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Antibody-mediated rejection (AMR) after liver transplantation is uncommon but, when present, manifests as graft dysfunction. We report the case of a 54-year-old woman who developed portal hypertension with pleural effusion and ascites secondary to sinusoidal obstruction syndrome (SOS) due to acute AMR following an ABO-matched liver transplantation for autoimmune cirrhosis and hepatocellular carcinoma. Initial immunosuppression comprised basiliximab, decreasing prednisone, tacrolimus, and mycophenolate mofetil. After 1 month, she presented with the massive pleural effusion, slight ascites, and normal liver tests. After excluding common causes of pleural effusion, we performed a liver biopsy that showed atypical rejection with the involvement of large centrilobular veins partially occluded by marked endotheliitis and lax fibrosis suggestive of SOS. Direct immunofluorescence study of C4d showed diffuse endothelial sinusoidal staining, and de novo donor-specific anti-human leukocyte antigen antibodies were detected in his blood. Thus, we diagnosed AMR focused on centrilobular veins and initiated treatment with defibrotide, steroid pulses, and diuretics. However, this was ineffective, and the pleural effusion only resolved when plasmapheresis and intravenous immunoglobulin were started. This case shows that AMR can cause SOS with portal hypertension and present with a pleural effusion, and as such, it should be suspected after excluding other more common causes of effusion.

Introduction: The access of surgeons to liver transplant teams in Spain is heterogeneous. This study aims to portray the current human resources of Spanish transplant teams, distribution of transplant duties among team members, how transplant team members acquire their skills, their leaders' view of their future, as well the motivations of Spanish General Surgery residents to choose transplantation as their future career choice. Methods: Two different surveys were created, one for head surgeons and one for residents, about the number of team members and their training, recruitment, organization of tasks and motivation to work in transplantation. The questionnaires were e-mailed to both the transplant program directors and the surgical residents. Results: There are on average 8 surgeons in each transplant unit. More than four surgeons perform the hepatectomy in 54.2% of the groups, while the graft implantation is performed by more than 4 surgeons at just 25% of the centers. Forty-two percent of the transplant chiefs advocated a fellowship training system, and 87.5% believe that generational turnover is guaranteed. Out of 525 residents, 101 responded. Regarding training, 12.8% had no interest in transplantation. Concerning their work preferences, 37.6% were not interested in transplantation because it is excessively demanding, and 52.5% would not like to be part of a liver transplant team in the future. Conclusions: The generational turnover seems to be guaranteed according to liver transplant program directors. The new generations of surgeons generally opt for other areas of surgery other than transplantation. Studies with a greater number of responses are necessary to validate these results (C) 2019 AEC. Published by Elsevier Espana, S.L.U. All rights reserved.

Several techniques have been proposed for liver transplantation with inadequate hepatic artery (HA) anastomosis. We aimed to analyze outcomes of arterial reconstruction with the splenic artery (SA). This was a prospective study of our experience with recipients who underwent arterial anastomosis on the SA compared with patients who underwent standard HA. We included 54 patients in the SA group and 1405 in the HA group. Patients in SA group were more frequently retransplantation (31% vs. 8%; P = 0.001), required more transfusion (11 ± 12 vs. 6 ± 9.9 PRC; P = 0.001), had longer surgeries (424 ± 95 vs. 394 ± 102 min; P = 0.03), and longer hospital stays (28 ± 29 vs. 20 ± 18 days; P = 0.002). There were no differences in vascular and biliary complications (15% and 7%; P = 0.18; and 32% and 23%; P = 0.32), primary dysfunction (11% and 9%; P = 0.74), reoperation (12% and 10%; P = 0.61), postoperative mortality (13% and 7%; P = 0.12) and 5 years survival (66% vs. 63%; P = 0.71). Following primary transplantation, there were no differences. The outcomes of arterial reconstruction using the recipients' SA in adult liver transplantation are comparable to those for standard HA reconstruction after a first transplant.

Objective To evaluate the short- and long-term outcomes of renoportal anastomosis (RPA) in a large multicentric series. Summary background The current knowledge on RPA for portal reconstruction during liver transplantation (LT) in patients with diffuse portal vein thrombosis (PVT) and a large splenorenal shunt (SRS) is poor and limited to case reports and small case series. Methods All consecutive LTs with RPA performed in 5 centers between 1998 and 2020 were included. RPA was physiological provided it drained the splanchnic venous return through a large SRS (≥1 cm diameter). Complications of portal hypertension (PHT), long-term RPA patency, and patient and graft survival were assessed. RPA success was achieved provided the 3 following criteria were all fulfilled: patients were alive with patent RPA and without clinical PHT. Results RPA was attempted and feasible in 57 consecutive patients and was physiological in 51 patients (89.5%). Ninety-day mortality occurred in 5 (8.5%) patients, and PHT-related complications occurred in 42.9% of patients. With a median follow-up of 63 months, the 1-, 3- and 5-year patient and graft survival rates were 87%, 83%, and 76% and 82%, 80%, and 73%, respectively. The primary and primary-assisted patency rates at 5 years were 84.5% and 94.3%, respectively. Success was achieved in 90% (27/30) of patients with a follow-up ≥ 5 years. Conclusions Despite a high rate of PHT-related complications, excellent long-term patient and graft survival could be achieved. RPA could be considered successful in the vast majority of patients. The expanded use of RPA is warranted.

