Fairness and pitfalls of the Italian waiting list for elective liver transplantation: The ECALITA registry study.

BACKGROUND: The challenge of transplant waiting-lists is to provide organs for all candidates while maintaining efficiency and equity. AIMS: We investigated the probability of being transplanted or of waiting-list dropout in Italy. METHODS: Data from 12,749 adult patients waitlisted for primary liver-transplantation from January 2012 to December 2022 were collected from the National Transplant-Registry.The cohort was divided into Eras:1 (2012-2014);2 (2015-2018);and 3 (2019-2022). RESULTS: The one-year probability of undergoing transplant increased (67.6 % in Era 1vs73.8 % in Era 3,p < 0001) with a complementary 46 % decrease in waiting-list failures. Patients with hepatocellular-carcinoma were transplanted more often than cirrhotics[at model for end-stage liver-disease (MELD)-15:HR = 1.28,95 %CI:1.21-1.35;at MELD-25:HR = 1.04,95 %CI:0.92-1.19) and those with other indications (at MELD-15:HR = 1.27,95 %CI:1.11-1.46) across all eras. Candidates with Hepatitis-B-virus (HBV)related disease had a greater probability of transplant than those with Hepatitis-C virus-related (HR = 1.13,95 %CI:1.07-1.20), alcohol-related (HR = 1.13,95 %CI:1.05-1.21), and metabolic-related (HR = 1.18,95 %CI:1.09-1.28)disease. Waiting-list failures increased by 27 % every 5 MELD-points and by 14 % for every 5-year increase in recipient-age and decreased by 10 % with each 10-cm increase in stature. Blood-group O patients showed the highest probability of waiting-list failure (HR = 1.28,95 %CI:1.15-1.43). CONCLUSIONS: Liver-transplantation waiting-list success-rates have significantly improved in Italy, with patients with hepatocellular-carcinoma and/or HBV-related diseases being favored. High MELD-score, old-age, short-stature, and blood-group O were significant risk-factors for waiting-list failure. Efforts to improve organ-allocation and prioritization-policies are underway.

Waiting list mortality and 5-year transplant survival benefit of patients with MASLD: An Italian liver transplant registry study.

Background & Aims: International consensus has recently introduced a new definition of metabolic dysfunction-associated steatotic liver disease (MASLD). We sought to analyse epidemiological trends, prognostic features, and transplant survival benefits of patients with MASLD and without MASLD waiting for liver transplantation (LT) in Italy. Methods: Using the Italian Liver Transplant Registry database, we analysed data from adult patients listed for primary LT attributable to end-stage chronic liver disease between January 2012 and December 2022. Independent multivariable waiting lists and post-transplant survival models were developed for patients with and without hepatocellular carcinoma (HCC). A Monte Carlo simulation was used to create 5-year transplant benefit distributions based on the presence of MASLD, HCC, and model for end-stage liver disease (MELD)-sodium values. Results: A total sample of 1,941 patients with MASLD and 11,201 patients without MASLD was considered. A significant increase in the prevalence of MASLD as an indication for LT was observed from 2012 to 2022, for both cohorts with HCC (from 17.7 to 30%) and without HCC (from 9.5 to 11.8%) cohorts. Projections suggest that, as early as next year, MASLD will overcome HCV as the second most common indication for transplantation after alcoholic liver disease in Italy. According to univariate and multivariate analyses, MASLD was not an independent predictive factor for patient survival after transplantation. However, it increased the risk of death for patients on the waiting list without HCC (hazard ratio 1.62, p <0.001). At the same MELD-sodium, the 5-year transplant benefit was higher in patients with non-HCC MASLD, followed by patients with HCC, whereas it was lower in patients without HCC and without MASLD. Conclusions: Patients with non-HCC MASLD had an increased waitlist mortality and 5-year transplant survival benefit compared with other candidates. Impact and implications: The present research addresses the critical need to understand the evolving landscape of liver transplantation indications, mainly focusing on metabolic dysfunction-associated steatotic liver disease (MASLD) in Italy. Given the significant rise in MASLD cases, these findings highlight that patients with non-HCC MASLD face increased waitlist mortality and benefit more from liver transplantation within 5 years compared with other candidates. The significance of these results lies in their emphasis on the necessity of focusing on patients with MASLD on waiting lists to improve outcomes. By tailoring transplant eligibility criteria and resource allocation, the study provides actionable insights to improve patient survival and optimise liver transplantation practices.

