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.

Distal Pancreatectomy for Body Pancreatic Ductal Adenocarcinoma: Is Splenectomy Necessary? A Propensity Score Matched Study.

BACKGROUND: The value of splenectomy for body localization (≥ 5 cm from spleen hilum) of pancreatic ductal adenocarcinoma (B-PDAC) is uncertain. This study assessed spleen-preserving distal pancreatectomy (SPDP) results for B-PDAC. PATIENTS AND METHODS: This single-center study included patients who underwent SPDP (Warshaw's technique) or distal splenopancreactomy (DSP) for B-PDAC from 2008 to 2019. Propensity score matching was performed to balance SPDP and DSP patients regarding sex, age, American Society of Anesthesiologists (ASA), body mass index (BMI), laparoscopy, pathological features [American Joint Committee on Cancer (AJCC)/tumor node metastasis classification (TNM)], margins, and neoadjuvant/adjuvant therapies. RESULTS: A total of 129 patients (64 male, median age 68 years, median BMI 24 kg/m2) were enrolled with a median follow-up of 63 months (95% CI 52-96 months), including 59 (46%) SPDP and 70 (54%) DSP patients. A total of 39 SPDP patients were matched to 39 DSP patients. SPDP patients had fewer harvested nodes (19 vs 22; p = 0.038) with a similar number of positive nodes (0 vs 0; p = 0.237). R0 margins were achieved similarly in SPDP and DSP patients (75% vs 71%; p = 0.840). SPDP patients were associated with decreased comprehensive complication index (CCI, 8.7 vs 16.6; p = 0.004), rates of grade B/C postoperative pancreatic fistula (POPF, 14% vs 29%; p = 0.047), and hospital stay (11 vs 16 days; p < 0.001). SPDP patients experienced similar disease-free survival (DFS, 5 years: 38% vs 32%; p = 0.180) and overall survival (OS, 5 years 54% vs 44%; p = 0.710). After matching, SPDP patients remained associated with lower CCI (p = 0.034) and hospital stay (p = 0.028) while not associated with risks of local recurrence (HR 0.85; 95% CI 0.28-2.62; p = 0.781), recurrence (HR 1.04; 95% CI 0.61-1.78; p = 0.888), or death (HR 1.20; 95% CI 0.68-2.11; p = 0.556). CONCLUSION: SPDP for B-PDAC is associated with less postoperative morbidity than DSP, without impairing oncological outcomes.

Genome-wide DNA methylation and transcriptomic analysis of liver tissues subjected to early ischemia/reperfusion injury upon human liver transplantation.

INTRODUCTION AND OBJECTIVES: Epigenetic changes represent a mechanism connecting external stresses with long-term modifications of gene expression programs. In solid organ transplantation, ischemia-reperfusion injury (IRI) appears to induce epigenomic changes in the graft, although the currently available data are extremely limited. The present study aimed to characterize variations in DNA methylation and their effects on the transcriptome in liver transplantation from brain-dead donors. PATIENTS AND METHODS: 12 liver grafts were evaluated through serial biopsies at different timings in the procurement-transplantation process: T0 (warm procurement, in donor), T1 (bench surgery), and T2 (after reperfusion, in recipient). DNA methylation (DNAm) and transcriptome profiles of biopsies were analyzed using microarrays and RNAseq. RESULTS: Significant variations in DNAm were identified, particularly between T2 and T0. Functional enrichment of the best 1000 ranked differentially methylated promoters demonstrated that 387 hypermethylated and 613 hypomethylated promoters were involved in spliceosomal assembly and response to biotic stimuli, and inflammatory immune responses, respectively. At the transcriptome level, T2 vs. T0 showed an upregulation of 337 and downregulation of 61 genes, collectively involved in TNF-α, NFKB, and interleukin signaling. Cell enrichment analysis individuates macrophages, monocytes, and neutrophils as the most significant tissue-cell type in the response. CONCLUSIONS: In the process of liver graft procurement-transplantation, IRI induces significant epigenetic changes that primarily act on the signaling pathways of inflammatory responses dependent on TNF-α, NFKB, and interleukins. Our DNAm datasets are the early IRI methylome literature and will serve as a launch point for studying the impact of epigenetic modification in IRI.

Refining Auxiliary Orthotopic Liver Transplantation (AOLT) Improves Outcomes in Adult Patients With Acute Liver Failure.

