Identification and characterization of a hepatic IL-13-producing ILC3-like population potentially involved in liver fibrosis.

BACKGROUND AND AIMS: Human innate lymphoid cells (ILCs) are critically involved in the modulation of homeostatic and inflammatory processes in various tissues. However, only little is known about the composition of the intrahepatic ILC pool and its potential role in chronic liver disease. Here, we performed a detailed characterization of intrahepatic ILCs in both healthy and fibrotic livers. APPROACH AND RESULTS: A total of 50 livers (nonfibrotic = 22, and fibrotic = 29) were analyzed and compared with colon and tonsil tissue (each N = 14) and peripheral blood (N = 32). Human intrahepatic ILCs were characterized ex vivo and on stimulation using flow cytometry and single-cell RNA sequencing. ILC differentiation and plasticity were analyzed by both bulk and clonal expansion experiments. Finally, the effects of ILC-derived cytokines on primary human HSteCs were studied. Unexpectedly, we found that an "unconventional" ILC3-like cell represented the major IL-13-producing liver ILC subset. IL-13 + ILC3-like cells were specifically enriched in the human liver, and increased frequencies of this cell type were found in fibrotic livers. ILC3-derived IL-13 production induced upregulation of proinflammatory genes in HSteCs, indicating a potential role in the regulation of hepatic fibrogenesis. Finally, we identified KLRG1-expressing ILC precursors as the potential progenitor of hepatic IL-13 + ILC3-like cells. CONCLUSIONS: We identified a formerly undescribed subset of IL-13-producing ILC3-like cells that is enriched in the human liver and may be involved in the modulation of chronic liver disease.

Effect of Extracerebral Contamination on Near-infrared Spectroscopy as Revealed during Organ Donation: A Prospective Observational Study in Brain-dead Organ Donors.

BACKGROUND: Near-infrared spectroscopy (NIRS) has been utilized widely in anesthesia and intensive care to monitor regional cerebral oxygen saturation (rScO2). A normal oxygenation of extracerebral tissues may overlay and thereby mask cerebral desaturations, a phenomenon known as extracerebral contamination. The authors investigated the effect of a cessation of extracerebral tissue perfusion on rScO2 in patients with anoxic brains. METHODS: In a single-center, prospective, observational study, brain-dead adults undergoing organ donation were investigated. rScO2 was measured bifrontally using the INVOS 5100C/7100 as well as the ForeSight Elite system. To achieve an efficient conservation of organs and to prevent a redistribution of the perfusion fluid to other tissues, the aorta was clamped before organ perfusion. rScO2 was monitored until at least 40 min after aortic clamping. The primary outcome was the amount of extracerebral contamination as quantified by the absolute decrease in rScO2 after aortic clamping. Secondary outcomes were the absolute rScO2 values obtained before and after clamping. RESULTS: Twelve organ donors were included. Aortic clamping resulted in a significantly (P < 0.001) greater absolute decrease in rScO2 when comparing the INVOS (43.0 ± 9.5%) to the ForeSight (27.8 ± 7.1%) monitor. Before aortic clamping, near-normal rScO2 values were obtained by the INVOS (63.8 ± 6.2%) and the ForeSight monitor (67.7 ± 6.5%). The rScO2 significantly (P < 0.001) dropped to 20.8 ± 7.8% (INVOS) and 39.9 ± 8.1% (ForeSight) 30 min after clamping, i.e., a condition of a desaturation of both extracerebral and cerebral tissues. CONCLUSIONS: The abrupt end of extracerebral contamination, caused by aortic clamping, affected both NIRS monitors to a considerable extent. Both the INVOS and the ForeSight monitor were unable to detect severe cerebral hypoxia or anoxia under conditions of normal extracerebral oxygenation. While both NIRS monitors may guide measures to optimize arterial oxygen supply to the head, they should not be used with the intention to detect isolated cerebral desaturations.

Surgical site infections are independently associated with the development of postoperative acute-on-chronic liver failure in liver cirrhosis.

