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The aim of the surveys conducted by the Idiopathic Nephrotic Syndrome Working Group of the ESPN was to study the possible variability of treatment in Europe at different stages of the disease by means of questionnaires sent to members of the Working Group. Four surveys have been completed: treatment of the first flare, treatment of the first relapse and the issue of steroid dependency, use of rituximab, and the management of steroid-resistant patients. A uniform treatment of the first flare was applied in only three countries, and ten additional centers have adopted one of the three main protocols. Reported treatment of the first relapse was relatively uniform, whereas the use of additional immunosuppressants in steroid dependency was widely variable. Rituximab had already been used in hundreds of patients, although the formal evidence of efficiency in steroid dependency was relatively recent at the time of the survey. The definition of steroid resistance was variable in the European centers, but strikingly, the first-line treatment was uniform throughout the centers and included the combination of prednisone plus calcineurin antagonists. The variability in the approach of idiopathic nephrotic syndrome is unexpectedly large and affects treatment of the first flare, strategies in the case of steroid dependency, as well as the definitions of steroid resistance. What is Known: • Steroids and immunosuppressants are the universal treatment of idiopathic nephrotic syndrome. What is New: • The variability of treatments and strategy of treatment in European centers of pediatric nephrology

Background & Aims:The current organ allocation system for liver transplantation (LT) creates an imbalance between patients with and without hepatocellular carcinoma (HCC). We describe a model designed to re-establish allocation equity among patient groups using transplant benefit as the common endpoint. Methods:We enrolled consecutive adult patients entering the waiting list (WL group, n = 2697) and undergoing LT (LT group, n = 1702) during the period 2004‐2009 in the North Italy Transplant program area. Independent multivariable regressions (WL and LT models) were created for patients without HCC and for those with stage T2 HCC. Monte Carlo simulation was used to create distributions of transplant benefit, and covariates such as Model for End-stage Liver Disease (MELD) and alpha-fetoprotein (AFP) were combined in regression equations. These equations were then calibrated to create an ‘‘MELD equivalent’’ which matches HCC patients to non-HCC patients having the same numerical MELD score. Results:Median 5 year transplant benefit was 15.12 months (8.75‐25.35) for the non-HCC patients, and 28.18 months (15.11‐36.38) for the T2-HCC patients (p

Background Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates. Aim To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response. Methods Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 μ/kg/week plus RBV 8–10 mg/kg/day for 24 weeks. Those with ‘early virological response at week 24’ (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C). Results Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02–106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR. Conclusions Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with ≥2 log10 drop in HCV-RNA at week 24

Erratum to ‘‘A method for establishing allocation equity among patients with and without hepatocellular carcinoma on a common liver transplant waiting list’’ [J Hepatol 2013;60:290–297] Alessandro Vitale, Michael L. Volk, Tullia Maria De Feo, Patrizia Burra1,⇑, Anna Chiara Frigo, Rafael Ramirez Morales, Luciano De Carlis, Luca Belli, Michele Colledan, Stefano Fagiuoli, Giorgio Rossi, Enzo Andorno, Umberto Baccarani, Enrico Regalia, Marco Vivarelli, Matteo Donataccio, Umberto Cillo, on behalf of the Liver Transplantation North Italy Transplant program (NITp) working group

The safety of minimally invasive procedures during COVID pandemic remains hotly debated, especially in a country, like Italy, where minimally invasive techniques have progressively and pervasively entered clinical practice, in both the hepatobiliary and pancreatic community. A nationwide snapshot of the management of HPB minimally invasive surgery activity during COVID-19 pandemic is provided: a survey was developed and conducted within AICEP (Italian Association of HepatoBilioPancreatic Surgeons) with the final aim of conveying the experience, knowledge, and opinions into a unitary report enabling more efficient crisis management. Results from the survey (81 respondents) show that, in Italian hospitals, minimally invasive surgery maintains its role despite the COVID-19 pandemic, with the registered reduction of cases being proportional to the overall reduction of the HPB surgical activity. Respondents agree that the switch from minimally invasive to open technique can be considered as a valid option for cases with a high technical complexity. Several issues merit specific attention: screening for virus positivity should be universally performed; only expert surgical teams should operate on positive patients and specific technical measures to lower the biological risk of contamination during surgery must be followed. Future studies specifically designed to establish the true risks in minimally invasive surgery are suggested. Furthermore, a standard and univocal process of prioritization of patients from Regional Healthcare Systems is advisable. Electronic supplementary material The online version of this article (10.1007/s13304-020-00815-5) contains supplementary material, which is available to authorized users.

When the standard arterial reconstruction is not feasible during liver transplantation (LT), aorto-hepatic arterial reconstruction (AHAR) can be the only solution to save the graft. AHAR can be performed on the infrarenal (IR) or supraceliac (SC) tract of the aorta, but the possible effect on outcome of selecting SC versus IR reconstruction is still unclear. One hundred and twenty consecutive patients who underwent liver transplantation with AHAR in six European centres between January 2003 and December 2018 were retrospectively analysed to ascertain whether the incidence of hepatic artery thrombosis (HAT) was influenced by the type of AHAR (IR-AHAR vs. SC-AHAR). In 56/120 (46.6%) cases, an IR anastomosis was performed, always using an interposition arterial conduit. In the other 64/120 (53.4%) cases, an SC anastomosis was performed; an arterial conduit was used in 45/64 (70.3%) cases. Incidence of early (

Background: We aimed to assess the ability of comprehensive complication index (CCI) and Clavien-Dindo complication (CDC) scale to predict excessive length of hospital stay (e-LOS) in patients undergoing liver resection for hepatocellular carcinoma. Methods: Patients were identified from an Italian multi-institutional database and randomly selected to be included in either a derivation or validation set. Multivariate logistic regression models and ROC curve analysis including either CCI or CDC as predictors of e-LOS were fitted to compare predictive performance. E-LOS was defined as a LOS longer than the 75th percentile among patients with at least one complication. Results: A total of 2669 patients were analyzed (1345 for derivation and 1324 for validation). The odds ratio (OR) was 5.590 (95%CI 4.201, 7.438) for CCI and 5.507 (4.152, 7.304) for CDC. The AUC was 0.964 for CCI and 0.893 for CDC in the derivation set and 0.962 vs. 0.890 in the validation set, respectively. In patients with at least two complications, the OR was 2.793 (1.896, 4.115) for CCI and 2.439 (1.666, 3.570) for CDC with an AUC of 0.850 and 0.673, respectively in the derivation cohort. The AUC was 0.806 for CCI and 0.658 for CDC in the validation set. Conclusions: When reporting postoperative morbidity in liver surgery, CCI is a preferable scale.

Introduction: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been described to treat hepatocellular carcinoma (HCC) but burdened, in its pioneering phase, by high morbidity and mortality. With the advent of minimally invasive (MI) techniques in liver surgery, surgical complications, including posthepatectomy liver failure (PHLF), have been dramatically reduced. The primary endpoint of this study was to compare the short-term outcomes of MI-versus open-ALPPS for HCC, with specific focus on PHLF. Methods: Data of patients submitted to ALPPS for HCC between 2012 and 2020 were identified from the ALPPS Italian Registry. Patients receiving an MI Stage 1 (MI-ALPPS) constituted the study group, whereas the patients who received an open Stage 1 (open-ALPPS) constituted the control group. Results: Sixty-six patients were enrolled from 12 Italian centers. Stage 1 of ALPPS was performed in 14 patients using an MI approach (21.2%). MI-ALPPS patients were discharged after Stage 1 at a significantly higher rate compared with open-ALPPS (78.6% versus 9.6%, P < .001). After Stage 2, major morbidity after MI-ALPPS was 8.3% compared with 28.6% reported after open-ALPPS. Mortality was nil after MI-ALPPS. Length of hospital stay was significantly shorter in MI-ALPPS (12 days versus 22 days, P < .001). Univariate logistic regression analysis (Firth method) found that both MI-ALPPS (odds ratio [OR] = 0.05, P = .040) and partial parenchymal transection (OR = 0.04, P = .027) were protective against PHLF. Conclusion: This national multicenter study showed that a less invasive approach to ALPPS first stage was associated with a lower overall risk of PHLF.

