Immunosuppression in adult liver transplant recipients: a 2024 update from the Italian Liver Transplant Working Group.

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.

The Effects of Sustained Immunosuppression Withdrawal After Liver Transplantation on Metabolic Syndrome.

BACKGROUND: Liver transplant (LT) recipients often experience adverse effects of immunosuppressive (IS) drugs, especially on metabolic profiles. Selected LT recipients can achieve successful IS withdrawal; however, its effects on metabolic syndrome (MS) are unknown. METHODS: This is a retrospective single-center study investigating the incidence and/or regression of MS in 75 selected LT recipients who were previously enrolled in prospective IS withdrawal trials between 1999 and 2017. Patients who were transplanted due to nonalcoholic steatohepatitis/metabolic-associated fatty liver disease were excluded, as well as those with a follow-up <3 y after IS weaning. RESULTS: Forty-four patients (58.7%) achieved sustained withdrawal or minimization of immunosuppression (WMIS) and 31 patients (41.3%) required reintroduction of immunosuppression (no-WMIS). Among LT recipients who were metabolically healthy (n = 52, 69.3%) before the start of IS weaning, there was a significantly lower rate of de novo MS in WMIS patients compared with no-WMIS patients after 5 y (8.3% and 47.8%, respectively, P = 0.034). Of 23 LT recipients (30.7%) who had MS at the time of commencing IS withdrawal, complete regression of MS was observed in 47.1% of WMIS patients and in none (0%) of the no-WMIS patients after 5 y (P = 0.054). Furthermore, individual components of MS were better controlled in IS-weaned patients, such as arterial hypertension and abnormal serum lipids. CONCLUSIONS: Achievement of sustained IS withdrawal reduces the incidence of de novo MS development in metabolically healthy patients and increases the likelihood of MS regression in patients with established MS. The foreseeable long-term beneficial effects of these favorable metabolic changes on morbidity and mortality of LT recipients require further investigation.

Cancer mortality after kidney transplantation: A multicenter cohort study in Italy.

Kidney transplant (KT) recipients are known to be at risk of developing several cancer types; however, cancer mortality in this population is underinvestigated. Our study aimed to assess the risk of cancer death among Italian KT recipients compared to the corresponding general population. A cohort study was conducted among 7373 individuals who underwent KT between 2003 and 2020 in 17 Italian centers. Date and cause of death were retrieved until 31 December 2020. Indirect standardization was used to estimate standardized mortality ratios (SMRs) and corresponding 95% confidence intervals (CIs). Cancer was the most common cause of death among the 7373 KT recipients, constituting 32.4% of all deaths. A 1.8-fold excess mortality (95% CI: 1.59-2.09) was observed for all cancers combined. Lymphomas (SMR = 6.17, 95% CI: 3.81-9.25), kidney cancer (SMR = 5.44, 95% CI: 2.97-8.88) and skin melanoma (SMR = 3.19, 95% CI: 1.03-6.98) showed the highest excess death risks. In addition, SMRs were increased about 1.6 to 3.0 times for cancers of lung, breast, bladder and other hematopoietic and lymphoid tissues. As compared to the general population, relative cancer mortality risk remained significantly elevated in all age groups though it decreased with increasing age. A linear temporal increase in SMR over time was documented for all cancers combined (P < .01). Our study documented significantly higher risks of cancer death in KT recipients than in the corresponding general population. Such results support further investigation into the prevention and early detection of cancer in KT recipients.

Superiority of the new sex-adjusted models to remove the female disadvantage restoring equity in liver transplant allocation.

