Right Ex-situ split grafts for adult liver transplantation - A Multicenter Benchmarking Analysis.

OBJECTIVE: To analyse outcomes after adult right ex-situ split graft liver transplantations (RSLT) and compare with available outcome benchmarks from whole liver transplantation (WLT). SUMMARY BACKGROUND DATA: Ex-situ SLT may be a valuable strategy to tackle the increasing graft shortage. Recently established outcome benchmarks in WLT offer a novel reference to perform a comprehensive analysis of results after ex-situ RSLT. METHODS: This retrospective multicenter cohort study analyzes all consecutive adult SLT performed using right ex-situ split grafts from 01.01.2014 to 01.06.2022. Study endpoints included 1 year graft and recipient survival, overall morbidity expressed by the comprehensive complication index (CCI©) and specific post-LT complications. Results were compared to the published benchmark outcomes in low-risk adult WLT scenarii. RESULTS: In 224 adult right ex-situ SLT, 1y recipient and graft survival rates were 96% and 91.5%, within the WLT benchmarks. The 1y overall morbidity was also within the WLT benchmark (41.8 CCI points vs. <42.1). Detailed analysis, revealed cut surface bile leaks (17%, 65.8% Grade IIIa) as a specific complication without a negative impact on graft survival. There was a higher rate of early hepatic artery thrombosis (HAT) after SLT, above the WLT benchmark (4.9% vs. ≤4.1%), with a significant impact on early graft but not patient survival. CONCLUSION: In this multicentric study of right ex-situ split graft LT, we report 1-year overall morbidity and mortality rates within the published benchmarks for low-risk WLT. Cut surface bile leaks and early HAT are specific complications of SLT and should be acknowledged when expanding the use of ex-situ SLT.

European validation of the classification for the anticipated difficulty of liver transplantation.

BACKGROUND: Appropriate risk stratification for the difficulty of liver transplantation (LT) is essential to guide the selection and acceptance of grafts and avoid morbidity and mortality. METHODS: Based on 987 LTs collected from 5 centers, perioperative outcomes were analyzed across the 3 difficulty levels. Each LT was retrospectively scored from 0 to 10. Scores of 0-2, 3-5 and 6-10 were then translated into respective difficulty levels: low, moderate and high. Complications were reported according to the comprehensive complication index (CCI). RESULTS: The difficulty level of LT in 524 (53%), 323 (32%), and 140 (14%) patients was classified as low, moderate and high, respectively. The values of major intraoperative outcomes, such as cold ischemia time (p = 0.04) and operative time (p < 0.0001) increased gradually with statistically significant values among difficulty levels. There was a corresponding increase in CCI (p = 0.04), severe complication rates (p = 0.05) and length of ICU (p = 0.01) and hospital (p = 0.004) stays across the different difficulty levels. CONCLUSION: The LT difficulty classification has been validated.

Patients' perceptions of the definition of a textbook outcome following liver transplantation.

BACKGROUND: A textbook outcome (TO) describes the results of a successful liver transplantation (LT) in which all aspects of the LT and posttransplant courses were uneventful. We compared patient perceived experience of a TO with clinically defined TO. METHODS: This was a single-institution cohort study with retrospective chart review including patients who underwent LT from 2019 to 2021. Patients were asked to complete the survey at a scheduled posttransplant visit. The survey was designed to assess their viewpoints on the definition of a TO. A clinically defined TO was defined as no mortality, no severe complications, no need for reintervention, no prolonged hospital and intensive care unit stays, and no readmission. RESULTS: Of the 182 patients who were contacted, 132 (72.5%) completed the survey. Overall, 98 patients (74%) considered that they had experienced a TO. The clinically defined TO rate was 22.0%. Multivariate analysis showed that patients who did not experience severe complications were more likely to consider that they had a TO (P = 0.01; odds ratio: 3.2; 95% confidence interval: 1.3-7.9). CONCLUSIONS: From patients' perspectives, survival and avoidance of complications were the major characteristics of a TO.

