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•DAAs have dramatically improved the outcome of cirrhotic patients with HCV infection.•Since the advent of DAAs there has been a 50% decline in the number of liver transplants.•At ...least 600 liver grafts every year can currently be allocated to indications other than HCV.•Survival of LT recipients with HCV or HBV infection is currently comparable, because of DAAs.
Direct-acting antivirals (DAAs) have dramatically improved the outcome of patients with hepatitis C virus (HCV) infection including those with decompensated cirrhosis (DC). We analyzed the evolution of indications and results of liver transplantation (LT) in the past 10 years in Europe, focusing on the changes induced by the advent of DAAs.
This is a cohort study based on data from the European Liver Transplant Registry (ELTR). Data of adult LTs performed between January 2007 to June 2017 for HCV, hepatitis B virus (HBV), alcohol (EtOH) and non-alcoholic steatohepatitis (NASH) were analyzed. The period was divided into different eras: interferon (IFN/RBV; 2007-2010), protease inhibitor (PI; 2011-2013) and second generation DAA (DAA; 2014-June 2017).
Out of a total number of 60,527 LTs, 36,382 were performed in patients with HCV, HBV, EtOH and NASH. The percentage of LTs due to HCV-related liver disease varied significantly over time (p <0.0001), decreasing from 22.8% in the IFN/RBV era to 17.4% in the DAA era, while those performed for NASH increased significantly (p <0.0001). In the DAA era, the percentage of LTs for HCV decreased significantly (p <0.0001) from 21.1% (first semester 2014) to 10.6% (first semester 2017). This decline was more evident in patients with DC (HCV-DC, −58.0%) than in those with hepatocellular carcinoma (HCC) associated with HCV (HCV-HCC, −41.2%). Conversely, three-year survival of LT recipients with HCV-related liver disease improved from 65.1% in the IFN/RBV era to 76.9% in the DAA era, and is now comparable to the survival of recipients with HBV infection (p = 0.3807).
In Europe, the number of LTs due to HCV infection is rapidly declining for both HCV-DC and HCV-HCC indications and post-LT survival has dramatically improved over the last three years. This is the first comprehensive study of the overall impact of DAA treatment for HCV on liver transplantation in Europe.
After the advent of direct-acting antivirals in 2014, a dramatic decline was observed in the number of liver transplants performed both in patients with decompensated cirrhosis due to hepatitis C virus (HCV), minus 60%, and in those with hepatocellular carcinoma associated with HCV, minus 41%. Furthermore, this is the first large-scale study demonstrating that the survival of liver transplant recipients with HCV-related liver disease has dramatically improved over the last three years and is now comparable to the survival of recipients with hepatitis B virus infection. The reduction in HCV-related indications for LT means that there is a greater availability of livers, at least 600 every year, which can be allocated to patients with indications other than HCV.
It is a well-recognized fact that implementing new guidelines in clinical practice may be difficult; therefore the Italian Society for Organ and Tissue Transplantation (SITO) set out to define ...practical immunosuppression tools for the management of liver transplantation patients. In 2017, an Italian Working Group of liver transplant experts and hepatologists issued a set of consensus statements along with evidence-based recommendations on the use of everolimus after liver transplantation. This article presents the evidence- and consensus-based algorithms developed within the Italian Working Group, which are aimed towards guiding clinicians in the selection of immunosuppressive regimens for the management of adult liver transplant recipients in real-life practice. The liver transplant recipient population, typically managed in clinical practice, was divided into the following categories: (1) standard patients; (2) critically ill patients; (3) patients with a specific etiology; (4) patients with hepatocellular carcinoma; (5) and patients with de novo malignancies. The algorithms are divided into two parts, according to the time from transplantation (0–3 months and > 3 months) and are discussed here along with relevant supporting literature, when available. Ultimately, it is hoped that the evidence- and consensus-based algorithms developed within the Italian Working Group, and presented here, contribute to simplify, personalize, and optimize immunosuppression of liver transplantation recipients in clinical practice.
Background
Preliminary experience in laparoscopic liver surgery is usually suggested prior to implementation of a robotic liver resection program.
