Dual aortic and portal perfusion at procurement prevents ischaemic-type biliary lesions in liver transplantation when using octogenarian donors: a retrospective cohort study.

Several risk factors for ischaemic-type biliary lesions (ITBL) after liver transplantation (LT) have been identified, but the role of portal vein perfusion at graft procurement is still unclear. This was a prospective study on double aortic and portal perfusion (DP) of liver grafts stratified by donor's decade (<60 yo; 60-69 yo; 70-79 yo and ≥80 yo) versus similar historical cohorts of primary, adult grafts procured with single aortic perfusion (SP) only. The primary study aim was to assess the role of DP on the incidence of ITBL. There was no difference in the incidence of overall biliary complications according to procurement technique for recipients of grafts <80 years. A higher incidence of ITBL was observed for patients receiving grafts ≥80 years and perfused through the aorta only (1.9 vs. 13.4%; P = 0.008). When analysing octogenarian grafts, donor male gender (HR = 6.4; P = 0.001), haemodynamic instability (HR = 4.9; P = 0.008), and type-2 diabetes mellitus (DM2) (HR = 3.0; P = 0.03) were all independent risk factors for ITBL, while double perfusion at procurement (HR = 0.1; P = 0.04) and longer donor intensive care unit (ICU) stay (HR = 0.7; P = 0.04) were protective factors. Dual aortic and portal perfusion has the potential to reduce post-transplant ITBL incidence for recipients of octogenarian donor grafts. Larger series are needed to confirm this preliminary experience.

Safety and feasibility of electrochemotherapy in patients with unresectable colorectal liver metastases: A pilot study.

BACKGROUND AND OBJECTIVES: Electrochemotherapy is a novel ablation technique combining chemotherapeutic agents with reversible cell membrane electroporation. Previous experiences have shown its efficacy for cutaneous tumors. Its application for deep-seated malignancies is under investigation. We performed a prospective, pilot study to evaluate the feasibility, safety, and efficacy of intraoperative electrochemotherapy for otherwise unresectable colorectal liver metastases. METHODS: Electrochemotherapy with bleomycin was combined with open liver resection and performed with linear or hexagonal needle electrodes according to an individualized pretreatment plan. The primary endpoints were: feasibility, as ratio of completed to planned treatments; safety, and efficacy, as per response assessed at 30 days with MRI and according to RECIST. The secondary endpoint was overall and progression-free survival at month 6. RESULTS: A total of 9 colorectal liver metastases were treated in 5 patients with 20 electrode applications. No intraoperative complications were observed. At day 30, complete response was 55.5% and stable disease 45.5%. All (5) patients reached a 6 months overall survival, and 4 out of 5 patients had 6 months progression free survival. CONCLUSIONS: Electrochemotherapy is a feasible and safe adjunct to open surgery for treatment of unresectable colorectal liver metastases. Larger studies and longer follow-ups are favored to better define its role in the treatment of secondary liver malignancies.

Modification of immunosuppressive therapy as risk factor for complications after liver transplantation.

Management of complications post-liver transplantation (LT) includes immunosuppressive manipulations with the aim to reduce the overall burden of immunologic suppression and compensate for renal, cardiovascular, metabolic toxicities, and for the increased oncologic risk. Two approaches can be implemented to reduce immunosuppression-related adverse events: upfront schedules tailored to the pretransplant individual patient's risk profile versus downstream modifications in the event of immunosuppression-related complications. Upfront strategies are supported by evidence originating from prospective randomized trials and consist of triple/quadruple schedules whereby calcineurin inhibitors (CNI)-exposure is reduced with combination of anti-CD25 monoclonal antibodies, antimetabolites and corticosteroids. Quadruple regimens allow for staggering of CNI introduction and higher renal function in the early term, but their superiority in the long term has not yet been established. A more recent upfront schedule contemplates early (4 weeks) introduction of mammalian target of rapamycin inhibitor (mTORi) everolimus and allows for reduction of CNI up to 4 years posttransplantation. Incorporation of mTORi has the potential to prolong time to recurrence for patients with hepatocellular carcinoma. However, as suggested by the available evidence, downstream immunosuppressive manipulations are more frequently adopted in clinical practice. These encompass CNI replacement and immunosuppression withdrawal. Switching CNI to mTORi monotherapy is the option most commonly adopted to relieve renal function and compensate for posttransplant malignancies. Its impact is dependent on interval from transplantation and underlying severity of renal impairment. Introduction of mTORi is associated with longer overall survival for patients with extrahepatic posttransplant malignancies, but results are awaited for recurrences of hepatocellular carcinoma. Immunosuppression withdrawal seems feasible (70%) in very long term survivors (>10 years), but is not associated with reversal of immunosuppression-related complications. Awaiting novel immunosuppressive drug categories, integration of upfront strategies with the aim to reduce CNI-exposure and a low threshold for adjustment in the posttransplant course are both advisable to improve long-term outcomes of LT.