Auxiliary Liver Transplantation for Cirrhosis: From APOLT to RAPID: A Scoping Review.

OBJECTIVE: To survey the available literature regarding the use of auxiliary liver transplantation (ALT) in the setting of cirrhosis. SUMMARY OF BACKGROUND: ALT is a type of liver transplantation (LT) procedure in which part of the cirrhotic liver is resected and part of the liver graft is transplanted. The cirrhotic liver left in situ acts as an auxiliary liver until the graft has reached sufficient volume. Recently, a 2-stage concept named RAPID (Resection and Partial Liver segment 2/3 transplantation with Delayed total hepatectomy) was developed, which combines hypertrophy of the small graft followed by delayed removal of the native liver. METHODS: A scoping review of the literature on ALT for cirrhosis was performed, focusing on the historical background of RAPID and the status of RAPID for this indication. The new comprehensive nomenclature for hepatectomy ("New World" terminology) was used in this review. RESULTS: A total of 72 cirrhotic patients underwent ALT [heterotopic (n = 34), orthotopic (Auxiliary partial orthotopic liver transplantation, n = 34 including 5 followed by resection of the native liver at the second stage) and RAPID (n = 4)]. Among the 9 2-stage LTs (APOLT, n = 5; RAPID, n = 4), portal blood flow modulation was performed in 6 patients by deportalization of the native liver (n = 4), portosystemic shunt creation (n = 1), splenic artery ligation (n = 3) or splenectomy (n = 1). The delay between the first and second stages ranged from 18 to 90 days. This procedure led to an increase in the graft-to-recipient weight ratio between 33% and 156%. Eight patients were alive at the last follow-up. CONCLUSIONS: Two-stage LT and, more recently, the RAPID procedure are viable options for increasing the number of transplantations for cirrhotic patients by using small grafts.

Novel Composite Endpoint for Assessing Outcomes in Liver Transplantation: Arterial and Biliary Complication-Free Survival.

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 split-liver 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.

Distinct immunopathological mechanisms of EBV-positive and EBV-negative posttransplant lymphoproliferative disorders.

EBV-positive and EBV-negative posttransplant lymphoproliferative disorders (PTLDs) arise in different immunovirological contexts and might have distinct pathophysiologies. To examine this hypothesis, we conducted a multicentric prospective study with 56 EBV-positive and 39 EBV-negative PTLD patients of the K-VIROGREF cohort, recruited at PTLD diagnosis and before treatment (2013-2019), and compared them to PTLD-free Transplant Controls (TC, n = 21). We measured absolute lymphocyte counts (n = 108), analyzed NK- and T cell phenotypes (n = 49 and 94), and performed EBV-specific functional assays (n = 16 and 42) by multiparameter flow cytometry and ELISpot-IFNγ assays (n = 50). EBV-negative PTLD patients, NK cells overexpressed Tim-3; the 2-year progression-free survival (PFS) was poorer in patients with a CD4 lymphopenia (CD4+ <300 cells/mm3 , p <  .001). EBV-positive PTLD patients presented a profound NK-cell lymphopenia (median = 60 cells/mm3 ) and a high proportion of NK cells expressing PD-1 (vs. TC, p = .029) and apoptosis markers (vs. TC, p < .001). EBV-specific T cells of EBV-positive PTLD patients circulated in low proportions, showed immune exhaustion (p = .013 vs. TC) and poorly recognized the N-terminal portion of EBNA-3A viral protein. Altogether, this broad comparison of EBV-positive and EBV-negative PTLDs highlight distinct patterns of immunopathological mechanisms between these two diseases and provide new clues for immunotherapeutic strategies and PTLD prognosis.

