumor diameter is one of the main parameter in the decision making process for nonfunctioning forms. Generally, small lesions can be treated conservatively whereas larger tumors should be treated with standard surgical resection and lymphadenectomy. Functioning tumors should be resected regardless the dimension of the lesion. Locally advanced and metastatic disease should be also treated with extended resections, keeping in consideration the grading, size, Ki67, and presence of extra-abdominal disease. In the case of metastases the panel of operative treatment includes resection, ablation, up to liver transplantation.