BACKGROUND AND AIMS: Model for End-stage Liver Disease (MELD) and MELDNa are used worldwide to guide graft allocation in liver transplantation (LT). Evidence exists that females are penalized in the present allocation systems. Recently, new sex-adjusted scores have been proposed with improved performance respect to MELD and MELDNa. GEMA-Na, MELD 3.0, and sex-adjusted MELDNa were developed to improve the 90-day dropout prediction from the list. The present study aimed at evaluating the accuracy and calibration of these scores in an Italian setting. METHODS: The primary outcome of the present study was the dropout from the list up to 90 days because of death or clinical deterioration. We retrospectively analysed data from 855 adults enlisted for liver transplantation in the Lazio region (Italy) (2012-2018). Ninety-day prediction of GEMA-Na, MELD 3.0 and sex-adjusted MELDNa with respect to MELD and MELDNa was analysed. Brier score and Brier Skill score were used for accuracy, and the Greenwood-Nam-D'Agostino test was used to evaluate the calibration of the models. RESULTS: GEMA-Na (concordance = .82, 95% CI = .75-.89), MELD 3.0 (concordance = .81, 95% CI = .74-.87) and sex-adjusted MELDNa (concordance = .81, 95% CI = .74-.88) showed the best 90-day dropout prediction. GEMA-Na showed a higher increase in accuracy with respect to MELD (p = .03). No superiority was shown with respect to MELDNa. All the tested scores showed a good calibration of the models. Using GEMA-Na instead of MELD would potentially save one in nine dropouts and could save one dropout per 285 patients listed. CONCLUSIONS: Validation and reclassification of the sex-adjusted score GEMA-Na confirm its superiority in predicting short-term dropout also in an Italian setting when compared with MELD.

Evaluation of Humoral Response following SARS-CoV-2 mRNA-Based Vaccination in Liver Transplant Recipients Receiving Tailored Immunosuppressive Therapy.

Background: The role of tailored immunosuppression (IS) in the development of the humoral response (HR) to SARS-CoV-2 mRNA-based vaccination in liver transplant (LT) recipients is unknown. Methods: This is a single-centre prospective study of patients who underwent LT between January 2015 and December 2021 and who have received three doses of mRNA-based SARS-CoV-2 vaccination. Patients undergoing Tacrolimus-based immunosuppression (TAC-IS) were compared with those undergoing Everolimus-based immunosuppression (EVR-IS). Patients receiving the TAC-EVR combination were divided into two groups based on trough TAC concentrations, i.e., above or below 5 ng/mL. HR (analysed with ECLIA) was assessed at 30 to 135 days after vaccination. The primary outcome was the presence of a positive antibody titre (≥0.8 U/mL). Secondary outcomes were the presence of a highly protective antibody titre (≥142 U/mL), median antibody titre, and incidence of COVID-19. Results: Sixty-one participants were included. Twenty-four (40%) were receiving TAC-IS and thirty-seven (60%) were receiving EVR-IS. At the median follow-up of 116 (range: 89-154) days, there were no significant differences in positive antibody titre (95.8% vs. 94.6%; p = 0.8269), highly-protective antibody titre (83.3% vs. 81.1%; p = 0.8231), median antibody titre (2410 [IQ range 350-2500] vs. 1670 [IQ range 380-2500]; p = 0.9450), and COVID-19 incidence (0% vs. 5.4%; p = 0.5148). High serum creatinine and low estimated glomerular filtration rate were risk factors for a weak or absent HR. Conclusions: Three doses of mRNA-based SARS-CoV-2 vaccination yielded a highly protective HR in LT recipients. The use of TAC or EVR-based IS does not appear to influence HR or antibody titre, while renal disease is a risk factor for a weak or null HR.

Cell transplantation-based regenerative medicine in liver diseases.

This review aims to evaluate the current preclinical state of liver bioengineering, the clinical context for liver cell therapies, the cell sources, the delivery routes, and the results of clinical trials for end-stage liver disease. Different clinical settings, such as inborn errors of metabolism, acute liver failure, chronic liver disease, liver cirrhosis, and acute-on-chronic liver failure, as well as multiple cellular sources were analyzed; namely, hepatocytes, hepatic progenitor cells, biliary tree stem/progenitor cells, mesenchymal stromal cells, and macrophages. The highly heterogeneous clinical scenario of liver disease and the availability of multiple cellular sources endowed with different biological properties make this a multidisciplinary translational research challenge. Data on each individual liver disease and more accurate endpoints are urgently needed, together with a characterization of the regenerative pathways leading to potential therapeutic benefit. Here, we critically review these topics and identify related research needs and perspectives in preclinical and clinical settings.