International audience; Transplant and patient survival are the validated endpoints to assess the success of liver transplantation (LT). This study evaluates arterial and biliary complication-free survival (ABCFS) as a new metric. ABC, considered as an event, was an arterial or biliary complication of Dindo-Clavien grade ≥III complication dated at the interventional, endoscopic, or surgical treatment required to correct it. ABCFS was defined as the time from the date of LT to the dates of first ABC, death, relisting, or last follow-up (transplant survival is time from LT to repeat LT or death). Following primary whole LT (n = 532), 106 ABCs occurred and 99 (93%) occurred during the first year after LT. An ABC occurring during the first year after LT (overall rate 19%) was an independent factor associated with transplant survival (hazard ratio [HR], 3.17; P < 0.001) and patient survival (HR, 2.7; P = 0.002) in univariate and multivariate analyses. This result was confirmed after extension of the cohort to splitliver graft, donation after circulatory death, or re-LT (n = 658). Data from 2 external cohorts of primary whole LTs (n = 249 and 229, respectively) confirmed that the first-year ABC was an independent prognostic factor for transplant survival but not for patient survival. ABCFS was correlated with transplant and patient survival (ρ = 0.85 [95% CI, 0.78-0.90] and 0.81 [95% CI, 0.71-0.88], respectively). Preoperative factors known to influence 5-year transplant survival influenced ABCFS after 1 year of follow-up. The 1-year ABCFS was indicative of 5-year transplant survival. ABCFS is a reproducible metric to evaluate the results of LT after 1 year of follow-up and could serve as a new endpoint in clinical trials.

Background Hereditary transthyretin (ATTRv) amyloidosis is an autosomal dominant disease linked to transthyretin gene mutations which cause instability of the transthyretin tetramer. After dissociation and misfolding they reassemble as insoluble fibrils (i.e. amyloid). Apart from the common Val30Met mutation there is a very heterogeneous group of non-Val30Met mutations. In some cases, the clinical picture is dominated by a rapidly evolving restrictive and hypertrophic cardiomyopathy. Methods A case series of four liver recipients with the highly clinically relevant, rare and particularly aggressive Val122del mutation is presented. Medical and surgical therapeutic options, waiting list policy for ATTRv-amyloidosis, including the need for heart transplantation, and status of heart-liver transplantation are discussed. Results Three patients needed a staged (1 patient) or simultaneous (2 patients) heart-liver transplant due to rapidly progressing cardiac failure and/or neurologic disability. Domino liver transplantation was impossible in two due to fibrotic hepatic transformation caused by cardiomyopathy. After a follow-up ranging from 3.5 to 9.5 years, cardiac (allograft) function was maintained in all patients, but neuropathy progressed in three patients, one of whom died after 80 months. Conclusions This is the first report in (liver) transplant literature about the rare Val122del ATTRv mutation. Due to its aggressiveness, symptomatic patients should be prioritized on the liver and, in cases with cardiomyopathy, heart waiting lists in order to avoid the irreversible neurological and cardiac damage that leads to a rapid lethal outcome.

BACKGROUND Delaying initiation of tacrolimus after liver transplantation (LT) is a potential renal-sparing strategy. We assessed safety and efficacy of delayed initiation of prolonged-release tacrolimus (PR-T) in de novo LT. MATERIAL AND METHODS This was a single-center, single-arm, prospective, 12-month observational study of hepatitis C virus-negative orthotopic LT patients. Immunosuppression included PR-T (initially 0.1 or 0.2 mg/kg/day) initiated on Day 3 post LT, basiliximab (20 mg) on post-transplantation Day 0 and Day 4, and intraoperative corticosteroids (500 mg). Patients received maintenance corticosteroids and mycophenolate mofetil (MMF) according to center protocol. MMF dose was adjusted according to thrombocyte count. The primary endpoint was the estimated glomerular filtration rate (eGFR) measured using the Modification of Diet in Renal Disease 4-variable formula at 12 months. Secondary endpoints included biopsy-confirmed acute rejection (BCAR) and dialysis requirement. Adverse events were recorded. RESULTS Sixty-nine patients (mean age 55.0 years) were included. Most patients started MMF on Day 1 (60.9%) or Day 2 (10.1%), and PR-T on Day 3 (55.1%) or Day 4 (29.0%). Mean tacrolimus trough levels (ng/mL) were: Day 7, 9.5±6.3; Day 10, 9.4±5.4; Month 1, 8.0±3.1; Month 3, 7.8±3.7; Month 6, 8.0±4.1; and Month 12, 7.2±3.1. Mean 12-month eGFR was 77.2±24.5 mL/min/1.73 m2; 72.5% of patients had eGFR >60 mL/min/1.73 m² at 12 months; 89.9% had no eGFR measurements

OBJECTIVE: To use the concept of benchmarking to establish robust and standardized outcome references after pancreatico-duodenectomy (PD). BACKGROUND: Best achievable results after PD are unknown. Consequently, outcome comparisons among different cohorts, centers or with novel surgical techniques remain speculative. METHODS: This multicenter study analyzes consecutive patients (2012-2015) undergoing PD in 23 international expert centers in pancreas surgery. Outcomes in patients without significant comorbidities and major vascular resection (benchmark cases) were analyzed to establish 20 outcome benchmarks for PD. These benchmarks were tested in a cohort with a poorer preoperative physical status (ASA class ≥3) and a cohort treated by minimally invasive approaches. RESULTS: Two thousand three hundred seventy-five (38%) low-risk cases out of a total of 6186 PDs were analyzed, disclosing low in-hospital mortality (≤1.6%) but high morbidity, with a 73% benchmark morbidity rate cumulated within 6 months following surgery. Benchmark cutoffs for pancreatic fistulas (B-C), severe complications (≥ grade 3), and failure-to-rescue rate were 19%, 30%, and 9%, respectively. The ASA ≥3 cohort showed comparable morbidity but a higher in hospital-mortality (3% vs 1.6%) and failure-to-rescue rate (16% vs 9%) than the benchmarks. The proportion of benchmark cases performed varied greatly across centers and continents for both open (9%-93%) and minimally invasive (11%-62%) PD. Centers operating mostly on complex PD cases disclosed better results than those with a majority of low-risk cases. CONCLUSION: The proposed outcome benchmarks for PD, established in a large-scale international patient cohort and tested in 2 different cohorts, may allow for meaningful comparisons between different patient cohorts, centers, countries, and surgical techniques.

