High-Dimensional Single-Cell Analysis Identifies Organ-Specific Signatures and Conserved NK Cell Subsets in Humans and Mice.

Natural killer (NK) cells are innate lymphoid cells (ILCs) involved in antimicrobial and antitumoral responses. Several NK cell subsets have been reported in humans and mice, but their heterogeneity across organs and species remains poorly characterized. We assessed the diversity of human and mouse NK cells by single-cell RNA sequencing on thousands of individual cells isolated from spleen and blood. Unbiased transcriptional clustering revealed two distinct signatures differentiating between splenic and blood NK cells. This analysis at single-cell resolution identified three subpopulations in mouse spleen and four in human spleen, and two subsets each in mouse and human blood. A comparison of transcriptomic profiles within and between species highlighted the similarity of the two major subsets, NK1 and NK2, across organs and species. This unbiased approach provides insight into the biology of NK cells and establishes a rationale for the translation of mouse studies to human physiology and disease.

Liver transplantation plus chemotherapy versus chemotherapy alone in patients with permanently unresectable colorectal liver metastases (TransMet): results from a multicentre, open-label, prospective, randomised controlled trial.

BACKGROUND: Despite the increasing efficacy of chemotherapy, permanently unresectable colorectal liver metastases are associated with poor long-term survival. We aimed to assess whether liver transplantation plus chemotherapy could improve overall survival. METHODS: TransMet was a multicentre, open-label, prospective, randomised controlled trial done in 20 tertiary centres in Europe. Patients aged 18-65 years, with Eastern Cooperative Oncology Group performance score 0-1, permanently unresectable colorectal liver metastases from resected BRAF-non-mutated colorectal cancer responsive to systemic chemotherapy (≥3 months, ≤3 lines), and no extrahepatic disease, were eligible for enrolment. Patients were randomised (1:1) to liver transplantation plus chemotherapy or chemotherapy alone, using block randomisation. The liver transplantation plus chemotherapy group underwent liver transplantation for 2 months or less after the last chemotherapy cycle. At randomisation, the liver transplantation plus chemotherapy group received a median of 21·0 chemotherapy cycles (IQR 18·0-29·0) versus 17·0 cycles (12·0-24·0) in the chemotherapy alone group, in up to three lines of chemotherapy. During first-line chemotherapy, 64 (68%) of 94 patients had received doublet chemotherapy and 30 (32%) of 94 patients had received triplet regimens; 76 (80%) of 94 patients had targeted therapy. Transplanted patients received tailored immunosuppression (methylprednisolone 10 mg/kg intravenously on day 0; tacrolimus 0·1 mg/kg via gastric tube on day 0, 6-10 ng/mL days 1-14; mycophenolate mofetil 10 mg/kg intravenously day 0 to <2 months and switch to everolimus 5-8 ng/mL), and postoperative chemotherapy, and the chemotherapy group had continued chemotherapy. The primary endpoint was 5-year overall survival analysed in the intention to treat and per-protocol population. Safety events were assessed in the as-treated population. The study is registered with ClinicalTrials.gov (NCT02597348), and accrual is complete. FINDINGS: Between Feb 18, 2016, and July 5, 2021, 94 patients were randomly assigned and included in the intention-to-treat population, with 47 in the liver transplantation plus chemotherapy group and 47 in the chemotherapy alone group. 11 patients in the liver transplantation plus chemotherapy group and nine patients in the chemotherapy alone group did not receive the assigned treatment; 36 patients and 38 patients in each group, respectively, were included in the per-protocol analysis. Patients had a median age of 54·0 years (IQR 47·0-59·0), and 55 (59%) of 94 patients were male and 39 (41%) were female. Median follow-up was 59·3 months (IQR 42·4-60·2). In the intention-to-treat population, 5-year overall survival was 56·6% (95% CI 43·2-74·1) for liver transplantation plus chemotherapy and 12·6% (5·2-30·1) for chemotherapy alone (HR 0·37 [95% CI 0·21-0·65]; p=0·0003) and 73·3% (95% CI 59·6-90·0) and 9·3% (3·2-26·8), respectively, for the per-protocol population. Serious adverse events occurred in 32 (80%) of 40 patients who underwent liver transplantation (from either group), and 69 serious adverse events were observed in 45 (83%) of 54 patients treated with chemotherapy alone. Three patients in the liver transplantation plus chemotherapy group were retransplanted, one of whom died postoperatively of multi-organ failure. INTERPRETATION: In selected patients with permanently unresectable colorectal liver metastases, liver transplantation plus chemotherapy with organ allocation priority significantly improved survival versus chemotherapy alone. These results support the validation of liver transplantation as a new standard option for patients with permanently unresectable liver-only metastases. FUNDING: French National Cancer Institute and Assistance Publique-Hôpitaux de Paris.

