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BackgroundAs literature largely focuses on long-term outcomes, this study aimed at elucidating the perioperative outcomes of liver transplant patients receiving a graft from two groups of unconventional expanded criteria donors: brain dead aged > 80 years and cardiac dead.MethodsData of 247 cirrhotic patients transplanted at two high volume liver transplant centers were analysed. Confounders were balanced using a stabilized inverse probability therapy weighting and a propensity score for each patient on the original population was generated. The score was created using a multivariate logistic regression model considering a Comprehensive Complication Index ≥ 42 (no versus yes) as the dependent variable and 11 possible clinically relevant confounders as covariate.ResultsForty-four patients received the graft from a cardiac-dead donor and 203 from a brain-dead donor aged > 80 years. Intraoperatively, cardiac-dead donors liver transplant cases required more fresh frozen plasma units (P P = 0.80). In the Intensive Care Unit, both the groups presented a comparable low need for blood transfusions, renal replacement therapy and inotropes. Cardiac-dead donors liver transplantations required more time to tracheal extubation (P P P = 0.52). ICU stay (P = 0.97), total hospital stay (P = 0.57), in hospital (P = 1.00) and 6 months (P = 1.00) death were similar.ConclusionSelected octogenarian and cardiac-dead donors can be used safely for liver transplantation.

Although machine perfusion (MP) is being increasingly adopted in liver transplantation, indications, timing, and modality are debated. To investigate current indications for MP a web-based Google Forms survey was launched in January 2021 and addressed to 127 experts in the field, identified among first and corresponding Authors of MP literature in the last 10years. The survey presented 10 real-life cases of donor-recipient matching, asking whether the liver would be accepted (Q1), whether MP would be used in that particular setting (Q2) and, if so, by which MP modality (Q3) and at what timing during preservation (Q4). Respondents could also comment on each case. The agreement was evaluated using Krippendorff's alpha coefficient. Answers from 39 (30.1%) participants disclosed significant heterogeneity in graft acceptance, MP indications, technique, and timing. Agreement between respondents was generally poor (Q1, α=0.11; Q2, α=0.14; Q3, α=0.12, Q4, α=0.11). Overall, respondents preferred hypothermic MP and an end-ischemic approach in 56.3% and 81.1% of cases, respectively. A total of 18 (46.2%) participants considered only one MP approach, whereas 17 (43.6%) and 3 (7.7%) considered using alternatively 2 or 3 different techniques. Of 38 comments, 17 (44.7%) were about the use of MP for graft viability assessment before implantation. This survey shows considerable variability in MP indications, emphasizing the need to identify scenarios of optimal utilization for each technique. Viability assessment emerges as a fundamental need of transplant professionals when considering the use of MP.

Background: The achievement of high rates of sustained virological response (SVR) with direct-acting antivirals (DAAs) in hepatitis C virus (HCV) infected patients will reduce decompensating terminal events. Aims: To investigate whether hepatocellular carcinoma (HCC) occurrence could change due to the DAA-induced increase in life-expectancy. Methods: A Markov model was built on clinical data of 494 cirrhotic patients and available literature to estimate probabilities of “death before HCC” and of “HCC occurrence” without and with DAA. Results: In comparison to untreated patients, DAA therapy reduced the 20-year mortality before HCC by 21.9% in patients without varices and by 21.5% in those with varices, considering an SVR of 95% and no direct effect on hepatocarcinogenesis. Tumour occurrence increased by 5%–8.2% and the proportion of HCCs diagnosed in compensated stages increased to >98%. If we consider DAA as having “anti-tumoral” effects, the benefit becomes greater, achieving a 20-year survival of 81.5% in patients without varices, and 52.2% in patients with varices. Instead, if we consider DAA as having a “pro-tumoral” effect, then, the increased incidence of HCC nullifies the survival benefits. Conclusion: DAAs drastically reduce the mortality caused by the liver function worsening, increasing the proportion of HCCs diagnosed in compensated stages. Knowledge of the DAA effect on hepatocarcinogenesis remains pivotal. © 2017 Editrice Gastroenterologica Italiana S.r.l.