Enhanced Recovery in Liver Transplantation: A Feasibility Study.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) programmes after surgery are effective in reducing length of stay, functional recovery and complication rates in liver surgery (LS) with the indirect advantage of reducing hospitalisation costs. Preoperative comorbidities, challenging surgical procedures and complex post-operative management are the points that liver transplantation (LT) shares with LS. Nevertheless, there is little evidence regarding the feasibility and safety of ERAS programmes in LT. METHODS: We designed a pilot, small-scale, feasibility study to assess the impact on hospital stay, protocol compliance and safety of an ERAS programme tailored for LT. The ERAS arm was compared with a 1:2 match paired control arm with similar characteristics. All patients with MELD <25 were included. A dedicated LT-tailored protocol was derived from publications on ERAS liver surgery. RESULTS: Ten patients were included in the Fast-Trans arm. It was observed a 47% reduction of the total LOS, as compared to the control arm: 9.5 (9.0-10.5) days versus 18.0 (14.3-24.3) days, respectively, p <0.001. The protocol achieved 72.9% compliance. No differences were observed in terms of post-operative complications or readmission rates after discharge between the two arms. Overall, it was observed a reduction of length of stay in ICU and surgical ward in the Fast-Trans arm compared with the control arm. CONCLUSION: Considered the main points in common between LS and LT, this small-scale study suggests that the application of an ERAS programme tailored to the LT setting is feasible. Further testing will be appropriate to generalise these findings.

Nonalcoholic fatty liver disease increases the risk of hepatocellular carcinoma in patients with alcohol-associated cirrhosis awaiting liver transplants.

BACKGROUND & AIMS: Many patients with alcohol-associated cirrhosis also have diabetes, obesity, or insulin resistance-mediated steatosis, but little is known about how these disorders affect the severity of liver disease. We analyzed the prevalence and prognostic implications of metabolic risk factors (MRFs) such as overweight, diabetes, dyslipidemia, and hypertension in patients with alcohol-associated cirrhosis awaiting liver transplants. METHODS: We performed a retrospective study of 110 patients with alcohol-associated cirrhosis (77% male; mean age, 55 y; 71% with >6 mo of abstinence) who received liver transplants at a single center in Paris, France, from 2000 through 2013. We collected data on previous exposure to MRFs, steatosis (>10% in the explant), and histologically confirmed hepatocellular carcinoma (HCC). RESULTS: HCC was detected in explants from 29 patients (26%). Steatosis was detected in explants from 47 patients (70% were abstinent for ≥6 mo); 50% had a history of overweight or type 2 diabetes. Fifty-two patients (47%) had a history of MRFs and therefore were at risk for nonalcoholic fatty liver disease. A higher proportion of patients with MRF had HCC than those without MRF (46% vs 9%; P < .001). A previous history of overweight or type 2 diabetes significantly increased the risk for HCC (odds ratio, 6.23; 95% confidence interval [CI], 2.47-15.76, and odds ratio, 4.63; 95% CI, 1.87-11.47, respectively; P < .001). MRF, but not steatosis, was associated with the development of HCC (odds ratio, 11.76; 95% CI, 2.60-53; P = .001) independent of age, sex, amount of alcohol intake, or severity of liver disease. CONCLUSIONS: Patients with alcohol-associated cirrhosis who received transplants frequently also had nonalcoholic fatty liver disease. MRFs, particularly overweight, obesity, and type 2 diabetes, significantly increase the risk of HCC.

Base-catalyzed intramolecular hydroamination of cyclohexa-2,5-dienes: insights into the mechanism through DFT calculations and application to the total synthesis of epi-elwesine.

The base-catalyzed intramolecular hydroamination of 1-ethylaminocyclohexa-2,5-dienes is described. The transformation proceeds through isomerization of the cyclohexa-1,4-dienyl fragment into the corresponding conjugated 1,3-diene prior to the hydroamination step. Attaching a chiral glycinol ether auxiliary on the amino group allows the protonation to occur with complete diastereocontrol. The resulting lithium amide then adds onto the 1,3-dienyl moiety, affording the desired fused pyrrolidine ring along with the corresponding lithium allylic anion. Protonation of the latter then proceeds with high regiocontrol to favor the resulting allylic amines. In contrast, when the reaction was performed on primary amines, fused pyrrolidines bearing a homoallylic amino group were obtained. The stereochemical course of the process and determination of the reaction pathways were established based on calculations performed at the DFT level. Finally, application of the methodology to the enantioselective synthesis of (+)-epi-elwesine, a crinane alkaloid, is described.

