Sublethal necroptosis signaling promotes inflammation and liver cancer.

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

Predicting futility of upfront surgery in perihilar cholangiocarcinoma: Machine learning analytics model to optimize treatment allocation.

BACKGROUND: While resection remains the only curative option for perihilar cholangiocarcinoma, it is well known that such surgery is associated with a high risk of morbidity and mortality. Nevertheless, beyond facing life-threatening complications, patients may also develop early disease recurrence, defining a "futile" outcome in perihilar cholangiocarcinoma surgery. The aim of this study is to predict the high-risk category (futile group) where surgical benefits are reversed and alternative treatments may be considered. METHODS: The study cohort included prospectively maintained data from 27 Western tertiary referral centers: the population was divided into a development and a validation cohort. The Framingham Heart Study methodology was used to develop a preoperative scoring system predicting the "futile" outcome. RESULTS: A total of 2271 cases were analyzed: among them, 309 were classified within the "futile group" (13.6%). American Society of Anesthesiology (ASA) score ≥ 3 (OR 1.60; p = 0.005), bilirubin at diagnosis ≥50 mmol/L (OR 1.50; p = 0.025), Ca 19-9 ≥ 100 U/mL (OR 1.73; p = 0.013), preoperative cholangitis (OR 1.75; p = 0.002), portal vein involvement (OR 1.61; p = 0.020), tumor diameter ≥3 cm (OR 1.76; p < 0.001), and left-sided resection (OR 2.00; p < 0.001) were identified as independent predictors of futility. The point system developed, defined three (ie, low, intermediate, and high) risk classes, which showed good accuracy (AUC 0.755) when tested on the validation cohort. CONCLUSIONS: The possibility to accurately estimate, through a point system, the risk of severe postoperative morbidity and early recurrence, could be helpful in defining the best management strategy (surgery vs. nonsurgical treatments) according to preoperative features.

The Influence of Hepatic Steatosis and Fibrosis on Postoperative Outcomes After Major Liver Resection of Perihilar Cholangiocarcinoma.

BACKGROUND: Surgical resection for perihilar cholangiocarcinoma (pCCA) is associated with high operative risks. Impaired liver regeneration in patients with pre-existing liver disease may contribute to posthepatectomy liver failure (PHLF) and postoperative mortality. This study aimed to determine the incidence of hepatic steatosis and fibrosis and their association with PHLF and 90-day postoperative mortality in pCCA patients. METHODS: Patients who underwent a major liver resection for pCCA were included in the study between 2000 and 2021 from three tertiary referral hospitals. Histopathologic assessment of hepatic steatosis and fibrosis was performed. The primary outcomes were PHLF and 90-day mortality. RESULTS: Of the 401 included patients, steatosis was absent in 334 patients (83.3%), mild in 58 patients (14.5%) and moderate to severe in 9 patients (2.2%). There was no fibrosis in 92 patients (23.1%), periportal fibrosis in 150 patients (37.6%), septal fibrosis in 123 patients (30.8%), and biliary cirrhosis in 34 patients (8.5%). Steatosis (≥ 5%) was not associated with PHLF (odds ratio [OR] 1.36; 95% confidence interval [CI] 0.69-2.68) or 90-day mortality (OR 1.22; 95% CI 0.62-2.39). Neither was fibrosis (i.e., periportal, septal, or biliary cirrhosis) associated with PHLF (OR 0.76; 95% CI 0.41-1.41) or 90-day mortality (OR 0.60; 95% CI 0.33-1.06). The independent risk factors for PHLF were preoperative cholangitis (OR 2.38; 95% CI 1. 36-4.17) and future liver remnant smaller than 40% (OR 2.40; 95% CI 1.31-4.38). The independent risk factors for 90-day mortality were age of 65 years or older (OR 2.40; 95% CI 1.36-4.23) and preoperative cholangitis (OR 2.25; 95% CI 1.30-3.87). CONCLUSION: In this study, no association could be demonstrated between hepatic steatosis or fibrosis and postoperative outcomes after resection of pCCA.

Diagnostic accuracy of cross-sectional and endoscopic imaging in ampullary tumours: systematic review.