Liver transplantation for primary sclerosing cholangitis (PSC) can be complicated by recurrence of PSC (rPSC). This may compromise graft survival but the effect on patient survival is less clear. We investigated the effect of post-transplant rPSC on graft and patient survival in a large European cohort. Registry data from the European Liver Transplant Registry regarding all first transplants for PSC between 1980 and 2015 were supplemented with detailed data on rPSC from 48 out of 138 contributing transplant centres, involving 1,549 patients. Bayesian proportional hazards models were used to investigate the impact of rPSC and other covariates on patient and graft survival. Recurrence of PSC was diagnosed in 259 patients (16.7%) after a median follow-up of 5.0 years (quantile 2.5%-97.5%: 0.4-18.5), with a significant negative impact on both graft (HR 6.7; 95% CI 4.9-9.1) and patient survival (HR 2.3; 95% CI 1.5-3.3). Patients with rPSC underwent significantly more re-transplants than those without rPSC (OR 3.6, 95% CI 2.7-4.8). PSC recurrence has a negative impact on both graft and patient survival, independent of transplant-related covariates. Recurrence of PSC leads to higher number of re-transplantations and a 33% decrease in 10-year graft survival. ispartof: TRANSPLANT INTERNATIONAL vol:34 issue:8 pages:1455-1467 ispartof: location:Switzerland status: published

Background and aims Cholangiocarcinoma (CCA) is a very aggressive cancer showing the presence of high cancer stem cells (CSCs). Doublecortin-like kinase1 (DCLK1) has been demonstrated as a CSC marker in different gastroenterological solid tumors. Our aim was to evaluate in vitro the expression and the biological function of DCLK1 in intrahepatic CCA (iCCA) and perihilar CCA (pCCA). Approach and results Specimens surgically resected of human CCA were enzymatically digested, submitted to immunosorting for specific CSC markers (LGR5 [leucine-rich repeat-containing G protein-coupled receptor], CD [clusters of differentiation] 90, EpCAM [epithelial cell adhesion molecule], CD133, and CD13), and primary cell cultures were prepared. DCLK1 expression was analyzed in CCA cell cultures by real-time quantitative PCR, western blot, and immunofluorescence. Functional studies have been performed by evaluating the effects of selective DCLK1 inhibitor (LRRK2-IN-1) on cell proliferation (MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay, cell population doubling time), apoptosis, and colony formation capacity. DCLK1 was investigated in situ by immunohistochemistry and real-time quantitative PCR. DCLK1 serum concentration was analyzed by enzyme-linked immunosorbent assay. We describe DCLK1 in CCA with an increased gene and protein DCLK1 expression in pCCALGR5+ and in iCCACD133+ cells compared with unsorted cells. LRRK2-IN-1 showed an anti-proliferative effect in a dose-dependent manner. LRRK2-IN-1 markedly impaired cell proliferation, induced apoptosis, and decreased colony formation capacity and colony size in both iCCA and pCCA compared with the untreated cells. In situ analysis confirmed that DCLK1 is present only in tumors, and not in healthy tissue. Interestingly, DCLK1 was detected in the human serum samples of patients with iCCA (high), pCCA (high), HCC (low), and cirrhosis (low), but it was almost undetectable in healthy controls. Conclusions DCLK1 characterizes a specific CSC subpopulation of iCCACD133+ and pCCALGR5+ , and its inhibition exerts anti-neoplastic effects in primary CCA cell cultures. Human DCLK1 serum might represent a serum biomarker for the early CCA diagnosis.

Spreading of SARS‐CoV‐2 infection in Italy has challenged the practice of liver transplantation in an unprecedented way. We report on initiatives implemented at a high‐volume transplant center to handle an anticipated increase in waiting list time, deferral of pre‐transplant care and temporary postponement of routine post‐transplant follow up. All of the strategies we implemented were derived from the chronic care model and based on productive interaction across healthcare professionals, communities, authorities and patients.