Postoperative and long-term outcomes after redo surgery for failed colorectal or coloanal anastomosis: retrospective analysis of 50 patients and review of the literature.

INTRODUCTION: Redo surgery for failed colorectal or coloanal anastomosis is a surgical challenge, but despite its technical difficulties and the high associated morbidity risk, it may represent the only valuable option to improve patients' quality of life by avoiding a permanent stoma and decreasing chronic pelvic symptoms. OBJECTIVES: This study aimed to analyze postoperative and long-term outcomes, with particular focus on functional results, in patients undergoing redo surgery in comparison with previously published studies. DESIGN: This was a retrospective review of prospectively collected data in an institutional database. SETTING: The study was conducted in the colorectal unit of a tertiary referral teaching hospital in France. PATIENTS: Consecutive patients who underwent redo surgery for failed colorectal or coloanal anastomosis from 1998 to 2011 were included. RESULTS: A total of 50 patients (23 men, 27 women) were included. The median age at redo surgery was 62 years (range, 40-84). Twenty-six patients (52%) underwent a redo colorectal anastomosis and 24 patients a redo coloanal anastomosis (48%). Indications were anastomotic stricture (n = 20), chronic pelvic sepsis (n = 14), rectovaginal fistula (n = 3), prior Hartmann's procedure for complication of initial anastomosis (n = 8), and anastomotic cancer recurrence (n = 5). The median operative time was 435 minutes. Postoperative mortality was 0% and morbidity was 26%. No anastomotic leakage occurred. After a median follow-up of 21 (range, 1-137) months, 44 patients (88%) were evaluated for functional results. The median number of bowel movements per day was 2 (range, 1-10), with 70% of patients having fewer than 3 per day. LIMITATION: The study was limited by its retrospective nature and lack of data on quality of life. CONCLUSIONS: Redo surgery for failed colorectal or coloanal anastomosis is a valuable surgical option which allows avoidance of a permanent stoma in nearly 90% of patients. It remains a major undertaking with high intraoperative and postoperative morbidity.

Perceptions of surgical difficulty in liver transplantation: A European survey and development of the Pitié-Salpêtrière classification.

BACKGROUND: Significant variations exist regarding the definition of difficult liver transplantation. The study goals were to investigate how liver transplant surgeons evaluate the surgical difficulty of liver transplantation and to use the identified factors to classify liver transplantation difficulty. METHODS: A Web-based online European survey was presented to liver transplant surgeons. The survey was divided into 3 parts: (1) participant demographics and practices; (2) various situations based on recipient, liver disease, tumor treatment, and technical factors; and (3) 8 real-life clinical vignettes with different levels of complexity. In part 3 of the survey, respondents were asked whether they would perform liver transplantation but were not aware that these patients eventually underwent liver transplantation. RESULTS: A total of 143 invites were sent out, and 97 (67.8%) participants completed the survey. Most participants considered previous spontaneous bacterial peritonitis, previous supra-mesocolic surgery, hypertrophy of segment I, and obesity to be recipient factors for high-difficulty liver transplantation. Most participants considered liver transplantation to be challenging in patients with Budd-Chiari syndrome, Kasai surgery, polycystic liver disease, diffuse portal vein thrombosis, and a history of open hepatectomy. The proportion of participants indicating that liver transplantation was warranted varied across the 8 cases, from 69% to 100%. Our classification of the surgical difficulty of liver transplantation employed these recipient-related, surgical history-related, and liver disease-related variables and 3 difficulty groups were identified: low, intermediate, and high difficulty groups. CONCLUSION: This survey provides an overview of the surgical difficulty of various situations in liver transplantation that could be useful for further benchmark and textbook outcome studies.