Evaluation of a delayed liver transplantation strategy for patients with HCC receiving bridging therapy: the DELTA-HCC study.

BACKGROUND & AIMS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015 in patients listed for any single HCC treated with resection or thermal ablation during the waiting phase. The DS involves postponing LT until recurrence. The purpose of this study was to evaluate the DS to make sure that it did not hamper pre- and post-LT outcomes. METHODS: Patients listed for HCC in France between 2015 and 2018 were studied. After data extraction from the national LT database, 2,025 patients were identified and classified according to six groups: single tumor entering DS, single tumor not entering DS, multiple tumors, no curative treatment, untreatable HCC or T1 tumors. Kaplan-Meier estimates of the 18-month risk of dropout for death, too sick to be transplanted or tumor progression before LT, 5-year post-LT HCC recurrence and post-LT survival rates were compared. RESULTS: Median waiting-time in the DS group was 910 days. Pre-LT dropout probability was significantly lower in the DS group compared to other groups (13% vs. 19%, p = 0.0043) and significantly higher in the T1 group (25.4%, p = 0.05). Post-LT HCC recurrence rate in the multiple nodules group was significantly higher (19.6%, p = 0.019), while 5-year post-LT survival did not differ among groups and was 74% in the DS group (p = 0.22). CONCLUSION: The DELTA-HCC study shows that DS does not negatively impact either pre- nor post-LT patient outcomes, and has the potential to allow for redistribution of organs to patients in more urgent need of LT. It can reasonably be proposed and pursued. The unexpectedly high risk of dropout in T1 patients seems related to the MELD-based offering rules underserving this subgroup. IMPACTS AND IMPLICATIONS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy was adopted in France in 2015. It involves postponing LT until recurrence in patients listed for any single HCC curatively treated by surgical resection or thermal ablation. The DELTA-HCC study was conducted to evaluate this nationwide strategy. It shows in a European LT program that delayed strategy does not negatively impact pre- nor post-LT patient outcomes and is relevant to up to 20% of LT candidates; thus, it could potentially enable the redistribution of organs to patients in more urgent need of LT. Such a delayed strategy can reasonably be pursued and extended to other LT programs. Of note, an unexpectedly high risk of dropout in T1 patients, seemingly related to MELD-based offering rules which underserve these patients, calls for further scrutinization and revision of allocation rules in this subgroup.

Autoimmune hepatitis recurrence after liver transplantation: "Les jeux sont faits".

Autoimmune hepatitis (AIH) may recur after liver transplantation (LT). The aims of this study were to evaluate the incidence and risk factors for recurrent autoimmune hepatitis (rAIH). A multicenter retrospective French nationwide study, including all patients aged ≥16 transplanted for AIH, with at least 1 liver biopsy 1 year after LT, was conducted between 1985 and 2018. Risk factors for rAIH were identified using a multivariate Cox regression model. Three hundred and forty-four patients were included (78.8% women) with a median age at LT of 43.6 years. Seventy-six patients (22.1%) developed recurrence in a median time of 53.6 months (IQR, 14.1-93.2). Actuarial risk for developing rAIH was 41.3% 20 years after LT. In multivariate analysis, the strongest risk factor for rAIH was cytomegalovirus D+/R- mismatch status (HR=2.0; 95% CI: 1.1-3.6; p =0.03), followed by associated autoimmune condition. Twenty-one patients (27.6% of rAIH patients) developed liver graft cirrhosis after rAIH. Independent risk factors for these severe forms of rAIH were young age at LT, IgG levels >20.7 g/L, and LT in the context of (sub)fulminant hepatitis. Immunosuppression, especially long-term maintenance of corticosteroid therapy, was not significantly associated with rAIH. Recurrence of AIH after LT is frequent and may lead to graft loss. Recurrence is more frequent in young patients with active disease at the time of LT, yet systematic corticosteroid therapy does not prevent it.

