PURPOSE:Advances in surgical procedures and immunosuppressive therapies have considerably improved the outcomes of patients who have undergone liver transplantation in the past few decades. In 2020, the Italian Liver Transplant Working Group published practice-oriented algorithms for immunosuppressive therapy (IT) in adult liver transplant (LT) recipients. Due to the rapidly evolving LT field, regular updates to the recommendations are required. This review presents a consensus- and evidence-based update of the 2020 recommendations. METHODS:The Italian Liver Transplant Working Group set out to address new IT issues, which were discussed based on supporting literature and the specialists' personal experiences. The panel deliberated on and graded each statement before consensus was reached. RESULTS:A series of consensus statements were formulated and finalized on: (i) oncologic indications for LT; (ii) management of chronic LT rejection; (iii) combined liver-kidney transplantation; (iv) immunosuppression for transplantation with an organ donated after circulatory death; (v) transplantation in the presence of frailty and sarcopenia; and (vi) ABO blood group incompatibility between donor and recipient. Algorithms were updated in the following LT groups: standard patients, critical patients, oncology patients, patients with specific etiology, and patients at high immunologic risk. A steroid-free approach was generally recommended, except for patients with autoimmune liver disease and those at high immunologic risk. CONCLUSION:The updated consensus- and evidence-based 2024 recommendations for immunosuppression regimens in adult patients with ABO-compatible LT address a range of clinical variables that should be considered to optimize the choice of the immunosuppression treatment in clinical practice in Italy.

Prompted by the utilization of extended criteria donors, dual hypothermic oxygenated machine perfusion (D-HOPE) was introduced in liver transplantation to improve preservation. When donors after neurological determination of death (DBD) are used, D-HOPE effect on graft outcomes is unclear. To assess D-HOPE value in this setting and to identify ideal scenarios for its use, data on primary adult liver transplant recipients from January 2014 to April 2021 were analyzed using inverse probability of treatment weighting, comparing outcomes of D-HOPE-treated grafts (n = 121) with those preserved by static cold storage (n = 723). End-ischemic D-HOPE was systematically applied since November 2017 based on donor and recipient characteristics and transplant logistics. D-HOPE use was associated with a significant reduction of early allograft failure (OR: 0.24; 0.83; p = .024), grade ≥3 complications (OR: 0.57; p = .046), comprehensive complication index (-7.20 points; p = .003), and improved patient and graft survival. These results were confirmed in the subset of elderly donors (>75-year-old). Although D-HOPE did not reduce the incidence of biliary complications, its use was associated with a reduced severity of ischemic cholangiopathy. In conclusion, D-HOPE improves postoperative outcomes and reduces early allograft loss in extended criteria DBD grafts.