Background Delayed gastric emptying (DGE) is the most important cause of an extended hospital stay after pancreatoduodenectomy. Reports suggest that a Roux-en-Y gastroenteric anastomosis may have lower incidence of DGE than a Billroth II reconstruction. The primary aim of this RCT was to compare Billroth II (single loop) and Roux-en-Y (double loop) after pancreatoduodenectomy to determine whether Roux-en-Y reconstruction is associated with a lower incidence of DGE. Secondary endpoints were postoperative complications. Methods This was a randomized unblinded single-centre trial without masked evaluation of the main outcome. Patients undergoing pancreatoduodenectomy between 2013 and 2015 were randomized to undergo one of two types of gastroenteric anastomosis for reconstruction. Results A total of 80 patients were randomized, 40 in each group. The incidence of DGE was the same in patients undergoing Billroth II or Roux-en-Y gastroenteric anastomosis (both 18 of 40 patients; P = 1·000). The grade of DGE was also similar in the Billroth II and Roux-en-Y groups (grade A, both 10 of 40; grade B, 5 of 40 versus 6 of 40; grade C, 3 of 40 versus 2 of 40; P = 0·962). The mortality rate was 3 per cent, with no significant difference between the two groups. There were no differences in the overall rate of postoperative morbidity, relaparotomy rate or duration of hospital stay. Conclusion The incidence and severity of DGE does not differ between single- or double-loop gastroenteric anastomosis performed after pancreatoduodenectomy. Registration number: NCT00915863 (http://www.clinicaltrials.gov).

BackgroundNeoadjuvant therapy (NAT) for pancreatic adenocarcinoma (PDAC) patients has shown promising results in non-randomized trials. This is a multi-institutional phase II trial of NAT in resectable PDAC patients.MethodsPatients with confirmed resectable PDAC after agreement by two expert radiologists were eligible. Patients received three cycles of GEM (1000mg/m(2)/week) plus daily erlotinib (ERL) (100mg/day). After re-staging, patients without progressive disease underwent 5 weeks of therapy with GEM (300mg/m(2)/week), ERL 100mg/day and concomitant radiotherapy (45Gy). Efficacy was assessed using tumor regression grade (TRG) and resection margin status. Using a single-arm Simon's design, considering the therapy not useful if R070% (alpha 5%, beta 10%), 24 patients needed to be recruited. This trial was registered at ClinicalTrials.gov, number NCT01389440.ResultsTwenty-five patients were enrolled. Adverse effects of NAT were mainly mild gastrointestinal disorders. Resectability rate was 76%, with a R0 rate of 63.1% among the resected patients. Median overall survival (OS) and disease-free survival (DFS) were 23.8 (95% CI 11.4-36.2) and 12.8 months (95% CI 8.6-17.1), respectively. R0 resection patients had better median OS, compared with patients with R1 resection or not resected (65.5 months vs. 15.5 months, p=0.01). N0 rate among the resected patients was 63.1%, and showed a longer median OS (65.5 vs. 15.2 months, p=0.009).ConclusionThe results of this study confirm promising oncologic results with NAT for patients with resectable PDAC. Therefore, the present trial supports the development of phase II randomized trials comparing NAT vs. upfront surgery in resectable pancreatic cancer.

A survey on peri-operative nutritional support in pancreatic and biliary surgery among Spanish hospitals in 2007 showed that few surgical groups followed the 2006 ESPEN guidelines. Ten years later we sent a questionnaire to check the current situation. Methods: a questionnaire with 21 items sent to 38 centers, related to fasting time before and after surgery, nutritional screening use and type, time and type of peri-operative nutritional support, and number of procedures. Results: thirty-four institutions responded. The median number of pancreatic resections (head/total) was 29.5 (95% CI: 23.0-35; range, 5-68) (total, 1002); of surgeries for biliary malignancies (non-pancreatic), 9.8 (95% CI: 7.3-12.4; range, 2-30); and of main biliary resections for benign conditions, 10.4 (95% CI: 7.6-13.3; range, 2-33). Before surgery, only 41.2% of the sites used nutritional support (< 50% used any nutritional screening procedure). The mean duration of preoperative fasting for solid foods was 9.3 h (range, 6-24 h); it was 6.6 h for liquids (range, 2-12). Following pancreatic surgery, 29.4% tried to use early oral feeding, but 88.2% of the surveyed teams used some nutritional support; 26.5% of respondents used TPN in 100% of cases. Different percentages of TPN and EN were used in the other centers. In malignant biliary surgery, 22.6% used TPN always, and EN in 19.3% of cases. Conclusions: TPN is the commonest nutrition approach after pancreatic head surgery. Only 29.4% of the units used early oral feeding, and 32.3% used EN; 22.6% used TPN regularly after surgery for malignant biliary tumours. The 2006 ESPEN guideline recommendations are not regularly followed 12 years after their publication in our country. Introducción: realizamos una encuesta sobre soporte nutricional perioperatorio en cirugía pancreática y biliar en hospitales españoles en 2007, que mostró que pocos grupos quirúrgicos seguían las guías de ESPEN 2006. Diez años después enviamos un cuestionario para comprobar la situación actual. Métodos: treinta y ocho centros recibieron un cuestionario con 21 preguntas sobre tiempo de ayunas antes y después de la cirugía, cribado nutricional, duración y tipo de soporte nutricional perioperatorio, y número de procedimientos. Resultados: respondieron 34 grupos. La mediana de pancreatectomías (cabeza/total) fue de 29,5 (IC 95 %: 23,0-35; rango, 5-68) (total, 1002), la de cirugías biliares malignas de 9,8 (IC 95 %: 7,3-12,4; rango, 2-30) y la de resecciones biliares por patología benigna de 10,4 (IC 95 %: 7,6-13,3; rango, 2-33). Solo el 41,2 % de los grupos utilizaban soporte nutricional antes de la cirugía (< 50 % habian efectuado un cribado nutricional). El tiempo medio de ayuno preoperatorio para sólidos fue de 9,3 h (rango, 6-24 h), y de 6,6 h para líquidos (rango, 2-12). Tras la pancreatectomía, el 29,4 % habían intentado administrar una dieta oral precoz, pero el 88,2 % de los grupos usaron algún tipo de soporte nutricional y el 26,5 % usaron NP en el 100 % de los casos. Los demás grupos usaron diferentes porcentajes de NP y NE en sus casos. En la cirugía biliar maligna, el 22,6 % utilizaron NP siempre y NE en el 19,3 % de los casos. Conclusiones: la NP es el soporte nutricional más utilizado tras la cirugía de cabeza pancreática. Solo el 29,4 % de las unidades usan nutrición oral precoz y el 32,3 % emplean la NE tras este tipo de cirugía. El 22,6 % de las instituciones usan NP habitualmente tras la cirugía de tumores biliares malignos. Las guías ESPEN 2006 no se siguen de forma habitual en nuestro país tras más de 10 años desde su publicación.