Recipient age influences survival after liver transplant: Results of the French national cohort 2007-2017.

BACKGROUND: In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality. METHODS: All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality. RESULTS: Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results. CONCLUSION: Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT.

Surgical versus endoscopic gastroenterostomy for gastric outlet obstruction: a retrospective multicentric comparative study of technical and clinical success.

PURPOSE: Gastric outlet obstruction (GOO) is mainly due to advanced malignant disease. GOO can be treated by surgical gastroenterostomy (SGE), endoscopic enteral stenting (EES), or endoscopic ultrasound-guided gastroenterostomy (EUS-GE) to improve the quality of life. METHODS: Between 2009 and 2022, patients undergoing SGE or EUS-GE for GOO were included at three centers. Technical and clinical success rates, post-procedure adverse events (AEs), length of hospital stay (LOS), 30-day all-cause mortality, and recurrence of GOO were retrospectively analyzed and compared between SGE and EUS-GE. Predictive factors for technical and clinical failure after SGE and EUS-GE were identified. RESULTS: Of the 97 patients included, 56 (57.7%) had an EUS-GE and 41 (42.3%) had an SGE for GOO, with 62 (63.9%) GOO due to malignancy and 35 (36.1%) to benign disease. The median follow-up time was 13,4 months (range 1 days-106 months), with no difference between the two groups (p = 0.962). Technical (p = 0.133) and clinical (p = 0.229) success rates, severe morbidity (p = 0.708), 30-day all-cause mortality (p = 0.277) and GOO recurrence (p = 1) were similar. EUS-GE had shorter median procedure duration (p < 0.001), lower post-procedure ileus rate (p < 0.001), and shorter median LOS (p < 0.001) than SGE. In univariate analysis, no risk factors for technical or clinical failure in SGE were identified and abdominal pain reported before the procedure was a risk factor for technical failure in the EUS-GE group. No risk factor for clinical failure was identified for EUS-GE. In the subgroup of GOO due to benign disease, SGE was associated with better technical success (p = 0.035) with no difference in clinical success rate compared to EUS-GE (p = 1). CONCLUSION: EUS-GE provides similar long-lasting symptom relief as SGE for GOO whether for benign or malignant disease. SGE may still be indicated in centers with limited experience with EUS-GE or may be reserved for patients in whom endoscopic technique fails.

Comparing indications, complexity and outcomes of laparoscopic liver resection between centers with and without a liver transplant program: a French nationwide study.

BACKGROUND: There are no data to evaluate the difference in populations and impact of centers with liver transplant programs in performing laparoscopic liver resection (LLR). METHODS: This was a multicenter study including patients undergoing LLR for benign and malignant tumors at 27 French centers from 1996 to 2018. The main outcomes were postoperative severe morbidity and mortality. RESULTS: A total of 3154 patients were included, and 14 centers were classified as transplant centers (N = 2167 patients, 68.7 %). The transplant centers performed more difficult LLRs and more resections for hepatocellular carcinoma (HCC) in patients who more frequently had cirrhosis. A higher rate of performing the Pringle maneuver, a lower rate of blood loss and a higher rate of open conversion (all p < 0.05) were observed in the transplant centers. There was no association between the presence of a liver transplant program and either postoperative severe morbidity (<10 % in each group; p = 0.228) or mortality (1 % in each group; p = 0.915). CONCLUSIONS: Most HCCs, difficult LLRs, and cirrhotic patients are treated in transplant centers. We show that all centers can achieve comparable safety and quality of care in LLR independent of the presence of a liver transplant program.

Treatment of donor-specific anti-HLA antibodies-mediated rejection after liver transplantation: A French nationwide retrospective study.