BACKGROUND: Differentiation between adenomas and carcinomas of the ampulla of Vater is crucial for therapy and prognosis. This was a systematic review of the literature on the accuracy of diagnostic modalities used to differentiate between benign and malignant ampullary tumours. METHODS: A literature search was conducted in PubMed, Embase, CINAHL, and the Cochrane Library. Studies were included if they reported diagnostic test accuracy information among benign and malignant ampullary tumours, and used pathological diagnosis as the reference standard. Risk of bias was assessed using Quality Assessment on Diagnostic Accuracy Studies (QUADAS) 2 and QUADAS-C. RESULTS: Ten studies comprising 397 patients were included. Frequently studied modalities were (CT; 2 studies), endoscopic ultrasonography (EUS; 3 studies), intraductal ultrasonography (IDUS; 2 studies), and endoscopic forceps biopsy (3 studies). For CT, the reported sensitivity for detecting ampullary carcinoma was 44 and 95%, and the specificity 58 and 60%. For EUS, the sensitivity ranged from 63 to 89% and the specificity between 50 and 100%. A sensitivity of 88 and 100% was reported for IDUS, with a specificity of 75 and 93%. For forceps biopsy, the sensitivity ranged from 20 to 91%, and the specificity from 75 to 86%. The overall risk of bias was scored as moderate to poor. Data were insufficient for meta-analysis. CONCLUSION: To differentiate benign from malignant ampullary tumours, EUS and IDUS seem to be the best diagnostic modalities. Sufficient high-quality evidence, however, is lacking.

Liver regeneration after portal and hepatic vein embolization improves overall survival compared with portal vein embolization alone: mid-term survival analysis of the multicentre DRAGON 0 cohort.

BACKGROUND: The purpose of this study was to compare 3-year overall survival after simultaneous portal (PVE) and hepatic vein (HVE) embolization versus PVE alone in patients undergoing liver resection for primary and secondary cancers of the liver. METHODS: In this multicentre retrospective study, all DRAGON 0 centres provided 3-year follow-up data for all patients who had PVE/HVE or PVE, and were included in DRAGON 0 between 2016 and 2019. Kaplan-Meier analysis was undertaken to assess 3-year overall and recurrence/progression-free survival. Factors affecting survival were evaluated using univariable and multivariable Cox regression analyses. RESULTS: In total, 199 patients were included from 7 centres, of whom 39 underwent PVE/HVE and 160 PVE alone. Groups differed in median age (P = 0.008). As reported previously, PVE/HVE resulted in a significantly higher resection rate than PVE alone (92 versus 68%; P = 0.007). Three-year overall survival was significantly higher in the PVE/HVE group (median survival not reached after 36 months versus 20 months after PVE; P = 0.004). Univariable and multivariable analyses identified PVE/HVE as an independent predictor of survival (univariable HR 0.46, 95% c.i. 0.27 to 0.76; P = 0.003). CONCLUSION: Overall survival after PVE/HVE is substantially longer than that after PVE alone in patients with primary and secondary liver tumours.

Laparoscopic Living donor liver transplantation in irresectable intrahepatic cholangiocarcinoma in primary sclerosing cholangitis associated liver cirrhosis.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor and usually associated with a poor oncological prognosis. The current gold standard is the surgical resection of the tumor with subsequent adjuvant therapy. However, in case of irresectability e.g. in case of liver cirrhosis, a palliative treatment regime is conducted.This report demonstrates the case of an irresectable iCCA in liver cirrhosis due to primary sclerosing cholangitis (PSC) treated by living-donor liver transplantation (LDLT) facilitated by minimal invasive donor hepatectomy. No postoperative complications were observed in the donor and the donor was released on the 6th postoperative day. Further, after a follow-up of 1.5 years, no disease recurrence was detected in the recipient.According to the recent international literature, liver transplantation can be evaluated in case of small solitary iCCA (< 3 cm) in cirrhosis. Less evidence is provided for transplantation in advanced tumors which are surgically not resectable due to advanced liver disease or infiltration of major vessels, however some reports display adequate long-term survival after strict patient selection. The selection criteria comprise the absence of distant metastases and locoregional lymph node metastases as well as partial remission or stable disease after neoadjuvant chemotherapy. Due to no established graft allocation for iCCA in Germany, LDLT is currently the best option to realize transplantation in these patients. Developments in the last decade indicate that LDLT should preferentially be performed in minimal invasive manner (laparoscopic or robotic) as this approach is associated with less overall complications and a shorter hospitalization. The presented case illustrates the possibilities of modern surgery and the introduction of transplant oncology in the modern therapy of patients combining systemic therapy, surgical resection and transplantation to achieve optimal long-term results in patients which were initially indicated for palliative treatment.