Liver transplantation (LT) after neoadjuvant chemoradiotherapy in patients with unresectable hilar cholangiocarcinoma (HC) is an accepted treatment strategy [1]. Neoadjuvant therapy is associated with an increased risk of arterial and portal complications after LT [1,2]. In most cases, radiation therapy makes the use of the native hepatic artery inadvisable, and an aortic anastomosis is needed, either with or without a graft [2]. The development of a mycotic pseudoaneurysm after LT is a rare complication that is associated with a high incidence of graft failure and mortality. Radiotherapy, local infections and the use of grafts are known risk factors for the development of a mycotic pseudoaneurysm, which is always challenging to manage [3].

Background and aim Given their poor prognosis, patients with residual disease (RD) in the re-resection specimen of an incidental gallbladder carcinoma (IGBC) could benefit from a better selection for surgical treatment. The Gallbladder Cancer Risk Score (GBRS) has been proposed to preoperatively identify RD risk more precisely than T-stage alone. The aim of this study was to assess the prognostic value of RD and to validate the GBRS in a retrospective series of patients. Material and methods A prospectively collected database including 59 patients with IGBC diagnosed from December 1996 to November 2015 was retrospectively analyzed. Three locations of RD were established: local, regional, and distant. The effect of RD on overall survival (OS) was analyzed with the Kaplan-Meier method. To identify variables associated with the presence of RD, characteristics of patients with and without RD were compared using Fisher’s exact test. The relative risk of RD associated with clinical and pathologic factors was studied with a univariate logistic regression analysis. Results RD was found in 30 patients (50.8%). The presence of RD in any location was associated with worse OS (29% vs. 74.2%, p = 0.0001), even after an R0 resection (37.7% vs 74.2%, p = 0.003). There was no significant difference in survival between patients without RD and with local RD (74.2% vs 64.3%, p = 0.266), nor between patients with regional RD and distant RD (16.1% vs 20%, p = 0.411). After selecting patients in which R0 resection was achieved (n = 44), 5-year survival rate for patients without RD, local RD, and regional RD was, respectively, 74.2%, 75%, and 13.9% (p = 0.0001). The GBRS could be calculated in 25 cases (42.3%), and its usefulness to predict the presence of regional or distant RD (RDRD) was confirmed (80% in high-risk patients and 30% in intermediate risk p = 0.041). Conclusion RDRD, but not local RD, represents a negative prognostic factor of OS. The GBRS was useful to preoperatively identify patients with high risk of RDRD. An R0 resection did not improve OS of patients with regional RD.

MicroRNAs from the miR-200 family are commonly associated with the inhibition of the metastatic potential of cancer cells, following inhibition of ZEB transcription factors expression and epithelial-to-mesenchymal transition. However, previous studies performed in pancreatic adenocarcinoma revealed a more complex picture challenging this canonical model. To gain better insights into the role of miR-200 family members in this disease, we analyzed the expression of miR-200a, miR-200b, miR-200c, miR-141, miR-429, and miR-205, and ZEB1, ZEB2, and CDH1 in pancreatic tumors and matching normal adjacent parenchyma and patient-derived xenografts. We found that miR-200a, miR-429, and miR-205 are frequently overexpressed in pancreatic tumors, whereas CDH1 is downregulated, and ZEB1 and ZEB2 levels remain unchanged. Furthermore, we measured a positive correlation between miR-200 family members and CDH1 expression, and a negative correlation between ZEB1 and miR-200c, miR-141, and miR-205 expression, respectively. Interestingly, we identified significant changes in expression of epithelial-to-mesenchymal transition regulators and miR-200 members in patient-derived xenografts. Lastly, functional studies revealed that miR-141 and miR-429 inhibit the tumorigenic potential of pancreatic cancer cells. Taken together, this comprehensive analysis strongly suggests that miRNAs from the miR-200 family, and in particular miR-429, may act as a tumor suppressor gene in pancreatic cancer. Keywords: pancreatic cancer, patient-derived xenograft, miR-200 family, miR-429