A Keynesian perspective on the health economics of kidney transplantation would strengthen the value of the whole organ donation and transplantation service.

Background: In this study, the Keynesian principle "savings may be used as investments in resources" is applied to Kidney Transplantation (KT), contextualizing the whole Organs Donation and Transplantation (ODT) service as a unique healthcare entity. Our aim was to define the financial resources that may be acquired in the form of savings from the KT activity. Methods: We analyzed registry and funding data for ODT in our region, between 2015 and 2019. Our hypotheses aimed to evaluate whether the savings would offset the Organ Donation (OD) costs, define the scope for growth, and estimate what savings could be generated by higher KT activity. To facilitate the evaluation of the resources produced by KT, we defined a coefficient generated from the combination of clinical outcomes, activity, and costs. Results: The ODT activity reached a peak in 2017, declining through 2018-2019. The savings matured in 2019 from the KT activity exceeded €15 million while the OD costs were less than €9 million. The regional KT activity was superior to the national average but inferior to international benchmarks. The estimated higher KT activity would produce savings between €16 and 20 million. Conclusion: The financial resources produced by KT contribute to defining a comprehensive perspective of ODT finance. The optimization of the funding process may lead to the financial self-sufficiency of the ODT service. The reproducible coefficient allows a reliable estimate of savings, subsequently enabling adequate investments and budgeting. Applying such a perspective jointly with reliable estimates would establish the basis for an in-hospital fee-for-value funding methodology for ODT.

Successful clinical and virological outcomes of liver transplantation for HDV/HBV-related disease after long-term discontinuation of hepatitis B immunoglobulins.

BACKGROUND: Indefinite, long-term administration of hepatitis B immunoglobulins (HBIg), together with a third generation nucleos(t)ide analog (NA), is the currently recommended prophylactic strategy to prevent viral recurrence after liver transplantation (LT) for Hepatitis Delta virus (HDV)/Hepatitis B virus (HBV)-related disease. METHODS: We retrospectively analyzed the safety and long-term clinical and virological outcomes of a consecutive cohort of 16 patients (10 males, median age 64.5, range 41-75) transplanted for HDV/HBV-related cirrhosis at our Institution, who discontinued HBIg after a median of 24.5 months (range 15-116) after transplant. All patients continued prophylaxis with same NA used before LT. Recurrence of HDV/HBV infection was defined as reappearance of serum HDV-RNA with detectable serum HBsAg and/or HBV-DNA. RESULTS: The median follow-up after LT was 138 months (range 73-316) and 110 months (range 52-200) after HBIg withdrawal. All patients were HBsAg-positive, HBV-DNA negative, and anti-HDV positive at the time of LT and without coinfections with HCV or HIV. Patients were followed with biochemical and virological tests every 3-6 months after HBIg withdrawal. No recurrences of HDV/HBV infection or disease were observed during monoprophylaxis with NA. In addition, eight patients (50%) spontaneously developed anti-HBs titers above 10 IU/L at a median of 74 months (range 58-140) following HBIG discontinuation. CONCLUSIONS: HBIg withdrawal after LT is a safe and efficacious strategy in patients transplanted for HDV/HBV disease and is frequently associated with the spontaneous development of serological immunity against HBV. These data call for a revision of current prophylactic recommendations in this setting.

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 Enhanced Recovery after Surgery (ERAS) Pathway Is a Safe Journey for Kidney Transplant Recipients during the "Extended Criteria Donor" Era.