Potential conflict of interest: Dr. Romagnoli advises Biotest Italia and consults for Kedrion Biopharma. Dr. Brunetto advises, is on the speakers' bureau for, and received grants from AbbVie; she is on the speakers' bureau for and received grants from Gilead; she advises Abbott, Janssen, and Roche; she is on the speakers' bureau for MSD and BMS. Dr. Lupo received grants from Chiesi; he consults for Astellas and Novartis. The other authors have nothing to report. TO THE EDITOR: Italy was the first Western nation to face the corona virus disease of 2019 (COVID‐19) outbreak, and all efforts have been taken to preserve liver transplant (LT) activity. Nevertheless, a 25% reduction of procured organs was observed during the first 4 weeks of the epidemic.(1) Little is known about COVID‐19 consequences in transplant candidates. On March 21, 2020, a 39‐year‐old woman was admitted to our liver unit for decompensated autoimmune cirrhosis (Model for End‐Stage Liver Disease [MELD] score 24). She had no comorbidities and was not a smoker. On March 25, she was listed for LT (MELD score 26) with normal chest computed tomography (CT). On March 30, in the setting of persistent fever, without respiratory symptoms, and with normal chest CT, she tested positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) RNA on a nasopharyngeal swab (NPS) (DiaSorin Molecular Simplexa COVID‐19 Direct Assay System). She was moved to a COVID‐19 ward and was started on hydroxychloroquine for 7 days. In the following days, she developed mild lymphopenia and profound coagulopathy (Fig. 1). On April 2, her oxygen saturation dropped to 85% with an arterial oxygen partial pressure to fractional inspired oxygen ratio of 138 and she required noninvasive ventilation; 24 hours later, her blood gases markedly improved and she was transferred back to the COVID‐19 ward with oxygen given by nasal cannula at 2 L/minute. On April 6 and 7, two consecutive SARS‐CoV‐2 RNA NPSs tested negative, allowing her to be transferred back to our liver unit. On April 7, a negative SARS‐CoV‐2 real‐time polymerase chain reaction (RT‐PCR) was confirmed on bronchoalveolar lavage (BAL) fluid and a new chest CT was again negative. Thus, she was reactivated on the LT waiting list (MELD score 36). The day after, an ABO blood type‐identical liver from a 46‐year‐old deceased donor became available and she underwent LT. Immunosuppression consisted of basiliximab, steroids, tacrolimus, and mycophenolate. She made an uneventful recovery and was discharged home on postoperative day (POD) 9. A second SARS‐CoV‐2 RT‐PCR on BAL performed on POD 2 tested negative.FIG. 1: Diagram of patient course, including MELD trend, timing and modality of SARS‐CoV‐2 testing, COVID‐19 treatment, and timing of plasma and red blood cell transfusions. The patient received 500 and 1,000 mL of plasma 10 and 6 days before transplant, respectively, and 3,000 mL during the transplant operation. She was transfused with 2 units of packed red blood cells 4 days before transplant, 7 units during the transplant operation, and 1 unit 4 days after. Abbreviations: bid, bis in die (twice daily); CPAP, continuous positive airway pressure; FFP, fresh‐frozen plasma; ITU, intensive therapy unit; PRBC, packed red blood cells. *represents the exact day when FFP and red blood cells were infused.Serology for SARS‐CoV‐2 infection was performed by testing anti‐Spike S1 total antibodies and immunoglobulin M on the day of LT and on POD 7; both samples tested negative, which can be explained by early testing after symptom onset, interference of immunosuppressive treatment on the development of a full humoral response, and a hemodilution effect by multiple transfusions. In our case, LT appeared as the only way forward and we felt that the expected benefit of a timely LT outweighed the risks linked to the recent COVID‐19 infection. The favorable outcome suggests that LT soon after recovery from COVID‐19 should be considered as a viable option for candidates with severely compromised liver function. In conclusion, to the best of our knowledge, this is the first report of an LT candidate recovering from a mild form of COVID‐19 and undergoing successful LT shortly after. Aggressive care should be maintained in patients with decompensated cirrhosis who are positive for SARS‐CoV‐2 in order to overcome viral infection and to proceed as soon as possible with life‐saving treatment.

INTRODUCTION: Once considered a contraindication to liver transplantation, portal vein thrombosis still represents a significant challenge to the liver transplant surgeon. Yerdel grade 3 thrombosis is usually managed by interposing a donor iliac vein jump graft between graft portal vein and distal superior mesenteric vein. Venous patch is normally placed in a retrogastric position to avoid its kinking. PRESENTATION OF CASE: We report a new technical variant of standard mesoportal jump graft, in which a U-shaped graft was obtained using iliac bifurcation. This technique was used to manage a case of grade 3 portal vein thrombosis in which portal vein was unsuitable due to severe pylephlebitis and pylorus dissection had to be abandoned due to inflammatory changes issue of chronic pancreatitis. The venous patch was of sufficient length and shape to bypass pancreatic head and first duodenum, avoiding the need for its retrogastric placement and pylorus dissection. DISCUSSION: This case is a further demonstration that technical approach to portal vein thrombosis must be tailored according to its extent and surgical scenario. In selected cases, use of a curved U-shaped jump graft may represent a valuable option. CONCLUSION: This technical option should be included among options for the management of portal vein thrombosis and be part of the armamentarium of liver transplant surgeon. (C) 2020 The Author( s). Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.

We read with pleasure the letter from Gruttadauria et al. (1) depicting an interesting case of poor hepatic artery (HA) flow due to portal hyperperfusion (PHP) in a liver transplant (LT) recipient with a difficult vascular anatomy. This is indeed a good opportunity to further share our experience confirming that, although unusual, PHP might constitute an issue also in the setting of whole-graft LT.