Background and study aims: the use of endoscopic ultrasound-guided biliary drainage (EUS-BD) has increased in cases of failed endoscopic retrograde cholangiopancreatography (ERCP) and there are some concerns. The main aim of the study was to determine the role of EUS-BD in a palliative case cohort. The secondary aim was to compare the efficacy, safety and survival of EUS-BD and ERCP procedures. Patients and methods: this was an observational study at a single tertiary institution, with a consecutive inclusion from January 2015 to December 2016. The inclusion criteria were unresectable tumors of the biliopancreatic region with an indication of BD. Statistical comparison analysis was performed between the ERCP and EUS-BD groups. The incidence between groups was compared using the Chi-square and Fisher exact tests. The log rank test was used to compare the risk of death. Results: fifty-two cases with an indication of palliative BD were included in the study. Transpapillary drainage via ERCP was possible in 44 procedures and EUS-BD was required in eight cases; 15.4% of the cohort and seven using lumen apposing metal stent (LAMS). The technical and clinical success of global endoscopic BD was 100% and 88.5% (ERCP: 84.6% and 78.9%; EUS-BD: 100% and 62.5%, respectively). Pancreatitis was the most frequent adverse event (AE) in the ERCP group (9.62%) and bleeding in the EUS-BD (25%). There were fatal AEs in ERCP (1.9%) and EUS-BD (25%) cases. Patient survival was higher with ERCP transpapillary stents compared to EUS-guided stents, which was statistically significant (p = 0.007). Conclusions: the requirement of EUS-BD in palliative biliopancreatic pathology is not marginal. EUS-BD is associated with a lower survival rate and a higher rate of fatal AE, which argues against its use as a first choice procedure.

The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience. ispartof: TRANSPLANT INTERNATIONAL vol:31 issue:12 pages:1293-1317 ispartof: location:Switzerland status: published

A national, multicenter, retrospective study was conducted to assess the results obtained for liver transplant recipients with conversion to everolimus in daily practice. The study included 477 recipients (481 transplantations). Indications for conversion to everolimus were renal dysfunction (32.6% of cases), hepatocellular carcinoma (HCC; 30.2%; prophylactic treatment for 68.9%), and de novo malignancy (29.7%). The median time from transplantation to conversion to everolimus was 68.7 months for de novo malignancy, 23.8 months for renal dysfunction, and 7.1 months for HCC and other indications. During the first year of treatment, mean everolimus trough levels were 5.4 (standard deviation [SD], 2.7) ng/mL and doses remained stable (1.5 mg/day) from the first month after conversion. An everolimus monotherapy regimen was followed by 28.5% of patients at 12 months. Patients with renal dysfunction showed a glomerular filtration rate (4-variable Modification of Diet in Renal Disease) increase of 10.9 mL (baseline mean, 45.8 [SD, 25.3] versus 57.6 [SD, 27.6] mL/minute/1.73 m(2)) at 3 months after everolimus initiation (P < 0.001), and 6.8 mL at 12 months. Improvement in renal function was higher in patients with early conversion (

Venous outflow is critical to the success of liver transplantation (LT). In domino liver transplantation (DLT), the venous cuffs should be shared between the donor and the recipient, and the length can be compromised. The aim of this study was to describe and compare the technical options for outflow reconstruction used at our institution. This was a retrospective analysis of 39 consecutive DLT recipients between January 1997 and May 2013. Twenty-seven men and 12 women (mean age, 61.8 ± 4.3 years) underwent LT and consented to receive a liver from a donor with familial amyloid polyneuropathy (FAP). The main indications were hepatocellular carcinoma and hepatitis C virus cirrhosis. All recipients underwent transplantation by a piggyback technique. Liver procurement in the FAP donors was performed with the classic technique in 22 patients and with the piggyback technique in the last 17. In these latter cases, for vascular outflow reconstruction, a cadaveric venous graft was interposed between the hepatic vein (HV) stump of the FAP liver and the recipient HV in 11 cases (28%). Since 2011, we have employed arterial grafts to be interposed between the vessels stumps: a tailored arterial graft in 5 patients and an aortic graft in 1 case. There was no postoperative mortality. Arterial and portal complications presented in 2 (5.1) and 4 patients (10.3), respectively. Postoperative outflow complications (post-LT subacute Budd-Chiari syndrome) occurred in 4 patients, and all of them had received a venous interposed graft for reconstruction. The incidence of outflow complications tended to be higher among patients with venous grafts than those with arterial graft interposition. Overall patient survival at 1, 3, 5, and 10 years was 97%, 79%, respectively. Arterial grafts constitute a feasible and safe option for vascular outflow reconstruction in DLT because they are associated with a relatively low incidence of complications. The recently proposed Bellvitge arterial graft technique should be added to the current range of available surgical modalities. Liver Transpl 21:1051-1055, 2015. © 2015 AASLD.

Introduction: chronic kidney disease is a frequent complication after liver transplantation. The use of calcineurin inhibitors is one of the causes of this complication. Current immunsuppression regimens that reduce the use of calcineurin inhibitors may be associated with an improved preservation of renal function. Objective: the study aimed to assess the evolution of renal function after liver transplantation in the current routine clinical practice. Methods: an observational, prospective, multicenter study in adult liver transplant recipients was performed. Two hundred and thirty patients with a good renal function before transplantation were assessed six months post-transplantation (baseline) and every six months until month 30. Results: at baseline, 32% of the patients had a reduction in the glomerular filtration rate below 60 ml/min/1.73 m2. The mean glomerular filtration rate increased from 72.3 to 75.6 ml/min/1.73 m2 at baseline and month 30 respectively (p < 0.01). The mean serum creatinine levels (mg/dl) decreased from 1.13 to 1.09 (p < 0.01). The percentage of patients with stage 3 chronic kidney disease decreased from 31.7% to 26.4%, whereas the percentage of patients with stage 4 remained unchanged (0.4% at baseline and 0.5% at month 30). No patients progressed to end-stage kidney disease that required dialysis or renal transplantation. Conclusion: in the routine clinical practice, a moderate deterioration of renal function is frequent after liver transplantation. However, advanced chronic kidney disease is infrequent in patients with a good pre-transplant renal function.