Enhanced recovery after surgery (ERAS) protocols are still underused in kidney transplantation (KT) due to recipients' "frailty" and risk of postoperative complications. We aimed to evaluate the feasibility and safety of ERAS in KT during the "extended-criteria donor" era, and to identify the predictive factors of prolonged hospitalization. In 2010−2019, all patients receiving KT were included in ERAS program targeting a discharge home within 5 days of surgery. Recipient, transplant, and outcomes data were analyzed. Of 454 KT [male: 280, 63.9%; age: 57 (19−77) years], 212 (46.7%) recipients were discharged within the ERAS target (≤5 days), while 242 (53.3%) were discharged later. Patients within the ERAS target (≤5 days) had comparable recipient and transplant characteristics to those with longer hospital stays, and they had similar post-operative complications, readmission rates, and 5 year graft/patient survival. In the multivariate analysis, DGF (HR: 2.16, 95% CI: 1.08−4.34, p < 0.030) and in-hospital dialysis (HR: 3.68, 95% CI: 1.73−7.85, p < 0.001) were the only predictive factors for late discharge. The ERAS approach is feasible and safe in all KT candidates, and its failure is primarily related to the postoperative graft function, rather than the recipient's clinical status. ERAS pathways, integrated with strict collaboration with local nephrologists, allow early discharge after KT, with clinical benefits.

Temporal trends of waitlistings for liver transplantation in Italy: The ECALITA (Evolution of IndiCAtion in LIver transplantation in ITAly) registry study.

BACKGROUND: Over the last decades relevant epidemiological changes of liver diseases have occurred, together with greatly improved treatment opportunities. AIM: To investigate how the indications for elective adult liver transplantation and the underlying disease etiologies have evolved in Italy. METHODS: We recruited from the National Transplant Registry a cohort comprising 17,317 adults patients waitlisted for primary liver transplantation from January-2004 to December-2020. Patients were divided into three Eras:1(2004-2011),2(2012-2014) and 3(2015-2020). RESULTS: Waitlistings for cirrhosis decreased from 65.9% in Era 1 to 46.1% in Era 3, while those for HCC increased from 28.7% to 48.7%. Comparing Eras 1 and 3, waitlistings for HCV-related cirrhosis decreased from 35.9% to 12.1%, yet those for HCV-related HCC increased from 8.5% to 26.7%. Waitlistings for HBV-related cirrhosis remained almost unchanged (13.2% and 12.4%), while those for HBV-related HCC increased from 4.0% to 11.6%. ALD-related cirrhosis decreased from 16.9% to 12.9% while ALD-related HCC increased from 1.9% to 3.9%. CONCLUSIONS: A sharp increase in liver transplant waitlisting for HCC and a concomitant decrease of waitlisting for cirrhosis have occurred In Italy. Despite HCV infection has noticeably decreased, still remains the primary etiology of waitlisting for HCC, while ALD and HBV represent the main causes for cirrhosis.

Pancreatic Adeno-MiNEN, a Rare Newly Defined Entity with Challenging Diagnosis and Treatment: A Case Report with Systematic Literature Review and Pooled Analysis.