Acute-on-chronic liver failure (ACLF) is associated with organ failure and high short-term mortality. Bacterial infections and surgery have been reported as major precipitants for ACLF. However, detailed characterization of postoperative infections after elective surgery in patients with liver cirrhosis and their impact on the development of ACLF have not been investigated yet. A total of 235 patients with cirrhosis without ACLF and proven bacterial infections undergoing elective surgery were included. The primary end point was the development of ACLF within 28 days after surgery, and secondary end points were infection development within 28 days and 3-month ACLF-related mortality. Cox regression analysis was used for identification of risk factors associated with ACLF development, infection development, and mortality. A total of 86 patients (37%) developed ACLF within 28 days after surgery. Patients with new postoperative infections had significantly higher rates of associated ACLF episodes within 28 days (51% vs. 24%, p < 0.001) and higher 3-month mortality ( p < 0.05) than patients without postoperative infections. New infections after surgery [HR: 2.43 (1.59-3.71), p < 0.001] and organ/space surgical site infections [HR: 2.46 (1.26-4.80), p = 0.01] in particular were independent risk factors associated with ACLF development 28 days after surgery. Extensive procedures were associated with the development of new postoperative infection episodes within 28 days. Infections treated with initial appropriate empirical antibiotic strategies showed significantly improved survival. This study characterizes and identifies bacterial infections in general and organ/space surgical site infection in particular as precipitating events for the development of ACLF after elective surgery in patients with cirrhosis. Postoperative ACLF combined with infections leads to higher postoperative short-term mortality than each condition separately, especially in extensive procedures. Interdisciplinary care, early identification of postoperative ACLF and infections, and adequate, broad, and early treatment strategies are needed to improve postoperative outcome.

Persisting dental foci increase the risk for bacterial infections before and after liver transplant.

BACKGROUND: Patients awaiting liver transplant are usually assessed for presence of dental foci to prevent bacterial infection post-transplant, but evidence to support dental examination and treatment is limited. We investigated if treatment of dental foci decreased bacterial infections before and after transplant. METHODS: Patients transplanted at the university hospital of Bonn were retrospectively assessed for occurrence of bacterial infections before and after transplant according to presence and treatment of dental foci. RESULTS: 35/110 patients showed good oral health, 39/110 patients received dental care and 36/110 patients did not receive dental care despite poor oral health. Patients with alcohol-associated liver disease presented with the highest rate of dental foci. Bleeding complications due to oral care occurred in five patients with poor coagulation. After transplant, the number of infections per patient was higher in patients with poor oral health (2.9) compared to patients after dental care (1.9) or with good oral health (1.8) (p = .02), with streptococcal infections being more frequent in patients with poor oral health. Before transplant, bacterial infections, in particular bacteraemia and spontaneous bacterial peritonitis, were also more common in patients with untreated dental foci. Streptococci and Staphylococci were more often detected in patients with dental foci. Dental treatment was associated with a reduction in bacterial infections. CONCLUSION: Presence of dental foci is associated with an increased risk for bacterial infections not only after but also before liver transplant. Dental treatment might be a safe and effective procedure to mitigate this risk.

Regulatory T Cell Inhibition by P60 Combined with Adenoviral AFP Transduced Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma.

BACKGROUND & AIMS: Vaccination with tumor-associated antigen-pulsed dendritic cells leads to specific T-cell response against hepatocellular carcinoma. However, clinical response has been shown to be limited. High regulatory T-cell count is associated with poor prognosis and seems to mediate immune tolerance in hepatocellular carcinoma. Forkhead box P3-peptide inhibitor P60 has been shown to specifically inhibit regulatory T-cell function in murine models. Aim of this study was to investigate whether P60 can improve the immune response induced by vaccination with adenovirus-transduced dendritic cells expressing alpha-fetoprotein in subcutaneous and orthotopic murine models for hepatocellular carcinoma. METHODS: Mice developing subcutaneous or orthotopic HCC received daily treatment with P60 starting at different tumor stages. Additionally, mice were vaccinated twice with dendritic cells expressing alpha-fetoprotein. RESULTS: In a preventive setting prior to tumor engraftment, vaccination with alpha-fetoprotein-expressing dendritic cells significantly decreased tumor growth in a subcutaneous model (p = .0256), but no further effects were achieved by addition of P60. However, P60 enhanced the antitumoral effect of a vaccination with alpha-fetoprotein-expressing dendritic cells in established subcutaneous and orthotopic hepatocellular carcinoma characterized by high Treg levels (p = .011). CONCLUSION: In this study, we showed that vaccination with alpha-fetoprotein-expressing dendritic cells in combination with a specific inhibition of regulatory T-cells by using P60 leads to synergistic tumor inhibition and prolonged survival. This emphasizes the importance of regulatory T-cells inhibition for obtaining an effective antitumoral immune response in hepatocellular carcinoma.