Key Points Question Can the individual risk estimation for early allograft failure (EAF) be improved in view of liver retransplant? Findings In this multicenter cohort study investigating the association between donor-recipient factors and EAF, a novel Early Allograft Failure Simplified Estimation (EASE) score was developed. The score includes Model for End-stage Liver Disease score, transfused packed red blood cells, and hepatic vessel early thrombosis as well as transaminases, platelet, and bilirubin kinetics as variables on day 10 after transplant. The EASE score outperformed previous model scores, estimating EAF risk with 87% accuracy on day 90 after transplant; EASE was developed on a multicenter Italian database (1609 recipients) and validated on an external UK database (538 recipients). Meaning In this study, the EASE score rated the EAF risk (0%-100%) and identified cases at unsustainable risk to be listed for retransplant., Importance Expansion of donor acceptance criteria for liver transplant increased the risk for early allograft failure (EAF), and although EAF prediction is pivotal to optimize transplant outcomes, there is no consensus on specific EAF indicators or timing to evaluate EAF. Recently, the Liver Graft Assessment Following Transplantation (L-GrAFT) algorithm, based on aspartate transaminase, bilirubin, platelet, and international normalized ratio kinetics, was developed from a single-center database gathered from 2002 to 2015. Objective To develop and validate a simplified comprehensive model estimating at day 10 after liver transplant the EAF risk at day 90 (the Early Allograft Failure Simplified Estimation [EASE] score) and, secondarily, to identify early those patients with unsustainable EAF risk who are suitable for retransplant. Design, Setting, and Participants This multicenter cohort study was designed to develop a score capturing a continuum from normal graft function to nonfunction after transplant. Both parenchymal and vascular factors, which provide an indication to list for retransplant, were included among the EAF determinants. The L-GrAFT kinetic approach was adopted and modified with fewer data entries and novel variables. The population included 1609 patients in Italy for the derivation set and 538 patients in the UK for the validation set; all were patients who underwent transplant in 2016 and 2017. Main Outcomes and Measures Early allograft failure was defined as graft failure (codified by retransplant or death) for any reason within 90 days after transplant. Results At day 90 after transplant, the incidence of EAF was 110 of 1609 patients (6.8%) in the derivation set and 41 of 538 patients (7.6%) in the external validation set. Median (interquartile range) ages were 57 (51-62) years in the derivation data set and 56 (49-62) years in the validation data set. The EASE score was developed through 17 entries derived from 8 variables, including the Model for End-stage Liver Disease score, blood transfusion, early thrombosis of hepatic vessels, and kinetic parameters of transaminases, platelet count, and bilirubin. Donor parameters (age, donation after cardiac death, and machine perfusion) were not associated with EAF risk. Results were adjusted for transplant center volume. In receiver operating characteristic curve analyses, the EASE score outperformed L-GrAFT, Model for Early Allograft Function, Early Allograft Dysfunction, Eurotransplant Donor Risk Index, donor age × Model for End-stage Liver Disease, and Donor Risk Index scores, estimating day 90 EAF in 87% (95% CI, 83%-91%) of cases in both the derivation data set and the internal validation data set. Patients could be stratified in 5 classes, with those in the highest class exhibiting unsustainable EAF risk. Conclusions and Relevance This study found that the developed EASE score reliably estimated EAF risk. Knowledge of contributing factors may help clinicians to mitigate risk factors and guide them through the challenging clinical decision to allocate patients to early liver retransplant. The EASE score may be used in translational research across transplant centers., This multicenter cohort study develops and validates a simplified comprehensive model that estimates on day 10 after liver transplant the risk of early allograft failure with 90 days among patients who undergo liver transplant.

To implement split liver transplantation (SLT) a mandatory-split policy has been adopted in Italy since August 2015: donors aged 18-50years at standard risk are offered for SLT, resulting in a left-lateral segment (LLS) graft for children and an extended-right graft (ERG) for adults. We aim to analyze the impact of the new mandatory-split policy on liver transplantation (LT)-waiting list and SLT outcomes, compared to old allocation policy. Between August 2015 and December 2016 out of 413 potentially “splittable” donors, 252 (61%) were proposed for SLT, of whom 53 (21%) donors were accepted for SLT whereas 101 (40.1%) were excluded because of donor characteristics and 98 (38.9%) for absence of suitable pediatric recipients. The SLT rate augmented from 6% to 8.4%. Children undergoing SLT increased from 49.3% to 65.8% (P=.009) and the pediatric LT-waiting list time dropped (229 [10-2121] vs 80 [12-2503] days [P=.045]). The pediatric (4.5% vs 2.5% [P=.398]) and adult (9.7% to 5.2% [P20kg (HR=5.113, P=.048) in LLS, and ischemic time >8hours (HR=2.475, P=.048) in ERG were identified as predictors of graft failure. A national mandatory-split policy maximizes the SLT donor resources, whose selection criteria can be safely expanded, providing favorable impact on the pediatric LT-waiting list and priority for adult sick LT candidates.

Background Laparoscopic resection of posterosuperior (PS) segments of the liver is hindered by limited visualization and curvilinear resection planes. The aim of this study was to compare outcomes after open and laparoscopic liver resections of PS segments. Methods Patients who underwent minor open liver resection (OLR) and laparoscopic liver resection (LLR) between 2006 and 2014 were identified from the institutional databases of seven tertiary referral European hepatobiliary surgical units. Propensity score-matched analysis was used to match groups for known confounders. Perioperative outcomes including complications were assessed using the Dindo–Clavien classification, and the comprehensive complication index was calculated. Survival was analysed with the Kaplan–Meier method. Results Some 170 patients underwent OLR and 148 had LLR. After propensity score-matched analysis, 86 patients remained in both groups. Overall postoperative complication rates were significantly higher after OLR compared with LLR: 28 versus 14 per cent respectively (P = 0·039). The mean(s.d.) comprehensive complication index was higher in the OLR group, although the difference was not statistically significant (26·7(16·6) versus 18·3(8·0) in the LLR group; P = 0·108). The mean(s.d.) duration of required analgesia and the median (range) duration of postoperative hospital stay were significantly shorter in the LLR group: 3·0(1·1) days versus 1·6(0·8) days in the OLR group (P < 0·001), and 6 (3–44) versus 4 (1–11) days (P < 0·001), respectively. The 3-year recurrence-free survival rates for patients with hepatocellular carcinoma (37 per cent for OLRversus 30 per cent for LLR; P = 0·534) and those with colorectal liver metastases (36 versus 36 per cent respectively; P = 0·440) were not significantly different between the groups. Conclusion LLR of tumours in PS segments is feasible in selected patients. LLR is associated with fewer complications and does not compromise survival compared with OLR.