OBJECTIVE: To investigate whether and how experience accumulation and technical refinements simultaneously implemented in auxiliary orthotopic liver transplantation (AOLT) may impact on outcomes. BACKGROUND: AOLT for acute liver failure (ALF) provides the unique chance of complete immunosuppression withdrawal after adequate native liver remnant regeneration but is a technically demanding procedure. Our department is a reference center for ALF and an early adopter of AOLT. METHODS: This is a single-center retrospective before/after study of a prospectively maintained cohort of 48 patients with ALF who underwent AOLT between 1993 and 2019. In 2012, technical refinements were implemented to improve outcomes: (i) favoring the volume of the graft rather than that of the native liver, (ii) direct anastomosis of graft hepatic artery with recipient right hepatic artery instead of the use of large size vessels, (iii) end-to-side hepaticocholedocostomy instead of bilioenteric anastomosis. Early experience (1993-2011) group (n=26) and recent experience (2012-2019) group (n=22) were compared. Primary endpoint was 90-day severe morbidity rate (Clavien-Dindo≥IIIa) and secondary endpoints were overall patient survival and complete immunosuppression withdrawal rates. RESULTS: Compared with the earlier experience group, the recent experience group was associated with a lower severe complication rate (27% vs 65%, P <0.001), as well as less biliary (18% vs 54%, P =0.017) and arterial (0% vs 15%, P =0.115) complications. The 1-, 3-, and 5-year patient survival was significantly improved (91%, 91%, 91% vs 76%, 61%, 60%, P =0.045). The rate of complete immunosuppression withdrawal increased to 94% vs 70%, ( P =0.091) with no need of long-term graft explant. CONCLUSION: These technical refinements favoring the liver graft and reducing morbidity may promote AOLT implementation among LT centers.

The role of antiplatelet therapies on incidence and mortality of hepatocellular carcinoma.

AIM: To evaluate the impact of antiplatelet therapy (APT)on the incidence of hepatocellular carcinoma (HCC) and mortality following its treatment. METHODS: A systematic literature search was performed using PubMed and Cochrane Central Register of Controlled Trials Databases. Two HCC clinical settings were explored: (i) incidence, and (ii) death after any HCC treatment. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated to compare the pooled data between patients who received or did not receive APT. RESULTS: A total of 20 studies were identified, of whom 15 focused on HCC incidence, including 2,685,009 patients, and five on post-treatment death, including 3281 patients. APT was associated with an overall reduced risk of HCC incidence (OR: 0.63; 95%CI = 0.51-0.79; p < 0.001) as well as of post-treatment mortality (OR: 0.54; 95%CI = 0.35-0.83; p = 0.006). CONCLUSIONS: Current data suggest that APT correlated with higher HCC incidence and poor overall survival following tumour treatment.

Endothelial autophagy is not required for liver regeneration after partial hepatectomy in mice with fatty liver.

BACKGROUND & AIMS: Patients with non-alcoholic fatty liver disease (NAFLD) have impaired liver regeneration. Liver endothelial cells play a key role in liver regeneration. In non-alcoholic steatohepatitis (NASH), liver endothelial cells display a defect in autophagy, contributing to NASH progression. We aimed to determine the role of endothelial autophagy in liver regeneration following liver resection in NAFLD. METHODS: First, we assessed autophagy in primary endothelial cells from wild type mice fed a high fat diet and subjected to partial hepatectomy. Then, we assessed liver regeneration after partial hepatectomy in mice deficient (Atg5lox/lox ;VE-cadherin-Cre+ ) or not (Atg5lox/lox ) in endothelial autophagy and fed a high fat diet. The role of endothelial autophagy in liver regeneration was also assessed in ApoE-/- hypercholesterolemic mice and in mice with NASH induced by methionine- and choline-deficient diet. RESULTS: First, autophagy (LC3II/protein) was strongly increased in liver endothelial cells following hepatectomy. Then, we observed at 40 and 48 h and at 7 days after partial hepatectomy, that Atg5lox/lox ;VE-cadherin-Cre+ mice fed a high fat diet had similar liver weight, plasma AST, ALT and albumin concentration, and liver protein expression of proliferation (PCNA), cell-cycle (Cyclin D1, BrdU incorporation, phospho-Histone H3) and apoptosis markers (cleaved Caspase-3) as Atg5lox/lox mice fed a high fat diet. Same results were obtained in ApoE-/- and methionine- and choline-deficient diet fed mice, 40 h after hepatectomy. CONCLUSION: These results demonstrate that the defect in endothelial autophagy occurring in NASH does not account for the impaired liver regeneration occurring in this setting.