Transarterial Radioembolization Can Downstage Intermediate and Advanced Hepatocellular Carcinoma to Liver Transplantation.

BACKGROUND: Transarterial radioembolization (TARE) is an effective treatment to control tumor growth and improve survival in hepatocellular carcinoma (HCC). The role of TARE in downstaging patients to liver transplantation (LT) is unclear. The aim of this study was to investigate the downstaging efficacy of TARE for intermediate and advanced HCC. METHODS: Intention-to-treat analysis with multistate modeling was performed. Patients moved through 5 health states: (1) from TARE to listing, (2) from TARE to death without listing, (3) from listing to LT, (4) from listing to death without LT, and (5) from transplant to death. Factors affecting the chance of death after TARE were considered to stratify outcomes. RESULTS: Two hundred fourteen patients underwent TARE. Of those, 43.9% had radiological response, 29.9% were listed, and 22.8% were transplanted. The probability of being alive without LT was 40.5% 1 y after TARE and 11.5% at 5 y. The chance of being listed was 9.4% at 1 y and 0.9% at 5 y. The probability of dying after TARE without LT was 38% at 1 y and 73% at 5 y. The overall survival of patients receiving LT was 61% at 5 y after transplant. Tumor beyond up-to-seven criteria, alfafetoprotein >400 ng/mL, and albumin-bilirubin ≥2 were associated with death. Three risk groups were associated with different response, chances of being listed, and receiving LT. Median survival was 3 y for low-risk, 1.9 y for intermediate-risk, and 9 mo for high-risk patients (P < 0.001). CONCLUSIONS: In intermediate and advanced HCC, TARE allows for a 44% chance of response, 30% downstaging, and 23% probability of permitting LT. Patient's and tumor's characteristics allow for risk stratification and predict survival from TARE.

Impact of neoadjuvant multimodal therapy in the setting of locally advanced hepatocellular carcinoma.

Immunotherapy and the implementation of more aggressive treatment schemes for locally advanced hepatocellular carcinomas have expanded the boundaries of curative options. Because of these advancements, patients who were once considered beyond the aim of a cure are now eligible for liver transplantation and resection.

Cornerstones and divergencies in the implementation and use of liver hypertrophy techniques: results from a nationwide survey for the set-up of the prospective registry.

BACKGROUND: The aim of this national survey on liver hypertrophy techniques was to track the trends of their use and implementation in Italy and to detect analogies and heterogeneities among centers. METHODS: In December 2022, Italian centers with liver resection activity were specifically contacted and asked to fill an online questionnaire composed of 6 sections including a total of 51 questions. RESULTS: 46 Italian centers filled the questionnaire. The proportion of major/total number of liver resections was 27% and the use of hypertrophy techniques was required in 6,2% of cases. The most frequent reason of drop out was disease progression in 58.5% of cases. Most frequently used techniques were PVE and ALPPS with an increasing use of hepatic venous deprivation (HVD). Heterogeneous answers were provided regarding the cutoff values to indicate the need for hypertrophy techniques. Criteria to allocate a patient to different hypertrophy techniques are not standardized. CONCLUSIONS: The use of hypertrophy techniques is deep-rooted in Italy, documenting the established value of their role in improving resectability rate. While an evolution of techniques is detectable, still significant heterogeneity is perceived in terms of cutoff values, indications and managing protocols.

Recipient hepatectomy technique may affect oncological outcomes of liver transplantation for hepatocellular carcinoma.

To date, caval sparing (CS) and total caval replacement (TCR) for recipient hepatectomy in liver transplantation (LT) have been compared only in terms of surgical morbidity. Nonetheless, the CS technique is inherently associated with an increased manipulation of the native liver and later exclusion of the venous outflow, which may increase the risk of intraoperative shedding of tumor cells when LT is performed for HCC. A multicenter, retrospective study was performed to assess the impact of recipient hepatectomy (CS vs. TCR) on the risk of posttransplant HCC recurrence among 16 European transplant centers that used either TCR or CS recipient hepatectomy as an elective protocol technique. Exclusion criteria comprised cases of non-center-protocol recipient hepatectomy technique, living-donor LT, HCC diagnosis suspected on preoperative imaging but not confirmed at the pathological examination of the explanted liver, HCC in close contact with the IVC, and previous liver resection for HCC. In 2420 patients, CS and TCR approaches were used in 1452 (60%) and 968 (40%) cases, respectively. Group adjustment with inverse probability weighting was performed for high-volume center, recipient age, alcohol abuse, viral hepatitis, Child-Pugh class C, Model for End-Stage Liver Disease score, cold ischemia time, clinical HCC stage within Milan criteria, pre-LT downstaging/bridging therapies, pre-LT alphafetoprotein serum levels, number and size of tumor nodules, microvascular invasion, and complete necrosis of all tumor nodules (matched cohort, TCR, n = 938; CS, n = 935). In a multivariate cause-specific hazard model, CS was associated with a higher risk of HCC recurrence (HR: 1.536, p = 0.007). In conclusion, TCR recipient hepatectomy, compared to the CS approach, may be associated with some protective effect against post-LT tumor recurrence.