Although studies suggest decreased incident hepatocellular carcinoma (HCC) after treatment with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection, data are conflicting regarding risk and aggressiveness of recurrence in patients who have a history of treated HCC. This review analyses data available in literature in order to elucidate the impact of DAAs on the risk of HCC recurrence after successful treatment of the tumor. Overall 24 papers were identified. The available data cannot be considered definitive, but the initial alarmist data indicating an increased risk of recurrence have not been confirmed by most subsequent studies. The suggested aggressive pattern (rapid growth and vascular invasion) of tumor recurrence after DAAs still remains to be confirmed. Several limitations of the available studies were highlighted, and should drive future researches. The time-to-recurrence should be computed since the last HCC treatment and results stratified for cirrhosis and sustained viral response. Any comparison with historical series is of limited interest because of a number of biases affecting these studies and differences between enrolled patients. Prospective intention-to-treat analyses will be probably the best contribution to drive clinical practice, provided that a randomized trial can be difficult to design.

With the introduction of direct-acting antiviral agents (DAA), the rate of sustained virological response (SVR) in the treatment of hepatitis C virus (HCV) has radically improved to over 95%. Robust scientific evidence supports a beneficial role of SVR after interferon therapy in the progression of cirrhosis, resulting in a decreased incidence of hepatocellular carcinoma (HCC). However, a debate on the impact of DAAs on the development of HCC is ongoing. This review aimed to analyse the scientific literature regarding the risk of HCC in terms of its recurrence and occurrence after the use of DAAs to eradicate HCV infection. Among 11 studies examining HCC occurrence, the de novo incidence rate ranged from 0 to 7.4% (maximum follow-up: 18 mo). Among 18 studies regarding HCC recurrence, the rate ranged from 0 to 54.4% (maximum "not well-defined" followup: 32 mo). This review highlights the major difficulties in interpreting data and reconciling the results of the included studies. These difficulties include heterogeneous cohorts, potential misclassifications of HCC prior to DAA therapy, the absence of an adequate control group, short follow-up times and different kinds of follow-up. Moreover, no clinical feature-based scoring system accounts for the molecular characteristics and pathobiology of the tumours. Nonetheless, this review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy in patients with previous HCV infection. © 2018 The Author(s). Published by Baishideng Publishing Group Inc. All rights reserved.

Additional file 2. Immunohistochemistry (IHC) semi-quantitative score for COL3A1 expression in samples obtained from each patient.

This article is the first description of a spontaneous hepatic rupture in a young bodybuilder with a history of clenbuterol and ephedrine alkaloid use. The patient presented with a sudden mid-epigastric pain and vomiting. Hemoglobin levels decreased a few hours later and a computed tomography scan was performed which revealed a rupture of the right liver capsule and hemoperitoneum. Two attempts at transarterial embolization did not control the bleeding and a right hemihepatectomy was performed. The pathological report identified a hepatic adenoma, a capsular tear and diffuse peliosis hepatis. The patient was discharged in a good condition after eleven days. Spontaneous hepatic ruptures are rare and life-threatening and are usually described in association with tumors, connective tissue diseases and gestosis. This article is a review of the available literature with regard to this condition, with a focus on its relation to peliosis hepatis and banned substance used by body image fanatics. The present case highlights the challenging diagnosis of this potentially fatal liver complication in a healthy appearing male, the risk associated with the online trade of performance enhancing drugs and its relation with peliosis hepatis.

presenting list of used antibodies and their application(s). (DOC 40 kb)

presenting positive and negative controls. (DOC 30 kb)

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it is difficult to diagnose because of its nonspecific presentation. This condition frequently occurs in association with an extreme physical stress and may lead to acute adrenal insufficiency or death if not promptly and properly treated. We report a rare case of acute bilateral adrenal hemorrhage with adrenal insufficiency following duodenopancreatectomy for ampulloma in absence of surgical complications. Early diagnosis and corticosteroid replacement with aggressive management of the precipitating pathology are essential to enable a successful outcome.