Background Although laparoscopic liver resection has become the standard for minor resections, evidence is lacking for more complex resections such as the right posterior sectionectomy (RPS). We aimed to compare surgical outcomes between laparoscopic (LRPS) and open right posterior sectionectomy (ORPS). Methods An international multicenter retrospective study comparing patients undergoing LRPS or ORPS (January 2007—December 2018) was performed. Patients were matched based on propensity scores in a 1:1 ratio. Primary endpoint was major complication rate defined as Accordion ≥ 3 grade. Secondary endpoints included blood loss, length of hospital stay (LOS) and resection status. A sensitivity analysis was done excluding the first 10 LRPS patients of each center to correct for the learning curve. Additionally, possible risk factors were explored for operative time, blood loss and LOS. Results Overall, 399 patients were included from 9 centers from 6 European countries of which 150 LRPS could be matched to 150 ORPS. LRPS was associated with a shorter operative time [235 (195–285) vs. 247 min (195–315) p = 0.004], less blood loss [260 (188–400) vs. 400 mL (280–550) p = 0.009] and a shorter LOS [5 (4–7) vs. 8 days (6–10), p = 0.002]. Major complication rate [n = 8 (5.3%) vs. n = 9 (6.0%) p = 1.00] and R0 resection rate [144 (96.0%) vs. 141 (94.0%), p = 0.607] did not differ between LRPS and ORPS, respectively. The sensitivity analysis showed similar findings in the previous mentioned outcomes. In multivariable regression analysis blood loss was significantly associated with the open approach, higher ASA classification and malignancy as diagnosis. For LOS this was the open approach and a malignancy. Conclusion This international multicenter propensity score-matched study showed an advantage in favor of LRPS in selected patients as compared to ORPS in terms of operative time, blood loss and LOS without differences in major complications and R0 resection rate.

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.

Although octogenarian livers have been transplanted successfully in elective settings, their safety in the case of fulminant hepatic failure has not yet been reported. From November 1998 to June 2003, we transplanted 3 livers from 80-, 82-, and 86-year-old donors. The donors were hemodynamically stable with an intensive care unit stay ranging from 24-48 hours. Cold ischemia time was from 260 minutes to 526 minutes. Mild macrosteatosis was present in 2 donors. Donor and recipient characteristics as well as posttransplantation evolution were evaluated. Two cases had uneventful courses and all recipients are well at 39, 21, and 5 months, respectively. The second recipient underwent retransplantation at 15 days due to technical complications. Livers from octogenarian donors may be safely used in an emergency to save patients. Age does not represent a limit for individually assessed and highly selected donors.

There are few reports of combined heart and liver transplantation (CHLT) for familial amyloidotic polyneuropathy (FAP). The technique for the operation remains to be defined. Four CHLTs were performed for amyloidogenic transthyretin-related (variant Glu89Gln-ATTR Glu89Gln) cardiomyopathy in our center. Patients 1 and 4 had no serious involvement of other organs, whereas patients 2 and 3 had evident peripheral neuropathy and gastrointestinal motility alterations. Patient 3 also had high-grade orthostatic hypotension. All four patients underwent cardiac and sequential hepatic transplantation with organs procured from the same donor. Venovenous bypass was used in patients 1 and 4 who experienced uncomplicated procedures. The amyloidotic liver of patient 4 was successfully utilized for a domino procedure to treat a patient with hepatocellular carcinoma on cirrhosis. The cardiac performance of patients 1 and 4 remains normal; there has been no progression of amyloidosis at 42 and 1 months after transplantation. Patient 2 had no intraoperative complications but experienced postoperative bleeding, renal failure, sepsis, and heart failure, and finally died of multiorgan failure 2 months after transplant. In patient 3, right hemicolectomy was required intraoperatively due to intestinal ischemia, without significant hemodynamic instability, while extracardiac symptoms of amyloidosis gradually worsened postoperatively. In conclusion, CHLT for ATTR Glu89Gln may be performed even in patients with advanced disease. However, the most compromised patients are more likely to display intraoperative risks, postoperative complications, and worsening of extracardiac, extrahepatic symptoms.

Objective: Major hepatectomy in cirrhotic patients still represents a great challenge for liver surgeons. Hence, the aim in the present study is to investigate the clinical impact of major hepatectomy and to assess whether the surgical approach influences the outcome of cirrhotic patients. Methods: Multicenter retrospective study including cirrhotic patients undergoing major laparoscopic (mjLLR) and open liver resection (mjOLR) in 14 Western liver centers was performed (2009–2020). Clinical, demographic, and perioperative data were compared using propensity score matching (PSM). Long-term outcome after resection for hepatocellular carcinoma was analyzed. Results: Overall, 352 patients were included; 108 after mjLLR and 244 after mjOLR. After PSM, 88 patients were matched in each group. In the mjLLR group, compared to mjOLR, less blood loss (P=.042), lower overall and severe complication (P&nbsp

BACKGROUND: We compared, through the European Liver Transplant Registry, long-term liver transplantation outcomes with prolonged-release tacrolimus (PR-T) versus immediate-release tacrolimus (IR-T)-based immunosuppression. This retrospective analysis comprises up to 8-year data collected between 2008 and 2016, in an extension of our previously published study. METHODS: Patients with

Rationale & Objective: Primary membranoproliferative glomerulonephritis (MPGN) is a rare glomerulopathy characterized by complement dysregulation. MPGN progresses rapidly to kidney failure when it is associated with nephrotic syndrome. We assessed the effects of C5 convertase blockade in patients with MPGN and terminal complement activation. Study Design: Prospective off-on-off-on open-label clinical trial. Setting & Participants: Consenting patients with immune complex–mediated MPGN (n = 6) or C3 glomerulonephritis (n = 4) with sC5b-9 (serum complement membrane attack complex) plasma levels > 1,000 ng/mL and 24-hour proteinuria with protein excretion > 3.5 g identified from the Italian Registry of MPGN and followed up at the Istituto di Ricerche Farmacologiche Mario Negri IRCCS (Bergamo, Italy) between March 4, 2014, and January 7, 2015. Intervention: Anti-C5 monoclonal antibody eculizumab administered during 2 sequential 48-week treatment periods separated by one 12-week washout period. Outcomes: Primary outcome was change in 24-hour proteinuria (median of 3 consecutive measurements) at 24 and 48 weeks. Results: Median proteinuria decreased from protein excretion of 6.03 (interquartile range [IQR], 4.8-12.4) g/d at baseline to 3.74 (IQR, 3.2-4.4) g/d at 24 weeks (P = 0.01) and to 5.06 (IQR, 3.1-5.8) g/d (P = 0.006) at 48 weeks of treatment, recovered toward baseline during the washout period, and did not significantly decrease thereafter. Hypoalbuminemia, dyslipidemia, and glomerular sieving function improved during the first treatment period. 3 patients achieved partial remission of nephrotic syndrome and all had undetectable C3 nephritic factors before treatment. Mean measured glomerular filtration rate was 69.7 ± 35.2 versus 87.4 ± 55.1 and 75.8 ± 42.7 versus 76.6 ± 44.1 mL/min/1.73 m2 at the start versus the end of the first and second treatment periods, respectively, among all 10 study participants. Unlike C3, sC5b-9 plasma levels normalized during both treatment periods and recovered toward baseline during the washout in all patients. Limitations: Single-arm design, small sample size. Conclusions: Eculizumab blunted terminal complement activation in all patients with immune complex–mediated MPGN or C3 glomerulonephritis and nephrotic syndrome, but persistently reduced proteinuria in just a subgroup. Trial Registration: Registered in the EU Clinical Trials Register with study no. 2013-003826-10.