The Italian data on SARS-CoV-2 infection in transplanted patients support an organ specific immune response in liver recipients.

Introduction: The study of immune response to SARSCoV-2 infection in different solid organ transplant settings represents an opportunity for clarifying the interplay between SARS-CoV-2 and the immune system. In our nationwide registry study from Italy, we specifically evaluated, during the first wave pandemic, i.e., in non-vaccinated patients, COVID-19 prevalence of infection, mortality, and lethality in liver transplant recipients (LTRs), using non-liver solid transplant recipients (NL-SOTRs) and the Italian general population (GP) as comparators. Methods: Case collection started from February 21 to June 22, 2020, using the data from the National Institute of Health and National Transplant Center, whereas the data analysis was performed on September 30, 2020.To compare the sex- and age-adjusted distribution of infection, mortality, and lethality in LTRs, NL-SOTRs, and Italian GP we applied an indirect standardization method to determine the standardized rate. Results: Among the 43,983 Italian SOTRs with a functioning graft, LTRs accounted for 14,168 patients, of whom 89 were SARS-CoV-2 infected. In the 29,815 NL-SOTRs, 361 cases of SARS-CoV-2 infection were observed. The geographical distribution of the disease was highly variable across the different Italian regions. The standardized rate of infection, mortality, and lethality rates in LTRs resulted lower compared to NL-SOTRs [1.02 (95%CI 0.81-1.23) vs. 2.01 (95%CI 1.8-2.2); 1.0 (95%CI 0.5-1.5) vs. 4.5 (95%CI 3.6-5.3); 1.6 (95%CI 0.7-2.4) vs. 2.8 (95%CI 2.2-3.3), respectively] and comparable to the Italian GP. Discussion: According to the most recent studies on SOTRs and SARS-CoV-2 infection, our data strongly suggest that, in contrast to what was observed in NL-SOTRs receiving a similar immunosuppressive therapy, LTRs have the same risk of SARS-CoV-2 infection, mortality, and lethality observed in the general population. These results suggest an immune response to SARS-CoV-2 infection in LTRS that is different from NL-SOTRs, probably related to the ability of the grafted liver to induce immunotolerance.

Improving outcomes of in situ split liver transplantation in Italy over the last 25 years.

BACKGROUND & AIMS: Split liver transplant(ation) (SLT) is still considered a challenging procedure that is by no means widely accepted. We aimed to present data on 25-year trends in SLT in Italy, and to investigate if, and to what extent, outcomes have improved nationwide during this time. METHODS: The study included all consecutive SLTs performed from May 1993 to December 2019, divided into three consecutive periods: 1993-2005, 2006-2014, and 2015-2019, which match changes in national allocation policies. Primary outcomes were patient and graft survival, and the relative impact of each study period. RESULTS: SLT accounted for 8.9% of all liver transplants performed in Italy. A total of 1,715 in situ split liver grafts were included in the analysis: 868 left lateral segments (LLSs) and 847 extended right grafts (ERGs). A significant improvement in patient and graft survival (p <0.001) was observed with ERGs over the three periods. Predictors of graft survival were cold ischaemia time (CIT) <6 h (p = 0.009), UNOS status 2b (p <0.001), UNOS status 3 (p = 0.009), and transplant centre volumes: 25-50 cases vs. <25 cases (p = 0.003). Patient survival was significantly higher with LLS grafts in period 2 vs. period 1 (p = 0.008). No significant improvement in graft survival was seen over the three periods, where predictors of graft survival were CIT <6 h (p = 0.007), CIT <6 h vs. ≥10 h (p = 0.019), UNOS status 2b (p = 0.038), and UNOS status 3 (p = 0.009). Retransplantation was a risk factor in split liver graft recipients, with significantly worse graft and patient survival for both types of graft (p <0.001). CONCLUSIONS: Our analysis showed Italian SLT outcomes to have improved over the last 25 years. These results could help to dispel reservations regarding the use of this procedure. IMPACT AND IMPLICATIONS: Split liver transplant(ation) (SLT) is still considered a challenging procedure and is by no means widely accepted. This study included all consecutive in situ SLTs performed in Italy from May 1993 to December 2019. With more than 1,700 cases, it is one of the largest series, examining long-term national trends in in situ SLT since its introduction. The data presented indicate that the outcomes of SLT improved during this 25-year period. Improvements are probably due to better recipient selection, refinements in surgical technique, conservative graft-to-recipient matching, and the continuous, yet carefully managed, expansion of donor selection criteria under a strict mandatory split liver allocation policy. These results could help to dispel reservations regarding the use of this procedure.