The deleterious effect of donor-specific anti-HLA antibodies (DSA) after liver transplantation (LT) has been increasingly recognized during the past decade. Antibody-mediated rejection (AMR) represents a rare but severe complication in the presence of DSA. However, little is known concerning the treatment of AMR after LT. The nationwide French study aimed to describe LT recipients who received specific treatment of AMR. We performed a multicenter retrospective study on 44 patients who were treated with B-cell targeting agents from January 2008 to December 2020. Median patient age at the time of AMR treatment was 51.6 years (range: 17.9-68.0). AMR was classified as acute (n = 19) or chronic (n = 25). The diagnosis of AMR was made after a median time of 16.8 months (range: 0.4-274.2) after LT. The main therapeutic combination was plasma exchange/rituximab/IVIG (n = 25, 56.8%). The median follow-up after the treatment of AMR was 32 months (range: 1-115). After the treatment, 1-, 5- and 10-year patient and graft survivals were 77%, 55.9%, and 55.9%, and 69.5%, 47.0%, and 47.0%, respectively. Initial total bilirubin (Q1-Q3 vs. Q4) was significantly associated with patient survival (log-rank test, p = 0.005) and graft survival (log-rank test, p = 0.002). After a median follow-up of 21 months (range: 12-107), DSA became undetectable in 15/38 patients (39.5%) with available DSA monitoring. In conclusion, specific treatment of AMR in LT recipients has slowly emerged in France during the past decade and has probably been considered in the most severe patients; this explains the global poor outcome, even if the outcome was favorable in some cases.

Liver transplantation for autoimmune hepatitis: Pre-transplant does not predict the early post-transplant outcome.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare indication (<5%) for liver transplantation (LT). The aim of this study was to describe the early outcome after LT for AIH. METHODS: A multicenter retrospective nationwide study including all patients aged ≥16 transplanted for AIH in France was conducted. Occurrences of biliary and vascular complications, rejection, sepsis, retransplantation and death were collected during the first year after LT. RESULTS: A total of 344 patients (78.8% of women, 17.0% of (sub)fulminant hepatitis and 19.2% of chronic liver diseases transplanted in the context of acute-on-chronic liver failure [ACLF]) were included, with a median age at LT of 43.6 years. Acute rejection, sepsis, biliary and vascular complications occurred in respectively 23.5%, 44.2%, 25.3% and 17.4% of patients during the first year after LT. One-year graft and patient survivals were 84.3% and 88.0% respectively. The main cause of early death was sepsis. Pre-LT immunosuppression was not associated with an increased risk for early infections or surgical complications. Significant risk factors for septic events were LT in the context of (sub)fulminant hepatitis or ACLF, acute kidney injury at the time of LT (AKI) and occurrence of biliary complications after LT. AKI was the only independent factor associated with graft (HR = 2.5; 95% CI: 1.1-5.4; p = .02) and patient survivals (HR = 2.6; 95% CI: 1.0-6.5; p = .04). CONCLUSION: Early prognosis is good after LT for AIH and is not impacted by pre-LT immunosuppression but by the presence of AKI at the time of LT.

Long-term outcome of liver transplantation for autoimmune hepatitis: A French nationwide study over 30 years.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a rare indication for liver transplantation (LT). The aims of this study were to evaluate long-term survival after LT for AIH and prognostic factors, especially the impact of recurrent AIH (rAIH). METHODS: A multicentre retrospective nationwide study including all patients aged ≥16 transplanted for AIH in France was conducted. Early deaths and retransplantations (≤6 months) were excluded. RESULTS: The study population consisted of 301 patients transplanted from 1987 to 2018. Median age at LT was 43 years (IQR, 29.4-53.8). Median follow-up was 87.0 months (IQR, 43.5-168.0). Seventy-four patients (24.6%) developed rAIH. Graft survival was 91%, 79%, 65% at 1, 10 and 20 years respectively. Patient survival was 94%, 84% and 74% at 1, 10 and 20 years respectively. From multivariate Cox regression, factors significantly associated with poorer patient survival were patient age ≥58 years (HR = 2.9; 95% CI, 1.4-6.2; p = 0.005) and occurrence of an infectious episode within the first year after LT (HR = 2.5; 95% CI, 1.2-5.1; p = 0.018). Risk factors for impaired graft survival were: occurrence of rAIH (HR = 2.7; 95% CI, 1.5-5.0; p = 0.001), chronic rejection (HR = 2.9; 95% CI, 1.4-6.1; p = 0.005), biliary (HR = 2.0; 95% CI, 1.2-3.4; p = 0.009), vascular (HR = 1.8; 95% CI, 1.0-3.1; p = 0.044) and early septic (HR = 2.1; 95% CI, 1.2-3.5; p = 0.006) complications. CONCLUSION: Our results confirm that survival after LT for AIH is excellent. Disease recurrence and chronic rejection reduce graft survival. The occurrence of an infectious complication during the first year post-LT identifies at-risk patients for graft loss and death.