Annals of surgical oncology (2020). doi:10.1245/s10434-019-08192-z, Published by Springer, Berlin [u.a.]

Summary Background Indications for liver transplantation for hepatocellular carcinoma are evolving and so-called expanded criteria remain debated. Locoregional therapies are able to downstage hepatocellular carcinoma from beyond to within the Milan criteria. We aimed to investigate the efficacy of liver transplantation after successful hepatocellular carcinoma downstaging. Methods We did an open-label, multicentre, randomised, controlled trial designed in two phases, 2b and 3, at nine Italian tertiary care and transplantation centres. Patients aged 18–65 years with hepatocellular carcinoma beyond the Milan criteria, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7) were recruited and underwent tumour downstaging with locoregional, surgical, or systemic therapies according to multidisciplinary decision. After an observation period of 3 months, during which sorafenib was allowed, patients with partial or complete responses according to modified Response Evaluation Criteria in Solid Tumors were randomly assigned (1:1) by an interactive web-response system to liver transplantation or non-transplantation therapies (control group). A block randomisation (block size of 2), stratified by centre and compliance to sorafenib treatment, was applied. Liver transplantation was done with whole or split organs procured from brain-dead donors. The control group received sequences of locoregional and systemic treatment at the time of demonstrated tumour progression. The primary outcomes were 5-year tumour event-free survival for phase 2b and overall survival for phase 3. Analyses were by intention to treat. Organ allocation policy changed during the course of the study and restricted patient accrual to 4 years. This trial is registered with ClinicalTrials.gov , NCT01387503 . Findings Between March 1, 2011, and March 31, 2015, 74 patients were enrolled. Median duration of downstaging was 6 months (IQR 4–11). 29 patients dropped out before randomisation and 45 were randomly assigned: 23 to the transplantation group versus 22 to the control group. At data cutoff on July 31, 2019, median follow-up was 71 months (IQR 60–85). 5-year tumour event-free survival was 76·8% (95% CI 60·8–96·9) in the transplantation group versus 18·3% (7·1–47·0) in the control group (hazard ratio [HR] 0·20, 95% CI 0·07–0·57; p=0·003). 5-year overall survival was 77·5% (95% CI 61·9–97·1) in the transplantation group versus 31·2% (16·6–58·5) in the control group (HR 0·32, 95% CI 0·11–0·92; p=0·035). The most common registered grade 3–4 serious adverse events were hepatitis C virus recurrence (three [13%] of 23 patients) and acute transplant rejection (two [9%]) in the transplantation group, and post-embolisation syndrome (two [9%] of 22 patients) in the control group. Treatment-related deaths occurred in four patients: two (8%) of 23 patients in the transplantation group (myocardial infarction and multi-organ failure) versus two (9%) of 22 patients in the control group (liver decompensation). Interpretation Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumour event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumour response could contribute to the expansion of hepatocellular carcinoma transplantation criteria. Funding Italian Ministry of Health.

Objective: To assess the risk factors associated with R1 resection in patients undergoing OLS and LLS for CRLMs. Background: The clinical impact of R1 resection in liver surgery for CRLMs has been continuously appraised, but R1 risk factors have not been clearly defined yet. Methods: A cohort study of patients who underwent OLS and LLS for CRLMs in 9 European high-volume referral centers was performed. A multivariate analysis and the receiver operating characteristic curves were used to investigate the risk factors for R1 resection. A model predicting the likelihood of R1 resection was developed. Results: Overall, 3387 consecutive liver resections for CRLMs were included. OLS was performed in 1792 cases whereas LLS in 1595; the R1 resection rate was 14% and 14.2%, respectively. The risk factors for R1 resection were: the type of resection (nonanatomic and anatomic/nonanatomic), the number of nodules and the size of tumor. In the LLS group only, blood loss was a risk factor, whereas the Pringle maneuver had a protective effect. The predictive size of tumor for R1 resection was >45 mm in OLS and >30 mm in LLS, > 2 lesions was significative in both groups and blood loss >350 cc in LLS. The model was able to predict R1 resection in OLS (area under curve 0.712; 95% confidence interval 0.665 – 0.739) and in LLS (area under curve 0.724; 95% confidence interval 0.671 – 0.745). Conclusions: The study describes the risk factors for R1 resection after liver surgery for CRLMs, which may be used to plan better the perioperative strategies to reduce the incidence of R1 resection during OLS and LLS.

Importance: Textbook outcome (TO) is a composite measure that captures the most desirable surgical outcomes as a single indicator, yet to date TO has not been defined and assessed in the field of laparoscopic liver resection (LLR) and open liver resection (OLR). Objective: To obtain international agreement on the definition of TO in liver surgery (TOLS) and to assess the incidence of TO in LLR and OLR in a large international multicenter database using a propensity-score matched analysis. Design, Setting, and Participants: Patients undergoing LLR or OLR for all liver diseases between January 2011 and October 2019 were analyzed using a large international multicenter liver surgical database. An international survey was conducted among all members of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA) and International Hepato-Pancreato-Biliary Association (IHPBA) to reach agreement on the definition of TOLS. The rate of TOLS was assessed for LLR and OLR before and after propensity-score matching. Factors associated with achieving TOLS were investigated. Main Outcomes and Measures: Textbook outcome, with TOLS defined as the absence of intraoperative incidents of grade 2 or higher, postoperative bile leak grade B or C, severe postoperative complications, readmission within 30 days after discharge, in-hospital mortality, and the presence of R0 resection margin. Results: A total of 8188 patients (4559 LLR; median age, 65 years [interquartile range, 55-73 years]; 2529 were male [55.8%] and 3629 OLR; median age, 64 years [interquartile range, 56-71 years]; 2204 were male [60.7%]) were included in the analysis of whom 69.1% achieved TOLS; 74.8% for LLR and 61.9% for OLR (P 10 cm = OR, 0.550 [95% CI, 0.366-0.826]; P =.004) were associated with a worse TOLS rate. Conclusions and Relevance: In this multicenter study, TOLS was found to be a useful tool for assessing patient-level hospital performance and may have utility in optimizing patient outcomes after LLR and OLR..

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.

Aim We aimed to analyze 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. Methods We performed a retrospective study on a nationwide multicenter cohort of 157 HIV-infected patients submitted to liver transplantation in 6 Italian transplant units between 2004 to 2014. Results The median preoperative model for end-stage liver disease score was 18 (interquartile range 12-26.5). An early relaparotomy was performed in 24.8% of patients, and the underlying clinical causes were biliary leak (8.2%), bleeding (8.2%), intestinal perforation (4.5%), and suspected vascular complications (3.8%). The OS at 1, 3, and 5 years was 74.3%, 68.0%, and 60.0%, respectively, and an early relaparotomy was not a prognostic factor itself, but an increasing number of relaparotomies was associated with decreased survival (hazard ratio = 1.40, 95% confidence interval [CI] 1.07-1.81, P = .01). In the multivariate analysis, preoperative refractory ascites (odds ratio 3.32, 95% CI 1.18-6.47, P = .02) and Roux-en-Y choledochojejunostomy reconstruction (odds ratio 12.712, 95% CI 2.47-65.38, P ≤ .01) were identified as significant risk factors for early relaparotomy. Conclusions In HIV-infected liver transplant recipients, an increasing number of early relaparotomies due to surgical complications did negatively affect the OS. Preoperative refractory ascites reflecting a severe portal hypertension and a difficult biliary tract reconstruction requiring a Roux-en-Y choledochojejunostomy were associated with an increased risk of early relaparotomy.