Risk analysis of ischemic-type biliary lesions after liver transplant using octogenarian donors.

The use of octogenarian donors to increase the donor pool in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk of ischemic-type biliary lesions (ITBL). The aim of this study was to investigate retrospectively the role of a number of different pre-LT risk factors for ITBL in a selected population of recipients of octogenarian donor grafts. Between January 2003 and December 2013, 123 patients underwent transplantation at our institution with deceased donor grafts from donors of age ≥80 years. Patients were divided into 2 groups based on the presence of ITBL in the posttransplant course. Exclusion criteria were retransplantations, presence of vascular complications, and no availability of procurement liver biopsy. A total of 88 primary LTs were included, 73 (83.0%) with no posttransplant ITBLs and 15 (17.0%) with ITBLs. The median follow-up after LT was 2.1 years (range, 0.7-5.4 years). At multivariate analysis, donor hemodynamic instability (hazard ratio [HR], 7.6; P = 0.005), donor diabetes mellitus (HR, 9.5; P = 0.009), and donor age-Model for End-Stage Liver Disease (HR, 1.0; P = 0.04) were risk factors for ITBL. Transplantation of liver grafts from donors of age ≥80 years is associated with a higher risk for ITBL. However, favorable results can be achieved with accurate donor selection. Donor hemodynamic instability, a donor history of diabetes mellitus, and allocation to higher Model for End-Stage Liver Disease score recipient all increase the risk of ITBL and are associated with worse graft survival when octogenarian donors are used. Liver Transplantation 22 588-598 2016 AASLD.

Lymphoepithelioma-like hepatocellular carcinoma: Case report and review of the literature.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a rare form of undifferentiated carcinoma of the liver characterized by the presence of an abundant lymphoid infiltrate. Here, a case of LEL-HCC is described. An 81-year-old woman with a chronic hepatitis C infection was referred to the general surgery department of our hospital in August 2013 with a diagnosis of HCC. A past ultrasound examination had revealed a 60 mm-diameter nodular lesion in the third segment of the liver. After a needle biopsy, the lesion was diagnosed as HCC. The patient underwent surgery with a liver segmentectomy. Two additional nodes on the gastric wall were detected during the surgical operation. The histology of the removed specimen showed a poorly differentiated HCC with significant lymphoid stroma. Immunohistochemical studies revealed that the epithelial component was reactive for CK CAM5.2, CK8, CK18, CEA (polyclonal) and was focally positive for hepar-1 and that the lymphoid infiltrate was positive for CD3, CD4 and CD8. The tumor cells were negative for Epstein-Barr virus. The gastric nodes were ultimately determined to be two small gastrointestinal stromal tumors (GISTs). The synchronous occurrence of HCC and GIST is another very uncommon finding rarely described in the literature. Here, we report the clinicopathological features of our case, along with a review of the few cases present in the literature.

Transjugular intrahepatic portosystemic shunt for hepatitis C virus-related portal hypertension after liver transplantation.

This is a single center retrospective review of 19 consecutive liver transplant (LT) patients with hepatitis C virus (HCV)-related graft recurrent hepatitis who underwent transjugular intrahepatic portosystemic shunt (TIPS) at a median interval of 21 months (range: 5-50) from LT. Indications were refractory ascites in 11 patients (57.9%), hydrothorax in six (31.6%), and both in two (10.5%). TIPS was successful in 94.7% of cases (18/19) with only one procedure-related mortality (5.3%) owing to sepsis on day 35. At a median follow-up of 23 months (range: one month-nine yr), TIPS allowed for symptoms resolution in 16 patients (84.2%), with ascites resolving in all cases and hydrothorax persisting in 2. Post-TIPS patient survival at six months, one yr, and three yr was 84.2%, 73.7%, and 56.8%, respectively. We compared these results with a control group of 29 patients with HCV recurrence but without unresponsive ascites or hydrothorax. Patients in the control group had better survival than patients undergoing TIPS placement. However, survival of TIPS patients with a MELD score lower than or equal to 12 was similar to that of the control group. We conclude that TIPS may be used to treat complications secondary to HCV.