Optimization of donor-recipient matching is a common concept in liver transplantation. In emergency transplant for acute liver failure, outcome is influenced by timing, patient clinical condition, and graft quality. Although factors like advanced donor age have been linked to a poorer outcome, use of suboptimal or marginal grafts can be inevitable in very unstable patients, if no other graft is available. We present a case of a liver transplant performed in an extremely sick patient suffering from HBV-related fulminant hepatitis, in which a compatible graft from a 76-year-old deceased donor became available only after 3 days of waiting time, during which his conditions further deteriorated. Given the suboptimal matching, normothermic machine perfusion was applied to minimize ischemia-reperfusion injury. Use of machine perfusion could find an indication to modulate the risk associated with an unfavorable donor-recipient matching in high-risk cases.

A correction to this paper has been published: https://doi.org/10.1007/s12072-021-10178-7

Covid-19 pandemic is deeply affecting transplant activity worldwide. It is unclear whether solid organ transplant recipients are at increased risk of developing severe complications and how they should be managed, also concerning immunosuppression. This is a report about the course and management of SARS-CoV-2 infection in liver transplant recipients from a single center in Northwestern Italy in the period March-April 2020. Three patients who were treated at our institution are reported in detail, whereas summary data are provided for those managed at peripheral Hospitals. Presentation varied from asymptomatic to rapidly progressive respiratory failure due to bilateral interstitial pneumonia. Accordingly, treatment and changes to immunosuppression were adapted to the severity of the disease. Overall mortality was 20%, whereas Covid-related mortality was 10%. Two cases of prolonged (>2 months) viral carriage were observed in two asymptomatic patients who contracted the infection in the early course after transplant. Besides depicting Covid-19 course and possible treatment scenarios in liver transplant patients, these cases are discussed in relation to the changes in our practice prompted by Covid-19 epidemic, with potential implications for other transplant programs.

Hypothermic oxygenated machine perfusion (HOPE) was introduced in liver transplantation (LT) to mitigate ischemia-reperfusion injury. Available clinical data mainly concern LT with donors after circulatory-determined death, whereas data on brain-dead donors (DBD) are scarce. To assess the impact of end-ischemic HOPE in DBD LT, data on primary adult LTs performed between March 2016 and June 2018 were analyzed. HOPE was used in selected cases of donor age >80 years, apparent severe graft steatosis, or ischemia time ≥10 hours. Outcomes of HOPE-treated cases were compared with those after static cold storage. Propensity score matching (1:2) and Bayesian model averaging were used to overcome selection bias. During the study period, 25 (8.5%) out of 294 grafts were treated with HOPE. After matching, HOPE was associated with a lower severe post-reperfusion syndrome (PRS) rate (4% versus 20%, p = 0.13) and stage 2–3 acute kidney injury (AKI) (16% versus 42%, p = 0.046). Furthermore, Bayesian model averaging showed lower transaminases peak and a lower early allograft dysfunction (EAD) rate after HOPE. A steeper decline in arterial graft resistance throughout perfusion was associated with lower EAD rate. HOPE determines a significant reduction of ischemia reperfusion injury in DBD LT.

OBJECTIVES:Veno-occlusive disease after liver transplant has been sporadically reported, and significant uncertainty exists concerning the best treatment and the long-term outcomes. Here, we reviewed our experience to evaluate clinical presentation, treatment, and the long-term outcomes of these patients.MATERIALS AND METHODS:Between 2000 and 2015, 2165 patients underwent liver transplant at our center. The incidence of veno-occlusive disease was 0.3% (7/2165).RESULTS:Timing of veno-occlusive disease onset (median 4.7 mo; interquartile range, 2.5-11.1 mo) varied widely as did clinical presentation, which was characterized by a variable association of liver failure and portal hypertension and different disease pro-gression rates. In all cases, diagnosis of veno-occlusive disease was confirmed by liver biopsy. Six patients (85.7%) presented with veno-occlusive disease after a previous episode of acute cellular rejection. Three patients died due to veno-occlusive disease (n = 2) or due to hepatocellular carcinoma recurrence (n = 1). Two patients were treated by increasing immunosuppression and with interventional procedures (pleurodesis and transjugular intrahepatic portosystemic shunt, respectively), and 2 had successful retransplants. 5-year patient and graft survival rates were 57.1% and 28.6%, respectively.CONCLUSIONS:A tailored approach based on clinical features and including retransplant can achieve acceptable long-term survival in patients with veno-occlusive disease after liver transplant.