Background Bloodstream infections (BSI) due to Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) have become an important problem and they are associated with a high mortality rate. The aim of our study was to evaluate the clinical and epidemiological characteristics of KPC-Kp from BSIs. Methods In this retrospective cohort study, conducted in a tertiary referral center in Italy, 112 patients with KPC-Kp BSIs diagnosed between February 2011 and December 2015 were identified. We evaluated the mortality at 30 days from the first positive blood culture. Survivor and non-survivor subgroups were compared to identify predictors of mortality. Results The overall crude mortality was 35%. APACHE II score ≥ 15, septic shock at BSI onset, immunosuppressive therapy during the 30 days before the BSI onset, and the lack of a combination therapy with at least 2 active drugs emerged as independent predictors of mortality. Excluding patients with inadequate therapy, the mortality decreased to 25% while an APACHE II score ≥ 15 and the presence of septic shock remained independently associated with a negative outcome. Two different pulsotypes were identified: pulsotype A belonged to ST512 and carried KPC-3 and pulsotype B belonged to ST307 and carried KPC-2. Conclusions This study confirmed a high mortality rate of KPC-Kp BSIs. The outcome is heavily influenced by the patient’s clinical conditions. A therapeutic approach including a combination with at least two active drugs in vitro can improve the prognosis, unless patients received an appropriate therapy.

Introduction Resection of perihilar cholangiocarcinoma (PHC) entails high-risk surgery with postoperative mortality reported up to 18%, even in specialized centers. The aim of this study was to compare outcomes of PHC patients who underwent associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) to patients who underwent resection without ALPPS. Methods All patients who underwent ALPPS for PHC were identified from the international ALPPS registry and matched controls were selected from a standard resection cohort from two centers based on future remnant liver size. Outcomes included morbidity, mortality, and overall survival. Results ALPPS for PHC was associated with 48% (14/29) 90-day mortality. 90-day mortality was 13% in 257 patients who underwent major liver resection for PHC without ALPPS. The 29 ALPPS patients were matched to 29 patients resected without ALPPS, with similar future liver remnant volume (P = 0.480). Mortality in the matched control group was 24% (P = 0.100) and median OS was 27 months, comparted to 6 months after ALPPS (P = 0.064). Discussion Outcomes of ALPPS for PHC appear inferior compared to standard extended resections in high-risk patients. Therefore, portal vein embolization should remain the preferred method to increase future remnant liver volume in patients with PHC. ALPPS is not recommended for PHC.

Background: Posthepatectomy liver failure is one of the most feared complications in extended hepatic resections. In 2012, a novel two-stage liver resection was developed, able to induce rapid and extensive hypertrophy by portal vein ligation and in situ liver splitting - Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS). The technique became more widely employed but its use remained controversial due to reporting of high complication and mortality rates. Method: A national audit was performed to gather information about the safety of the procedure and to better understand the complications. The audit was offered to all high-volume hepatobiliary centers in Italy. Results: Of all Italian centers approached in January 2012, 12 centers with experience in ALPPS enrolled and participated in collection of data. Fifty patients underwent ALPPS between 2012 and 2014. In 48/50 patients completion of hepatectomy was performed successfully. Major morbidity occurred in 54% with a 20% 90-day mortality. Uni- and multivariate analysis showed that ALPPS for cholangiocarcinoma and a peak of bilirubin over 5 mg/dl between stages was associated with increase of 90 day mortality and worse survival. Discussion: It is proposed that a moratorium be introduced for classic ALPPS in cholangiocarcinoma and to abort ALPPS in patients who develop an interstage increase in bilirubin, due to the high risk of liver failure and mortality.

BACKGROUND AND AIMS: The outcome of hepatic resection in cirrhotic patients has improved remarkably in recent years with improved surgical techniques and perioperative care; however, the role of portal hypertension is still uncertain. The aim of this study was to elucidate surgical outcomes of hepatectomy in patients with portal hypertension. METHODS: Data from 241 cirrhotic patients who underwent resection for hepatocellular carcinoma were retrospectively collected and analyzed: patients were divided into 2 groups according to the presence (n = 89) or absence (n = 152) of portal hypertension at the time of surgery. To overcome biases owing to the different distribution of covariates throughout the 2 groups, a one-to-one match was created using propensity score analysis: after match, intraoperative, and postoperative course and survival rates were analyzed. RESULTS: Patients with portal hypertension experienced worse preoperative liver function (mean model for end-stage liver disease [MELD] score, 9.5 +/- 7.8 vs. 8.4 +/- 1.3; P = 0.001) and survival rates (P = 0.008) in comparison to those without portal hypertension: after one-to-one matching, patients with (n = 78) and without portal hypertension (n = 78) had the same preoperative characteristics and showed the same intraoperative course, postoperative occurrence of liver failure, morbidity, length of in-hospital stay and survival rates (P = ns in all cases). The only predictors of postoperative liver failure were MELD score (P = 0.001) and extent of hepatectomy (P = 0.005). CONCLUSIONS: Faced with the same MELD score and extent of hepatectomy planning, presence of portal hypertension should not be considered as a contraindication for hepatic resection in cirrhotic patients.

Conventional criteria for liver transplantation for patients with hepatocellular carcinoma are single HCC

Advanced donor age is a risk factor for poor outcome in liver transplantation (LT). We reviewed 553 consecutive transplants according to donor age categories [group 1 (n = 173): or =80 years]. Clinical parameters were comparable between groups. Group 5 had the highest proportion of pretransplant liver biopsy (85%), with only 1 graft showing macrovesicular steatosis > 30%, and the lowest ischemia time. Five-year graft survival was significantly higher in group 1 (75%) versus groups 3 (60%) and 4 (62%; P = 0.01 and P = 0.001, respectively) and in group 5 (81%) versus groups 3 and 4 (P = 0.04 and P = 0.01, respectively). Donor age of 60-79 years, recipient hepatitis C virus-positive status, Model for End-Stage Liver Disease score > or = 25, and emergency LT were predictors of poor survival. In hepatitis C virus-positive patients, 5-year graft survival was 72% in group 1, 85% in group 2, 52% in group 3, 65% in group 4, and 71% in group 5 (group 1 versus group 3, P = 0.04; group 2 versus group 3, P = 0.03). In conclusion, older donor grafts managed with routine graft biopsy and short ischemia time may work effectively, regardless of the severity of the recipient's liver disease.

Purpose We sought to evaluate liver function recovery after isolated intestinal transplantation in adults with irreversible intestinal failure. Patients and Methods Over a 5-year period, we transplanted 34 adult patients, 25 of whom received an isolated intestinal graft, 4 a multivisceral graft without a liver, and 5, a multivisceral graft with a liver. Among the group of patients transplanted with the isolated graft we selected 14 recipients with pretransplant liver dysfunction, namely, a serum bilirubin >2 mg/dL (normal value: 1.2) and/or transaminases >100 IU/mL (NV, 37/40). Other inclusion criteria were total parenteral nutrition, period > 3 months, no diagnosis of portal hypertension or cirrhosis. Two patients had biopsy-proven liver fibrosis. Results At discharge, all patients recovered liver function to normal values: mean bilirubin blood level was 0.9 ± 0.96 mg/dL (range: 0.3–1.6) and mean transaminases were 26 ± 9 and 31 ± 18 IU/mL (range: 10–44/27–65). After a mean follow-up of 2 years, only one patient has an elevated alanine aminotransferase level without clinical signs of liver disease. Type of pretransplant liver disease did not impact on survival rates. Conclusion In selected cases, an isolated intestinal or a multivisceral graft without a liver can represent a “liver salvage therapy” for an early failing liver in patients with irreversible intestinal failure. Pretransplant liver disease is not a negative prognostic factor.