A single-staggered dose of calcineurin inhibitor may be associated with neurotoxicity and nephrotoxicity immediately after liver transplantation.

The aim of the present work was to assess the incidence of neuro-nephrotoxicity after a single-staggered dose of calcineurin inhibitors (CI) with different immunosuppressive approaches. From January to December 2006, all liver transplantation (LT) recipients at risk of renal or neurological complications treated with extracorporeal photopheresis (ECP) + mycophenolate mofetil + steroids and staggered introduction of CI (ECP group) were compared with a historical control group on standard CI-based immunosuppression. The ECP group included 24 patients with a mean model for end-stage liver disease (MELD) score of 19.9 +/- 11.1. The control group consisted of 18 patients with a mean MELD score of 12.5 +/- 5.2 (p = 0.012). In the ECP group CI were introduced at a mean of 9.2 +/- 6.2 d (4-31 d) after LT. Five patients in the ECP group presented acute neuro-nephrotoxicity after the first CI administration on post-transplant d 4, 5, 6, 6, and 14. Overall patient survival at one, six, and 12 months was 100%, 95.8%, and 95.8% in the ECP group vs. 94.4%, 77.7%, and 72.2% in the control group (p < 0.001). In conclusion, we showed that CI toxicity may occur after a single-staggered dose administration, ECP seems to be a valuable tool for managing CI-related morbidity regardless of the concomitant immunosuppressive regimen, being associated with a lower mortality rate in the early post-transplant course.

Conversion to everolimus monotherapy in maintenance liver transplantation: feasibility, safety, and impact on renal function.

We present the 12-month results of a prospective trial of conversion from calcineurin inhibitors (CNI) to everolimus (EVL) in maintenance liver transplant (LT) recipients. Forty (M:F = 28:12; 54.9 +/- 11 years) patients were enrolled at a mean interval of 45.5 +/- 31.2 months from transplantation. Conversion was with EVL at a dosage of 0.75 mg b.i.d., withdrawal of antimetabolites, and a 50%-per-week reduction of CNI to a complete stop within 4 weeks. The treatment success was conversion to EVL monotherapy at 12 months while failure was presence of CNI, death, and graft loss. Indication to conversion was deteriorating renal function in 36 (90%). At 12 months, patient- and graft survival were 100% and the success rate was 75% (30/40). Ten patients (25%) were failures: four (10%) for acute rejection; three hepatitis C virus-RNA positive patients (7.5%) for hypertransaminasemia; one (2.5%) for acute cholangitis; and two (5%) due to persistent pruritus and oral ulcers. In patients on EVL monotherapy, at 12 months the mean change of calculated creatinine clearance (cCrCl) was 4.03 +/- 12.6 mL/min and the only variable correlated with the probability of improvement was baseline cCrCl (P < 0.0001). Conversion from CNI to EVL is feasible in 75% of the cases and associated with improvement in renal function for patients with higher baseline cCrCl.

Severe liver trauma: the transplant surgeon's perspective. A case report.

Patients with severe liver trauma may be referred to liver transplantation (LT), even though no universal algorithm is currently agreed upon. LT is usually performed as a two-stage procedure after failure of primary surgery or in the event of surgery-related acute liver failure (ALF), but pre-transplant patient management, appropriate selection criteria and prompt referral to LT centers are paramount for a favorable graft outcome. This is a report on a patient who underwent LT as a two-stage procedure for sepsis-related ALF after extended right hepatectomy for a complex abdominal blunt trauma. Prompt referral to the Liver Transplant Unit of the Cisanello Hospital, Pisa, where the whole spectrum of surgical options and intensive care support are available was crucial to allow successful LT in a timely fashion. Therefore, the authors strongly advocate the whole algorithm for patients with severe liver traumas be put under control of an experienced LT team in order to improve surgical results.

Treatment of antibody-mediated rejection with high-dose immunoglobulins in ABO-incompatible liver transplant recipient.