GAL3ST1 Deficiency Reduces Epithelial-Mesenchymal Transition and Tumorigenic Capacity in a Cholangiocarcinoma Cell Line.

Cholangiocarcinoma (CCA), or bile duct cancer, is the second most common liver malignancy, with an increasing incidence in Western countries. The lack of effective treatments associated with the absence of early symptoms highlights the need to search for new therapeutic targets for CCA. Sulfatides (STs), a type of sulfoglycosphingolipids, have been found in the biliary tract, with increased levels in CCA and other types of cancer. STs are involved in protein trafficking and cell adhesion as part of the lipid rafts of the plasma membrane. We aimed to study the role of STs in CCA by the genetic targeting of GAL3ST1, an enzyme involved in ST synthesis. We used the CRISPR-Cas9 system to generate GAL3ST1-deficient TFK1 cells. GAL3ST1 KO cells showed lower proliferation and clonogenic activity and reduced glycolytic activity compared to TFK1 cells. Polarized TFK1 GAL3ST1 KO cells displayed increased transepithelial resistance and reduced permeability compared to TFK1 wt cells. The loss of GAL3ST1 showed a negative effect on growth in 30 out of 34 biliary tract cancer cell lines from the DepMap database. GAL3ST1 deficiency partially restored epithelial identity and barrier function and reduced proliferative activity in CCA cells. Sulfatide synthesis may provide a novel therapeutic target for CCA.

Intersurgeon Variability in Local Treatment Planning for Patients with Initially Unresectable Colorectal Cancer Liver Metastases: Analysis of the Liver Expert Panel of the Dutch Colorectal Cancer Group.

BACKGROUND: Consensus on resectability criteria for colorectal cancer liver metastases (CRLM) is lacking, resulting in differences in therapeutic strategies. This study evaluated variability of resectability assessments and local treatment plans for patients with initially unresectable CRLM by the liver expert panel from the randomised phase III CAIRO5 study. METHODS: The liver panel, comprising surgeons and radiologists, evaluated resectability by predefined criteria at baseline and 2-monthly thereafter. If surgeons judged CRLM as resectable, detailed local treatment plans were provided. The panel chair determined the conclusion of resectability status and local treatment advice, and forwarded it to local surgeons. RESULTS: A total of 1149 panel evaluations of 496 patients were included. Intersurgeon disagreement was observed in 50% of evaluations and was lower at baseline than follow-up (36% vs. 60%, p < 0.001). Among surgeons in general, votes for resectable CRLM at baseline and follow-up ranged between 0-12% and 27-62%, and for permanently unresectable CRLM between 3-40% and 6-47%, respectively. Surgeons proposed different local treatment plans in 77% of patients. The most pronounced intersurgeon differences concerned the advice to proceed with hemihepatectomy versus parenchymal-preserving approaches. Eighty-four percent of patients judged by the panel as having resectable CRLM indeed received local treatment. Local surgeons followed the technical plan proposed by the panel in 40% of patients. CONCLUSION: Considerable variability exists among expert liver surgeons in assessing resectability and local treatment planning of initially unresectable CRLM. This stresses the value of panel-based decisions, and the need for consensus guidelines on resectability criteria and technical approach to prevent unwarranted variability in clinical practice.

No difference in outcomes between large- and small-pore meshes in a prospective, randomized, multicenter trial investigating open retromuscular meshplasty for incisional hernia repair.