The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells' exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.

Bridging therapies for patients with hepatocellular carcinoma awaiting liver transplantation: A systematic review and meta-analysis on intention-to-treat outcomes.

INTRODUCTION: Locoregional therapies are commonly used as bridging strategies to decrease the drop-out of patients with hepatocellular carcinoma (HCC) awaiting liver transplantation (LT). The present paper aims to assess the outcomes of bridging therapies in patients with HCC considered for LT according to an intention-to-treat (ITT) survival analysis. MATERIAL AND METHODS: Medline and Web of Science databases were searched for reports published before May 2021. Papers assessing adult patients with HCC considered for LT and reporting ITT survival outcomes were included. Two reviewers independently identified, extracted the data, and evaluated the papers according to Newcastle-Ottawa criteria. Outcomes analyzed were: drop-out rate; time on the waiting list; 1-, 3-, and 5-year survival after LT and based on an ITT analysis. RESULTS: The search identified 3106 records; six papers (1043 patients) met the inclusion criteria. Patients with HCC, listed for LT and submitted to bridging therapies presented a longer waiting time before LT (MD 3.77, 95% CI 2.07-5.48) in comparison with the non-interventional group. However, they presented a raised post LT after 1-year (OR 2.00, 95% CI 1.18-3.41), 3-years (OR 1.47, 95% CI 1.01-2.15), and 5-years (OR 1.50, 95% CI 1.06-2.13) survival. CONCLUSION: Patients submitted to bridging procedures, despite having a longer interval on the waiting list, presented better post-LT survival outcomes. Bridging therapies for selected patients at low risk of post-procedural complications and long expected intervals on the waiting list should be encouraged. However, further clinical trials should confirm the survival benefit of bridging therapies in patients with HCC listed for LT.

Downstaging Therapies for Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation: A Systematic Review and Meta-Analysis on Intention-to-Treat Outcomes.

Background: Locoregional therapies (LRTs) are commonly used to increase the number of potential candidates for liver transplantation (LT). The aim of this paper is to assess the outcomes of LRTs prior to LT in patients with hepatocellular carcinoma (HCC) beyond the listing criteria. Methods: In accordance with the PRISMA guidelines, we searched the Medline and Web of Science databases for reports published before May 2021. We included papers assessing adult patients with HCC considered for LT and reporting intention-to-treat (ITT) survival outcomes. Two reviewers independently identified and extracted the data and evaluated the papers. Outcomes analysed were drop-out rate; time on the waiting list; and 1, 3 and 5 year survival after LT and based on an ITT analysis. Results: The literature search yielded 3,106 records, of which 11 papers (1874 patients) met the inclusion criteria. Patients with HCC beyond the listing criteria and successfully downstaged presented a higher drop-out rate (OR 2.05, 95% CI 1.45−2.88, p < 0.001) and a longer time from the initial assessment to LT than those with HCC within the listing criteria (MD 1.93, 95% CI 0.91−2.94, p < 0.001). The 1, 3 and 5 year survival post-LT and based on an ITT analysis did not show significant differences between the two groups. Patients with HCC beyond the listing criteria, successfully downstaged and then transplanted, presented longer 3 year (OR 3.77, 95% CI 1.26−11.32, p = 0.02) and 5 year overall survival (OS) (OR 3.08, 95% CI 1.15−8.23, p = 0.02) in comparison with those that were not submitted to LT. Conclusions: Patients with HCC beyond the listing criteria undergoing downstaging presented a higher drop-out rate in comparison with those with HCC within the listing criteria. However, the two groups did not present significant differences in 1, 3 and 5 year survival rates based on an ITT analysis. Patients with HCC beyond the listing, when successfully downstaged and transplanted, presented longer 3 and 5-year OS in comparison with those who were not transplanted.