Surgical treatment for pancreatic cystic lesions-implications from the multi-center and prospective German StuDoQ|Pancreas registry.

PURPOSE: The detection of pancreatic cystic lesions (PCL) causes uncertainty for physicians and patients, and international guidelines are based on low evidence. The extent and perioperative risk of resections of PCL in Germany needs comparison with these guidelines to highlight controversies and derive recommendations. METHODS: Clinical data of 1137 patients who underwent surgery for PCL between 2014 and 2019 were retrieved from the German StuDoQ|Pancreas registry. Relevant features for preoperative evaluation and predictive factors for adverse outcomes were statistically identified. RESULTS: Patients with intraductal papillary mucinous neoplasms (IPMN) represented the largest PCL subgroup (N = 689; 60.6%) while other entities (mucinous cystic neoplasms (MCN), serous cystic neoplasms (SCN), neuroendocrine tumors, pseudocysts) were less frequently resected. Symptoms of pancreatitis were associated with IPMN (OR, 1.8; P = 0.012) and pseudocysts (OR, 4.78; P < 0.001), but likewise lowered the likelihood of MCN (OR, 0.49; P = 0.046) and SCN (OR, 0.15, P = 0.002). A total of 639 (57.2%) patients received endoscopic ultrasound before resection, as recommended by guidelines. Malignancy was histologically confirmed in 137 patients (12.0%), while jaundice (OR, 5.1; P < 0.001) and weight loss (OR, 2.0; P = 0.002) were independent predictors. Most resections were performed by open surgery (N = 847, 74.5%), while distal lesions were in majority treated using minimally invasive approaches (P < 0.001). Severe morbidity was 28.4% (N = 323) and 30d mortality was 2.6% (N = 29). Increased age (P = 0.004), higher BMI (P = 0.002), liver cirrhosis (P < 0.001), and esophageal varices (P = 0.002) were independent risk factors for 30d mortality. CONCLUSION: With respect to unclear findings frequently present in PCL, diagnostic means recommended in guidelines should always be considered in the preoperative phase. The therapy of PCL should be decided upon in the light of patient-specific factors, and the surgical strategy needs to be adapted accordingly.

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.

Management of post-operative pancreatic fistulas following Longmire-Traverso pylorus-preserving pancreatoduodenectomy by endoscopic vacuum-assisted closure therapy.

BACKGROUND: Pylorus-preserving pancreatoduodenectomy (PPPD) with pancreatogastrostomy is a standard surgical procedure for pancreatic head tumors, duodenal tumors and distal cholangiocarcinomas. Post-operative pancreatic fistulas (POPF) are a major complication causing relevant morbidity and mortality. Endoscopic vacuum therapy (EVT) has become a widely used method for the treatment of intestinal perforations and leakages. Here we report on a pilot single center series of 8 POPF cases specifically caused by dehiscences of the pancreatogastric anastomosis (PGD), successfully managed by EVT. METHODS: We included all patients with PGD after PPPD, who were treated with EVT between 07/2017 and 08/2020. For EVT a vacuum drainage film (EVT film) or open-pore polyurethane foam sponge (EVT sponge) was fixed to a 14Fr or 16Fr suction catheter and placed endoscopically within the PGD for intracavitary EVT with continuous suction between - 100 and - 150 mmHg. The EVT film/sponge was exchanged twice per week. EVT was discontinued when the PGD was sufficiently healed. RESULTS: PGD closure was achieved in 7 of 8 patients after a mean EVT time of 16 days (range 8-38) and 3 EVT film/sponge exchanges (range 1-9). One patient died on day 18 after PPPD from acute hemorrhagic shock, unlikely related to EVT, before effectiveness of EVT could be fully achieved. There were no adverse events directly attributable to EVT. CONCLUSIONS: EVT could be an effective and safe addition to our therapeutic armamentarium in the management of POPF with PGD. Unless prospective comparative studies are available, EVT as minimally invasive therapeutic alternative should be considered individually by an interdisciplinary team involving endoscopists, surgeons and radiologists.