To confirm recent observations about the relationship between immunosuppression and the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT), we retrospectively analyzed 70 consecutive HCC patients who underwent LT and received cyclosporine (CsA)-based immunosuppression. CsA trough blood levels, measured with the same technique (fluorescence polarization immunoassay), were analyzed at different time points after transplantation. The exposure to the drug was calculated with the trapezoidal rule in each patient. CsA was associated with steroids in 26 patients and steroids and azathioprine in 44 patients. HCC recurred in 7 patients (10.0%). Different immunosuppressive schedules (CsA and steroids vs. CsA, steroids, and azathioprine) or the cumulative dosage of steroids and azathioprine did not influence HCC recurrence that was associated instead with CsA exposure (278.3 +/- 86.4 ng/mL in recurrent vs. 169.9 +/- 33.3 in tumor-free patients; P < 0.001); CsA exposure above 189.6 ng/mL was related to HCC recurrence at the receiver operating characteristic analysis (ROC). The relationship between CsA exposure; various clinical (sex, age, viral- vs. non-viral-related cirrhosis, preoperative vs. incidental diagnosis of HCC, alpha-fetoprotein [AFP] blood level), pathologic (pathologic tumor staging [pT] stage, presence of Milan criteria), and histologic (grading, presence of microvascular tumor invasion) parameters; and tumor recurrence were assessed. AFP (P = 0.032), microvascular tumor invasion (P = 0.044), and CsA exposure (P < 0.001) influenced recurrence-free survival at the univariate analysis; CsA exposure was the only independent prognostic determinant at multivariate analysis (P < 0.001). High CsA exposure favors tumor recurrence; CsA blood levels should be kept to the effective minimum in HCC patients. In the presence of pathologic and histologic risk factors, specific immunosuppressive protocols should be considered.

Wilson's disease (WD) is an autosomal recessive disorder characterized by copper overload. In this disease, inadequate hepatic excretion leads to copper accumulation in the liver, brain, kidney, and cornea. Severe neurological symptoms can develop in patients with WD, often in the absence of relevant liver damage: it is unclear whether liver transplantation (LT) could reverse neurological symptoms, and at present LT is not recommended in this setting. We report a case of regression of neurological symptoms in a patient affected by WD with prevalent neurological involvement. A 19-year-old man with disabling neuropsychiatric symptoms from WD that included frontal ataxia, akinesia, dystonia, tremors, and behavioral disorders in the presence of preserved liver function (Model for End-Stage Liver Disease score=7; Child-Turcotte-Pugh score=A5) underwent LT in November 2009. At the time of LT, encephalic magnetic resonance imaging (MRI) indicated diffuse neurodegenerative alterations involving subtentorial and supratentorial structures; bilateral Kayser-Fleischer ring was present. Four years after LT, laboratory tests show normalized copper metabolism and excellent liver function test results. Encephalic MRI shows a substantial improvement of already-known signal alterations at nuclei thalamus and putamen, mesencephalon, and pons. Kayser-Fleischer ring disappeared from the right eye, but a little remnant is still visible in the left eye. At neurological examination, all of the previous symptoms and signs are no longer present and behavioral disorders are no longer present; psychosocial functions are completely restored. The present case provides some evidence that LT may be a valid therapeutic option for WD patients with marked neurological impairment, particularly in those no longer responsive to chelation therapy.

The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered 2 recurrences over the previous year and were in steroid-induced remission for 1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P

Introduction The shortage of donors has made it necessary to consider older subjects, those with mild or moderate steatosis, and those who are HBcAb- or hepatitis C virus (HCV)-positive as marginal donors. Materials and methods From April 1986 to January 2002, 690 orthotopic liver transplantations (OLTs) were performed in 603 patients. In this series we used 68 donors older than 70 years, 51 with steatosis (38 mild, 12 moderate, and 1 severe), 44 were HBcAb-positive and 6 were HCV-positive. Results Of 68 grafts from donors older than 70 years, 65 were used as a first OLT. These grafts showed 3 PNF, 11 arterial complications, 12 re-OLTs, and 14 deaths with graft survival of 72.3% and 61.34% at 1 and 3 years, respectively. All patients who received the other 3 grafts, which were used for re-OLT, died between postoperative day 21 and 720. Among the 51 grafts with steatosis, we observed 2 PNF of those within the mild steatosis group and graft survival rates of 76.8% and 70.9% at 1 and 3 years, respectively. Forty-four grafts from HBcAb-positive subjects were used in 18 HBsAg-negative and 26 HBsAg-positive recipients. Among the untreated patient group, 1 patient demonstrated hepatitis B virus (HBV) reinfection and 1 patient had de-novo HBV. No reinfection or de novo infections were observed in the 13 patients treated with immunoglobulin or in the 19 patients treated with lamivudine plus immunoglobulin, or in the only patient treated with lamivudine. Graft survival rates were 64.1% and 54.7% at 1 and 3 years, respectively. Among who received 6 patients transplants from HCV-positive donors, we observed 1 recurrence of chronic hepatitis, 1 re-OLT for hepatic vein stenosis, and 1 PNF. Conclusion Old donors, those with moderate steatosis, or those who are HBcAb- and HCV-positive can be safely used in selected recipients to reduce waiting list mortality.

AIM: To assess the safety and effectiveness of prophylaxis for venous thromboembolism (VTE) in a large population of patients with hepatocellular carcinoma (HCC) on cirrhosis. METHODS: Two hundred and twenty nine consecutive cirrhotic patients with HCC who underwent hepatic resection were retrospectively evaluated to assess whether there was any difference in the incidence of thrombotic or hemorrhagic complications between those who received and those who did not receive prophylaxis with low-molecular weight heparin. Differences and possible effects of the following parameters were investigated: age, sex, Child-Pugh and model for end-stage liver disease (MELD) score, platelet count, presence of esophageal varices, type of hepatic resection, duration of surgery, intraoperative transfusion of blood and fresh frozen plasma (FFP), body mass index, diabetes and previous cardiovascular disease. RESULTS: One hundred and fifty seven of 229 (68.5%) patients received antithromboembolic prophylaxis (group A) while the remaining 72 (31.5%) patients did not (group B). Patients in group B had higher Child-Pugh and MELD scores, lower platelet counts, a higher prevalence of esophageal varices and higher requirements for intraoperative transfusion of FFP. The incidence of VTE and postoperative hemorrhage was 0.63% and 3.18% in group A and 1.38% and 1.38% in group B, respectively; these differences were not significant. None of the variables analyzed including prophylaxis proved to be risk factors for VTE, and only the presence of esophageal varices was associated with an increased risk of bleeding. CONCLUSION: Prophylaxis is safe in cirrhotic patients without esophageal varices; the real need for prophylaxis should be better assessed.