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.

It is the lymph node ratio that determines survival and recurrence patterns in resected distal cholangiocarcinoma. A multicenter international study.

BACKGROUND: Distal cholangiocarcinoma (dCC) is still associated with a poor overall survival (OS). This study aims to investigate the impact of novel prognostic scores in comparison with more traditional ones. METHODS: Multicentric retrospective analysis of patients who underwent a pancreatoduodenectomy (PD) for dCC. An unadjusted analysis was used to identify predictors of decreased survival. Significant variables were introduced in a multivariable model that assessed OS, recurrence-free survival (RFS), early recurrence (defined as a recurrence within the first 12 months from the PD), local and distant recurrence. Prognostic scores evaluated included the TNM staging system, the lymph-node ratio (LNR), the platelet-lymphocyte ratio (PLR), the neutrophil-lymphocyte ratio (NLR) and the systemic inflammation index (SII). RESULTS: The study included 232 patients with resected dCC. The optimal cut-off value for LNR was 15% (LNR15). On the unadjusted analysis T stage (p = 0.012), N stage (p < 0.001), LNR15 (p < 0.001), grade (p < 0.001), perineural invasion (p < 0.001) and the R1 status of resection margin (p = 0.001) accounted for the decreased OS. No significant association between survival and PLR, NLR and SII were found. On the multivariable analysis only LNR15, perineural invasion and R1 were independent predictors of decreased RFS (p = 0.003, p = 0.021 and p = 0.009, respectively) and OS (p = 0.001, p = 0.016 and p = 0.013, respectively). Additionally, LNR15 was an independent predictor of early recurrence (p = 0.003) and both LNR15 and R1 were associated with increased local (p < 0.001 and p = 0.010) and distant recurrence (p < 0.001 and p = 0.003). CONCLUSIONS: LNR15 is an independent predictor of DFS, OS, early, local and distal recurrence, combined with the status of the resection margin and perineural invasion.

Liver resection in elderly patients with extensive CRLM: Are we offering an adequate treatment? A propensity score matched analysis.

BACKGROUND: Data on the management of elderly patients with extensive colorectal liver metastases (CRLM) are scarce and conflicting. This study assesses differences in management and long-term oncological outcomes between older and younger patients with CRLM and a high Tumour Burden Score (TBS). METHODS: International multicentre retrospective study on patients with CRLM and a category 3 TBS, submitted to liver resection. Patients were divided into two groups according to their age (younger and older than 75) and were compared using propensity score matching (PSM) analysis and multivariable regression models. Differences in management and oncological outcomes including recurrence-free survival (RFS) and overall survival (OS) were assessed. RESULTS: The study included 386 patients, median follow-up was 48 months. The unmatched comparison revealed a higher ASA score (p = 0.035), less synchronous CRLM (47% vs 68%, p = 0.003), a lower median number of lesions (1 vs 3, p = 0.004) and less perioperative chemotherapy (CTx) (66% vs 88%, p < 0.001) in the elderly group. Despite the absence of CTx being an independent predictor of decreased RFS and OS (HR 0.760, p = 0.044 and HR 0.719, p = 0.049, respectively), the elderly group still received less CTx (OR 0.317, p = 0.001) than the younger group. After PSM (n = 100 patients), the two groups were comparable, however, CTx administration was still significantly lower in the elderly group. CONCLUSION: Liver resection should be considered in patients aged 75 and older, even if they present with extensive liver disease. Despite CTx being associated with improved oncological outcomes, a large percentage of elderly patients with CRLM are undertreated.

The Italian Consensus on minimally invasive simultaneous resections for synchronous liver metastasis and primary colorectal cancer: A Delphi methodology.