Active smokers show ameliorated delayed gastric emptying after pancreatoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) is the most common complication following pancreatoduodenectomy (PD). The data about active smoking in relation to gastric motility have been inconsistent and specifically the effect of smoking on gastric emptying after PD has not yet been investigated in detail. METHODS: 295 patients at our department underwent PD between January 2009 and December 2019. Patients were analyzed in relation to demographic factors, diagnosis, pre-existing conditions, intraoperative characteristics, hospital stay, mortality and postoperative complications with special emphasis on DGE. All complications were classified according to the definitions of the International Study Group on Pancreatic Surgery. RESULTS: 274 patients were included in the study and analyzed regarding their smoking habits (non or former smokers, n = 88, 32.1% vs. active smokers, n = 186, 68.6%). Excluded were patients for whom no information about their smoking habits was available (n = 3), patients who had had gastric resection before (n = 4) and patients with prolonged postoperative resumption to normal diet independently from DGE (long-term ventilation > 7 days, fasting due to pancreatic fistula) (n = 14). Smokers were younger than non-smokers (61 vs. 69 years, p ≤ 0.001) and mainly male (73% male vs. 27% female). Smoking patients showed significantly more pre-existing pulmonary conditions (19% vs. 8%, p = 0.002) and alcohol abuse (48% vs. 23%, p ≤ 0.001). We observe more blood loss in smokers (800 [500-1237.5] vs. 600 [400-1000], p = 0.039), however administration of erythrocyte concentrates did not differ between both groups (0 [0-2] vs. 0 [0-2], p = 0.501). 58 out of 88 smokers (66%) and 147 out of 186 of non-smokers (79%) showed malign tumors (p = 0.019). 35 out of 88 active smokers (40%) and 98 out of 188 non- or former smokers (53%) developed DGE after surgery (p = 0.046) and smokers tolerated solid food intake more quickly than non-smokers (postoperative day (POD7 vs. POD10, p = 0.004). Active smokers were less at risk to develop DGE (p = 0.051) whereas patients with pulmonary preexisting conditions were at higher risk for developing DGE (p = 0.011). CONCLUSIONS: Our data show that DGE occurs less common in active smokers and they tolerate solid food intake more quickly than non-smokers. Further observation studies and randomized, controlled multicentre studies without the deleterious effect of smoking, for instance by administration of a nicotine patch, are needed to examine if this effect is due to nicotine administration.

The Development and Outcome of Acute-on-Chronic Liver Failure After Surgical Interventions.

Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality. Precipitating events, including hemorrhage and infections, contribute to ACLF development, but the role of surgery remains unknown. We investigated the development of ACLF in patients with cirrhosis undergoing surgery. In total, 369 patients with cirrhosis were included in the study. The clinical and laboratory data were collected prior to and on days 1-2, 3-8, and 9-28, and at 3 and 12 months after surgery. Surgery type was classified as limited or extensive, as well as liver and nonliver surgery. A total of 39 patients had baseline ACLF. Surgery was performed during acute decompensation in 35% of the rest of the 330 patients, and 81 (24.5%) developed ACLF within 28 days after surgery. Surrogate markers of systemic inflammation were similar in patients who developed ACLF or not. Age, sex, serum sodium, baseline bacterial infection, and abdominal nonliver surgery were independent predictors for the development of ACLF after surgery. Patients who developed ACLF within 28 days after surgery had a higher mortality at 3, 6, and 12 months. Survival did not differ between patients with ACLF at surgery and those developing ACLF after surgery. Development of ACLF within 28 days after surgery and elevated alkaline phosphatase and international normalized ratio were independent predictors of 90-day mortality. Independent predictors of 1-year all-cause mortality were alkaline phosphatase, Model for End-Stage Liver Disease score, and preoperative hepatic encephalopathy, whereas nonliver surgery was associated with improved survival. ACLF frequently develops in patients with cirrhosis undergoing surgery, especially in those with active bacterial infection, lower serum sodium, and kidney or coagulation dysfunction. Prognoses of ACLF both at and after surgery are similarly poor. Patients with cirrhosis should be carefully managed perioperatively.