Right colon to rectal anastomosis (Deloyers procedure) as a salvage technique for low colorectal or coloanal anastomosis: postoperative and long-term outcomes.

BACKGROUND: After extended left colectomy, it may be difficult to take down a well-vascularized colon into the pelvis and perform a tension-free colorectal or coloanal anastomosis. The Deloyers procedure comprising complete mobilization and rotation of the right colon while maintaining the ileocolic artery may be used in this circumstance. OBJECTIVE: The aim of this study is to report postoperative and long-term outcomes after the Deloyers procedure as a salvage technique for colorectal anastomosis or coloanal anastomosis. DESIGN: From a prospective database, we retrospectively reviewed all patients who underwent a Deloyers procedure. SETTING: This study was conducted at the Colorectal Unit in a tertiary referral teaching hospital. PATIENTS: Between 1998 and 2011, 48 consecutive patients underwent a Deloyers procedure. Indications were as following: Hartmann reversal (n = 17), previous colorectal anastomosis-related complications (n = 11), diverticular disease (n = 6), left colon cancer (n = 6), ischemic colitis (n = 3), iterative colectomy for cancer (n = 3), rectal cancer local recurrence (n = 1), and synchronous colon cancer (n = 1). RESULTS: There were 38 men and 10 women (median age at surgery, 67 years). Colorectal anastomosis and coloanal anastomosis were performed in 38 and 10 patients. Thirty-one patients had defunctioning stoma. Mortality and early morbidity rate was 2% and 23%. Three patients (6%) had severe complications (Dindo ≥ 3). There was no anastomotic leakage. Reoperation was required in 2 patients for intra-abdominal hemorrhage. The median hospital stay was 12 days. The median follow-up was 26 months. All patients had their ileostomy closed. Twenty-three percent of patients developed late complications. The median number of bowel movements per day was 3 (range, 1-7), but 67% of patients had fewer than 3. One patient required an ileostomy refashioning because of poor functional results, and 23% of patients routinely take loperamide-based medication. LIMITATION: The retrospective nature of the study was a limitation. CONCLUSIONS: The Deloyers procedure is safe, associated with low morbidity and good long-term functional results. It represents a safe alternative to total colectomy and ileorectal anastomosis.

Removable directing groups in organic synthesis and catalysis.

Directing groups have been widely used in recent years to achieve control over all aspects of reaction selectivity in a wide range of transformations involving transition-metal catalysis and organometallic reagents. In cases when the existing functional group within a substrate is unsuited to achieve efficient intramolecular delivery of a reagent or catalyst, the specific introduction of an appropriately designed removable reagent-directing group can be a solution to this problem. In this Review we give an overview of the state of the art in this area, including the stoichiometric and catalytic use of directing groups.

Functionalization and rearrangement of spirocyclohexadienyl oxindoles: experimental and theoretical investigations.

The preparation and functionalization of spirocyclohexa-2,5-diene oxindoles is described. The spirocyclic core of the title compounds was installed by using a SmI(2)-mediated cyclization of aryl iodobenzamides. Epoxidation with CF(3)CO(3)H was then carried out and was shown to occur with a high level of diastereocontrol: the reagent approaches the diene moiety syn to the amide group, which is likely to be as a consequence of hydrogen bonding between the amide C=O bond and the peracid hydrogen. Carbanionic functionalization of the spirocyclohexa-2,5-diene oxindoles was then examined, leading to an unprecedented rearrangement of the strained spiro system into dearomatized phenanthridinones. Upon treatment with lithium diisopropylamide (LDA) at -40 degrees C, the dienes rearranged to provide a phenanthridinone lithium enolate intermediate that was trapped by electrophiles including alkyl halides and aldehydes. Interestingly, alkylation and hydroxyalkylation occurred with different regiocontrol. DFT calculations were performed that rationalize the observed skeleton rearrangement, emphasizing the role of LDA/diisopropylamine in this rearrangement. The proposed mechanism thus relies on a thermodynamically driven diisopropylamine-mediated proton transfer with the cleavage of the diene-amide C=O bond as the key step.