Association between artificial nutrition in brain dead donors and early allograft function in liver transplant recipients: an observational study.

BACKGROUND: The role of nutrition in donor after brain deaths (DBDs) has yet to be adequately discussed. The primary aim of this study was to investigate whether the nutritional intake in the 48 h before organ retrieval may play a role on the graft functional recovery assessed with Model for Early Allograft Function (MEAF) Score. METHODS: Single-center retrospective study evaluating all liver transplants performed at the University Hospital of Udine from January 2010 to August 2020. Patients receiving grafts from DBD donors fed with artificial enteral nutrition in the 48 h prior to organ procurement (EN-group) or who did not (No-EN-group). Caloric debt was calculated using the difference between the calculated caloric needs and the effective calories delivered through enteral nutrition. RESULTS: Livers from EN-group presented a lower mean MEAF score compared to the no-EN-group: 3.39 ± 1.46 versus 4.15 ± 1.51, respectively (p = .04). A positive correlation between caloric debt and the MEAF score was found within the overall population (r = .227, p = .043) as well as in EN-group (r = .306, p = .049). CONCLUSIONS: Donor's nutritional intake in the final 48 h before organ procurement correlates with MEAF score, and nutrition probably plays a positive role on the functional recovery of the graft. Large future randomized controlled trials are needed to confirm this preliminary results.

Graft aberrant hepatic arteries in deceased donor liver transplantation: The "one liver, one artery" approach.

In liver transplantation (LT), graft aberrant hepatic arteries (aHAs) frequently require complex arterial reconstructions, potentially increasing the risk of post-operative complications. However, intrahepatic hilar arterial shunts are physiologically present and may allow selective aHA ligation. Thus, we performed a retrospective study from a single-center cohort of 618 deceased donor LTs where a selective reconstruction policy of aHAs was prospectively applied. In the presence of any aHA, the vessel with the largest caliber was first reconstructed. In case of adequate bilobar arterial perfusion assessed on intraparenchymal Doppler ultrasound, the remnant vessel was ligated; otherwise, it was reconstructed. Consequently, outcomes of three patient groups were compared: the "no aHAs" group (n = 499), the "reconstructed aHA" group (n = 25), and the "ligated aHA" group (n = 94). Primary endpoint was rate of biliary complications. Only 38.4% of right aHAs and 3.1% of left aHAs were reconstructed. Rates of biliary complications in the no aHA, reconstructed aHA, and ligated aHA groups were 23.4%, 28%, and 20.2% (p = 0.667), respectively. The prevalence rates of primary non-function (p = 0.534), early allograft dysfunction (p = 0.832), and arterial complications (p = 0.271), as well as patient survival (p = 0.266) were comparable among the three groups. Retransplantation rates were 3.8%, 4%, and 5.3% (p = 0.685), respectively. In conclusion, a selective reconstruction policy of aHAs based on Doppler assessment of bilobar intraparenchymal arterial flow did not increase post-operative morbidity and avoided unnecessary and complex arterial reconstructions.

Assessment of hepatic steatosis based on needle biopsy images from deceased donor livers.

BACKGROUND: Assessment of hepatic steatosis (HS) before transplantation requires the pathologist to read a graft biopsy. A simple method based on the evaluation of images from tissue samples with a smartphone could expedite and facilitate the liver selection. This study aims to assess the degree of HS by analysing photographic images from liver needle biopsy samples. METHODS: Thirty-three biopsy-images were acquired with a smartphone. Image processing was carried out using ImageJ: background subtraction, conversion to HSB colour space, segmentation of the biopsy area, and evaluation of statistical features of Hue, Saturation, Brightness, Red, Green, and Blue channels on the biopsy area. After feature extraction, correlations were made with gold standard HS percentage assessed at two levels (frozen-section vs glass-slide). Sensitivity, specificity, and accuracy were calculated for each feature. RESULTS: Correlations were found for H, S, R. The sensitivity, specificity, and accuracy of the final classifier based on the K* algorithm were 94%, 92%, 94%. LIMITATIONS: Accuracy assessment was performed considering macrovesicular steatosis on specimens with mostly < 30% HS. CONCLUSIONS: The steatosis assessment based on needle biopsy images, proved to be an effective and promising method. Deep learning approaches could also be experimented with a larger set of images.

miRNA expression profiles in liver grafts of HCV and HIV/HCV-infected recipients, 6 months after liver transplantation.

In hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infected patients, HIV enhances HCV replication and liver damage. Several microRNAs (miRNAs), active in pro-fibrotic and inflammatory pathways, have been implicated in the pathogenesis of this phenomenon. However, these miRNAs have been tested only in explanted cirrhotic livers, when the liver damage has become chronic and irreversible. No data are available on the early phase of viral infection, such as early after liver transplantation (LT). In the present study, the expression of miR-101, miR-122, miR-155, miR-192, miR-200c, miR-338, and miR-532 was determined by quantitative real-time polymerase chain reaction in liver biopsies of HCV (n = 19) and HCV/HIV-infected (n = 20) LT recipients, as well as in a control group (n = 18) of noninfected patients, transplanted for alcoholic cirrhosis. The timing of liver biopsy was 6 months post-LT. None of the patients was treated with direct-acting anti-HCV drugs. All co-infected recipients had suppressed HIV viral load. Grading and staging were assessed according to the Ishak Classification. HCV and HIV viral load were measured in the sera. miR-101 (p = .03), miR-122 (p = .012), and miR-192 (p = .038) were significantly downregulated in HCV/HIV co-infected and HCV mono-infected recipients when compared with noninfected recipients, and such downregulation was more pronounced in co-infected ones. Moreover, in co-infected recipients but not in mono-infected ones, miR-101 inversely correlated with the peripheral HCV-RNA levels (r = .41, p = .04) and miR-122 inversely correlated with peripheral HCV-RNA levels (r = .49, p = .03) and with the histological grading (r = .51, p = .02).  In conclusion, as early as 6 months after LT, the presence of HIV-HCV co-infection enhanced a significant downregulation of certain miRNAs that showed a direct correlation with HCV viral load and liver inflammation.

Hypothermic machine perfusion can safely prolong cold ischemia time in deceased donor kidney transplantation. A retrospective analysis on postoperative morbidity and graft function.

In deceased donor kidney transplantation (KT), a prolonged cold ischemia time (CIT) is a negative prognostic factor for KT outcome, and the efficacy of hypothermic machine perfusion (HMP) in prolonging CIT without any additional hazard is highly debated. We conducted a retrospective study on a cohort of 154 single graft deceased donor KTs, in which a delayed HMP, after a preliminary period of static cold storage (SCS), was used to prolong CIT for logistic reasons. Primary outcomes were postoperative complications as well as 1 year graft survival and function. 73 cases (47.4%) were managed with HMP and planned KT, while 81 (52.6%) with SCS and urgent KT. The median CIT in HMP group and SCS group was 29 hour:57 minutes [27-31 hour:45 minutes] and 11 hour:25 minutes [9-14 hour:30 minutes], respectively (P < .001). The period of SCS in the HMP group was significantly shorter than in the SCS group (10 vs. 11 hour:25 minutes, P = .02) as well as the prevalence of expanded criteria donors was significantly higher (43.8% vs. 18.5%, P < .01). After propensity score matching for these two baseline characteristics, the HMP and SCS groups showed comparable outcomes in terms of delayed graft function, vascular, and urologic complications, infections, and episodes of graft rejection. At 1 year follow-up, serum creatinine levels were comparable between the groups. Therefore, the use of HMP to prolong the CIT and convert KT into a planned procedure seemed to have an adequate safety profile, with outcomes comparable to KT managed as an urgent procedure and a CIT nearly three time shorter.

Impact of kidney transplant morbidity on elderly recipients' outcomes.