Five-year outcomes in liver transplant patients receiving everolimus with or without a calcineurin inhibitor: Results from the CERTITUDE study.

BACKGROUND AND AIMS: To report 5-year outcomes of the CERTITUDE study. METHODS: An observational study in patients with liver transplantation (LTx) compared the long-term impact of immunosuppression (with/without a calcineurin inhibitor) on renal function, cancers, major cardiovascular events (MACEs) and other safety parameters. All patients completing the 6-month SIMCER study were recruited and analysed according to treatment received at randomization and actual treatment received during the follow-up. RESULTS: Of the 143 enrolled patients, 119 completed the 5-year follow-up (everolimus [EVR], n = 55; tacrolimus [TAC], n = 64). The mean absolute change in estimated glomerular filtration rate was not statistically different between both groups (TAC, -15.53 ml/min/1.73 m2 and EVR, -14.56 ml/min/1.73 m2 ). In the treatment subgroups based on actual treatment received, renal function was preserved better in the EVR subgroup compared with other subgroups (p = .051). Treated biopsy-proven acute rejection was higher in the EVR group (15.4% vs. 6.4%); however, the majority of events were mild in severity. MACE occurred in 9.2% vs. 14.1% of patients in the EVR and TAC groups respectively (p = .370). De novo cancer was reported in 14 and 5 patients in EVR and TAC groups respectively. Hepatocellular carcinoma (HCC) recurrence was observed in the TAC group alone (n = 4). Adverse events and treatment discontinuation owing to an adverse event were higher in the EVR group. CONCLUSIONS: The CERTITUDE study demonstrated that EVR- and TAC-based regimens have comparable efficacy, safety and tolerability up to 5 years post-LTx.

Liver transplantation for NAFLD cirrhosis: Age and recent coronary angioplasty are major determinants of survival.

BACKGROUND AND AIMS: Liver transplantation (LT) is the treatment of end-stage non-alcoholic liver disease (NAFLD), that is decompensated cirrhosis and/or complicated by hepatocellular carcinoma (HCC). Few data on long-term outcome are available. The aim of this study was to evaluate overall patient and graft survivals and associated predictive factors. METHOD: This retrospective multicentre study included adult transplant patients for NAFLD cirrhosis between 2000 and 2019 in participating French-speaking centres. RESULTS: A total of 361 patients (69.8% of male) were included in 20 centres. The median age at LT was 62.3 years [57.4-65.9] and the median MELD score was 13.9 [9.1-21.3]; 51.8% of patients had HCC on liver explant. Between 2004 and 2018, the number of LT for NAFLD cirrhosis increased by 720%. A quarter of the patients had cardiovascular history before LT. Median follow-up after LT was 39.1 months [15.8-72.3]. Patient survival at 1, 5 and 10 years after LT was 89.3%, 79.8% and 68.1% respectively. The main causes of death were sepsis (37.5%), malignancies (29.2%) and cardiovascular events (22.2%). In multivariate analysis, three risk factors for overall mortality after LT were recipient pre-LT BMI < 32 kg/m2 at LT time (OR: 2.272; p = .012), pre-LT angioplasty during CV check-up (OR: 2.916; p = .016), a combined donor and recipient age over 135 years (OR: 2.020; 95%CI: p = .035). CONCLUSION: Survival after LT for NAFLD cirrhosis is good at 5 years. Donor and recipient age, and cardiovascular history, are major prognostic factors to consider.

Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin.