Methods
This was a retrospective cohort analysis of ...patients undergoing robotic (RLR) versus laparoscopic liver resection (LLR) for hepatocellular carcinoma at a center with concomitant initiation of robotic and laparoscopic programs
Results
A total of 92 consecutive patients operated on between May 2014 and February 2019 were included: 40 RLR versus 52 LLR. Median age (69 vs. 67;
p
= 0.74), male sex (62.5% vs. 59.6%;
p
= 0.96), incidence of chronic liver disease (97.5% vs.98.1%;
p
= 0.85), median model for end-stage liver disease (MELD) score (8 vs. 9;
p
= 0.92), and median largest nodule size (22 vs. 24 mm) were similar between RLR and LLR. In the LLR group, there was a numerically higher incidence of nodules located in segment 4 (20.0% vs. 16.6%;
p
= 0.79); a numerically higher use of Pringle’s maneuver (32.7% vs. 20%;
p
= 0.23), and a shorter duration of surgery (median of 165.5 vs. 217.5 min;
p
= 0.04). Incidence of complications (25% vs.32.7%;
p
= 0.49), blood transfusions (2.5% vs.9.6%;
p
= 0.21), and median length of stay (6 vs. 5;
p
= 0.54) were similar between RLR and LLR. The overall (OS) and recurrence-free (RFS) survival rates at 1 and 5 years were 100 and 79 and 95 and 26% for RLR versus 96.2 and 76.9 and 84.6 and 26.9% for LLR (log-rank
p
= 0.65 for OS and 0.72 for RFS).
Conclusions
Based on our results, concurrent implementation of a robotic and laparoscopic liver resection program appears feasible and safe, and is associated with similar oncologic long-term outcomes.
Apelin, a peptide of 77 amino acids, and its endogenous ligand, angiotensin-like-receptor 1 (APJ), play a key role in the development of tumors by enhancing angiogenesis, metastasis, cell ...proliferation, development of cancer stem cells and drug resistance and inhibiting apoptosis of cancer cells. However, little is known about Apelin/APJ system involvement in hepatocellular carcinoma (HCC). The aim of this study was to evaluate Apelin and APJ expression in liver specimens, obtained from subjects with HCV-positive HCC who underwent liver transplantation, according to liver disease severity (liver recipients, LR,
n
= 14, age 59.4 ± 1.8) and in donors (liver donors, LD,
n
= 14, age 62.1 ± 17.3). Apelin/APJ axis, apoptotic and inflammatory markers were evaluated by Real-Time PCR analysis. The Apelin/APJ system expression resulted significantly higher in LR in comparison with LD (
p
< 0.05), in particular in those with more severe liver disease. The apoptotic (Bcl-2, BAX, NOTCH-1, Casp-3) and inflammatory (IL-6, TNF-α) markers were increased as a function of disease severity (
p
< 0.05). Multiple significant positive correlations were found between Apelin/APJ axis and the other markers. Although further investigations are needed to better understand the role of Apelin/APJ axis in HCC, our result indicated a potential role of this axis in its development and progression as well as in recognizing novel therapeutic targets opening a new avenue for treatment.
The long pentraxin (PTX) 3 and the neuronal pentraxin (NPTX) 2 has been found to exert pleiotropic roles in cancers due to their action in inflammation. However, the accurate clinical significance of ...PTX3 and NPTX2 in hepatocellular carcinoma (HCC), one of the commonest cancers in the world has not been well-defined. The aim of the study was to analyze the expression profile of PTX3 and NPTX2 in liver biopsies of HCV-positive HCC patients (liver recipients, LR,
n
= 14, age 59.4 ± 1.8 years) undergoing liver transplantation and in donors (LD,
n
= 14, age 62.1 ± 17.3 years), trying both to identify them as predictive biomarkers of clinical liver severity in HCC patients and to understand if they were mutually substitutable. The PTX3 and NPTX2 transcripts were significantly up regulated in HCC tissues (
p
= 0.004 and
p
= 0.02 LD vs. LR, respectively). Dividing patients following MELD score, PTX3 expression increased as a function of liver disease severity, while this trend was not observed for NPTX2, which mRNA level increased similarly in both MELD group, reaching the significance only in patients with MELD score < 9 (
p
= 0.01). A positive correlation was found between PTX3 and NPTX2 expression (
p
= 0.001;
r
= 0.69). This is the first study that concerns PTX3 and NPTX2 as a function of clinical severity from which emerged that both of them are unequivocally involved in HCC, but only PTX3 could be considered a staging marker in these HCV-related HCC patients, unlike NPTX2, which could only play a role as an inflammatory marker.
The use of octogenarian donors to increase the donor pool in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk of ischemic‐type biliary lesions ...(ITBL). The aim of this study was to investigate retrospectively the role of a number of different pre‐LT risk factors for ITBL in a selected population of recipients of octogenarian donor grafts. Between January 2003 and December 2013, 123 patients underwent transplantation at our institution with deceased donor grafts from donors of age ≥80 years. Patients were divided into 2 groups based on the presence of ITBL in the posttransplant course. Exclusion criteria were retransplantations, presence of vascular complications, and no availability of procurement liver biopsy. A total of 88 primary LTs were included, 73 (83.0%) with no posttransplant ITBLs and 15 (17.0%) with ITBLs. The median follow‐up after LT was 2.1 years (range, 0.7‐5.4 years). At multivariate analysis, donor hemodynamic instability (hazard ratio HR, 7.6; P = 0.005), donor diabetes mellitus (HR, 9.5; P = 0.009), and donor age–Model for End‐Stage Liver Disease (HR, 1.0; P = 0.04) were risk factors for ITBL. Transplantation of liver grafts from donors of age ≥80 years is associated with a higher risk for ITBL. However, favorable results can be achieved with accurate donor selection. Donor hemodynamic instability, a donor history of diabetes mellitus, and allocation to higher Model for End‐Stage Liver Disease score recipient all increase the risk of ITBL and are associated with worse graft survival when octogenarian donors are used. Liver Transplantation 22 588‐598 2016 AASLD.
