Severe acute respiratory syndrome Coronavirus 2 (SARS‐Cov2) outbreak has caused a pandemic rapidly impacting on the way of life of the entire world. This impact in the specific setting of ...transplantation and immunosuppression has been poorly explored to date. Discordant data exist on the impact of previous coronavirus outbreaks on immunosuppressed patients. Overall, only a very limited number of cases have been reported in literature, suggesting that transplanted patients not necessarily present an increased risk of severe SARS‐Cov2‐related disease compared to the general population. We conducted a literature review related to the impact of immunosuppression on coronavirus infections including case reports and series describing immunosuppression management in transplant recipients. The role of steroids, calcineurin inhibitors, and mycophenolic acid has been explored more in detail. A point‐in‐time snapshot of the yet released literature and some considerations in relation to the use of immunosuppression in SARS‐Cov2 infected transplant recipients are provided here for the physicians dealing with immunocompromised patients.
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.
Prognosticating outcomes in liver transplant (LT) for hepatocellular carcinoma (HCC) continues to challenge the field. Although Milan Criteria (MC) generalized the practice of LT for HCC and improved ...outcomes, its predictive character has degraded with increasing candidate and oncological heterogeneity. We sought to validate and recalibrate a previously developed, preoperatively calculated, continuous risk score, the Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma (HALTHCC), in an international cohort. From 2002 to 2014, 4,089 patients (both MC in and out 25.2%) across 16 centers in North America, Europe, and Asia were included. A continuous risk score using pre‐LT levels of alpha‐fetoprotein, Model for End‐Stage Liver Disease Sodium score, and tumor burden score was recalibrated among a randomly selected cohort (n = 1,021) and validated in the remainder (n = 3,068). This study demonstrated significant heterogeneity by site and year, reflecting practice trends over the last decade. On explant pathology, both vascular invasion (VI) and poorly differentiated component (PDC) increased with increasing HALTHCC score. The lowest‐risk patients (HALTHCC 0‐5) had lower rates of VI and PDC than the highest‐risk patients (HALTHCC > 35) (VI, 7.7% 1.2‐14.2 vs. 70.6% 48.3‐92.9 and PDC:4.6% 0.1%‐9.8% vs. 47.1% 22.6‐71.5; P < 0.0001 for both). This trend was robust to MC status. This international study was used to adjust the coefficients in the HALTHCC score. Before recalibration, HALTHCC had the greatest discriminatory ability for overall survival (OS; C‐index = 0.61) compared to all previously reported scores. Following recalibration, the prognostic utility increased for both recurrence (C‐index = 0.71) and OS (C‐index = 0.63). Conclusion: This large international trial validated and refined the role for the continuous risk metric, HALTHCC, in establishing pre‐LT risk among candidates with HCC worldwide. Prospective trials introducing HALTHCC into clinical practice are warranted.
Background Liver cirrhosis has been known to be associated with increased intestinal permeability (IP); however, little is known about the modification of IP after liver transplantation (LT). The ...present study was aimed to assess IP after LT and evaluated its association with laboratory tests and clinical parameters, as well as with the development of infections. Methods LT recipients were consecutively enrolled and compared with an equal number of patients with liver cirrhosis and healthy subjects. IP was assessed by urinary excretion of chromium-51 ethylenediaminetetraacetic acid (.sup.51 Cr-EDTA). Results The median .sup.51 Cr-EDTA excretion was found to be higher in 35 LT recipients as compared with that in the healthy controls 4.77% (2.79-6.03) vs. 2.07% (1.57-2.42), p0.0001, and comparable to that in the cirrhotic patients 3.69% (2.34-6.57), p = 0.445. .sup.51 Cr-EDTA excretion was not associated with clinical variables, the type of immunosuppressive therapy, donor-related factors, comorbidities and incidence of infections infection/no infection: 4.97% (3.14-7.03) vs 4.62% (2.79-5.82), p = 0.938. Conclusion LT recipients show an increased IP, similar to that in patients with liver cirrhosis. However, it is not associated with a high risk of infections. Further investigations into the pathogenesis of this persistent impairment of the intestinal barrier are warranted.