NKp46+CD3- natural killer lymphocytes isolated from blood, lymphoid organs, lung, liver and uterus can produce granule-dependent cytotoxicity and interferon-gamma. Here we identify in dermis, gut lamina propria and cryptopatches distinct populations of NKp46+CD3- cells with a diminished capacity to degranulate and produce interferon-gamma. In the gut, expression of the transcription factor RORgammat, which is involved in the development of lymphoid tissue-inducer cells, defined a previously unknown subset of NKp46+CD3- lymphocytes. Unlike RORgammat- lamina propria and dermis natural killer cells, gut RORgammat+NKp46+ cells produced interleukin 22. Our data show that lymphoid tissue-inducer cells and natural killer cells shared unanticipated similarities and emphasize the heterogeneity of NKp46+CD3- cells in innate immunity, lymphoid organization and local tissue repair.

Long-term abdominal wall benefits of the laparoscopic approach in liver left lateral sectionectomy: a multicenter comparative study.

BACKGROUND: Laparoscopy is nowadays considered as the standard approach for hepatic left lateral sectionectomy (LLS), but its value in the prevention of incisional hernia (IH) has not been demonstrated. METHODS: Between 2012 and 2017, patients undergoing laparoscopic (LLLS) or open LLS (OLLS) in 8 centers were compared. Patients undergoing a simultaneous major abdominal procedure were excluded. The incidence of IH was assessed clinically and morphologically on computed tomography (CT) using inverse probability of treatment weighting (IPTW) and multivariable regression analysis. RESULTS: After IPTW, 84 LLLS were compared to 48 OLLS. Compared to OLLS, LLLS patients had reduced blood loss (100 [IQR: 50-200] ml vs. 150 [IQR: 50-415] ml, p = 0.023) and shorter median hospital stay (5 [IQR: 4-7] days vs. 7 [6-9] days, p < 0.001), but experienced similar rate of postoperative complications (mean comprehensive complication index: 12 ± 19 after OLLS versus 13 ± 20 after LLLS, p = 0.968). Long-term radiological screening was performed with a median follow-up of 27.4 (12.1-44.9) months. There was no difference between the two groups in terms of clinically relevant IH (10.7% [n = 9] after LLLS, 8.3% [n = 4] after OLLS, p = 0.768). The rate of IH detected on computed tomography was lower after LLLS than after OLLS (11.9% [n = 10] versus 29.2% [n = 14], p = 0.013). On multivariable analysis, the laparoscopic approach was the only independent factor influencing the risk of morphological IH (OR = 0.290 [95% CI: 0.094-0.891], p = 0.031). The 2 preferential sites for specimen extraction after LLLS were Pfannenstiel and midline incisions, with rates of IH across the extraction site of 2.3% [n = 1/44] and 23.8% [n = 5/21], respectively (p = 0.011). CONCLUSION: The laparoscopic approach for LLS decreases the risk of long-term IH as evidenced on morphological examinations, with limited clinical impact. Pfannenstiel's incision should be preferred to midline incision for specimen extraction after LLLS.

The white test for intraoperative screening of bile leakage: a potential trigger factor for acute pancreatitis after liver resection-a case series.

BACKGROUND: Acute pancreatitis after liver resection is a rare but serious complication, and few cases have been described in the literature. Extended lymphadenectomy, and long ischemia due to the Pringle maneuver could be responsible of post-liver resection acute pancreatitis, but the exact causes of AP after hepatectomy remain unclear. CASES PRESENTATION: We report here three cases of AP after hepatectomy and we strongly hypothesize that this is due to the bile leakage white test. 502 hepatectomy were performed at our center and 3 patients (0.6%) experienced acute pancreatitis after LR and all of these three patients underwent the white test at the end of the liver resection. None underwent additionally lymphadenectomy to the liver resection. All patient had a white-test during the liver surgery. We identified distal implantation of the cystic duct in these three patients as a potential cause for acute pancreatitis. CONCLUSION: The white test is useful for detection of bile leakage after liver resection, but we do not recommend a systematic use after LR, because severe acute pancreatitis can be lethal for the patient, especially in case of distal cystic implantation which may facilitate reflux in the main pancreatic duct.

Oncological relevance of major hepatectomy with inferior vena cava resection for intrahepatic cholangiocarcinoma.