BACKGROUND AND AIMS: Nowadays, advanced age does not represent an absolute contraindication to kidney transplantation (KT). However, aging is frequently associated with multiple comorbidities and lower performance status, making KT candidates less surgically fit. Limited data are available on the impact of KT morbidity on elderly recipients' outcomes. METHODS: Retrospective study on a single center cohort of 130 KT recipients over 65 years old, representing 16.2% of KT clinical series, during the period 2000-2018. Number and severity of comorbidities were evaluated with the Charlson Comorbidity index (CCI). RESULTS: The median age at transplantation was 67 [IQR66-71] years and median CCI was 5 [IQR4-6]. The prevalence of postoperative complications with a Clavien-Dindo (C-D) severity score > 2 was 29%. Increasing age did not predict KT morbidity in terms of C-D score > 2, infectious, respiratory, cardiologic, urologic or vascular complications, delayed graft function, symptomatic lymphocele, bleeding, acute or chronic rejection. Conversely, CCI score was a predictor of overall complications with C-D score > 2, cardiologic, respiratory and vascular complications, and bleeding. Among others, CCI score, post-KT cardiologic complications, C-D score > 2 were identified as significant predictors of both early mortality and graft loss in univariate analysis. Increasing recipient age did not correlate with graft loss risk and graft loss did not impact patient survival. C-D score > 2 was a predictor of poor survival even in multivariate analysis. CONCLUSIONS: Elderly recipients showed a significant vulnerability to KT morbidity which correlates with CCI. While graft loss did not impact recipient survival, severe postoperative complications (C-D > 2) were independently associated increased mortality.

Indocyanine green dye clearance test: early graft (dys)-function and long-term mortality after liver transplant. Should we continue to use it? An observational study.

Early allograft dysfunction (EAD) can be a serious complication in the immediate postoperative period following liver transplantation. Our aim was to study the prognostic role of the indocyanine green plasma disappearance rate (ICG-PDR) in predicting early and late EAD and mortality at 3 and 12 months and 5 years after liver transplantation. ICG-PDR values were also assessed for association with the Donor Risk Index (DRI). 220 patients underwent orthotopic liver transplantation. In 77 patients, ICG-PDR was assessed on the 1st post-operative (PO) day. ICG, a water-soluble dye almost entirely excreted into the bile, was measured by spectrophotometry to evaluate graft (dys)-function. DRI was calculated in all patients. The primary study outcomes were the presence (or absence) of EAD after transplant and the results of mortality risk factor analysis. EAD occurred in 18 patients. 1st PO day ICG-PDR was significantly associated with EAD (p < 0.005). A threshold ICG-PDR value < 16%/min on the 1st PO day was also associated with patient probability to survive at 3 and 12 months and 5 years. The sensitivity and specificity of the AUC was good in predicting EAD, being 83% and 56%, respectively, for a 1st PO day ICG-PDR cut-off value < 16%/min. In this study, ICG-PDR on the 1st PO day following OLT can reliably predict EAD and survival at 3 and 12 months and 5 years. ICG-PDR should, therefore, be routinely performed on the 1st PO day following OLTx in all patients in light of its important prognostic role.

Association between indocyanine green clearance test and ischemic type biliary lesions within one year after orthotopic liver transplantation.

BACKGROUND: Ischemic type biliary lesions (ITBLs), a particular subset of non-anastomotic biliary strictures (NAS), are characterized by intra and extrahepatic strictures that occur in the absence of either hepatic artery thrombosis or stenosis. When they occur within the first year after liver transplantation their development is mostly related to ischemia-reperfusion injury (IRI). The indocyanine green plasma disappearance rate (ICG-PDR) might be able to predict the probability of IRI-induced graft damage after liver transplantation. OBJECTIVE: Our aim was to evaluate the association between ICG-PDR and the occurrence of ITBLs. Secondly, we searched for evidence of IRI in patients presenting ITBLs. METHODS: This retrospective single-center observational study assessed a cohort of 60 liver transplant patients. Each patient underwent ICG-PDR on the 1st postoperative day. ITBLs were identified by means of either cholangiography or magnetic resonance imaging evidence of a deformity and narrowing of the biliary tree in the absence of hepatic artery thrombosis/stenosis. RESULTS: ITBLs were discovered in 10 patients out of 60 liver recipients (16.67%) within one year after transplantation. A low ICG-PDR value was found to be a significant predictive factor for ITBL development, with an OR of 0.87 and a 95% CI of 0.77-0.97. Liver biopsies were performed in 56 patients presenting unexplained abnormal liver function test results. A statistically significant association was found between the development of ITBLs and anatomopathological evidence of IRI. LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: The findings from this study show a relationship between low ICG-PDR values on first post-operative-day and the occurrence of ITBLs within 1 year after transplantation.