STUDY DESIGN: A randomized, controlled, prospective multicenter clinical trial with a parallel group design was initiated in eight surgical centers to compare a large-pore polypropylene mesh (Ultrapro®) to a small-pore polypropylene mesh (Premilene®) within a standardized retromuscular meshplasty for incisional hernia repair. METHODS: Between 2004 and 2006, patients with a fascial defect with a minimum diameter of 4 cm after vertical midline laparotomy were recruited for the trial. Patients underwent retromuscular meshplasty with either a large-pore or a small-pore mesh to identify the superiority of the large-pore mesh. Follow-up visits were scheduled at 5 and 21 days and 4, 12, and 24 months after surgery. A clinical examination, a modified short form 36 (SF-36®), a daily activity questionnaire, and an ultrasound investigation of the abdominal wall were completed at every follow-up visit. The primary outcome criterion was foreign body sensation at the 12-month visit, and the secondary endpoint criteria were the occurrence of hematoma, seroma, and chronic pain within 24 months postoperatively. RESULTS: In 8 centers, 181 patients were included in the study. Neither foreign body sensation within the first year after surgery (27.5% Ultrapro®, 32.2% Premilene®) nor the time until the first occurrence of foreign body sensation within the first year was significantly different between the groups. Regarding the secondary endpoints, no significant differences could be observed. At the 2-year follow-up, recurrences occurred in 5 Ultrapro® patients (5.5%) and 4 Premilene® patients (4.4%). CONCLUSION: Despite considerable differences in theoretical and experimental works, we have not been able to identify differences in surgical or patient-reported outcomes between the use of large- and small-pore meshes for retromuscular incisional hernia repair. TRIAL REGISTRATION: Clinical Trials NCT04961346 (16.06.2021) retrospectively registered.

Survival after combined resection and ablation is not inferior to that after resection alone, in patients with four or more colorectal liver metastases.

PURPOSE: Colorectal liver metastases (CRLM) are the predominant factor limiting survival in patients with colorectal cancer. Multimodal treatment strategies are frequently necessary to achieve total tumor elimination. This study examines the efficacy of liver resection combined with local ablative therapy in comparison to liver resection only, in the treatment of patients with ≥ 4 CRLM. METHODS: This retrospective cohort study was conducted at the University Hospital RWTH Aachen, Germany. Patients with ≥ 4 CRLM in preoperative imaging, who underwent curative resection between 2010-2021, were included. Recurrent resections and deaths in the early postoperative phase were excluded. Ablation modalities included radiofrequency or microwave ablation, and irreversible electroporation. Differences in overall- (OS) and recurrence-free-survival (RFS) between patients undergoing combined resection-ablation vs. resection only, were examined. RESULTS: Of 178 included patients, 46 (27%) underwent combined resection-ablation and 132 (73%) resection only. Apart from increased rates of adjuvant chemotherapy in the first group (44% vs. 25%, p = 0.014), there were no differences in perioperative systemic therapy. Kaplan-Meier and log-rank test analyses showed no statistically significant differences in median OS (36 months for both, p = 0.638) or RFS (9 months for combined resection-ablation vs. 8 months, p = 0.921). Cox regression analysis showed a hazard ratio of 0.891 (p = 0.642) for OS and 0.981 (p = 0.924) for RFS, for patients undergoing resection only. CONCLUSION: For patients with ≥ 4 CRLM, combined resection-ablation is a viable option in terms of OS and RFS. Therefore, combined resection-ablation should be considered for complete tumor clearance, in patients with multifocal disease.

Influence of cholestasis on portal vein embolization-induced hypertrophy of the future liver remnant.

PURPOSE: In the pre-clinical setting, hepatocellular bile salt accumulation impairs liver regeneration following partial hepatectomy. Here, we study the impact of cholestasis on portal vein embolization (PVE)-induced hypertrophy of the future liver remnant (FLR). METHODS: Patients were enrolled with perihilar cholangiocarcinoma (pCCA) or colorectal liver metastases (CRLM) undergoing PVE before a (extended) right hemihepatectomy. Volume of segments II/III was considered FLR and assessed on pre-embolization and post-embolization CT scans. The degree of hypertrophy (DH, percentual increase) and kinetic growth rate (KGR, percentage/week) were used to assess PVE-induced hypertrophy. RESULTS: A total of 50 patients (31 CRLM, 19 pCCA) were included. After PVE, the DH and KGR were similar in patients with CRLM and pCCA (5.2 [3.3-6.9] versus 5.7 [3.2-7.4] %, respectively, p = 0.960 for DH; 1.4 [0.9-2.5] versus 1.9 [1.0-2.4] %/week, respectively, p = 0.742 for KGR). Moreover, pCCA patients with or without hyperbilirubinemia had comparable DH (5.6 [3.0-7.5] versus 5.7 [2.4-7.0] %, respectively, p = 0.806) and KGR (1.7 [1.0-2.4] versus 1.9 [0.8-2.4] %/week, respectively, p = 1.000). For patients with pCCA, unilateral drainage in FLR induced a higher DH than bilateral drainage (6.7 [4.9-7.9] versus 2.7 [1.5-4.2] %, p = 0.012). C-reactive protein before PVE was negatively correlated with DH (ρ = - 0.539, p = 0.038) and KGR (ρ = - 0.532, p = 0.041) in patients with pCCA. CONCLUSIONS: There was no influence of cholestasis on FLR hypertrophy in patients undergoing PVE. Bilateral drainage and inflammation appeared to be negatively associated with FLR hypertrophy. Further prospective studies with larger and more homogenous patient cohorts are desirable.