Liver is frequently involved and injured in blunt abdominal trauma. Although over the last three decades the management of blunt hepatic trauma has gradually shifted toward nonoperative approach whit a significant reduction in overall mortality, surgery remains the main option for hemodinamically unstable patients whit severe liver injuries. A 16-yr-old male in good health suffered a blunt abdominal trauma from a sport accident falling while playing football resulting in a grade V liver injury according to the American Association for the Surgery of Trauma Organ Injury Score. He underwent first to liver packing and next to an early right hepatectomy to arrest the clinical condition impairment In high grade liver injuries, liver resection makes possible to effectively control bleeding, remove necrotic tissue and prevent complications as bile leak. Nevertheless when patient's clinical condition continue to deteriorate despite optimal management a quickly and experienced hands performed hepatectomy may solve the situation.

Milan Criteria (MC) consent excellent survivals for hepatocellular carcinoma (HCC) after liver transplantation (LT). However, several new expanded criteria were proposed, with the intent to increase the HCC patients eligible for LT, maintaining acceptable recurrence rates. The aim of the present study was to analyze a cohort of HCC patients, evaluating the evolutions in its management during the last 20 years and comparing the disease-free survivals among three different periods.HCC patients (n = 122) were transplanted and stratified in three periods: 1st (1988-1998, liberal selection), 2nd (1999-2003, use of MC) and 3rd (2004-2008, use of UCSF criteria). The three periods were analyzed and their survivals were compared.Statistical differences were reported at univariate analysis regarding to both dimensional (total tumor diameter) and biological (alpha feto-protein, microvascular invasion) HCC features. Comparing the 5-year survival rates, a progressive increase was observed in the three periods (62.6%, 87.9% and 88.4%, respectively), with a significant difference between 1st and the second periods (p = 0.008).In our experience, use of UCSF criteria is safe, with a contemporaneous increased number of transplants and better survivals. Introduction of new selection criteria, also based on biological features, is on the way.

We report the surgical management of a bilateral renal artery aneurysm diagnosed in a 41-year-old patient with a history of recurrent abdominal pain. The preoperative contrast-enhanced computed tomography showed a complex saccular aneurysm on both renal arteries within the renal hilum. The characteristics of aneurysms precluded endovascular procedures, and a double-step bilateral ex vivo reconstruction with kidney autotransplantation was planned. The intra- and postoperative period was uneventful. Imaging and laboratory examinations show preservation of renal function, and patient is symptom-free at 10-month follow up.

Alpha-fetoprotein (AFP), des-γ-carboxy prothrombin (DCP), and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) have been developed with the intent to detect hepatocellular carcinoma (HCC) and for the surveillance of at-risk patients. However, at present, none of these tests can be recommended to survey cirrhotic patients at risk for HCC development because of their suboptimal ability for routine clinical practice in HCC diagnosis. Starting from these considerations, these markers have been therefore routinely and successfully used as predictors of survival and HCC recurrence in patients treated with curative intent. All these markers have been largely used as predictors in patients treated with hepatic resection or locoregional therapies, mainly in Eastern countries. In recent studies, AFP has been proposed as predictor of recurrence after liver transplantation and as selector of patients in the waiting list. Use of AFP modification during the waiting list for LT is still under investigation, potentially representing a very interesting tool for patient selection. The development of a new predictive model combining radiological and biological features based on biological markers is strongly required. New genetic markers are continuously discovered, but they are not already fully available in the clinical practice.

Alpha-fetoprotein (AFP), des-γ-carboxy prothrombin (DCP), and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) have been developed with the intent to detect hepatocellular carcinoma (HCC) and for the surveillance of at-risk patients. However, at present, none of these tests can be recommended to survey cirrhotic patients at risk for HCC development because of their suboptimal ability for routine clinical practice in HCC diagnosis. Starting from these considerations, these markers have been therefore routinely and successfully used as predictors of survival and HCC recurrence in patients treated with curative intent. All these markers have been largely used as predictors in patients treated with hepatic resection or locoregional therapies, mainly in Eastern countries. In recent studies, AFP has been proposed as predictor of recurrence after liver transplantation and as selector of patients in the waiting list. Use of AFP modification during the waiting list for LT is still under investigation, potentially representing a very interesting tool for patient selection. The development of a new predictive model combining radiological and biological features based on biological markers is strongly required. New genetic markers are continuously discovered, but they are not already fully available in the clinical practice.

