HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells.

OBJECTIVE: Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC. DESIGN: Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids. RESULTS: NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for HLA-DPA1*02:01~B1*01:01 (OR 1.99, p=6.7×10-50). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids. CONCLUSION: Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~DPB1*01:01 and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis.

Liver Histology Predicts Liver Regeneration and Outcome in ALPPS: Novel Findings From A Multicenter Study.

BACKGROUND AND AIMS: Alterations in liver histology influence the liver's capacity to regenerate, but the relevance of each of the different changes in rapid liver growth induction is unknown. This study aimed to analyze the influence of the degree of histological alterations during the first and second stages on the ability of the liver to regenerate. METHODS: This cohort study included data obtained from the International ALPPS Registry between November 2011 and October 2020. Only patients with colorectal liver metastases were included in the study. We developed a histological risk score based on histological changes (stages 1 and 2) and a tumor pathology score based on the histological factors associated with poor tumor prognosis. RESULTS: In total, 395 patients were included. The time to reach stage 2 was shorter in patients with a low histological risk stage 1 (13 vs 17 days, P ˂0.01), low histological risk stage 2 (13 vs 15 days, P <0.01), and low pathological tumor risk (13 vs 15 days, P <0.01). Regarding interval stage, there was a higher inverse correlation in high histological risk stage 1 group compared to low histological risk 1 group in relation with future liver remnant body weight ( r =-0.1 and r =-0.08, respectively), and future liver remnant ( r =-0.15 and r =-0.06, respectively). CONCLUSIONS: ALPPS is associated with increased histological alterations in the liver parenchyma. It seems that the more histological alterations present and the higher the number of poor prognostic factors in the tumor histology, the longer the time to reach the second stage.

Harmonizing Definitions and Perspectives in Extreme Liver Surgery: A Delphi Experts Consensus.

OBJECTIVE: To propose to our community a common language about extreme liver surgery. BACKGROUND: The lack of a clear definition of extreme liver surgery prevents convincing comparisons of results among centers. METHODS: We used a two-round Delphi methodology to quantify consensus among liver surgery experts. For inclusion in the final recommendations, we established a consensus when the positive responses (agree and totally agree) exceeded 70%. The study steering group summarized and reported the recommendations. In general, a five-point Likert scale with a neutral central value was used, and in a few cases multiple choices. Results are displayed as numbers and percentages. RESULTS: A two-round Delphi study was completed by 38 expert surgeons in complex hepatobiliary surgery. The surgeon´s median age was 58 years old (52-63) and the median years of experience was 25 years (20-31). For the proposed definitions of total vascular occlusion, hepatic flow occlusion and inferior vein occlusion, the degree of agreement was 97%, 81% and 84%, respectively. In situ approach (64%) was the preferred, followed by ante situ (22%) and ex situ (14%). Autologous or cadaveric graft for hepatic artery or hepatic vein repair were the most recommended (89%). The use of veno-venous bypass or portocaval shunt revealed the divergence depending on the case. Overall, 75% of the experts agreed with the proposed definition for extreme liver surgery. CONCLUSION: Obtaining a consensus on the definition of extreme liver surgery is essential to guarantee the correct management of patients with highly complex hepatobiliary oncological disease. The management of candidates for extreme liver surgery involves comprehensive care ranging from adequate patient selection to the appropriate surgical strategy.

Is an intraoperative liver function assessment possible? Application of the 13C-methacetin-breath-test during major liver resections - a pilot study.

BACKGROUND: As prevention of posthepatectomy-liver-failure is crucial, there is need of dynamic assessment of liver function, even intraoperatively. 13C-methacetin-breath-test estimates the organ's microsomal functional capacity. This is its first intraoperative evaluation in major liver surgery. METHODS: 30 patients planed for resection of ≥3 liver segments, between March-November 2019, were prospectively enrolled in this "single-center", pilot study. Using the 13C-methacetin-breath-test, liver function was assessed four times: preoperatively, intraoperatively before and after resection and postoperatively. The resulted maximum-liver-function-capacity (LiMAx)-values and delta-over-baseline (DOB)-curves were compared, further analyzed and correlated to respective liver volumes. RESULTS: The intraoperative LiMAx-values before resection were mostly lower than the preoperative ones (-11.3% ± 28%). The intraoperative measurements after resection resulted to mostly higher values than the postoperative ones (42.35% ± 46.19%). Pharmacokinetically, an interference between the two intraoperative tests was observed. There was no strong correlation between residual liver volume and function with a percentual residual-LiMAx mostly lower than the percentual residual volume (-17.7% ± 4.1%). CONCLUSIONS: Intraoperative application of the 13C-methacetin-breath-test during major liver resections seems to deliver lower values than the standard preoperative test. As multiple intraoperative tests interfere significantly to each other, a single intraoperative measurement is suggested. Multicentric standardized measurements could define the "normal" range for intraoperative measurements and control their predictive value.