Rate of employment after liver transplantation in France: a single-centre study.

BACKGROUND: A return to gainful employment is an important outcome parameter after liver transplantation (LT). A recent study in the USA has shown a very high rate of unemployment after LT (75%). To date, there are no available data in France, where the public health insurance programme guarantees financial protection for everyone. AIMS: The aim of this study was to assess the employment rate after LT in a French LT centre and to determine factors associated with employment after LT. METHODS: All patients who had undergone liver transplantation at our centre between January 2000 and April 2011 and who met the following criteria responded to a questionnaire: (i) between 18 and 65 years old at the time of LT, (ii) alive 1 year after LT, (iii) alive, not retired and released from the hospital at the time of survey, (iv) French residents who were affiliated with French national health insurance. RESULTS: A total of 345 LTs were performed in 314 patients during the study period. Of the patients, 109 were excluded from the study: 23 had died within the first year after LT, 28 had died at the time of the survey, three were still in the hospital, seven were living in a foreign country, 11 had retired and 37 were older than 65 years after LT. Two hundred five patients were included in the study. The response rate was 76.6% (157/205). Patients responded a mean 6.1 ± 0.9 years after LT, 77.7% were French nationals, 73.2% were men, and the mean age at LT was 48.8 ± 9.9 years. The aetiologies of liver disease were as follows: alcohol 32.5%, hepatitis C 26.1%, alcohol and hepatitis C 3.8%, hepatitis B 15.3%, biliary cirrhosis 5.1%, autoimmune 2.5% and other causes 14.7%. Two years after LT, 43.3% of patients were employed. The demographic variables associated with post-LT employment were male sex (P<0.001), age under 40 years at LT (P=0.02), a sedentary job (P=0.007), raising children under the age of 18 years at the time of LT (P=0.01), a high level of education (P=0.001), not being affiliated with the French universal health coverage or 'CMU' (P=0.001). Only 53.3% of the patients who did not return to work after LT stated that they felt like they had a physical disability. CONCLUSION: The rate of return to work after LT in France was 43.1%, which was higher than that reported in the US study. However, this rate remains low and policies supporting return to work are needed to help liver recipients who wish to work after LT.

Anti-hepatitis C virus potency of a new autophagy inhibitor using human liver slices model.

AIM: To evaluate the antiviral potency of a new anti-hepatitis C virus (HCV) antiviral agent targeting the cellular autophagy machinery. METHODS: Non-infected liver slices, obtained from human liver resection and cut in 350 µm-thick slices (2.7 × 10(6) cells per slice) were infected with cell culture-grown HCV Con1b/C3 supernatant (multiplicity of infection = 0.1) cultivated for up to ten days. HCV infected slices were treated at day 4 post-infection with GNS-396 for 6 d at different concentrations. HCV replication was evaluated by strand-specific real-time quantitative reverse transcription - polymerase chain reaction. The infectivity titers of supernatants were evaluated by foci formation upon inoculation into naive Huh-7.5.1 cells. The cytotoxic effect of the drugs was evaluated by lactate dehydrogenase leakage assays. RESULTS: The antiviral efficacy of a new antiviral drug, GNS-396, an autophagy inhibitor, on HCV infection of adult human liver slices was evidenced in a dose-dependent manner. At day 6 post-treatment, GNS-396 EC50 was 158 nmol/L without cytotoxic effect (compared to hydroxychloroquine EC50 = 1.17 µmol/L). CONCLUSION: Our results demonstrated that our ex vivo model is efficient for evaluation the potency of autophagy inhibitors, in particular a new quinoline derivative GNS-396 as antiviral could inhibit HCV infection in a dose-dependent manner without cytotoxic effect.