There is increasing evidence that early liver transplantation (eLT), performed within standardized protocols can improve survival in severe alcoholic hepatitis (sAH). The aim of the study was to ...assess outcomes after eLT for sAH in four Italian LT centers and to compare them with non‐responders to medical therapy excluded from eLT. Patients admitted for sAH (2013–2019), according to NIAAA criteria, were included. Patients not responding to medical therapy were placed on the waiting list for eLT after a strict selection. Histological features of explanted livers were evaluated. Posttransplant survival and alcohol relapse were evaluated. Ninety‐three patients with severe AH were evaluated (65.6% male, median IQR age: 47 42–56 years). Forty‐five of 93 patients received corticosteroids, 52 of 93 were non‐responders and among these, 20 patients were waitlisted. Sixteen patients underwent LT. Overall, 6‐, 12‐, and 24‐month survival rates were 100% significantly higher compared with non‐responders to medical therapy who were denied LT (45%, 45%, and 36%; p < .001). 2/16 patients resumed alcohol intake, one at 164 days and one at 184 days. Early LT significantly improves survival in sAH non‐responding to medical therapy, when a strict selection process is applied. Further studies are needed to properly assess alcohol relapse rates.
Early liver transplantation, after application of a strict selection process, significantly improves survival in severe alcoholic hepatitis non‐responsive to medical therapy.
Hepatocellular carcinoma is the most common primary liver tumor. Orthotopic liver transplant is one of the best treatment options, but its waiting list has to be considered. Bridge therapies have ...been introduced in order to limit this issue. The aim of this study is to evaluate if bridge therapies in advanced hepatocellular carcinoma can improve overall survival and reduce de-listing. We selected 185 articles. The search was limited to English articles involving only adult patients. These were deduplicated and articles with incomplete text or irrelevant conclusions were excluded. Sorafenib is the standard of care for advanced hepatocellular carcinoma and increases overall survival without any significant drug toxicity. However, its survival benefit is limited. The combination of transarterial chemoembolization + sorafenib, instead, delays tumor progression, although its survival benefit is still uncertain. A few studies have shown that patients undergoing transarterial chemoembolization + radiation therapy have similar or even better outcomes than those undergoing transarterial chemoembolization or sorafenib alone for rates of histopathologic complete response (89% had no residual in the explant). Also, the combined therapy of transarterial chemoembolization + radiotherapy + sorafenib was compared to the association of transarterial chemoembolization + radiotherapy and was associated with a better survival rate (24 vs. 17 months). Moreover, immunotherapy revealed new encouraging perspectives. Combination therapies showed the most encouraging results and could become the gold standard as a bridge to transplant for patients with advanced hepatocellular carcinoma.
Early everolimus (EVR) introduction and tacrolimus (TAC) minimization after liver transplantation may represent a novel immunosuppressant approach. This phase 2, multicenter, randomized, open‐label ...trial evaluated the safety and efficacy of early EVR initiation. Patients treated with corticosteroids, TAC, and basiliximab were randomized (2:1) to receive EVR (1.5 mg twice daily) on day 8 and to gradually minimize or withdraw TAC when EVR was stable at >5 ng/mL or to continue TAC at 6‐12 ng/mL. The primary endpoint was the proportion of treated biopsy‐proven acute rejection (tBPAR)–free patients at 3 months after transplant. As secondary endpoints, composite tBPAR plus graft/patient loss rate, renal function, TAC discontinuation rate, and adverse events were assessed. A total of 93 patients were treated with EVR, and 47 were controls. After 3 months from transplantation, 87.1% of patients with EVR and 95.7% of controls were tBPAR‐free (P = 0.09); composite endpoint‐free patients with EVR were 85% (versus 94%; P = 0.15). Also at 3 months, 37.6% patients were in monotherapy with EVR, and the tBPAR rate was 11.4%. Estimated glomerular filtration rate was significantly higher with EVR, as early as 2 weeks after randomization. In the study group, higher rates of dyslipidemia (15% versus 6.4%), wound complication (18.32% versus 0%), and incisional hernia (25.8% versus 6.4%) were observed, whereas neurological disorders were more frequent in the control group (13.9% versus 31.9%; P < 0.05). In conclusion, an early EVR introduction and TAC minimization may represent a suitable approach when immediate preservation of renal function is crucial.
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)
IntroductionViability 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 analysisThis is an observational prospective single-centre study on consecutive liver transplant donors and recipients.Primary objectiveTo 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%; β, 20%) using an IGT-PDR cut-off value of 13% to achieve a significant discrimination between viable and non-viable grafts.Secondary objectiveIGT-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 disseminationThis 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 numberNCT05228587.
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