Liver surgery in the 2020s: ante-situm and in-situ resection are still indicated - A single-center study.

BACKGROUND: Tumor infiltration of the hepatic outflow comprising all three hepatic veins and the inferior vena cava remains a surgical challenge. Liver resection under total vascular exclusion with or without extracorporeal bypass has been described as a therapeutic option for these tumors. Here, we present our experience with these complex surgical methods. METHODS: We searched our database for patients treated with an in-situ or ante-situm liver resection (ISR and ASR, respectively) with extracorporeal bypass. We collected demographic and perioperative data. RESULTS: From January 2010 to December 2021, we performed 2122 liver resections. Nine patients were treated with ASR and five were treated with ISR. Out of these 14 patients, six had colorectal liver metastases, six had cholangiocarcinoma, and two had non-colorectal liver metastases. The median operative time and bypass time in all patients were 536.5 and 150 min, respectively. Compared with ISR, ASR required a longer operative time (ASR 586 min and ISR 495 min) and a longer bypass time (ASR 155 min and ISR 122 min). Morbidity (Clavien-Dindo grade > 3A adverse events) occurred in 78.5% of patients. 90-day postoperative mortality was 7%. Median overall survival was 33 months. Seven patients experienced recurrence. In these patients, median disease-free survival was 9 months. CONCLUSION: Resection of tumors infiltrating the hepatic outflow poses a high risk for patients. However, with rigorous selection and an experienced perioperative team, these patients can be treated surgically with reasonable oncological outcomes.

Results from the european survey on preoperative management and optimization protocols for PeriHilar cholangiocarcinoma.

BACKGROUND: Major surgery, along with preoperative cholestasis-related complications, are responsible for the increased risk of morbidity and mortality in perihilar cholangiocarcinoma (pCCA). The aim of the present survey is to provide a snapshot of current preoperative management and optimization strategies in Europe. METHODS: 61 European centers, experienced in hepato-biliary surgery completed a 59-questions survey regarding pCCA preoperative management. Centers were stratified according to surgical caseload (<5 and ≥ 5 cases/year) and preoperative management protocols' application. RESULTS: The overall case volume consisted of 6333 patients. Multidisciplinary discussion was routinely performed in 91.8% of centers. Most respondents (96.7%) recognized the importance of a well-structured preoperative protocol. The preferred method for biliary drainage was percutaneous transhepatic biliary drainage (60.7%) while portal vein embolization was the preferred technique for liver hypertrophy (90.2%). Differences in preoperative pathologic confirmation of malignancy (35.8% vs 28.7%; p < 0.001), number of mismanaged referred patients (88.2% vs 50.8%; p < 0.001), biliary drainage (65.1% vs 55.6%; p = 0.015) and liver function evaluation (37.2% vs 5.6%; p = 0.001) were found between centers according to groups' stratification. CONCLUSION: The importance of a correct preoperative management is recognized. Nevertheless, the current lack of guidelines leads to wide heterogeneity of behaviors among centers. This survey can provide recommendations to improve pCCA perioperative outcomes.

Sex Disparities in Outcomes Following Major Liver Surgery: New Powers of Estrogen?