[The Impact of Supra- and Infracolic Reconstruction on Delayed Gastric Emptying Following Pancreatoduodenectomy]. / Varianten der retrokolischen Rekonstruktion nach partieller Pankreatoduodenektomie und deren Einfluss auf die Magenentleerung ­ infra- oder suprakolisch.

BACKGROUND: Delayed gastric emptying (DGE) is the most frequent complication following pancreatoduodenectomy. While antecolic and retrocolic reconstruction does not influence the occurrence of DGE, infracolic reconstruction might alleviate DGE due to the vertical position of the distal stomach compared to supracolic reconstruction. Supra- and infracolic reconstruction have not yet been compared. PATIENTS: 138 patients underwent pylorus-preserving pancreatoduodenectomy with retrocolic reconstruction at our department between 2011 and 2017. Of these, 105 were reconstructed with supracolic duodenoenterostomy and 33 with infracolic duodenoenterostomy. Patients were analysed with respect to demographic factors, diagnosis, pre-existing conditions, intraoperative characteristics, hospital stay and morbidity and mortality with special emphasis on DGE. All complications were classified according to the definitions of the International Study Group on Pancreatic Surgery. RESULTS: The two groups were comparable with respect to diagnosis, medical history, intraoperative characteristics, morbidity and mortality. DGE was equally distributed between supra- and infracolic reconstruction (DGE stage A/B/C25/14/10 vs. 12/5/2, p = 0.274). With DGE, intensive care unit stay (p = 0.007) and hospital stay (p = 0.001) are significantly delayed. Risk factor analysis showed that pre-existing diabetes (p = 0.047) and major complications (Clavien stage III - V, p = 0.048) are risk factors for DGE, while the use of somatostain-analogues seems to have a protective effect (p = 0.021). CONCLUSION: Supra- or infracolic reconstruction does not influence the frequency of DGE following pancreatoduodenectomy. When DGE occurs, hospital stay is delayed. Somatostatin analogues may act prophylactically on DGE.

Combination of CCl4 with alcoholic and metabolic injuries mimics human liver fibrosis.

Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl4) liver fibrosis model does not reflect human NAFLD or ALD, but CCl4 may serve as a fibrosis accelerator in addition to another injury. Ethanol in drinking water (16%) or Western diet (WD) were administered for 7 wk in mice either alone or in combination with CCl4 intoxications. Extent of fibrosis, steatosis, and inflammation was assessed by histology, transcription, and biochemistry. Furthermore, transcription of fibrosis, proliferation, and inflammation-related genes was studied on human liver samples with fibrosis resulting from hepatitis C virus infection (n = 7), NAFLD (n = 8), or ALD (n = 7). WD or ethanol alone induced only mild steatosis and inflammation. Combination of CCl4 and WD induced the most severe steatosis together with significant liver fibrosis and moderate inflammation. Combination of CCl4 and ethanol induced the strongest inflammation, with significant liver fibrosis and moderate steatosis. The relationship pattern between fibrosis, proliferation, and inflammation of human ALD was mostly similar in mice treated with CCl4 and ethanol. The combination of CCl4 intoxication with WD validates previous data suggesting it as an appropriate model for human nonalcoholic steatohepatitis. Especially, CCl4 plus ethanol for 7 wk induces ALD in mice, providing a model suitable for further basic research and drug testing.NEW & NOTEWORTHY Alcoholic fatty liver disease with significant fibrosis is generated within 7 wk using carbon tetrachloride as a fibrosis accelerator and administering gradually ethanol (up to 16%) in mice. The similarity in the pattern of steatosis, inflammation, and fibrosis involved in alcoholic fatty liver disease to those of the human condition renders this mouse model suitable as a preclinical model for drug development.

Compartment-specific distribution of human intestinal innate lymphoid cells is altered in HIV patients under effective therapy.