BACKGROUND: This study aimed to investigate the short- and long-terms outcomes of patients undergoing major hepatectomy (MH) with inferior vena cava (IVC) resection for intrahepatic cholangiocarcinoma (ICC). METHODS: Data from all patients who underwent MH for ICC with or without IVC resection between 2010 and 2018 were analysed retrospectively. Postoperative outcomes, overall survival (OS), and recurrence-free survival (RFS) were compared in the whole population. A propensity score matching (PSM) analysis and an inverse probability weighting analysis (IPW) were performed to assess the influence of IVC resection on short- and long-terms outcomes. RESULTS: Among the 78 patients who underwent MH, 20 had IVC resection (IVC patients). Overall, the mortality and severe complication rate were 8% and 20%, respectively. IVC patients required more extended hepatectomies (p = 0.001) and had increased rates of transfusions (p = 0.001), however they did not experience increased postoperative morbidity, even after PSM. The 1-, 3- and 5-years OS and DFS were 78%, 45%, and 32% and 48%, 20%, and 16%, respectively. IVC was not associated with decreased OS (p = 0.52) and/or RFS (p = 0.85), even after IPW. CONCLUSION: MH with IVC resection for ICC seems to provide acceptable short- and long-term results in a selected population of patients.

An ordinal model to predict the risk of symptomatic liver failure in patients with cirrhosis undergoing hepatectomy.

BACKGROUND & AIMS: Selection criteria for hepatectomy in patients with cirrhosis are controversial. In this study we aimed to build prognostic models of symptomatic post-hepatectomy liver failure (PHLF) in patients with cirrhosis. METHODS: This was a cohort study of patients with histologically proven cirrhosis undergoing hepatectomy in 6 French tertiary care hepato-biliary-pancreatic centres. The primary endpoint was symptomatic (grade B or C) PHLF, according to the International Study Group of Liver Surgery's definition. Twenty-six preoperative and 5 intraoperative variables were considered. An ordered ordinal logistic regression model with proportional odds ratio was used with 3 classes: O/A (No PHLF or grade A PHLF), B (grade B PHLF) and C (grade C PHLF). RESULTS: Of the 343 patients included, the main indication was hepatocellular carcinoma (88%). Laparoscopic liver resection was performed in 112 patients. Three-month mortality was 5.25%. The observed grades of PHLF were: 0/A: 61%, B: 28%, C: 11%. Based on the results of univariate analyses, 3 preoperative variables (platelet count, liver remnant volume ratio and intent-to-treat laparoscopy) were retained in a preoperative model and 2 intraoperative variables (per protocol laparoscopy and intraoperative blood loss) were added to the latter in a postoperative model. The preoperative model estimated the probabilities of PHLF grades with acceptable discrimination (area under the receiver-operating characteristic curve [AUC] 0.73, B/C vs. 0/A; AUC 0.75, C vs. 0/A/B) and the performance of the postoperative model was even better (AUC 0.77, B/C vs. 0/A; AUC 0.81, C vs. 0/A/B; p <0.001). CONCLUSIONS: By accurately predicting the risk of symptomatic PHLF in patients with cirrhosis, the preoperative model should be useful at the selection stage. Prediction can be adjusted at the end of surgery by also considering blood loss and conversion to laparotomy in a postoperative model, which might influence postoperative management. LAY SUMMARY: In patients with liver cirrhosis, the risk of a hepatectomy is difficult to appreciate. We propose a statistical tool to estimate this risk, preoperatively and immediately after surgery, using readily available parameters and on online calculator. This model could help to improve the selection of patients with the best risk-benefit profiles for hepatectomy.

Early Switch From Tacrolimus to Everolimus After Liver Transplantation: Outcomes at 2 Years.