AIM: To explore potential sex differences in outcomes and regenerative parameters post major hepatectomies. BACKGROUND: Although controversial, sex differences in liver regeneration have been reported for animals. Whether sex disparity exists in human liver regeneration is unknown. METHODS: Data from consecutive hepatectomy patients (55 females, 67 males) and from the international ALPPS (Associating-Liver-Partition-and-Portal-vein-ligation-for-Staged-hepatectomy, a two stage hepatectomy) registry (449 females, 729 males) were analyzed. Endpoints were severe morbidity (≥3b Clavien-Dindo grades), Model for End-stage Liver Disease (MELD) scores, and ALPPS interstage intervals. For validation and mechanistic insight, female-male ALPSS mouse models were established. t , χ 2 , or Mann-Whitney tests were used for comparisons. Univariate/multivariate analyses were performed with sensitivity inclusion. RESULTS: Following major hepatectomy (Hx), males had more severe complications ( P =0.03) and higher liver dysfunction (MELD) P =0.0001) than females. Multivariate analysis established male sex as a predictor of complications after ALPPS stage 1 (odds ratio=1.78; 95% confidence interval: 1.126-2.89; P =0.01), and of enhanced liver dysfunction after stage 2 (odds ratio=1.93; 95% confidence interval: 1.01-3.69; P =0.045). Female patients displayed shorter interstage intervals (<2 weeks, 64% females versus 56% males, P =0.01), however, not in postmenopausal subgroups. In mice, females regenerated faster than males after ALPPS stage 1, an effect that was lost upon estrogen antagonism. CONCLUSIONS: Poorer outcomes after major surgery in males and shorter ALPPS interstage intervals in females not necessarily suggest a superior regenerative capacity of female liver. The loss of interstage advantages in postmenopausal women and the mouse experiments point to estrogen as the driver behind these sex disparities. Estrogen's benefits call for an assessment in postmenopausal women, and perhaps men, undergoing major liver surgery.

Liver growth prediction in ALPPS - A multicenter analysis from the international ALPPS registry.

BACKGROUND: While ALPPS triggers a fast liver hypertrophy, it is still unclear which factors matter most to achieve accelerated hypertrophy within a short period of time. The aim of the study was to identify patient-intrinsic factors related to the growth of the future liver remnant (FLR). METHODS: This cohort study is composed of data derived from the International ALPPS Registry from November 2011 and October 2018. We analyse the influence of demographic, tumour type and perioperative data on the growth of the FLR. The volume of the FLR was calculated in millilitre and percentage using computed-tomography (CT) scans before and after stage 1, both according to Vauthey formula. RESULTS: A total of 734 patients were included from 99 centres. The median sFLR at stage 1 and stage 2 was 0.23 (IQR, 0.18-0.28) and 0.39 (IQR: 0.31-0.46), respectively. The variables associated with a lower increase from sFLR1 to sFLR2 were age˃68 years (p = .02), height ˃1.76 m (p ˂ .01), weight ˃83 kg (p ˂ .01), BMI˃28 (p ˂ .01), male gender (p ˂ .01), antihypertensive therapy (p ˂ .01), operation time ˃370 minutes (p ˂ .01) and hospital stay˃14 days (p ˂ .01). The time required to reach sufficient volume for stage 2, male gender accounts 40.3% in group ˂7 days, compared with 50% of female, and female present 15.3% in group ˃14 days compared with 20.6% of male. CONCLUSIONS: Height, weight, FLR size and gender could be the variables that most constantly influence both daily growths, the interstage increase and the standardized FLR before the second stage.

The rate of cholangiocarcinoma in Caroli Disease A German multicenter study.

BACKGROUND: Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts. CD/CS are associated with cholangiocarcinoma (CCA). However, the true incidence of CCA is still unclear, although it may serve as an indication for surgery. In this paper, we analyzed (I) the incidence of CCA in German centers, (II) reviewed our single center population together with its clinical presentation and (III) performed a thorough literature review. METHODS: 17 large HPB-centers across Germany were contacted and their patients after surgical treatment due to CD/CS with histopathology were included. Medline search for all studies published in English or German literature was performed. Patients who underwent surgery at our department between 2012 and 2020 due to CD or CS were analyzed. RESULTS: In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients. In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%). Between 2012 and 2020, 1661 liver resections were performed at our department. 14 patients underwent surgery due to CD or CS. Histological examination showed synchronous cholangiocarcinoma in one patient. The literature review revealed a CCA-rate of 7,3% in large series, whereas in case reports a rate of 6,8% was found. CONCLUSION: There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised. As certain patients with CS require transplantation, treatment should not be guided by the relatively low rate of CCA but by the concomitant diseases that come along with hepatic failure.

Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis.

BACKGROUND & AIMS: Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver. METHODS: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs. RESULTS: We identified a population of intrahepatic naive-like CD4+ T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (TH17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards TH17 cells. CONCLUSION: We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4+ T cells in PSC harbour the propensity to develop into TH17 cells. LAY SUMMARY: The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4+ T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches.

Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers.

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

Association of subcellular localization of TEAD transcription factors with outcome and progression in pancreatic ductal adenocarcinoma.

BACKGROUND: Transcriptional enhanced associated domain (TEAD) transcription factors are nuclear effectors of several oncogenic signalling pathways including Hippo, WNT, TGF-ß and EGFR pathways that interact with various cancer genes. The subcellular localization of TEAD regulates the functional output of these pathways affecting tumour progression and patient outcome. However, the impact of the TEAD family on pancreatic ductal adenocarcinoma (PDAC) and its clinical progression remain elusive. METHODS: A cohort of 81 PDAC patients who had undergone surgery was established. Cytoplasmic and nuclear localization of TEAD1, TEAD2, TEAD3 and TEAD4 was evaluated with the immunoreactive score (IRS) by immunohistochemistry (IHC) using paraffin-embedded tissue. Results were correlated with clinicopathological data, disease-free and overall survival. RESULTS: Nuclear staining of all four TEADs was increased in pancreatic cancer tissue. Patients suffering from metastatic disease at time of surgery showed a strong nuclear staining of TEAD2 and TEAD3 (p < 0.05). Furthermore, a nuclear > cytoplasmic ratio of TEAD2 and TEAD3 was associated with a shorter overall survival and TEAD2 emerged as an independent prognostic factor for disease-free survival. CONCLUSION: Our study underlines the importance of TEAD transcription factors in PDAC as a nuclear localization was found to be associated with metastatic disease and an unfavourable prognosis after surgical resection.

Repeated resection for recurrent intrahepatic cholangiocarcinoma: A retrospective German multicentre study.

BACKGROUND: Tumour recurrence is common after resection of intrahepatic cholangiocarcinoma (ICC). Repeated resection is a potential curative treatment, but outcomes are not well-defined thus far. The aim of this retrospective multicentre cohort study was to show the feasibility and survival of repeated resection of ICC recurrence. METHODS: Data were collected from 18 German hepato-pancreatico-biliary centres for patients who underwent repeated exploration of recurrent ICC between January 2008 and December 2017. Primary end points were overall (OS) and recurrence-free survival from the day of primary and repeated resection. RESULTS: Of 156 patients who underwent repeated exploration for recurrent ICC, 113 underwent re-resection. CA19-9 prior to primary resection, R status of first liver resection and median time to recurrence were significant determinants of repeated resectability. Median OS in the repeated resection group was 65.2 months, with consecutive 1-, 3- and 5-year OS of 98%, 78% and 57% respectively. After re-exploration, median OS from primary resection was 46.7 months, with a consecutive 1-, 3- and 5-year OS of 95%, 55% and 22% respectively. From the day of repeated resection, the median OS was 36.8 months, with a consecutive 1-, 3- and 5-year OS of 86%, 51% and 34% respectively. Minor morbidity (grade I+II) was present in 27%, grade IIIa-IVb morbidity in 20% and mortality in 3.5% of patients. CONCLUSION: Repeated resection of ICC has acceptable morbidity and mortality and seems to be associated with improved long-term survival. Structured follow-up after resection of ICC is necessary for early identification of these patients.

Appendicitis during the COVID-19 lockdown: results of a multicenter analysis in Germany.

PURPOSE: The COVID-19 pandemic has transformed medical care worldwide. General surgery has been affected in elective procedures, yet the implications for emergency surgery are unclear. The current study analyzes the effect of the COVID-19 lockdown in spring 2020 on appendicitis treatment in Germany. METHODS: Hospitals that provided emergency surgical care during the COVID-19 lockdown were invited to participate. All patients diagnosed with appendicitis during the lockdown period (10 weeks) and, as a comparison group, patients from the same period in 2019 were analyzed. Clinical and laboratory parameters, intraoperative and pathological findings, and postoperative outcomes were analyzed. RESULTS: A total of 1915 appendectomies from 41 surgical departments in Germany were included. Compared to 2019 the number of appendectomies decreased by 13.5% (1.027 to 888, p=0.003) during the first 2020 COVID-19 lockdown. The delay between the onset of symptoms and medical consultation was substantially longer in the COVID-19 risk group and for the elderly. The rate of complicated appendicitis increased (58.2 to 64.4%), while the absolute number of complicated appendicitis decreased from 597 to 569, (p=0.012). The rate of negative appendectomies decreased significantly (6.7 to 4.6%; p=0.012). Overall postoperative morbidity and mortality, however, did not change. CONCLUSION: The COVID-19 lockdown had significant effects on abdominal emergency surgery in Germany. These seem to result from a stricter selection and a longer waiting time between the onset of symptoms and medical consultation for risk patients. However, the standard of emergency surgical care in Germany was maintained.