Innate lymphocyte cells (ILCs), a novel family of innate immune cells are considered to function as key orchestrators of immune defences at mucosal surfaces and to be crucial for maintaining an intact intestinal barrier. Accordingly, first data suggest depletion of ILCs to be involved in human immunodeficiency virus (HIV)-associated damage of the intestinal mucosa and subsequent microbial translocation. However, although ILCs are preferentially localized at mucosal surfaces, only little is known regarding distribution and function of ILCs in the human gastrointestinal tract. Here, we show that in HIV(-) individuals composition and functional capacity of intestinal ILCs is compartment-specific with group 1 ILCs representing the major fraction in the upper gastrointestinal (GI) tract, whereas ILC3 are the predominant population in ileum and colon, respectively. In addition, we present first data indicating that local cytokine concentrations, especially that of IL-7, might modulate composition of gut ILCs. Distribution of intestinal ILCs was significantly altered in HIV patients, who displayed decreased frequency of total ILCs in ileum and colon owing to reduced numbers of both CD127(+)ILC1 and ILC3. Of note, frequency of colonic ILC3 was inversely correlated with serum levels of I-FABP and sCD14, surrogate markers for loss of gut barrier integrity and microbial translocation, respectively. Both expression of the IL-7 receptor CD127 on ILCs as well as mucosal IL-7 mRNA levels were decreased in HIV(+) patients, especially in those parts of the GI tract with reduced ILC frequencies, suggesting that impaired IL-7 responses of ILCs might contribute to incomplete reconstitution of ILCs under effective anti-retroviral therapy. This is the first report comparing distribution and function of ILCs along the intestinal mucosa of the entire human gastrointestinal tract in HIV(+) and HIV(-) individuals.

Increased myocardial contractility identifies patients with decompensated cirrhosis requiring liver transplantation.

Late allocation of organs for transplant impairs post-liver transplantation (LT) survival. Cardiac dysfunction, especially diastolic and autonomic dysfunction, is frequent and plays an important role in the prognosis of patients with cirrhosis. However, the role of myocardial contractility is unexplored, and its prognostic value is controversially discussed. This study analyses the role of myocardial contractility assessed by speckle tracking echocardiography in LT allocation. In total, 168 patients with cirrhosis (training cohort, 111; validation cohort [VC], 57) awaiting LT in 2 centers were included in this retrospective study. Also, 51 patients from the training and all patients from the VC were transplanted, 36 patients of the training and 38 of the VC were alive at the end of follow-up, and 21 nontransplanted patients died. Contractility of the left ventricle (LV) increased with severity of the Child-Pugh score. Interestingly, higher LV contractility in the training cohort patients, especially in those with Child-Pugh C, was an independent predictor of reduced transplant-free survival. In male patients, the effects on survival of increased left and right ventricular myocardial contractility were more pronounced. Notably, competing risk analysis demonstrated that increased contractility is associated with earlier LT, which could be confirmed in the VC. Importantly, LV myocardial contractility had no impact on survival of patients not receiving LT or on post-LT survival. In conclusion, this study demonstrates for the first time that increased myocardial contractility in decompensated patients identifies patients who require LT earlier, but without increased post-LT mortality. Liver Transplantation 24 15-25 2018 AASLD.

Circulating CXCL10 in cirrhotic portal hypertension might reflect systemic inflammation and predict ACLF and mortality.

BACKGROUND & AIMS: CXCR% ligands play an important role in hepatic injury, inflammation and fibrosis. While CXCL9 and CXCL11 are associated with survival in patients receiving transjugular intrahepatic portosystemic shunt (TIPS), the role of CXCL10 in severe portal hypertension remains unknown. METHODS: A total of 89 cirrhotic patients were analysed. CXCL10 protein levels were measured in portal and hepatic blood at TIPS insertion and 2 weeks later in 24 patients. CXCL10 and IL8 levels were assessed in portal, hepatic, cubital vein and right atrium blood in a further 25 patients at TIPS insertion. Furthermore, real-time PCR determined hepatic CXCL10-mRNA in 40 cirrhotic patients. RESULTS: Hepatic CXCL10 showed no association with decompensation. By contrast, circulating CXCL10-levels were higher in portal than in hepatic vein blood, suggesting an extrahepatic source of CXCL10 in cirrhosis. However, CXCL10 protein in blood samples from portal, hepatic, cubital veins and right atrium correlated excellently with each other and with IL-8 levels. Higher CXCL10 circulating levels were associated with presence of ascites and higher Child scores. Higher CXCL10 circulating protein levels were associated with acute decompensation, acute-on-chronic liver failure (ACLF) and independently with mortality. Moreover, a decrease in CXCL10 protein levels after TIPS insertion was associated with better survival in each cohort and analysed together. DISCUSSION: Circulating CXCL10 possibly reflects systemic inflammation and it is correlated with acute decompensation, ACLF and complications in patients with severe portal hypertension receiving TIPS. CXCL10 predicts survival in these patients and a decrease in CXCL10 after TIPS may be considered a good prognostic factor.