The observational CERTITUDE study follows liver transplant patients who completed the SIMCER trial. SIMCER randomized patients at month 1 after transplant to everolimus (EVR) with stepwise tacrolimus (TAC) withdrawal or to standard TAC, both with basiliximab induction and mycophenolic acid ± steroids. After completing SIMCER at 6 months after transplant, 65 EVR-treated patients and 78 TAC-treated patients entered CERTITUDE. At month 24 after transplant, 34/65 (52.3%) EVR-treated patients remained calcineurin inhibitor (CNI) free. Mean estimated glomerular filtration rate (eGFR) was significantly higher with EVR versus TAC during months 3-12. At month 24, eGFR values were 83.6 versus 75.3 mL/minute/1.73 m2 , respectively (P = 0.90) and adjusted mean change in eGFR from randomization was -8.0 versus -13.5 mL/minute/1.73 m2 (P = 0.15). At month 24, 45.9%, 31.1%, and 23.0% of EVR-treated patients had chronic kidney disease stages 1, 2, and 3, respectively, versus 25.7%, 45.7%, and 28.6% of TAC-treated patients (P = 0.05). Treated biopsy-proven acute rejection affected 4 EVR-treated patients and 2 TAC patients during months 6-24. Adverse events led to study discontinuation in 15.4% and 7.7% of EVR-treated and TAC-treated patients, respectively. Grade 3 or 4 hematological events were rare in both groups. A CNI-free EVR-based maintenance regimen appears feasible in approximately half of liver transplant patients. It preserves renal function effectively with good efficacy without compromising safety or hematological tolerance.

Short-term outcomes after major hepatic resection in patients with cirrhosis: a 75-case unicentric western experience.

BACKGROUND: The benefit of performing major hepatic resection (MHR) for hepatocellular carcinoma (HCC) in patients with cirrhosis remains controversial because of its high risk of posthepatectomy liver failure (PHLF). This study was conducted to assess the risk of MHR for HCC in patients with cirrhosis. METHODS: Patients with Child-Pugh A or B cirrhosis and HCC who underwent MHR from January 2000 to June 2014 were retrospectively identified. Risk factors for postoperative morbidity and mortality using univariate and multivariate analyses were evaluated. RESULTS: Seventy patients with Child-Pugh A (93%) and 5 (7%) with Child-Pugh B cirrhosis underwent MHR for HCC. Thirteen (17%) had Barcelona Clinic Liver Cancer (BCLC) stage A, 39 (50%) had BCLC B, and 23 (32%) had BCLC C disease. A perioperative blood transfusion was performed in 18 patients (24%). Ninety-day postoperative mortality was 9% (n=7). Major complications occurred in 16 patients (21%), including PHLF in 9 patients (12%). A multivariate analysis showed that perioperative blood transfusion was the main independent factor associated with mortality (OR= 6.5) and major morbidity (OR=10). CONCLUSION: In selected patients with HCC and cirrhosis, MHR is feasible and has acceptable mortality, but careful perioperative management and limiting blood loss are required.

Portal vein stenosis preconditioning of living donor liver in swine: early mechanisms of liver regeneration and gain of hepatic functional mass.

To reduce the morbidity and mortality risk for the donor in living donor liver transplantation (LDLT), we previously identified 20% left portal vein (LPV) stenosis as an effective preconditioning method to induce cell proliferation in the contralateral lobe without downstream ipsilateral atrophy. In this study, we report the pathways involved in the first hours after preconditioning and investigate the changes in liver volume and function. Fourteen pigs were used this study. Five pigs were used to study the genetic, cellular and molecular mechanisms set up in the early hours following the establishment of our preconditioning. The remaining nine pigs were equally divided into three groups: sham-operated animals, 20% LPV stenosis, and 100% LPV stenosis. Volumetric scanning and 99 mTc-Mebrofenin hepatobiliary scintigraphy were performed before preconditioning and 14 days after to study morphological and functional changes in the liver. We demonstrated that liver regeneration triggered by 20% LPV stenosis in the contralateral lobe involves TNF-α, IL-6, and inducible nitric oxide synthase 2 by means of STAT3 and hepatocyte growth factor. We confirmed that our preconditioning was responsible for an increase in the total liver volume. Finally, we demonstrated that this volumetric gain was associated with an increase in hepatic functional capacity. NEW & NOTEWORTHY We describe a new preconditioning method for major hepatectomy that is applicable to hepatectomy for donation. We identified 20% left portal vein stenosis as effective preconditioning that is capable of inducing cell proliferation in the contralateral lobe without the downstream ipsilateral atrophy. In this study, we report the pathways involved in the first hours following preconditioning, and we confirm that 20% left portal vein stenosis is responsible for an increase in the functional capacity and total liver volume in a porcine model.