Clinical determinants of hospital mortality in liver failure: a comprehensive analysis of 62,717 patients.

BACKGROUND: Liver failure (LF) is characterised by a loss of the synthetic and metabolic liver function and is associated with a high mortality. Large-scale data on recent developments and hospital mortality of LF in Germany are missing. A systematic analysis and careful interpretation of these datasets could help to optimise outcomes of LF. METHODS: We used standardised hospital discharge data of the Federal Statistical Office to evaluate current trends, hospital mortality and factors associated with an unfavourable course of LF in Germany between 2010 and 2019. RESULTS: A total of 62,717 hospitalised LF cases were identified. Annual LF frequency decreased from 6716 (2010) to 5855 (2019) cases and was higher among males (60.51%). Hospital mortality was 38.08% and significantly declined over the observation period. Mortality significantly correlated with patients' age and was highest among individuals with (sub)acute LF (47.5%). Multivariate regression analyses revealed pulmonary (ORARDS: 2.76, ORmechanical ventilation: 6.46) and renal complications (ORacute kidney failure: 2.04, ORhepatorenal syndrome: 2.92) and sepsis (OR: 1.92) as factors for increased mortality. Liver transplantation reduced mortality in patients with (sub)acute LF. Hospital mortality significantly decreased with the annual LF case volume and ranged from 47.46% to 29.87% in low- or high-case-volume hospitals, respectively. CONCLUSIONS: Although incidence rates and hospital mortality of LF in Germany have constantly decreased, hospital mortality has remained at a very high level. We identified a number of variables associated with increased mortality that could help to improve framework conditions for the treatment of LF in the future.

Extracellular Vesicles as Markers of Liver Function: Optimized Workflow for Biomarker Identification in Liver Disease.

Liver diseases represent a significant global health burden, necessitating the development of reliable biomarkers for early detection, prognosis, and therapeutic monitoring. Extracellular vesicles (EVs) have emerged as promising candidates for liver disease biomarkers due to their unique cargo composition, stability, and accessibility in various biological fluids. In this study, we present an optimized workflow for the identification of EVs-based biomarkers in liver disease, encompassing EVs isolation, characterization, cargo analysis, and biomarker validation. Here we show that the levels of microRNAs miR-10a, miR-21, miR-142-3p, miR-150, and miR-223 were different among EVs isolated from patients with nonalcoholic fatty liver disease and autoimmune hepatitis. In addition, IL2, IL8, and interferon-gamma were found to be increased in EVs isolated from patients with cholangiocarcinoma compared with healthy controls. By implementing this optimized workflow, researchers and clinicians can improve the identification and utilization of EVs-based biomarkers, ultimately enhancing liver disease diagnosis, prognosis, and personalized treatment strategies.

Value of prognostic scoring systems in the era of multimodal therapy for recurrent colorectal liver metastases.

BACKGROUND: Various predictive scoring systems have been developed to estimate outcomes of patients undergoing surgery for colorectal liver metastases (CRLM). However, data regarding their effectiveness in recurrent CRLM (recCRLM) are very limited. METHODS: Patients who underwent repeat hepatectomy for recCRLM at the University Hospital RWTH Aachen, Germany from 2010 to 2021 were included. Nine predictive scoring systems (Fong's, Nordlinger, Nagashima, RAS mutation, Tumor Burden, GAME, CERR, and Glasgow Prognostic score, Basingstoke Index) were evaluated by likelihood ratio (LR) χ2, linear trend (LT) χ2 and Akaike Information Criterion (AIC) for their predictive value regarding overall survival (OS) and recurrence free survival (RFS). RESULTS: Among 150 patients, median RFS was 9 (2-124) months with a 5-year RFS rate of 10%. Median OS was 39 (4-131) months with a 5-year OS rate of 32%. For RFS and OS, the Nagashima score showed the best prognostic ability (LT χ2 3.00, LR χ2 9.39, AIC 266.66 and LT χ2 2.91, LR χ2 20.91, 290.36). DISCUSSION: The Nagashima score showed the best prognostic stratification to predict recurrence as well as survival, and therefore might be considered when evaluating patients with recCRLM for repeat hepatectomy.

Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial.

Everolimus-facilitated reduced-exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard-exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy-proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m2 , difference: 4.1 mL/minute/1.73 m2 ; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m2 (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment-emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.

Deletion of mTOR in liver epithelial cells enhances hepatic metastasis of colon cancer.

Activation of the mechanistic target of rapamycin (mTOR) pathway is frequently found in cancer, but mTOR inhibitors have thus far failed to demonstrate significant antiproliferative efficacy in the majority of cancer types. Besides cancer cell-intrinsic resistance mechanisms, it is conceivable that mTOR inhibitors impact on non-malignant host cells in a manner that ultimately supports resistance of cancer cells. Against this background, we sought to analyze the functional consequences of mTOR inhibition in hepatocytes for the growth of metastatic colon cancer. To this end, we established liver epithelial cell (LEC)-specific knockout (KO) of mTOR (mTORLEC ) mice. We used these mice to characterize the growth of colorectal liver metastases with or without partial hepatectomy to model different clinical settings. Although the LEC-specific loss of mTOR remained without effect on metastasis growth in intact liver, partial liver resection resulted in the formation of larger metastases in mTORLEC mice compared with wildtype controls. This was accompanied by significantly enhanced inflammatory activity in LEC-specific mTOR KO livers after partial liver resection. Analysis of NF-ĸB target gene expression and immunohistochemistry of p65 displayed a significant activation of NF-ĸB in mTORLEC mice, suggesting a functional importance of this pathway for the observed inflammatory phenotype. Taken together, we show an unexpected acceleration of liver metastases upon deletion of mTOR in LECs. Our results support the notion that non-malignant host cells can contribute to resistance against mTOR inhibitors and encourage testing whether anti-inflammatory drugs are able to improve the efficacy of mTOR inhibitors for cancer therapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Clinical outcomes after one anastomosis gastric bypass versus sleeve gastrectomy in super-super-obese patients.

BACKGROUND: Bariatric surgery in super-super-obese (SSO) patients remains a continuous challenge due to intraabdominal fat masses, higher liver volume and existing comorbidities. A convenient procedure in SSO patients is one anastomosis gastric bypass (OAGB). The aim of this study was to compare the outcome of SSO patients undergoing OAGB in comparison to laparoscopic sleeve gastrectomy (LSG). METHODS: We retrospectively reviewed data from SSO patients who underwent OAGB and LSG in our institution between 2008 and 2020. Primary endpoints included percentage total body weight loss and percentage BMI loss at 12, 24, and 36 months after the operation. Secondary endpoints were perioperative complications, procedure length, length of hospital stay and outcome of comorbidities. RESULTS: 243 patients were included in this study. 93 patients underwent LSG and 150 underwent OAGB. At any of the time points evaluated, weight loss in patients after OAGB was greater than in LSG patients, while procedure length was significantly shorter for OAGB than LSG (81.4 vs. 92.1 min, p-value < 0.001). Additionally, mean length of hospital stay was shorter in the OAGB group (3.4 vs. 4.5 days, p-value < 0.001). There were more severe complications (Clavien-Dindo ≥ 3a) in the LSG group (11.8% vs 2.7%, p-value = 0.005). CONCLUSION: In this retrospective analysis, OAGB was superior to LSG in terms of weight loss in SSO patients. Procedure length and hospital stay were shorter after OAGB in comparison to LSG and there were fewer severe complications. OAGB can therefore be regarded a safe and effective treatment modality for SSO patients.

The role of re-resection in recurrent hepatocellular carcinoma.