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) are a peculiar entity that can occur throughout the whole gastrointestinal trait, and pancreatic localization is rare. Their main characteristic is the presence of at least a neuroendocrine and an epithelial component, each accounting for at least 30% of the tumour mass. The presence of epithelial ductal component defines adeno-MiNEN. We report a case of a 59-year-old woman affected by pancreatic adeno-MiNEN with challenging diagnosis and successfully treated. A systematic literature review and pooled analysis was also performed, aiming to define the management and outcomes of pancreatic adeno-MiNEN. Out of 190 identified records, 15 studies including 28 patients affected by pancreatic-adeno-MiNEN were included in the analysis. Pancreatic adeno-MiNEN occurred mainly in males (82.8%) and at a mean age of 61.7 (range: 24-82) years. Pre-operative diagnosis was possible only in 14.2% of cases. At presentation, the majority had already advanced disease (TNM stage III (53.8%) and stage IV 19.3%). Adjuvant therapy was performed in 55% of patients, and the tumour recurrence rate was in 30% of cases. Median disease-free survival (DFS) was 12 months (range: 0-216 months) with a 5-year DFS of 16.6%, while the median overall survival (OS) was 12 months (range: 0-288 months) with a 5-year OS of 23.5%. Pancreatic adeno-MiNENs are rare; as they have very heterogenous behaviour, they are rarely diagnosed preoperatively and have poor prognosis. Treatment of localised MiNEN still relies on radical surgical resection, which seems essential to achieve a good oncological prognosis. International registry on MiNEN is necessary to improve the knowledge on this rare tumour and to improve its outcomes.

Graft weight integration in the early allograft dysfunction formula improves the prediction of early graft loss after liver transplantation.

The role of the graft-to-recipient weight ratio (GRWR) in adult liver transplantation (LT) has been poorly investigated so far. The aim is to evaluate the contribution of the GRWR to the well-recognized early allograft dysfunction (EAD) model (i.e., Olthoff model) for the prediction of 90-day graft loss after LT in adults. Three hundred thirty-one consecutive adult patients undergoing LT between 2009 and 2018 at Tor Vergata and Sapienza University in Rome, Italy, served as the Training-Set. The Validation-Set included 123 LTs performed at the Erasmus Medical Center, Rotterdam, the Netherlands. The mEAD model for 90-day graft loss included the following variables: GRWR [Formula: see text] 1.57 = 2.5, GRWR [Formula: see text] 2.13 = 2.5, total bilirubin ≥ 10.0 mg/dL = 2.0, INR ≥ 1.60 = 2.3, and aminotransferase > 2000 IU/L = 2.2. The mEAD model showed an AUC = 0.74 (95%CI = 0.66-0.82; p < 0.001) and AUC = 0.68 (95%CI = 0.58-0.88; p = 0.01) in the Training-Set and Validation-Set, respectively, outperforming conventional EAD in both cohorts (Training-Set: AUC = 0.64, 95%CI = 0.57-0.72; p = 0.001; Validation-Set: AUC = 0.52, 95%CI = 0.35-0.69, p = 0.87). Incorporation of graft weight in a composite multivariate model allowed for better prediction of patients who presented an aminotransferase peak > 2000 IU/L after LT (OR = 2.39, 95%CI = 1.47-3.93, p = 0.0005). The GRWR is important in determining early graft loss after adult LT, and the mEAD model is a useful predictive tool in this perspective, which may assist in improving the graft allocation process.

Prophylactic drains in totally laparoscopic distal gastrectomy: are they always necessary?

Prophylactic drains have always been a useful tool to detect early complications and prevent postoperative fluid collections, particularly in gastrointestinal surgery. Recently, the utilization of such drains has been debated, due to mounting evidence that they could be harmful rather than beneficial. Based on recent published articles, Liu et al reported that the routine use of prophylactic drains in total laparoscopic distal gastrectomy might not be necessary for all patients. Herein, we express our opinion regarding this interesting publication.

High-priority liver transplantation and simultaneous sleeve gastrectomy in MELD 32 end-stage liver disease: a case report with long-term follow-up.