ABO-incompatible liver transplantation (LT) entails high risk of antibody-mediated rejection (AMR) and poor graft survival. Different treatment modalities have been reported, but none with use of a 2-week course of high-dose polyclonal i.v. immunoglobulins (IVIg) associated with plasmapheresis without the use of steroid pulses or monoclonal antibody. A 60-year-old male patient with blood-group O, Caucasian, underwent urgent LT for acute liver failure after hepatectomy for HCV-related hepatocellular carcinoma. He was grafted with a 66-year-old, blood-group A, HCV-positive liver graft. Pretransplant conditioning consisted of plasmapheresis and immunosuppression was triple with tacrolimus (TAC), steroids, and mycophenolate mofetil with anti-IL2-R monoclonal antibodies, plasmapheresis if hemagglutinin level >1:8, and extracorporeal photopheresis. After reduction of liver function tests to baseline, the patient presented a tenfold increase in alanine aminotransferases (ALT) levels 7 days post-transplantation. AMR was confirmed on histology. Treatment consisted of IVIg (1.5 g/Kg/daily for the first 7 days, and 1 g/Kg/daily from day 8 to 14) with a 14-day course of plasmapheresis. No side effect was observed and daily blood IgG levels ranged between 24.4 and 36.4 g/l. At the end of the scheduled course ALT returned to baseline. A control liver biopsy 55 days after LT showed no rejection and replacement of necrosis with fibrous strands. This case may support the role of high-dose IVIg for treatment and/or prophylaxis of severe AMR.

Avoiding calcineurin inhibitors in the early post-operative course in high-risk liver transplant recipients: The role of extracorporeal photopheresis.

The aim of this work is to report on the results of a single-center, prospective study on the feasibility of calcineurin-inhibitor (CNI)-staggered immunosuppression by use of extracorporeal photopheresis (ECP) in liver transplant (LT) recipients at risk of renal and neurological complications. Patients were matched on a 1:1 basis with historical controls on standard CNI immunosuppression. ECP patients were treated with ECP plus antimetabolites and/or steroids, while CNIs were withheld until clinically indicated. Thirty-six patients were evaluated: 18 ECP patients and 18 controls. ECP was tolerated in 100% of cases. CNI were introduced at a median of 8 days (4-55) in 17 ECP patients, while one patient was on a fully CNI-sparing regimen 22 months after LT. Acute rejection occurred in 27.7% patients in ECP (5/18) versus 16.7% in controls (3/18) (P = ns) with a shorter time to rejection in ECP (36 +/- 31.3 days vs. 83.6 +/- 65.6 days; P = ns). All rejection episodes were amenable to medical treatment. Neurological and renal complications occurred in 22.2% (4/18) of patients in either group, but led to in-hospital mortality in 3 patients among controls versus 1 in ECP (P = ns). One-, 6-, and 12-month survival rates were 94.4, 88.1, and 88.1% in ECP versus 94.4, 77.7, and 72.2% among controls (P < 0.0001). ECP seems to allow for management of high-risk LT recipients in the early post-transplant course and reduction of CNI-related mortality. Continued data validation is favored to assess the impact of ECP on long-term graft and patient survival.

Quality assurance, efficiency indicators and cost-utility of the evaluation workup for liver transplantation.

We report the results of a retrospective review of the outpatient pretransplantation workup for United Network for Organ Sharing (UNOS) 3 patients adopted at a liver transplantation (LT) center and illustrate the efficiency indicators used for quality evaluation and cost-analysis. A single-center, pre-LT evaluation workup was performed on an outpatient basis at a cost per patient evaluation of 2,770 Euros (). Objective measures were: the number of patients admitted to and excluded from each phase of the algorithm; the rate of patients admitted to pre-LT evaluation out of the total of referred patients (the referral efficiency rate); the rate of waitlisted patients out of those admitted to pre-LT evaluation (the evaluation efficiency rate); the rate of waitlisted patients out of those referred for LT (the process efficiency rate); and the cost per waitlisted patient, as the ratio of the cost per patient evaluation to the evaluation efficiency rate. From January 1, 1996, to October 1, 2004, 1,837 patients were referred for LT on an outpatient basis. Based on preemptive evaluation of the available clinical data, 412 patients (22.4%) were excluded from pre-LT evaluation and 1,425 (77.6%) were admitted to preliminary consultation. Among these, 603 (42.3%) were excluded from and 822 (57.7%) were admitted to pre-LT evaluation with a referral efficiency rate of 44.7% (822 of 1,837). Out of the patients evaluated for LT, 484 were waitlisted with a cost-utility and evaluation efficiency rate of 58.8% each (484 of 822). Of the 1,837 patients originally addressed for LT 484 were waitlisted, yielding a process efficiency rate of 26.3% (484 of 1,837) and a cost per waitlisted patient of 4,710.8. In conclusion, the 3 indicators allowed monitoring of the efficiency of the pre-LT evaluation algorithm. The current process efficiency rate at our center is low (26.3%), but avoiding early referrals we might increase it to 31.6%, with a 12% net saving on costs per waitlisted patient (from 4,710.8 to 4,165.4).