INTRODUCTION: Surgical approaches to complicated benign intestinal failure are accepted worldwide, especially in the pediatric population. Intestinal transplant surgery is thought to rescue patients in whom complications of total parenteral nutrition (TPN) develop. OBJECTIVE: To report our experience with surgical intestinal rescue in an adult population with intestinal failure. PATIENTS AND METHODS: An intestinal rehabilitation program initiated at our institution included comprehensive medical rehabilitation, surgical bowel rescue, and transplantation. From 2000 to 2009, of 81 adult patients referred by our gastroenterologists for bowel rehabilitation, 42 (51,8%) underwent 43 transplantations (32 isolated intestinal grafts and 11 multivisceral grafts). Underlying diseases were primarily short-bowel syndrome, Gardner syndrome, and intestinal pseudo-obstruction. Thirty-nine patients (48,2%) underwent surgical rescue (40 cases) consisting of bowel resection, adhesiolysis, stricturoplasty, liver transplantation with portocaval hemitransposition (6 cases in 5 patients). Underlying diseases were primarily intestinal fistulas, stenosis, or perforations, short-bowel syndrome, cocoon syndrome, and complete portal thrombosis. RESULTS: After a mean (SD) follow-up of 1043 (1016) days, in the transplantation population, 21 patients (50%) are alive, with a 1-, 3-, 5-year patient survival of 76%, 59%, and 52%, respectively, and graft survival of 66%, 54%, and 48%, respectively. After 901 (404) days in the rescue population, 32 patients (82%) are alive (2 died, and 5 were lost to follow-up); in 75%, TPN 25% was discontinued, and are receiving oral feeding with TPN support. The 1- and 3-year survival rate was 100% and 83%, respectively. CONCLUSIONS: Deaths occurred primarily in the transplantation population. Intestinal surgical rescue, when possible, is optimal.

Background Tumor recurrence represents the main limitation of liver transplantation in patients with hepatocellular carcinoma (HCC) and can be favored by exposure to calcineurin inhibitors. Methods We investigated the effect of an immunosuppressant schedule that minimizes the exposure to calcineurin inhibitors on patients transplanted for HCC to ascertain whether this can reduce the tumor recurrence rate. For this purpose, we conducted a matched-cohort study: 31 patients with HCC transplanted between 2004 and 2007 who received sirolimus as part of their immunosuppression (group A) were compared with a control group of 31 patients (group B) transplanted in the same period who had the same prognostic factors but were given standard immunosuppression based on tacrolimus. Results Three-year recurrence-free survival was 86% in group A and 56% in group B (P=0.04). Although the prevalence of microvascular invasion G3-G4 grading and alpha-fetoprotein more than 200 ng/mL was identical in the two groups, exposure to tacrolimus was significantly higher in patients of group B (median, 8.54; range, 5.5-13.5) in comparison with those of group A (median, 4.6; range, 1.8-9.1) (P=0.0001). Conclusions By using sirolimus, exposure to calcineurin inhibitors can be minimized, reducing the risk of HCC recurrence.

Sirolimus (SRL) is a newer immunosuppressant whose possible benefits and side effects in comparison to calcineurin inhibitors (CNIs) still have to be addressed in the liver transplantation setting. We report the results of the use of SRL in 86 liver transplant recipients, 38 of whom received SRL as the main immunosuppressant in a CNI-sparing regimen. Indications for the use of SRL were: impaired renal function (n = 32), CNI neurotoxicity (n = 16), hepatocellular carcinoma (HCC) at high risk of recurrence (n = 21), recurrence of HCC (n = 6), de novo malignancies (n = 4), cholangiocarcinoma (n = 1), and the need to reinforce immunosuppression (n = 6). Among patients on SRL-based treatment, four episodes of acute rejection were observed, three of which occurred during the first postoperative month. Renal function significantly improved when sirolimus was introduced within the third postoperative month, while no change was observed when it was introduced later. Neurological symptoms resolved completely in 14/16 patients. The 3-year recurrence-free survival of patients with HCC on SRL was 84%. Sixty-two patients developed side effects that required drug withdrawal in seven cases. There was a reduced prevalence of hypertension and new-onset diabetes among patients under SRL. In conclusion, SRL was an effective immunosuppressant even when used in a CNI-sparing regimen. It was beneficial for patients with recently developed renal dysfunction or neurological disorders.

Malignant mixed tumors of the liver in adults are extremely rare. To our knowledge, only a few cases have been reported in the literature. Nested stromal-epithelial tumors (NSET) of the liver are characterized by non-hepatocytic, non-biliary tumors with nests of epithelial and spindle cells, an associated myofibroblastic stroma, as well as variable calcifications and ossifications. We report a case of NSET of the liver affecting a young woman and provide detailed histological and clinical follow-up data, adding an additional case of this extremely rare pathology to the literature.

Background Allograft rejection in intestinal transplantation occurs frequently, and bacterial, fungal, and viral infections related to strong immunosuppression regimens remain an important complication posttransplantation. Induction therapy has enabled improvement in graft and patient survival rates. Objectives In analyze the effects of daclizumab and alemtuzumab as induction therapies on inflections complications and incidence of acute cellular rejection (ACR) during the early posttransplantation period. Patients and Methods Between December 2000 and August 2009, we performed 43 intestinal transplantation procedures in 42 adult recipients (median [SD] age, 34.8 [9.5] years; male-female ratio, 22:20; isolated or multivisceral graft, 32/11), and compared findings during the first 30 days posttransplantation in 40 recipients. Patients were divided into 2 groups: 12 treated with daclizumab (Zenapax; Hoffman-La Roche Ltd, Basel, Switzerland): 8 isolated intestinal grafts and 4 multivisceral grafts) and 28 treated with alemtuzumab (Campath-1H: 22 isolated intestinal grafts and 6 multivisceral grafts). Maintenance immunosuppression was based on tacrolimus and steroids in the first group and low-dose tacrolimus in the second group. Results During the first month posttransplantation, 8 daclizumab recipients (66.6%) experienced 9 episodes of mild ACR, which were successfully treated with steroid therapy, and 8 patients (66.6%) developed a bacterial infection requiring treatment. Fourteen episodes of ACR occurred in 12 alemtuzumab recipients (42.8%): 11 mild, 1 mild to moderate, and 2 moderate; 16 patients (57.1%) required treatment for infections. Five-year patient cumulative survival was 66% in daclizumab recipients and 43% in alemtuzumab recipients. Five-year graft survivals was 66% in daclizumab recipients and 41% in alemtuzumab recipients. In both groups, P was not statistically significative. Conclusions The infection rate is considerably high with both protocols. Alemtuzumab seems to offer better immunosuppression against ACRs during the first month posttransplantation.

BACKGROUND: Split liver transplantation (SLT) for two adult recipients is still considered a challenging procedure, especially when subjected to model for end-stage liver disease (MELD)-based allocation criteria. METHODS: Twenty-two SLTs were performed in adult recipients in a European center operating within a MELD-oriented system. Thirteen right-sided grafts and nine left-sided grafts were used. Right-sided grafts included 11 extended right grafts and two full right grafts. Left-sided grafts included six left lateral segment grafts and three full left grafts. Ninety-three percent of donors were allocated based on MELD score. Median graft-to-recipient body weight ratio was 1.53 (range 1.07-2.11) with right-sided grafts and 0.81 (range 0.67-1.11) with left-sided grafts. Liver cirrhosis (46%) and metabolic/genetic disorders (56%) were the main indications for transplant in recipients of right and left grafts, respectively. RESULTS: Overall patient and graft survival were 90% and 86%. Patient survival was 84% in recipients of right grafts and 100% in recipients of left grafts. Graft survival was 84% and 89%, respectively. Vascular and biliary complications occurred in 14% and 4% of cases. Postoperative serum levels of total bilirubin were significantly higher in recipients of left-sided grafts versus right-sided grafts on postoperative days 7 and 14. Prothrombin activity was significantly lower in recipients of left-sided grafts versus right-sided grafts on postoperative days 3 and 7. CONCLUSIONS: SLT for two adult recipients can be successfully performed even using left lateral segments by assigning one graft according to MELD score, and with a more liberal allocation of the second graft.