A retrospective cohort multicenter study was conducted to analyze the risk factors for tumor recurrence after liver transplantation (LT) in cirrhotic patients found to have an intrahepatic cholangiocarcinoma (iCCA) on pathology examination. We also aimed to ascertain whether there existed a subgroup of patients with single tumors 2cm (very early) in which results after LT can be acceptable. Twenty-nine patients comprised the study group, eight of whom had a very early iCCA (four of them incidentals). The risk of tumor recurrence was significantly associated with larger tumor size as well as larger tumor volume, microscopic vascular invasion and poor degree of differentiation. None of the patients in the very early iCCA subgroup presented tumor recurrence compared to 36.4% of those with single tumors >2cm or multinodular tumors, p=0.02. The 1-, 3- and 5-year actuarial survival of those in the very early iCCA subgroup was 100%, 73% and 73%, respectively. The present is the first multicenter attempt to ascertain the risk factors for tumor recurrence in cirrhotic patients found to have an iCCA on pathology examination. Cirrhotic patients with iCCA 2cm achieved excellent 5-year survival, and validation of these findings by other groups may change the current exclusion of such patients from transplant programs. This multicenter study analyzes the outcome of patients transplanted for hepatocellular carcinoma who were found to have an intrahepatic cholangiocarcinoma at pathology examination, and focuses on the excellent posttransplant outcome of patients with single intrahepatic cholangiocarcinomas 2 cm.

Early detection of pancreatic and periampullary neoplasms is critical to improve their clinical outcome. The present authors previously demonstrated that DNA hypermethylation of adenomatous polyposis coli (APC), histamine receptor H2 (HRH2), cadherin 13 (CDH13), secreted protein acidic and cysteine rich (SPARC) and engrailed-1 (EN-1) promoters is frequently detected in pancreatic tumor cells. The aim of the present study was to assess their prevalence in pancreatic juice of carcinomas of the pancreas and periampullary area. A total of 135 pancreatic juices obtained from 85 pancreatic cancer (PC), 26 ampullary carcinoma (AC), 10 intraductal papillary mucinous neoplasm (IPMN) and 14 chronic pancreatitis (CP) patients were analyzed. The methylation status of the APC, HRH2, CDH13, SPARC and EN-1 promoters was analyzed using methylation specific-melting curve analysis (MS-MCA). Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were also tested with allele-specific quantitative polymerase chain reaction amplification. Out of the 5 promoters analyzed, APC (71%) and HRH2 (65%) were the most frequently methylated in PC juice. APC methylation was also detected at a high frequency in AC (76%) and IPMN (80%), but only occasionally observed in CP (7%). APC methylation had a high sensitivity (71-80%) for all types of cancer analyzed. The panel (where a sample scored as positive when ≥2 markers were methylated) did not outperform APC as a single marker. Finally, KRAS detection in pancreatic juice offered a lower sensitivity (50%) and specificity (71%) for detection of any cancer. APC hypermethylation in pancreatic juice, as assessed by MS-MCA, is a frequent event of potential clinical usefulness in the diagnosis of pancreatic and periampullary neoplasms.

BACKGROUND Concomitant quantification of multiple mutant KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) alleles may provide information in addition to that provided by standard mutation-detection procedures. We assessed the feasibility of a nanofluidic digital PCR array platform to detect and quantify KRAS mutations simultaneously in clinically relevant samples. METHODS We assessed 2 groups of patients (colorectal and pancreatic disease): Group 1 consisted of 27 patients with colorectal carcinomas, 14 patients with adenomas, and 5 control individuals; group 2 consisted of 42 patients with pancreatic carcinoma, 4 with adenocarcinomas of the ampulla, and 6 with chronic pancreatitis). Digital PCR was performed with the Digital Array Chip (Fluidigm). RESULTS Nanofluidic digital PCR detected mutant alleles at 0.05% to 0.1%, depending on the variant analyzed. For the colorectal disease group, conventional PCR detected 9 (64%) of 14 adenomas that were positive for KRAS mutants, whereas digital PCR increased this number to 11 (79%) of 14. Sixteen (59%) of 27 carcinomas showed KRAS mutation with conventional PCR. Two additional cases were detected with digital PCR. In 5 cases (3 adenomas, 2 carcinomas), the total number of mutant alleles changed. For the pancreatic disease group, digital PCR increased the number of positive cases from 26 to 34 (81%) and identified ≥2 mutant alleles in 25 cases, compared with conventional PCR, which identified multiple KRAS mutant alleles in only 12 cases. A good correlation was observed between results obtained with tumor biopsies and those obtained with pancreatic juice. CONCLUSIONS Digital PCR provides a robust, quantitative measure of the proportion of KRAS mutant alleles in routinely obtained samples. It also allows a better classification of tumors, with potential clinical relevance.

Cytomegalovirus (CMV) infection is an opportunistic infection frequently found after solid organ transplantation, and it contributes significantly to mortality and morbidity. CMV-seronegative recipients of grafts from CMV-seropositive donors have the highest risk of CMV disease. The most appropriate strategy for preventing CMV disease in this population is a matter of active debate. In this study, we compared prophylaxis and preemptive therapy for the prevention of CMV disease in donor-seropositive/recipient-seronegative (D+ /R-) liver recipients. To this end, we selected a retrospective cohort of liver recipients (1992-2009) for analysis. D+ /R- patients were identified from the liver transplant program database. Eighty of 878 consecutive liver recipients (9%) were D+ /R-. Six of these patients died within 30 days of transplantation and were excluded. Thirty-five of the remaining D+ /R- patients (47%) received prophylaxis, and 39 patients (53%) followed a preemptive strategy based on CMV antigenemia surveillance. Fifty-four (73%) were men, the median age was 49 years (range = 15-68 years), and the mean follow-up was 68 months (range = 8-214 months). The baseline characteristics and the initial immunosuppressive regimens were similar for the 2 groups. Ganciclovir or valganciclovir was the antiviral drug used initially in both strategy groups. CMV disease occurred more frequently among D+ /R- liver recipients receiving preemptive therapy (33.3% versus 8.6% for the prophylaxis group, P = 0.01), whereas late-onset CMV disease was found only in patients receiving prophylaxis (5.7% versus 0% for the preemptive therapy group, P = 0.22). No significant differences in acute allograft rejection, other opportunistic infections, or case fatality rates were observed. According to our data, prophylaxis was more effective than preemptive therapy in preventing CMV disease in high-risk liver transplant recipients.