[The Impact of Lockdown during the COVID-19 Pandemic on Care for Elective Patients (C-elective Study) - Results of a Multicenter Survey]. / Die Auswirkung des Lockdowns während der COVID-19-Pandemie auf die Versorgung von elektiven Patienten (C-elective-Studie).

BACKGROUND: Due to the COVID-19-related lockdown regulations, surgical clinics had to cut down elective procedures. The impact of the cancellation and postponing surgery on patients is unclear. METHODS: All patients from six hospitals with canceled surgery during the first lockdown (03/16-04/24/2020) were asked to answer a questionnaire. RESULTS: In total, 225 patients took part. In 88 (39.1%) patients, the disease-related complaints changed, mainly towards an increase in severity (82.6%). That was especially true for hernia patients (44.4%). In 4% of the cases, there was a complication requiring surgery in the time interval between the original date of the operation and the interview. For about a third, the cancelation of scheduled surgery caused major administrative difficulties. Most of the patients (76.3%) understood the measures taken, though 40.4% of them considered that their indication was very urgent. DISCUSSION AND CONCLUSION: The overall complication rate was low, and patients agreed to the measures taken; however, especially hernia patients showed increasing symptoms and some acute incarcerations. It seems reasonable to monitor symptomatic patients closely, in order to prioritise them when surgical capacity is restricted.

Impact of acute kidney injury after extended liver resections.

BACKGROUND: Complex liver resection is a risk factor for the development of AKI, which is associated with increased morbidity and mortality. Aim of this study was to assess risk factors for acute kidney injury (AKI) and its impact on outcome for patients undergoing complex liver surgery. METHODS: AKI was defined according to the KDIGO criteria. Primary endpoint was the occurrence of AKI after liver resection. Secondary endpoints were complications and mortality. RESULTS: Overall, 146 patients undergoing extended liver resection were included in the study. The incidence of AKI was 21%. The incidence of chronic kidney disease (CKD) and hepatocellular carcinoma were significantly higher in patients with AKI. In the AKI group, the proportion of extended right hepatectomies was the highest (53%), followed by ALPPS (43%). Increased intraoperative blood loss, increased postoperative complications and perioperative mortality was associated with AKI. Besides age and CKD, ALPPS was an independent risk factor for postoperative AKI. A small future liver remnant seemed to increase the risk of AKI in patients undergoing ALPPS. CONCLUSION: Following extended liver resection, AKI is associated with an increased morbidity and mortality. ALPPS is a major independent risk factor for the development of AKI and a sufficient future liver remnant could avoid postoperative AKI.

Repeated hepatectomy after ALPPS for recurrence of colorectal liver metastasis: the edge of limits?

BACKGROUND: Repeated liver resections for the recurrence of colorectal liver metastasis (CRLM) are described as safe and have similar oncological outcomes compared to first hepatectomy. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is performed in patients with conventionally non-resectable CRLM. Repeated resections after ALPPS has not yet been described. METHODS: Patients that underwent repeated liver resection in recurrence of CRLM after ALPPS were included in this study. The primary endpoint was morbidity and secondary endpoints were mortality, resection margin and survival. RESULTS: Thirty patients were included in this study. During ALPPS, most of the patients had classical split (60%, n = 18) and clearance of the FLR (77%, n = 23). Hepatic recurrence was treated with non-anatomical resection (57%, n = 17), resection combined with local ablation (13%, n = 4), open ablation (13%, n = 4), segmentectomy (10%, n = 3) or subtotal segmentectomy (7%, n = 2). Six patients (20%) developed complications (10% minor complications). No post-hepatectomy liver failure or perioperative mortality was observed. One-year patient survival was 87%. Five patients received a third hepatectomy. CONCLUSION: Repeated resections after ALPPS for CRLM in selected patients are safe and feasible with low morbidity and no mortality. Survival seems to be comparable with repeated resections after conventional hepatectomy.

Variation in complications and mortality following ALPPS at early-adopting centers.