According to transplant registries, grafts from elderly donors have lower survival rates. During 1999-2005, we evaluated the outcomes of 89 patients who received a liver from a donor aged > or = 60 years and managed with the low liver-damage strategy (LLDS), based on the preoperative donor liver biopsy and the shortest possible ischemia time (group D > or = 60-LLDS). Group D > or = 60-LLDS was compared with 198 matched recipients, whose grafts were not managed with this strategy (89 donors < 60 years, group D < 60-no-LLDS and 89 donors aged > or =60 years, group D > or = 60-no-LLDS). In the donors proposed from the age group of > or =60 years, the number of donors rejected decreased during the study period and the LLDS was found to be responsible for this in a significant manner (47% vs. 60%, respectively P < 0.01). Among the recipients transplanted, the clinical features (age, gender, viral infection, child and model for end-stage liver disease score) were comparable among groups, but group D > or = 60-LLDS had a lower mean ischemia time: 415 +/- 106 min vs. 465 +/- 111 (D < 60-no-LLDS), P < 0.05 and vs. 476 +/- 94 (D > or = 60-no-LLDS), P < 0.05. After a median follow-up of 3 years, the 1- and 3-year graft survival rates of group D > or = 60-LLDS (84% and 76%) were comparable with group D < 60-no-LLDS (89% and 76%) and were significantly higher than group D > or = 60-no-LLDS (71% and 54%), P < 0.005. In conclusion, the LLDS optimized the use of livers from elderly donors.

The presence of cirrhosis is the only risk factor that is advocated for recurrence of hepatocellular carcinoma (HCC) 2 years after hepatic resection compared with noncirrhotic control subjects; however, data for cohorts of exclusively patients with cirrhosis are lacking. This study was designed to assess risk factors and annual incidence of early (2 years) recurrence after resection of cirrhosis and to compare these findings with those of patients with cirrhosis enrolled in HCC surveillance programs (HCC occurrence). Data from 204 patients with cirrhosis resected for HCC and 150 surveilled for cirrhosis were retrospectively collected and compared using propensity score matching to overcome biases of nonrandomized study. Risk factors for early recurrence (incidence = 21.8%/year) were higher serum alpha-fetoprotein (AFP) levels, poorly differentiated tumor, and presence of microvascular invasion (P < 0.05). Risk factors for both late recurrence (18.4%/year) and HCC occurrence (3.3%/year) were male gender, older age, and higher serum transaminase levels; multiple primary tumors and higher AFP were additional risk factors for late recurrence and HCC occurrence respectively (P < 0.05). After propensity adjustment, resected patients with less than two risk factors for late recurrence showed an annual incidence of HCC (6.2%/year) similar to that of surveilled patients with > or =2 risk factors (5.8%/year; P = 0.898). Early and late recurrence of HCC for patients with cirrhosis after resection have distinct risk factors. Annual incidence of HCC 2 years or more after resection may be similar to that of general patients because the same risk factors are involved; assessment of these characteristics could be useful in tailoring clinical management.

Introduction: Induction therapy with daclizumab or alemtuzumab has been recently introduced for intestinal transplantation; however, the impact of such induction therapy on bacterial infections remains to be clarified. The purpose of this study was to evaluate the impact of induction therapy on the incidence of bacterial infections and long-term patient survival. Patients and methods: Over the past seven yr, we performed 39 intestinal (ITx) and multivisceral (MTVx) transplants in 38 adult patients. In the early period, daclizumab was used for induction, and tacrolimus and steroids were administered for maintenance [daclizumab and tacrolimus (DT) group; n = 11]. From 2002, we used alemtuzumab for induction, with low-dose tacrolimus maintenance [alemtuzumab and tacrolimus (AT) group; n = 23]. The incidence of bacterial infections and patient outcome were compared between the two groups. Results: There were no significant differences in recipient and donor demographics, procedure (ITx vs. MTVx), and cold and warm ischemic time between the two groups. Within 30 d after ITx, bacterial infections were observed in seven patients (64%) in the DT and in 14 patients (64%) in the AT group. Between 30 and 180 d after ITx, a total of 17 episodes of bacterial infections were observed in the DT and 26 episodes in the AT group. Three patients in the DT and eight in the AT group died, and all of the deaths were related to infectious complications except one each in DT and AT. Conclusion: There was no difference in incidence of bacterial infections and long-term patient survival between the two groups.

Liver resection (LR) for patients with small hepatocellular carcinoma (HCC) with preserved liver function, employing liver transplantation (LT) as a salvage procedure (SLT) in the event of HCC recurrence, is a debated strategy. From 1996 to 2005, we treated 227 cirrhotic patients with HCC transplantable: 80 LRs and 147 LTs of 293 listed for transplantation. Among 80 patients eligible for transplantation who underwent LR, 39 (49%) developed HCC recurrence and 12/39 (31%) of these patients presented HCC recurrence outside Milan criteria. Only 10 of the 39 patients underwent LT, a transplantation rate of 26% of patients with HCC recurrence. According to intention-to-treat analysis of transplantable HCC patients who underwent LR (n = 80), compared to all those listed for transplantation (n = 293), 5-year overall survival was 66% in the LR group versus 58% in patients listed for LT, respectively (p = NS); 5-year disease-free survival was 41% in the LR group versus 54% in patients listed for LT (p = NS). Comparable 5-year overall (62% vs. 73%, p = NS) and disease-free (48% vs. 71%, p = NS) survival rates were obtained for SLT and primary LT for HCC, respectively. LR is a valid treatment for small HCC and in the event of recurrence, SLT is a safe and effective procedure.

OBJECTIVE: We assessed the effect of tacrolimus on recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) and compared it with that of the other calcineurin inhibitor, cyclosporine. INTRODUCTION: HCC recurrence after LT can be favored by overexposure to cyclosporine. Tacrolimus is now the most widely used main immunosuppressant after LT; its possible effect on HCC recurrence has never been investigated. MATERIALS AND METHODS: One hundred and thirty nine HCC patients who had LT were reviewed; 60 of them were administered tacrolimus, and 79, cyclosporine. The exposure to the drugs was calculated with the trapezoidal rule in each patient, using blood levels measured after transplantation and compared with HCC recurrence together with several clinical and pathologic risk factors. RESULTS: HCC recurred in 12 of the 60 (20%) patients under tacrolimus in comparison with that in 9 of the 79 (11.4%) patients under cyclosporine; however, the proportion of poorly differentiated and more advanced tumors was significantly higher in the tacrolimus group than in the cyclosporine group. Exposure to tacrolimus was 11.6 +/- 1.5 ng/mL in patients with recurrence and 8.6 +/- 1.7 ng/mL in those without recurrence (P < 0.001). The optimal cut-off values of exposure identified with receiver operating characteristics analysis to categorize the risk of recurrence were 10 ng/mL for tacrolimus (area under the curve (AUC) = 0.913) and 220 ng/mL for cyclosporine (AUC = 0.752). In the tacrolimus group, high drug exposure independently predicted recurrence (P = 0.005). Multivariate analysis, including all patients (tacrolimus + cyclosporine) characterized higher exposure to immunosuppression (P = 0.01), alpha-fetoprotein levels (P = 0.001), tumor grading (P = 0.009), and microvascular invasion (P = 0.04) as independent predictors of HCC recurrence. CONCLUSIONS: Just as it is with cyclosporine, overexposure to tacrolimus increases the risk of HCC recurrence after LT. Careful management of calcineurin inhibitors is recommended in HCC patients.