[The Devascularisation Procedure for the Treatment of Fundic and Oesophageal Varices in Portal Hypertension - a Retrospective Analysis of 55 Cases]. / Die Devaskularisationsoperation zur Behandlung von Fundus- und Ösophagusvarizen bei portaler Hypertension ­ eine retrospektive Analyse von 55 Fällen.

BACKGROUND: The most dangerous complication of portal hypertension is the formation of oesophageal varices, as the risk of bleeding is up to 80%. In order to reduce pressure reduction in the portosystemic circulation and as secondary prophylaxis, the TIPSS procedure has proven successful. In patients with portal vein thrombosis, portosystemic shunt surgery is possible to reduce the risk of variceal bleeding. However, if thrombosis of the mesentericoportal axis or hepatic encephalopathy is imminent, interventional or surgical creation of a portosystemic shunt is contraindicated. As a last resort to avoid recurrent bleeding or in case of inexorable bleeding, a devascularisation procedure may be indicated. The aim of this study was to investigate perioperative complications, morbidity and mortality, the incidence of postoperative recurrent bleeding, and patient survival after devascularisation surgery. PATIENTS AND METHODS: We retrospectively analysed 55 patients with a history of variceal haemorrhage or acute bleeding without the possibility of an invasive or operative portosystemic shunt for complication rate, recurrent variceal recurrence, rebleeding and survival. RESULTS: While complications for elective surgery were 61%, they increased significantly in emergency surgeries (75%, p = 0.002), especially for severe complications (Dindo/Clavien grade III - V° [14 vs. 58%, p = 0.002]). Devascularisation significantly reduced varicosis occurrence. Furthermore, only 16% of patients suffered recurrent bleeding in a follow-up period of up to 24 years. Median survival (MS) after devascularisation surgery was 169 ± 23 months. After elective surgery, MS was 194 ± 25 months, but after emergency surgery only 49 ± 16 months. No patient showed any hepatic encephalopathy during their hospital stay. DISCUSSION: Devascularisation surgery is well suited for secondary prophylaxis in patients with fundic and oesophageal varices and portal hypertension with no possibility of portosystemic shunt or with impending hepatic encephalopathy. However, if the operation is performed in an emergency situation, significantly more major complications occur and the outcome is significantly worse. Therefore, especially in the absence of an opportunity of lowering pressure in the portal venous system and with progressive varices, elective devascularisation should be considered at an early stage.

Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis.