PURPOSE: While liver resection is a well-established treatment for primary HCC, surgical treatment for recurrent HCC (rHCC) remains the topic of an ongoing debate. Thus, we investigated perioperative and long-term outcome in patients undergoing re-resection for rHCC in comparative analysis to patients with primary HCC treated by resection. METHODS: A monocentric cohort of 212 patients undergoing curative-intent liver resection for HCC between 2010 and 2020 in a large German hepatobiliary center were eligible for analysis. Patients with primary HCC (n = 189) were compared to individuals with rHCC (n = 23) regarding perioperative results by statistical group comparisons and oncological outcome using Kaplan-Meier analysis. RESULTS: Comparative analysis showed no statistical difference between the resection and re-resection group in terms of age (p = 0.204), gender (p = 0.180), ASA category (p = 0.346) as well as main preoperative tumor characteristics, liver function parameters, operative variables, and postoperative complications (p = 0.851). The perioperative morbidity (Clavien-Dindo ≥ 3a) and mortality were 21.7% (5/23) and 8.7% (2/23) in rHCC, while 25.4% (48/189) and 5.8% (11/189) in primary HCC, respectively (p = 0.851). The median overall survival (OS) and recurrence-free survival (RFS) in the resection group were 40 months and 26 months, while median OS and RFS were 41 months and 29 months in the re-resection group, respectively (p = 0.933; p = 0.607; log rank). CONCLUSION: Re-resection is technically feasible and safe in patients with rHCC. Further, comparative analysis displayed similar oncological outcome in patients with primary and rHCC treated by liver resection. Re-resection should therefore be considered in European patients diagnosed with rHCC.

Machine learning prediction model for postoperative outcome after perforated appendicitis.

PURPOSE: Appendectomy for acute appendicitis is one of the most common operative procedures worldwide in both children and adults. In particular, complicated (perforated) cases show high variability in individual outcomes. Here, we developed and validated a machine learning prediction model for postoperative outcome of perforated appendicitis. METHODS: Retrospective analyses of patients with clinically and histologically verified perforated appendicitis over 10 years were performed. Demographic and surgical baseline characteristics were used as competing predictors of single-patient outcomes along multiple dimensions via a random forest classifier with stratified subsampling. To assess whether complications could be predicted in new, individual cases, the ensuing models were evaluated using a replicated 10-fold cross-validation. RESULTS: A total of 163 patients were included in the study. Sixty-four patients underwent laparoscopic surgery, whereas ninety-nine patients got a primary open procedure. Interval from admission to appendectomy was 9 ± 12 h and duration of the surgery was 74 ± 38 min. Forty-three patients needed intensive care treatment. Overall mortality was 0.6 % and morbidity rate was 15%. Severe complications as assessed by Clavien-Dindo > 3 were predictable in new cases with an accuracy of 68%. Need for ICU stay (> 24 h) could be predicted with an accuracy of 88%, whereas prolonged hospitalization (greater than 7-15 days) was predicted by the model with an accuracy of 76%. CONCLUSION: We demonstrate that complications following surgery, and in particular, health care system-related outcomes like intensive care treatment and extended hospitalization, may be well predicted at the individual level from demographic and surgical baseline characteristics through machine learning approaches.

Elevated Serum Levels of CCL23 Are Associated with Poor Outcome after Resection of Biliary Tract Cancer.

Background: Surgical tumor resection is the only potentially curative treatment option for patients with biliary tract cancer (BTC). However, 5-year survival rates are still below 50% mainly due to tumor recurrence. The preoperative identification of ideal surgical candidates has remained a major challenge and easily accessible algorithms including parameters of the individual tumor biology are missing. Chemokine (C-C motif) ligand 23 (CCl23) has been associated with tumor progression in hepatocellular carcinoma (HCC), but its role in the context of BTC is largely unknown. Here, we evaluated circulating levels of CCL23 as potential diagnostic and prognostic biomarker in patients with resectable BTC. Methods: CCl23 serum levels were analyzed by multiplex immunoassay in a cohort of 119 BTC patients receiving surgical tumor resection as well as 50 healthy control samples and 11 patients with primary sclerosing cholangitis (PSC). Results: Baseline serum CCL23 levels were significantly elevated in BTC patients compared to PSC patients as well as healthy controls. CCL23 increased the diagnostic sensitivity and specificity of established tumor markers including CA19-9 and correlated with patients' age and makers of systemic inflammation. Elevated preoperative CCL23 levels were associated with a significantly impaired postoperative outcome. BTC patients with a preoperative CCL23 level above the optimal prognostic cut-off value of 702.4 pg/ml showed a median OS of only 110 days compared to 501 days for patients with low initial CCL23 levels. The prognostic value of circulating CCL23 was confirmed in Cox-regression analysis. Conclusion: Serum levels of CCL23 are elevated in patients with BTC, and high preoperative CCL23 levels were associated with an impaired postoperative survival. CCL23 serum levels could help to identify the ideal surgical candidates for BTC resection in the future.