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.

BACKGROUND & AIMS:The definition of new biomarkers of hepatocellular carcinoma (HCC) risk, especially in high-risk HBV/HCV-positive population, is urgently needed to improve HCC clinical management. This study focused on variants of UDP-glucuronosyltransferase 1A (UGT1A) enzymes that catalyse the reaction of glucuronidation, one of the most important chemical defence pathway of the body. The aim of this study was to elucidate the contribution of UGT1A polymorphisms in predicting HCC susceptibility in Caucasians.METHODS:In this retrospective case-control analysis, 192 HCC liver transplanted patients represent the study group. Two age/sex-matched groups were used as control, one composed of 167 HBV- and/or HCV-infected individuals, and the other of 192 healthy subjects. All the cases were characterized for a panel of UGT1A1, UGT1A7 and UGT1A9 variants. The study end-point was the association between UGT1A markers and HCC onset.RESULTS:UGT1A7*3 allele emerged as a protective marker for HCC development among both high-risk HBV/HCV-positive patients (OR=0.64, P=.0026), and healthy subjects (OR=0.47, P=.0051). UGT1A1*28 (OR=0.61, P=.0013) and UGT1A9*22 (OR=2.18, P=.0003) alleles were also associated to HCC occurrence, especially among healthy subjects. UGT1A haplotype, summarizing the UGT1A genetic alterations, confirmed the protective role against HCC development emerged for low-activity alleles. The observed associations could probably be linked to an increase of serum levels of health-beneficial molecules including free bilirubin.CONCLUSION:A predictive effect of UGT1A polymorphisms on HCC risk was identified. If confirmed, these findings could contribute to improve the HCC surveillance, treatment tailoring and patients care.

After a man is dead, the body…is not dissolved or decomposed at once, but may remain for a good while…for the body when shrunk and embalmed, as is the custom in Egypt, may remain almost entire through infinite ages; and even in decay, still there are some portions, such as the bones and ligaments, which are practically indestructible. (Plato, Phaedo, XXIX, 80 c-d) Even though the ancient Greeks had observed that parts of the human body could remain intact for a long time after death, it was only with the advent of transplant medicine that life after death became possible for solid organs.1 Focusing on organ lifetime limits, the fact that, today, donors of all ages are accepted for liver transplantation,2 is raising a question about the maximum lifespan of a liver, both in the donor and in the recipient. In this context, the very long-term outcomes of very old grafts, of those which had already breached the 80-year age barrier at the donor death, have not been reported yet. Our center pioneered the use of liver grafts from very old donors with 26 octogenarian livers being transplanted between 1998 and 2006, and 120 thereafter. Focusing on those 26 organs transplanted more than 10 years ago, we recorded the following actual 5-year and 10-year survival rates: 77% and 69% for the patient, 69% and 62% for the graft. Two patients were retransplanted early for allograft dysfunction and 1 later in the follow-up for a biliary complication. To date, 15 patients are alive thanks to a liver which is now more than 90 years, 2 of those organs being centenarian. Centenarian livers were, respectively, 84 and 86 years old at the time of transplantation, and their recipients are currently 66 and 76 years. At the time of transplant, those 26 grafts had a median donor risk index3 of 2.2, had no or mild macrovesicular steatosis (never involving more than 15% of the hepatocytes), and were transplanted with a cold ischemia time always below 11 hours. Recipients had a median age of 59 years, a median Model for End-Stage Liver Disease score of 16 and were affected by hepatocellular carcinoma in 35% (9/26) of the cases. Concerning the causes for graft loss, 6 livers were lost early due to organ dysfunction and/or infections, 3 suffered from a severe recurrence of hepatitis C, and 2 were lost due to tumours (de novo lung cancer and recurrent hepatocellular carcinoma). Although already satisfactory, these results are expected to improve because the introduction of direct-acting antiviral drugs is cancelling the negative impact of hepatitis C virus reinfection on liver transplant outcomes,4 and the spreading use of dynamic preservation techniques is holding the promise of reducing ischemia-reperfusion injury in extended criteria grafts.5 Overall, our data reinforce the safety of evaluating all donor offers for potential utilization in a liver transplant, irrespective of the donor age, and evidence the uniqueness of the liver as an organ which has life extension potentialities that are still far to be fully appreciated.