Recent reports of the transmission of systemic transthyretin (TTR) amyloidosis after domino liver transplantation (DLT) using grafts from patients with familial amyloid polyneuropathy (FAP) have raised concerns about the procedure. The aim of this study was to evaluate the transmission incidence of systemic TTR amyloidosis after DLT with a complete clinical, neurological, and pathological assessment. At our institution, DLT has been performed 31 times with livers from patients with FAP. Seventeen of the 19 patients still alive in 2008 agreed to enter the study. This cross-sectional study of this cohort of patients included clinical assessments, rectal biopsy, and electroneuromyography (as well as sural nerve biopsy when it was indicated). The mean follow-up at the time of the study was 62.6 ± 2.9 months. Clinically, 3 patients complained of weak dysesthesia. When a focused study was performed, 8 patients reported some kind of neurological and/or gastrointestinal disturbance. Six of the rectal biopsy samples showed amyloid deposits (TTR-positive). Electromyography (EMG) showed signs of mild sensorimotor neuropathy in 3 cases and moderate to severe sensorimotor neuropathy in 1 case. Only 2 of the 4 patients with EMG signs of polyneuropathy showed amyloid deposits in their rectal biopsy samples. Sural nerve biopsy revealed amyloid deposits (TTR-positive) in all 4 patients with EMG signs of polyneuropathy. Two patients with normal EMG findings had TTR-positive amyloid deposits in their sural nerve biopsy samples. In conclusion, de novo systemic amyloidosis after DLT may be more frequent and appear earlier than was initially thought. In our opinion, however, the graft shortage still justifies DLT in selected patients, despite the risk of de novo systemic amyloidosis. Sural nerve biopsy with EMG and clinical correlation is mandatory for confirming the disease. Indeed, other causes of neuropathy should be excluded.

Objective To assess the reliability and validity of a Spanish version of the LDQOL 1.0 (Liver Disease Quality of Life questionnaire). Methods Observational, cross-sectional study in Spanish patients awaiting liver transplantation (LT). Feasibility was assessed by analyzing administration times and missing responses. Ceiling and floor effects were calculated and reliability was tested by examining internal consistency (Cronbach's alpha). Convergent validity was tested by examining correlations between LDQOL disease-specific and Short Form health survey with 36 questions (SF-36) dimensions. Known groups' validity was tested by examining the LDQOL's capacity to discriminate between groups defined by etiology and Child–Turcotte–Pugh (CTP) scores. Results A total of 200 patients were included for analysis. Mean age (SD) was 52.6 (9.8) years and 73% of the sample were male. The most common indication for LT was liver cancer (34%). Mean (SD) time to complete the questionnaire was 35.8 minutes (21.2 minutes). Missing responses were highest on the dimensions of sexual functioning and symptoms of liver disease. Ceiling effects were over 20% on 7 of the LDQOL's 12 disease-specific scales. Cronbach's alpha coefficients were over 0.70 on all but 2 dimensions. Correlations between SF-36 and LDQOL disease-specific dimensions generally fulfilled the hypotheses, with 35 of the 40 highest and lowest correlations (87.5%) being in the expected direction. The LDQOL discriminated well between patients in CTP class A and C, and as hypothesized, hepatocarcinoma and alcoholic cirrhosis patients scored better on most dimensions than patients with hepatitis C virus or other etiologies. Conclusions The Spanish version of the LDQOL 1.0 has shown satisfactory reliability and validity.

The purpose of this study was to evaluate the influence of a steroid-free immunosuppression on hepatitis C virus (HCV) recurrence. A total of 198 liver transplantation (LT) patients were randomized to receive immunosuppression with basiliximab and cyclosporine, either with prednisone (steroid [St] group) or without prednisone (no steroids [NoSt] group). The group of 89 HCV-infected patients was followed up with protocol biopsies for 2 years after LT. This group of HCV patients are the patients evaluated in the present study. The rejection rate was 19% (St: 21% versus NoSt: 17%; P = 0.67). Patients in the St group had a slightly higher rate of bacterial infections (59% versus 38%; P = 0.05). Almost all patients had histological HCV-recurrence (St: 39/40 (97%) versus NoSt: 40/41 (97%); P = 1). The percentage of accumulated biopsies with grade 4 portal inflammation at 6 months, 1 year, and 2 years were, 23%, 49%, and 49% in the NoSt group, compared to 33%, 55%, and 69% in the St group, respectively (P = 0.04 at 2 years). The percentage of accumulated biopsies with grade 3 or 4 fibrosis at 6 months, 1 year, and 2 years were 0%, 8%, and 22% in the NoSt group, compared to 8%, 19%, and 31% in the St group, respectively. Immunosuppression without steroids in HCV patients is safe, reduces bacterial infections and metabolic complications, and improves histological short-term evolution of HCV recurrence.

We aimed to establish whether the presence of hepatic steatosis influences outcome after resection of colorectal liver metastases (CLM).Patients operated between 1990 and 2014 were divided into four groups based on the degree of hepatic steatosis. The association between hepatic steatosis and outcome was analyzed, using a multivariate and a propensity score case-match analysis.No significant differences were observed between patients with and without steatosis in either mortality or morbidity in the complete series or after matching (3.2% vs. 3.5%/p = 0.845) (32.3% vs 31.4%/p = 0.802). Five-year survival in patients with and without steatosis were 56.5% and 46.5% respectively (p = 0.046). The steatosis had a significant protective effect in the univariate analysis (HR (95% CI) = 0.78 (0.62-0.99) p = 0.048), and was close to significance in the multivariate analysis (HR (95%) = 0.81 (0.63-1.03) p = 0.089). No significant differences were seen with regard to liver recurrence.The presence of steatosis does not predict short-outcome after resection of CLM, but appears to be a favorable prognostic factor for survival. This protective effect does not depend on a decrease in liver recurrence.