BACKGROUND: Morbid obesity is a worldwide epidemic closely linked to Non-Alcoholic Fatty Liver Disease (NAFLD), an ever more relevant indication for Liver Transplantation (LT). Obesity affects an increasing number of LT recipients, but the ideal management of these patients remain unclear. Bariatric surgery (BS) in LT setting is challenging but feasible, although the debate is still open about the best timing of bariatric surgery. Herein we report a case of high-priority LT and simultaneous sleeve gastrectomy (SG) in an obese young adult. CASE REPORT: A 45 years old man with morbid obesity (BMI 46 kg/m2) and severe NAFLD-related end-stage liver disease (ESLD) underwent simultaneous LT and sleeve gastrectomy (SG) in an emergency setting, due to a MELD score of 32. He had substantial weight loss during long-term follow-up and enjoyed resolution of diabetes and hypertension. At 4 years follow-up, he has normal allograft function with appropriate immunosuppressant blood levels and no ultrasound evidence of steatosis. CONCLUSION: In selected patients, combined LT and SG present several advantages in terms of transplant outcomes, weight loss and resolution of obesity-related comorbidities. In addition, it can be performed in the high-priority setting in case of severe ESLD with good results in the short- and long-term.

Renal Function, Adherence and Quality of Life Improvement After Conversion From Immediate to Prolonged-Release Tacrolimus in Liver Transplantation: Prospective Ten-Year Follow-Up Study.

Immunosuppression non-adherence is a major cause of graft failure after liver transplantation. The aim of this study was to evaluate practice surrounding conversion from immediate-release to prolonged-release Tacrolimus formulation and to assess patient adherence and quality of life (QoL). One hundred and seven adult liver transplant recipients, receiving immediate-release Tacrolimus for a minimum of 6 months, were converted to prolonged-release formulation, based on a dose ratio of one (1:1). The median follow-up was 120 [IQR, 120-123] months. Tacrolimus dosage and blood level, liver and renal function, lipid and glucose profiles were recorded. In addition, questionnaires were submitted to evaluate adherence and QoL following conversion. No rejection was recorded. The median serum Tacrolimus blood level decreased over 1 month (5.80, [IQR, 2.0-10.8] vs. 3.8 [IQR, 1.4-8.7]; p < 0.0005). Significant improvement in renal function was noted (median GFR was 81.7 [IQR, 43.4-128.6] vs. 73.9 [IQR, 27.1-130.2]; p = 0.0002). At the end of the follow-up, conversion resulted in an overall decrease in non-adherence of 53.3% (p = 0.0001) and an improvement in QoL was reported by 76.2% of patients. Thus, 1:1 conversion from immediate to prolonged-release Tacrolimus is safe, feasible and efficient, avoiding under-therapeutic and toxic peak concentrations, improving renal function, adherence to immunosuppression and overall patient QoL.

"Salus Populi Suprema Lex": Considerations on the Initial Response of the United Kingdom to the SARS-CoV-2 Pandemic.

In several countries worldwide, the initial response to coronavirus disease 2019 (COVID-19) has been heavily criticized by general public, media, and healthcare professionals, as well as being an acrimonious topic in the political debate. The present article elaborates on some aspects of the United Kingdom (UK) primary reaction to SARS-CoV-2 pandemic; specifically, from February to July 2020. The fact that the UK showed the highest mortality rate in Western Europe following the first wave of COVID-19 certainly has many contributing causes; each deserves an accurate analysis. We focused on three specific points that have been insofar not fully discussed in the UK and not very well known outside the British border: clinical governance, access to hospital care or intensive care unit, and implementation of non-pharmaceutical interventions. The considerations herein presented on these fundamental matters will likely contribute to a wider and positive discussion on public health, in the context of an unprecedented crisis.

Liver transplantation from active COVID-19 donors: A lifesaving opportunity worth grasping?