AIM To uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma (HCC) susceptibility in Caucasians. METHODS The present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two, independent, HCC-free, age/sex-matched control groups. The HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver transplantation. The first control group comprised 167 patients that were matched to the HCC cohort for the percentage of hepatitis B (HBV) and/or hepatitis C (HCV) infections. A second control group included 192 virus-free, healthy individuals that were used to evaluate the generalizability of the identified predictive markers. All cases and controls were Caucasian. The three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related pathways. The study end-point was to assess the association between genetic variants and HCC onset. RESULTS Five genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/HCV. According to a dominant model, reduced HCC risk was associated with three polymorphisms: ERCC1 rs3212986 (OR = 0.46, 95%CI: 0.30-0.71, P = 0.0005), GST-P1 rs1138272 (OR = 0.41, 95%CI: 0.21-0.81, P = 0.0097), and CYP17A1 rs743572 (OR = 0.50, 95%CI: 0.31-0.79, P = 0.0032). Conversely, according to a recessive model, increased HCC risk was associated with two polymorphisms: XRCC3 rs1799794 (OR = 3.70, 95%CI: 1.02-13.39, P = 0.0461) and ABCB1 rs1128503 (OR = 2.06, 95%CI: 1.18-3.61, P = 0.0111). These associations remained significant in a subgroup analysis, where patients were stratified according to viral status (HBV- or HCV-positive serology). Two variants exhibited a serology-specific effect: ABCB1 rs1128503 (OR = 4.18, 95%CI: 1.55-11.29, P = 0.0048) showed an effect in the HBV-positive subgroup; and ERCC1 rs3212986 (OR = 0.33, 95%CI: 0.18-0.60, P = 0.0003) showed an effect in the HCV-positive subgroup. Among the five markers identified, ERCC1 rs3212986 (OR = 0.43, P < 0.0001) and CYP17A1 rs743572 (OR = 0.73, P = 0.0310) had a different distribution in patients with HCC compared to healthy individuals. With a recursive partitioning approach, we also demonstrated that significant gene-gene interactions between ERCC1 rs3212986, CYP17A1 rs743572, GST-P1 rs1138272, and the previously described UGT1A7*3 predictive marker, played a role in the complex trait of HCC susceptibility. CONCLUSION We identified five polymorphisms and interactions that contributed crucially to predicting HCC risk. These findings represented an important step towards improving HCC diagnosis and management.

Background: Albeit accepted in the trauma setting, use of peri-hepatic gauze packing has been rarely reported during liver transplantation.Aims: To assess the results of packing in liver transplantation.Methods: We reviewed clinical characteristics, intraoperative events and postoperative outcome of consecutive adult liver transplantation recipients between 2003 and 2013. Patients treated with packing were compared to no-packing patients and to matched controls selected using a propensity score.Results: Of 1396 recipients, 107 were treated with packing for peri-hepatic bleeding (76.6%), allograft damage (12.1%) or partial outflow obstruction (11.2%). Urgent reoperation for ongoing haemorrhage was required in 6 (5.6%). Correction of haemodynamic and coagulation parameters was constantly achieved. Overall, patient (90% vs. 98%, p < 0.001) and graft (83.2% vs. 94.7%, p < 0.001) 3-month survival was significantly reduced in packing patients. However, after matching, no significant difference was observed in patient (89.3% vs. 95.2%, p = 0.12) and graft (83.5% vs. 92.2%, p = 0.06) 3-month survival. Patient survival was associated with recipient age (HR 2.59; p = 0.04) and donor age x recipient MELD (HR 2.04; p = 0.02), but not with packing (HR 1.81; p = 0.29).Conclusions: In our experience, packing was a valuable adjunct to conventional means of haemostasis during liver transplantation and, after accounting for confounding covariates, was not associated with inferior outcomes. (C) 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.