At the time of diagnosis synchronous colorectal cancer, liver metastases (SCRLM) account for 15-25% of patients. If primary tumour and synchronous liver metastases are resectable, good results may be achieved performing surgical treatment incorporated into the chemotherapy regimen. So far, the possibility of simultaneous minimally invasive (MI) surgery for SCRLM has not been extensively investigated. The Italian surgical community has captured the need and undertaken the effort to establish a National Consensus on this topic. Four main areas of interest have been analysed: patients' selection, procedures, techniques, and implementations. To establish consensus, an adapted Delphi method was used through as many reiterative rounds were needed. Systematic literature reviews were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses instructions. The Consensus took place between February 2019 and July 2020. Twenty-six Italian centres participated. Eighteen clinically relevant items were identified. After a total of three Delphi rounds, 30-tree recommendations reached expert consensus establishing the herein presented guidelines. The Italian Consensus on MI surgery for SCRLM indicates possible pathways to optimise the treatment for these patients as consensus papers express a trend that is likely to become shortly a standard procedure for clinical pictures still on debate. As matter of fact, no RCT or relevant case series on simultaneous treatment of SCRLM are available in the literature to suggest guidelines. It remains to be investigated whether the MI technique for the simultaneous treatment of SCRLM maintain the already documented benefit of the two separate surgeries.

An Italian survey on the use of T-tube in liver transplantation: old habits die hard!

There is enough clinical evidence that a T-tube use in biliary reconstruction at adult liver transplantation (LT) does not significantly modify the risk of biliary stricture/leak, and it may even sustain infective and metabolic complications. Thus, the policy on T-tube use has been globally changing, with progressive application of more restrictive selection criteria. However, there are no currently standardized indications in such change, and many LT Centers rely only on own experience and routine. A nation-wide survey was conducted among all the 20 Italian adult LT Centers to investigate the current policy on T-tube use. It was found that 20% of Centers completely discontinued the T-tube use, while 25% Centers used it routinely in all LT cases. The remaining 55% of Centers applied a selective policy, based on criteria of technical complexity of biliary reconstruction (72.7%), followed by low-quality graft (63.6%) and high-risk recipient (36.4%). A T-tube use > 50% of annual caseload was not associated with high-volume Center status (> 70 LT per year), an active pediatric or living-donor transplant program, or use of DCD grafts. Only 10/20 (50%) Centers identified T-tube as a potential risk factor for complications other than biliary stricture/leak. In these cases, the suspected pathogenic mechanism comprised bacterial colonization (70%), malabsorption (70%), interruption of the entero-hepatic bile-acid cycle (50%), biliary inflammation due to an indwelling catheter (40%) and gut microbiota changes (40%). In conclusion, the prevalence of T-tube use among the Italian LT Centers is still relatively high, compared to the European trend (33%), and the potential detrimental effect of T-tube, beyond biliary stricture/leak, seems to be somehow underestimated.

Clinical epigenetics and acute/chronic rejection in solid organ transplantation: An update.

The lack of a precise stratification algorithm for predicting patients at high risk of graft rejection challenges the current solid organ transplantation (SOT) clinical setting. In fact, the established biomarkers for transplantation outcomes are unable to accurately predict the onset time and severity of graft rejection (acute or chronic) as well as the individual response to immunosuppressive drugs. Thus, identifying novel molecular pathways underlying early immunological responses which can damage transplant integrity is needed to reach precision medicine and personalized therapy of SOT. Direct epigenetic-sensitive mechanisms, mainly DNA methylation and histone modifications, may play a relevant role for immune activation and long-term effects (e.g., activation of fibrotic processes) which may be translated in new non-invasive biomarkers and drug targets. In particular, the measure of DNA methylation by using the blood-based "epigenetic clock" system may be an added value to the donor eligibility criteria providing an estimation of the heart biological age as well as a predictive biomarkers. Besides, monitoring of DNA methylation changes may aid to predict acute vs chronic graft damage in kidney transplantation (KT) patients. For example, hypermethylation of genes belonging to the Notch and Wnt pathways showed a higher predictive value for chronic injury occurring at 12 months post-KT with respect to established clinical parameters. Detecting higher circulating cell-free DNA (cfDNA) fragments carrying hepatocyte-specific unmethylated loci in the inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), insulin like growth factor 2 receptor (IGF2R), and vitronectin (VTN) genes may be useful to predict acute graft injury after liver transplantation (LT) in serum samples. Furthermore, hypomethylation in the forkhead box P3 (FOXP3) gene may serve as a marker of infiltrating natural Treg percentage in the graft providing the ability to predict acute rejection events after heart transplantation (HTx). We aim to update on the possible clinical relevance of DNA methylation changes regulating immune-related pathways underlying acute or chronic graft rejection in KT, LT, and HTx which might be useful to prevent, monitor, and treat solid organ rejection at personalized level.