BACKGROUND: Various, often conflicting, estimates for post-operative morbidity and mortality following ALPPS have been reported in the literature, suggesting that considerable center-level variation exists. Some of this variation may be related to center volume and experience. METHODS: Using data from seventeen centers who were early adopters of the ALPPS technique, we estimated the variation, by center, in standardized 90-day mortality and comprehensive complication index (CCI) for patients treated between 2012 and 2018. RESULTS: We estimated that center-specific 90-day mortality following treatment with ALPPS varied from 4.2% (95% CI: 0.8, 9.9) to 29.1% (95% CI: 13.9, 50.9), and that center-specific CCI following treatment with ALPPS varied from 17.0 (95% CI: 7.5, 26.5) to 49.8 (95% CI: 38.1, 61.8). Declines in estimated 90-day mortality and CCI were observed over time, and almost all individual centers followed this trend. Patients treated at centers with a higher number of ALPPS cases performed over the prior year had a lower risk of post-operative mortality. CONCLUSION: Despite considerable center-level variation in ALPPS outcomes, perioperative outcomes following ALPPS have improved over time and treatment at higher volume centers results in a lower risk of 90-day mortality. Morbidity and mortality remain concerningly high at some centers.

First Long-term Oncologic Results of the ALPPS Procedure in a Large Cohort of Patients With Colorectal Liver Metastases.

OBJECTIVES: To analyze long-term oncological outcome along with prognostic risk factors in a large cohort of patients with colorectal liver metastases (CRLM) undergoing ALPPS. BACKGROUND: ALPPS is a two-stage hepatectomy variant that increases resection rates and R0 resection rates in patients with primarily unresectable CRLM as evidenced in a recent randomized controlled trial. Long-term oncologic results, however, are lacking. METHODS: Cases in- and outside the International ALPPS Registry were collected and completed by direct contacts to ALPPS centers to secure a comprehensive cohort. Overall, cancer-specific (CSS), and recurrence-free (RFS) survivals were analyzed along with independent risk factors using Cox-regression analysis. RESULTS: The cohort included 510 patients from 22 ALPPS centers over a 10-year period. Ninety-day mortality was 4.9% and median overall survival, CSS, and RFS were 39, 42, and 15 months, respectively. The median follow-up time was 38 months (95% confidence interval 32-43 months). Multivariate analysis identified tumor-characteristics (primary T4, right colon), biological features (K/N-RAS status), and response to chemotherapy (Response Evaluation Criteria in Solid Tumors) as independent predictors of CSS. Traditional factors such as size of metastases, uni versus bilobar involvement, and liver-first approach were not predictive. When hepatic recurrences after ALPPS was amenable to surgical/ablative treatment, median CSS was significantly superior compared to chemotherapy alone (56 vs 30 months, P < 0.001). CONCLUSIONS: This large cohort provides the first evidence that patients with primarily unresectable CRLM treated by ALPPS have not only low perioperative mortality, but achieve appealing long-term oncologic outcome especially those with favorable tumor biology and good response to chemotherapy.

CCL21-expression and accumulation of CCR7+ NK cells in livers of patients with primary sclerosing cholangitis.

The pathogenesis of primary sclerosing cholangitis (PSC), an autoimmune liver disease, remains unknown. The aim of this study was to characterize peripheral blood and intrahepatic NK cells from patients with PSC. Peripheral blood samples from patients with PSC, other autoimmune liver diseases, and from healthy control individuals were used, as well as liver tissues from PSC patients undergoing liver transplantation. Multiparameter flow cytometry showed that peripheral blood NK cells from PSC patients were significantly enriched for CCR7+ and CXCR3+ cells, and CCR7+ but not CXCR3+ cells were also significantly increased within intrahepatic NK cells. PSC patients undergoing liver transplantation furthermore had significantly higher plasma levels of the CCR7-ligand CCL21, and the CXCR3-ligands CXCL10 and CXCL11, and significantly higher levels of CCL21, but not CXCL10, were detected in liver tissues. CCR7+ and CXCR3+ NK cells from PSC patients exhibited significantly higher functional capacity in peripheral blood, but not liver tissues, consistent with chronic activation of these NK cells in the inflamed liver. These data show that PSC is characterized by intrahepatic CCL21 expression and accumulation of CCR7+ NK cells in the inflamed liver tissue.