Mitochondrial apurinic/apyrimidinic endonuclease 1 enhances mtDNA repair contributing to cell proliferation and mitochondrial integrity in early stages of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of primary liver cancers. Surveillance of individuals at specific risk of developing HCC, early diagnostic markers, and new therapeutic approaches are essential to obtain a reduction in disease-related mortality. Apurinic/apyrimidinic endonuclease 1 (APE1) expression levels and its cytoplasmic localization have been reported to correlate with a lower degree of differentiation and shorter survival rate. The aim of this study is to fully investigate, for the first time, the role of the mitochondrial form of APE1 in HCC. METHODS: As a study model, we analyzed samples from a cohort of patients diagnosed with HCC who underwent surgical resection. Mitochondrial APE1 content, expression levels of the mitochondrial import protein Mia40, and mtDNA damage of tumor tissue and distal non-tumor liver of each patient were analyzed. In parallel, we generated a stable HeLa clone for inducible silencing of endogenous APE1 and re-expression of the recombinant shRNA resistant mitochondrially targeted APE1 form (MTS-APE1). We evaluated mtDNA damage, cell growth, and mitochondrial respiration. RESULTS: APE1's cytoplasmic positivity in Grades 1 and 2 HCC patients showed a significantly higher expression of mitochondrial APE1, which accounted for lower levels of mtDNA damage observed in the tumor tissue with respect to the distal area. In the contrast, the cytoplasmic positivity in Grade 3 was not associated with APE1's mitochondrial accumulation even when accounting for the higher number of mtDNA lesions measured. Loss of APE1 expression negatively affected mitochondrial respiration, cell viability, and proliferation as well as levels of mtDNA damage. Remarkably, the phenotype was efficiently rescued in MTS-APE1 clone, where APE1 is present only within the mitochondrial matrix. CONCLUSIONS: Our study confirms the prominent role of the mitochondrial form of APE1 in the early stages of HCC development and the relevance of the non-nuclear fraction of APE1 in the disease progression. We have also confirmed overexpression of Mia40 and the role of the MIA pathway in the APE1 import process. Based on our data, inhibition of the APE1 transport by blocking the MIA pathway could represent a new therapeutic approach for reducing mitochondrial metabolism by preventing the efficient repair of mtDNA.

Controlling Nutritional Status score does not predict patients' overall survival or hepatocellular carcinoma recurrence after deceased donor liver transplantation.

BACKGROUND: The Controlling Nutritional Status (CONUT) score is a newly developed laboratory-derived immunonutritional score which has been validated as prognostic marker for survival and tumor recurrence in surgically treated patients with various tumor types, including hepatocellular carcinoma (HCC). The aim of the present study was to test the CONUT score performance in HCC patients treated with liver transplantation (LT). METHODS: A retrospective study on a bi-centers cohort of 280 HCC patients submitted to LT between 2006 and 2017 was performed. Indication to LT was limited to Milan criteria or UCSF criteria, defined by preoperative imaging. RESULTS: Median pre-LT CONUT score was 5 (interquartile range 3-7). Overall patients' survival at 1, 3, and 5 years was 84%, 76.6%, and 68.3%, respectively. Multivariate analysis showed that HCC recurrence (hazard ratio [HR] = 1.987, P = .012] and pre-LT neutrophil to lymphocyte ratio (NLR) (HR = 1.064, P = .003) were independent risk factors for reduced survival. Cumulative incidence of HCC recurrence at 1, 3, and 5 years was 5.1%, 11.5%, and 15.5%, respectively. Pre-LT platelet-to-lymphocyte ratio (PLR) (subdistribution hazard ratio [SHR] = 1.086, P = .044], tumor max diameter (SHR = 1.695, P < .001), and bilobar tumor distribution (SHR = 6.892, P = .006) were independent risk factors for tumor recurrence. The CONUT score did not show any prognostic value. CONCLUSIONS: The CONUT score did not predict poor survival or tumor recurrence in LT recipients.

Effect of pre-transplant sarcopenia on the estimation of standard liver volume in living-donor liver transplant candidates: risk factor for post-transplant small-for-size syndrome? A retrospective study.