In the last two decades, laparoscopy has revolutionized the field of surgery. Many procedures previously performed with an open access are now routinely carried out with the laparoscopic approach. Several advantages are associated with laparoscopic surgery compared to open procedures: reduced pain due to smaller incisions and hemorrhaging, shorter hospital length of stay, and a lower incidence of wound infections. Liver transplantation (LT) brought a radical change in life expectancy of patients with hepatic end-stage disease. Today, LT represents the standard of care for more than fifty hepatic pathologies, with excellent results in terms of survival. Surely, with laparoscopy and LT being one of the most continuously evolving challenges in medicine, their recent combination has represented an astonishing scientific progress. The intent of the present paper is to underline the current role of diagnostic and therapeutic laparoscopy in patients waiting for LT, in the living donor LT and in LT recipients.

Word file presenting supplementary materials and methods. (DOC 30 kb)

presenting list of used antibodies and their application(s). (DOC 40 kb)

BACKGROUND: Cell therapy of liver diseases with human biliary tree stem cells (hBTSCs) is biased by low engraftment efficiency. Coating the hBTSCs with hyaluronans (HAs), the primary constituents of all stem cell niches, could facilitate cell survival, proliferation, and, specifically, liver engraftment given that HAs are cleared selectively by the liver. METHODS: We developed a fast and easy method to coat hBTSCs with HA and assessed the effects of HA-coating on cell properties in vitro and in vivo. RESULTS: The HA coating markedly improved the viability, colony formation, and population doubling of hBTSCs in primary cultures, and resulted in a higher expression of integrins that mediate cell attachment to matrix components. When HA-coated hBTSCs were transplanted via the spleen into the liver of immunocompromised mice, the engraftment efficiency increased to 11% with respect to 3% of uncoated cells. Notably, HA-coated hBTSC transplantation in mice resulted in a 10-fold increase of human albumin gene expression in the liver and in a 2-fold increase of human albumin serum levels with respect to uncoated cells. Studies in distant organs showed minimal ectopic cell distribution without differences between HA-coated and uncoated hBTSCs and, specifically, cell seeding in the kidney was excluded. CONCLUSIONS: A ready and economical procedure of HA cell coating greatly enhanced the liver engraftment of transplanted hBTSCs and improved their differentiation toward mature hepatocytes. HA coating could improve outcomes of stem cell therapies of liver diseases and could be immediately translated into the clinic given that GMP-grade HAs are already available for clinical use.

presenting positive and negative controls. (DOC 30 kb)

Word file presenting supplementary materials and methods. (DOC 30 kb)

presenting end-point determination details.(DOC 30 kb)

Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC.

In this study, we investigated the role of the Wnt/β-catenin signaling pathway in antitumor immune responses. We report that the concentration of secreted Wnt3a was significantly higher in conditioned medium from tumor or nontumor tissues obtained from all hepatocellular carcinoma or colorectal cancer patients tested, than in serum of healthy donors or patients. In addition, both Wnt3a and β-catenin were overexpressed by tumor-infiltrating and nontumor-infiltrating CD4+ or CD8+ T cells. The majority of these T cells expressed a dysfunctional effector memory Eomes+T-bet−phenotype that we defined as partially exhausted, because they performed effector functions (in terms of interferon-γ and tumor necrosis factor-α production, as well as CD107a mobilization) despite their PD-1 expression. Wnt3a/β-catenin signaling in T naïve cells in vitro recapitulated the T-cell setting in vivo. Indeed, the differentiation of cultured T naïve cells was arrested, producing cells that resembled the EomeshighT-betlowβ-cateninhigh T cells with moderate effector functions that infiltrated tumor and nontumor areas. Wnt3a blockade improved the capacity of T naïve cells to differentiate into effector cells in vitro. However, Wnt3a blockade did not affect the function and phenotype of differentiated, partially exhausted, tumor-infiltrating T cells ex vivo. Taken together, our data suggest that Wnt3a blockade halts the capacity of Wnt/β-catenin signaling to inhibit the differentiation of T naïve cells, but it does not restore the dysfunction of differentiated T cells, in the tumor setting. Cancer Immunol Res; 6(8); 941–52. ©2018 AACR.