Little information is available on adipose tissue features in the human pancreas (AdTP). In the present study we performed morphologic and morphometric studies on AdTP of 9 overweight/obese ...nondiabetic (ND, age: 65±5 years; 4M/5F; BMI: 31.3±0.4 Kg/m2, mean±SEM) and 13 matched type 2 diabetic (T2D, age: 70±2 years, 8M/5F; BMI: 30.0±0.8 kg/m2) organ donors. Adipocytes were identified and quantified on a fluorescence DM5500 Leica microscope, using the MetaMorph v 1.8.0 software with a tresholded mask applied in exclusive mode. Macrophages were identified by immunohistochemistry using anti-CD68 (Dako) antibody. Assessment of insulin (Abcam Ab) and glucagon (Sigma Ab) positive cells was also performed. The number of adipocytes trended higher (+32.8%) in T2D (8.9±1.4/mm2) compared to ND (6.7±2.1/mm2) and their size was greater in T2D (9,319±1,028 μm2) than ND (5,639±639 μm2, p=0.01). AdTP area in relation to acinar tissue was 90.4% higher (p=0.07) in T2D (7.6±1.3%) than ND (3.9±1.5%). The amount of adipocytes with adjacent ≥ 3 CD68+ cells was higher (p=0.048) in T2D (31/281, 11%) than ND (7/147, 5%). Insulin positive area (T2D: 0.49±0.06%; ND: 0.55±0.09%) as well as glucagon positive area (T2D: 0.24±0.03%; ND: 0.32±0.07%) did not differ significantly between the two groups. Adipocyte size was negatively associated with islet number in ND+T2D (p=0.06) and positively with insulin area in ND (p=0.058); there was a significant, positive relationship between the amount of adipocytes and the number of islets in T2D (p=0.017).
In conclusion, we found significant differences in the AdTP of T2D as compared to ND, including increased adypocite size and presence of adipocyte adjacent CD68+ cells; some of these parameters correlated with islet morphometric indices.
Disclosure
M. Suleiman: None. C. De Luca: None. P. De Simone: None. U. Boggi: None. F. Grano: None. M. Bugliani: None. P. Marchetti: None. L. Marselli: None.
Funding
Innovative Medicines Initiative 2 Joint Undertaking (115881); European Union; European Federation of Pharmaceutical Industries and Associations; Swiss State Secretariat for Education, Research and Innovation (16.0097-2)
To implement split liver transplantation (SLT) a mandatory‐split policy has been adopted in Italy since August 2015: donors aged 18‐50 years at standard risk are offered for SLT, resulting in a ...left‐lateral segment (LLS) graft for children and an extended‐right graft (ERG) for adults. We aim to analyze the impact of the new mandatory‐split policy on liver transplantation (LT)‐waiting list and SLT outcomes, compared to old allocation policy. Between August 2015 and December 2016 out of 413 potentially “splittable” donors, 252 (61%) were proposed for SLT, of whom 53 (21%) donors were accepted for SLT whereas 101 (40.1%) were excluded because of donor characteristics and 98 (38.9%) for absence of suitable pediatric recipients. The SLT rate augmented from 6% to 8.4%. Children undergoing SLT increased from 49.3% to 65.8% (P = .009) and the pediatric LT‐waiting list time dropped (229 10‐2121 vs 80 12‐2503 days P = .045). The pediatric (4.5% vs 2.5% P = .398) and adult (9.7% to 5.2% P < .001) LT‐waiting list mortality reduced; SLT outcomes remained stable. Retransplantation (HR = 2.641, P = .035) and recipient weight >20 kg (HR = 5.113, P = .048) in LLS, and ischemic time >8 hours (HR = 2.475, P = .048) in ERG were identified as predictors of graft failure. A national mandatory‐split policy maximizes the SLT donor resources, whose selection criteria can be safely expanded, providing favorable impact on the pediatric LT‐waiting list and priority for adult sick LT candidates.
The introduction of a mandatory split policy in the Italian liver allocation system significantly increases the split liver transplantation rate, providing a favorable impact on the pediatric liver transplantation waiting list without harming the adult liver transplantation waiting list.
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