The aim of the present study was to investigate whether LT candidates with sarcopenia are at an increased risk of receiving an inappropriate standard liver volume (SLV) estimation by standard body weight (BW)-derived SLV formula. Non-BW-SLV estimation formulas were tested in 262 LDLT donors and compared to a standard BW-SLV formula. The anthropometric parameters used were the thoracic width (TW-SLV) and thoracoabdominal circumference (TAC-SLV). Subsequently, sarcopenic and non-sarcopenic LDLT candidates (total, 217 patients) were compared in terms of estimated BW-SLV (routine method) and non-BW-SLV. In donors, TW-SLV showed comparable concordance with CT scan measured total liver volume as BW-SLV. The performance of TAC-SLV was low. In recipients, the prevalence of pre-LT sarcopenia was 30.4%. Sarcopenic patients were attributed a significantly lower BW-SLV than non-sarcopenic (sarcopenia vs no-sarcopenia, 1063.8 ml [1004.1-1118.4] vs. 1220.7 ml [1115.0-1306.6], P < 0.001), despite comparable TW-SLV, age, body height, and gender prevalence. As a result, sarcopenic patients received a graft with a statistically lower weight at organ procurement and developed more frequently a small-for-size syndrome (SFSS) according to the Dahm et al. (27.7% vs. 6.8%, P < 0.01) and Kyushu (28.7% vs. 9.2%, P < 0.01) definition. Therefore, In sarcopenic patients, BW-SLV formulas are affected by an high risk of SLV underestimation, thus exposing them to an increased risk of post-LT SFSS.

Chronological changes in skeletal muscle mass following living-donor liver transplantation: An analysis of the predictive factors for long-term post-transplant low muscularity.

AIM: Sarcopenia is associated with high morbidity and mortality before and after liver transplantation (LT). The aim of the study was to evaluate the chronological changes in skeletal muscle mass (SMM) at different time points post-LT and to identify the risk factors for long-term low SMM. METHODS: The skeletal muscle index at L3 level (L3-SMI) was used for muscle mass measurement, and the recommended cutoff values of the Japanese Society of Hepatology guidelines were used as criteria for defining low muscularity. RESULTS: Preoperative low SMM was recognized in 35.1% of cases. At 1 year after LDLT, 28.9% of patients showed low SMM, without any significant prevalence change in comparison with the preoperative phase (35.1%) or 1 month post-LT (30.7%). Post-LT intensive care unit (ICU) length of stay (OR 1.14, P = 0.03), biliary complications (OR 5.88, P = 0.02), pre-LT low SMM (OR 3.36, P = 0.05), and 1 month post-LT low SMM (OR 10.16, P < 0.01) were found to be independent risk factors for low SMM at 1 year post-LT in multivariate analysis. The development of de novo low SMM at 1 year post-LT was a negative prognostic factor for OS (HR 9.08, P = 0.001). CONCLUSIONS: Intensive care unit length of stay, biliary complications and preoperative and 1 month post-LT low SMM were predictive factors for long-term low SMM. Newly developed low SMM at 1 year post-LT was a prognostic factor for a poor patient survival.

Early post-liver transplant surgical morbidity in HIV-infected recipients: risk factor for overall survival? A nationwide retrospective study.

The aim of the study was to analyse the risk factors for early surgical complications requiring relaparotomy and the related impact on overall survival (OS) in HIV-infected patients submitted to liver transplantation. Thus a retrospective investigation was conducted on a nationwide multicentre cohort of 157 HIV patients submitted to liver transplantation in six Italian Transplant Units between 2004 and 2014. An early relaparotomy was performed in 24.8% of cases and the underlying clinical causes were biliary leak (8.2%), bleeding (8.2%), intestinal perforation (4.5%) and suspect of vascular complications(3.8%). No differences in terms of prevalence for either overall or cause-specific early relaparotomies were noted when compared with a non-HIV control group, matched for MELD, recipient age, HCV-RNA positivity and HBV prevalence. While in the control group an early relaparotomy appeared a negative prognostic factor, such impact on OS was not noted in HIV recipients. Nonetheless increasing number of relaparotomies were associated with decreased survival. In multivariate analysis, preoperative refractory ascites and Roux-en-Y choledochojejunostomy reconstruction were significant risk factors for early relaparotomy. To conclude, in HIV liver transplanted patients, an increasing number of early relaparotomies because of surgical complications does negatively affect the OS. Preoperative refractory ascites reflecting a severe portal hypertension and a difficult biliary tract reconstruction requiring a Roux-en-Y choledochojejunostomy are associated with increased risk of early relaparotomy.