COVID-19 pandemic dramatically impacted transplantation landscape. Scientific societies recommend against the use of donors with active SARS-CoV-2 infection. Italian Transplant Authority recommended to test recipients/donors for SARS-CoV-2-RNA immediately before liver transplant (LT) and, starting from November 2020, grafts from deceased donors with active SARS-CoV-2 infection were allowed to be considered for urgent-need transplant candidates with active/resolved COVID-19. We present the results of the first 10 LTs with active COVID-19 donors within an Italian multicenter series. Only two recipients had a positive molecular test at LT and one of them remained positive up to 21 days post-LT. None of the other eight recipients was found to be SARS-CoV-2 positive during follow-up. IgG against SARS-CoV-2 at LT were positive in 80% (8/10) of recipients, and 71% (5/7) showed neutralizing antibodies, expression of protective immunity related to recent COVID-19. In addition, testing for SARS-CoV-2 RNA on donors' liver biopsy at transplantation was negative in 100% (9/9), suggesting a very low risk of transmission with LT. Immunosuppression regimen remained unchanged, according to standard protocol. Despite the small number of cases, these data suggest that transplanting livers from donors with active COVID-19 in informed candidates with SARS-CoV-2 immunity, might contribute to safely increase the donor pool.

Vascular Involvements in Cholangiocarcinoma: Tips and Tricks.

Cholangiocarcinoma (CCA) is an aggressive malignancy of the biliary tract. To date, surgical treatment remains the only hope for definitive cure of CCA patients. Involvement of major vascular structures was traditionally considered a contraindication for resection. Nowadays, selected cases of CCA with vascular involvement can be successfully approached. Intrahepatic CCA often involves the major hepatic veins or the inferior vena cava and might necessitate complete vascular exclusion, in situ hypothermic perfusion, ex situ surgery and reconstruction with autologous, heterologous or synthetic grafts. Hilar CCA more frequently involves the portal vein and hepatic artery. Resection and reconstruction of the portal vein is now considered a relatively safe and beneficial technique, and it is accepted as a standard option either with direct anastomosis or jump grafts. However, hepatic artery resection remains controversial; despite accumulating positive reports, the procedure remains technically challenging with increased rates of morbidity. When arterial reconstruction is not possible, arterio-portal shunting may offer salvage, while sometimes an efficient collateral system could bypass the need for arterial reconstructions. Keys to achieve success are represented by accurate selection of patients in high-volume referral centres, adequate technical skills and eclectic knowledge of the various possibilities for vascular reconstruction.

The Management of Immunosuppression in Kidney Transplant Recipients with COVID-19 Disease: An Update and Systematic Review of the Literature.

Background and Objectives: In the era of the coronavirus disease 2019 (COVID-19) pandemic, the management of immunosuppressive (IS) therapy in kidney transplant (KT) recipients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires attention. It is not yet understood whether IS therapy may protect from the cytokine storm induced by SARS-CoV-2 infection or a temporary adjustment/withdrawal of IS therapy to restore the immune system may be necessary. We performed a systematic literature review to investigate the current management of IS therapy in KT recipients with COVID-1. Materials and Methods: Out of 71 articles published from 1 February 2020 until 30 October 2020, 554 KT recipients with SARS-CoV-2 infection were identified. Results: Modifications of IS therapy were based on the clinical conditions. For asymptomatic patients or those with mild COVID-19 symptoms, a "wait and see approach" was mostly used; a suspension of antimetabolites drugs (347/461, 75.27%) or mTOR inhibitors (38/48, 79.2%) was adopted in the majority of patients with symptomatic COVID-19 infections. For CNIs, the most frequent attitude was their maintenance (243/502, 48.4%) or dose-reduction (99/502, 19.72%) in patients asymptomatic or with mild COVID-19 symptoms, while drug withdrawal was the preferred choice in severely symptomatic patients (160/450, 31.87%). A discontinuation of all IS drugs was used only in severely symptomatic COVID-19 patients on invasive mechanical ventilation. Renal function remained stable in 422(76.17%) recipients, while 49(8.84%) patients experienced graft loss. Eight (1.44%) patients experienced a worsening of renal function. The overall mortality was 21.84%, and 53(9.56%) patients died with functioning grafts. Conclusion: A tailored approach to the patient has been the preferred strategy for the management of IS therapy in KT recipients, taking into account the clinical conditions of patients and the potential interactions between IS and antiviral drugs, in the attempt to balance the risks of COVID-19-related complications and those due to rejection or graft loss.