The CYP2B1/cyclophosphamide (CPA) suicide gene therapy approach has been shown to be highly promising in clinical trials for the treatment of pancreatic cancer. However, delivering the therapeutic gene to a sufficient number of tumor cells able to trigger a complete response remains a challenge. Target-specific delivery of adenovirus to fibroblast growth factor receptors (FGFRs) has been obtained in a variety of tumor models and has been shown to highly increase transduction efficiency. In the present paper we have tested the therapeutic outcome of retargeting the adenoviral vector, Ad-CYP2B1, to FGFRs, using an FGF2-Fab' conjugate, in pancreatic cancer models. First, we show a heterogeneous subcellular distribution of overexpressed FGFR-1 in pancreatic cancer cells. Higher transduction efficiency was observed in five of the six cell lines studied after FGF2-AdGFPLuc infection. Interestingly, an association between FGFR-1 membrane cell expression and viral entry was found. Moreover, tumors injected with FGF2-AdGFPLuc showed enhanced and persistent transgene expression. Importantly, we demonstrate the relevant enhanced cytotoxic effect of the FGF2-Ad-CYP2B]/CPA system in four of the six cell lines studied. Moreover, retargeting Ad-CYP2B1/CPA to FGFRs resulted in a potent antitumoral effect and in an increased survival rate, in two human pancreatic xenograft models. Thus, our results indicate that redirecting adenoviruses to FGFRs highly increases the potency of the suicide system CYP2B1/CPA. Consequently, it may constitute a promising approach to the treatment of patients with pancreatic tumors, in which a high proportion of FGF receptors precisely localize to the plasma membrane.

We performed a prospective, randomized study of adult patients undergoing orthotopic liver transplantation, comparing hemodynamic and tissular oxygenation during reperfusion of the graft. In 30 patients, revascularization was started through the hepatic artery (i.e., initial arterial revascularization) and 10 minutes later the portal vein was unclamped; in 30 others, revascularization was started through the portal vein (i.e., initial portal revascularization) and 10 minutes later the hepatic artery was unclamped. The primary endpoints of the study were mean systemic arterial pressure and the gastric-end-tidal carbon dioxide partial pressure (PCO(2)) difference. The secondary endpoints were other hemodynamic and metabolic data. The pattern of the hemodynamic parameters and tissue oxygenation values during the dissection and anhepatic stages were similar in both groups At the first unclamping, initial portal revascularization produced higher values of mean pulmonary pressure (25 +/- 7 mm of Hg vs. 17 +/- 4 mm of Hg; P < 0.05) and wedge and central venous pressures. At the second unclamping, initial portal revascularization produced higher values of cardiac output and mean arterial pressure (87 +/- 15 mm of Hg vs. 79 +/- 15 mm of Hg; P < 0.05) and pulmonary blood pressure. Postreperfusion syndrome was present in 13 patients (42.5%) in the arterial group and in 11 patients (36%) in the portal group. During revascularization, the values of gastric and arterial pH decreased in both groups and recovered at the end of the procedure, but were more accentuated in the initial arterial revascularization group. In conclusion, we found that initial arterial revascularization of the graft increases pulmonary pressure less markedly, so it may be indicated for those patients with poor pulmonary and cardiac reserve. Nevertheless, for the remaining patients, initial portal revascularization offers more favorable hemodynamic and metabolic behavior, less inotropic drug use, and earlier normalization of lactate and pH values.

Aims of this study are to analyze the influence of endothelin-1 (ET-1) on hemodynamic evolution during liver transplantation (LT) and study the role of a temporary portacaval shunt in ET-1 synthesis. Forty LTs in patients with cirrhosis were studied. Two groups were analyzed: the first group had a temporary portacaval shunt during the anhepatic phase, and the second group did not. Portal and systemic ET-1 levels were measured at several times. At the end of the anhepatic phase, systemic (16.1 [plusmn] 6.5 pg/mL) and portal (19.2 [plusmn] 7 pg/mL) ET-1 levels increased, whereas they decreased after reperfusion (systemic, 11.8 [plusmn] 7.1 pg/mL; portal, 13.2 [plusmn] 6.8 pg/mL). Portal flow at the beginning of LT correlated with systemic ET-1 levels (R2 = 0.3; P = .004). A temporary portacaval shunt reduced portal pressure during the anhepatic phase, but did not modify ET-1 levels. Patients with reperfusion syndrome had greater systemic ET-1 levels in the anhepatic phase (19.1 [plusmn] 6.9 v 15.1 [plusmn] 6.1 pg/mL; P = .07). Although there is a relationship between ET-1 levels and portal flow and reperfusion syndrome, no clear clinical effect on hemodynamics could be shown. Creation of a portacaval shunt made no change in ET-1 levels. (Liver Transpl 2002;8:27-33.)

Domino liver transplantation (LT), using livers from familial amyloidotic polyneuropathy (FAP) patients, is a well described technique useful to expand donor pool. One of the main difficulties of this type of LT arises from the necessity to share the vascular pedicles between the graft and the donor. The most important challenge resides in restoring a proper hepatic venous outflow in the FAP-liver recipient. This is specially challenging when using the piggy-back technique, because the hepatic stumps may be too short. To overcome this issue, surgeons explored several techniques using different types of venous grafts. We describe a new technical option by using an arterial graft from the deceased donor. By using both iliac arteries a long graft is created and sutured as needed to the hepatic vein stump. We describe herein this new technique employed in a domino liver recipient who underwent retransplantation for ischemic cholangitis. The procedure was performed using the piggy-back technique; the venous stump of the FAP liver was reconstructed with the arterial graft. The patient had uneventful postoperative and mid-term hepatic function, and anastomosis was patent 24 months after LT.