OBJECTIVE: Angiotensin II (AngII) activates via angiotensin-II-type-I receptor (AT1R) Janus-kinase-2 (JAK2)/Arhgef1 pathway and subsequently RHOA/Rho-kinase (ROCK), which induces experimental and probably human liver fibrosis. This study investigated the relationship of JAK2 to experimental and human portal hypertension. DESIGN: The mRNA and protein levels of JAK2/ARHGEF1 signalling components were analysed in 49 human liver samples and correlated with clinical parameters of portal hypertension in these patients. Correspondingly, liver fibrosis (bile duct ligation (BDL), carbon tetrachloride (CCl4)) was induced in floxed-Jak2 knock-out mice with SM22-promotor (SM22Cre+-Jak2f/f). Transcription and contraction of primary myofibroblasts from healthy and fibrotic mice and rats were analysed. In two different cirrhosis models (BDL, CCl4) in rats, the acute haemodynamic effect of the JAK2 inhibitor AG490 was assessed using microsphere technique and isolated liver perfusion experiments. RESULTS: Hepatic transcription of JAK2/ARHGEF1 pathway components was upregulated in liver cirrhosis dependent on aetiology, severity and complications of human liver cirrhosis (Model for End-stage Liver disease (MELD) score, Child score as well as ascites, high-risk varices, spontaneous bacterial peritonitis). SM22Cre+- Jak2f/f mice lacking Jak2 developed less fibrosis and lower portal pressure (PP) than SM22Cre--Jak2f/f upon fibrosis induction. Myofibroblasts from SM22Cre+-Jak2f/f mice expressed less collagen and profibrotic markers upon activation. AG490 relaxed activated hepatic stellate cells in vitro. In cirrhotic rats, AG490 decreased hepatic vascular resistance and consequently the PP in vivo and in situ. CONCLUSIONS: Hepatic JAK2/ARHGEF1/ROCK expression is associated with portal hypertension and decompensation in human cirrhosis. The deletion of Jak2 in myofibroblasts attenuated experimental fibrosis and acute inhibition of JAK2 decreased PP. Thus, JAK2 inhibitors, already in clinical use for other indications, might be a new approach to treat cirrhosis with portal hypertension.

Sinusoidal obstruction syndrome in the animal model: influence on liver surgery.

PURPOSE: In recent years, multimodal treatment approaches have led to an increased median survival time of patients with colorectal liver metastases. In particular, this results from new perioperative chemotherapy regimens, which in turn are accompanied by an increased risk of perioperative bleeding and/or liver failure due to the hepatotoxic side effects. Nineteen to 58 % of patients treated with oxaliplatin develop sinusoidal obstruction syndrome (SOS). The influence of preexisting SOS on liver surgery remains controversial. METHODS: Animals were operated 4 days after SOS induction with monocrotaline and received either vascular occlusion in the form of Pringle maneuver (PM) or hepatectomy (LR; 70 %) or a combination of both (LR + PM). Postoperative liver function was assessed by determination of liver enzyme levels, bile production, and tissue oxygen saturation. RESULTS: Preexisting SOS impaired morbidity after liver resection, reflected by elevated liver enzyme levels, reduced bile secretion, and low liver tissue oxygenation levels. Mortality was increased by up to 25 %. Additional ischemia in the form of PM showed no further impact in the LR ± PM group compared to LR alone. CONCLUSION: PM without LR results in high enzyme distribution in the SOS group. SOS significantly affects the outcome after liver resection in our experimental rat model only without PM and showed no protective effect in ischemia in the form of PM.

Delayed gastric emptying following pancreatoduodenectomy with alimentary reconstruction according to Roux-en-Y or Billroth-II.

BACKGROUND: Delayed gastric emptying (DGE) remains the most frequent complication following pancreatoduodenectomy (PD) with published incidences as high as 61%. The present study investigates the impact of bowel reconstruction techniques on DGE following classic PD (Whipple-Kausch procedure) with pancreatogastrostomy (PG). METHODS: We included 168 consecutive patients who underwent PD with PG with either Billroth II type (BII, n = 78) or Roux-en-Y type reconstruction (ReY, n = 90) between 2004 and 2015. Excluded were patients with conventional single loop reconstruction after pylorus preserving procedures. DGE was classified according to the 2007 International Study Group of Pancreatic Surgery definition. Patients were analyzed regarding severity of DGE, morbidity and mortality, length of hospital stay and demographic factors. RESULTS: No difference was observed between BII and ReY regarding frequency of DGE. Overall rate for clinically relevant DGE was 30% (ReY) and 26% (BII). BII and ReY did not differ in terms of demographics, morbidity or mortality. DGE significantly prolongs ICU (four vs. two days) and hospital stay (20.5 vs. 14.5 days). Risk factors for DGE development are advanced age, retrocolic reconstruction, postoperative hemorrhage and major complications. CONCLUSIONS: The occurrence of DGE can not be influenced by the type of alimentary reconstruction (ReY vs. BII) following classic PD with PG. Old age and major complications could be identified as important risk factors in multivariate analysis. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00011860 . Registered 14 March 2017.