Lower uromodulin serum levels are associated with poorer prognosis in patients with cirrhosis and hepatorenal syndrome type 2.

Hepatorenal syndrome (HRS) is associated with a dismal prognosis in patients with cirrhosis, and therapeutic options are limited. Biomarkers to identify patients with poor response to therapy are urgently needed. This study aimed to evaluate the predictive value of serum levels of uromodulin (sUMOD) in patients with cirrhosis and HRS treated with terlipressin and albumin (T/A). In total, 156 patients [81 patients with HRS treated with T/A, 42 patients with cirrhosis without kidney injury, and 33 patients with cirrhosis with prerenal acute kidney injury (AKI)] were included. sUMOD levels were analyzed by ELISA. Patients with HRS were prospectively followed for the composite endpoint of hemodialysis-/liver transplantation-free survival (HD/LTx-free survival). Of the 81 patients with HRS, 40 had HRS type 1 and 41 type 2. In the cohort of patients with HRS treated with T/A, median sUMOD level was 100 ng/mL (IQR 64; 144). sUMOD differed significantly between patients with HRS compared with patients without AKI (P = 0.001) but not between patients with HRS and prerenal AKI (P = 0.9). In multivariable analyses, sUMOD levels in the lowest quartile were independently associated with a lower rate of complete response to T/A (OR 0.042, P = 0.008) and a higher risk for reaching the composite endpoint of HD/LTX-free survival (HR 2.706, P = 0.013) in patients with HRS type 2 treated with T/A. In contrast, sUMOD was not significantly associated with these outcomes in patients with HRS type 1. sUMOD may be a valuable biomarker for identifying patients with HRS type 2 treated with T/A to predict response and prognosis.NEW & NOTEWORTHY Biomarkers identifying patients with hepatorenal syndrome (HRS) and poor response to therapy are urgently needed. In this study, lower serum uromodulin (sUMOD) levels were associated with poorer response to therapy with terlipressin and albumin and consequently with poorer prognosis in patients with HRS type 2. In patients with HRS type 1, there was no association between sUMOD and poorer prognosis.

Minimal hepatic encephalopathy is associated with a higher risk of overt hepatic encephalopathy and poorer survival.

BACKGROUND AND AIMS: Minimal hepatic encephalopathy (MHE) is a frequent complication in patients with liver cirrhosis. Its impact on predicting the development of overt hepatic encephalopathy (OHE) and survival has not been studied in large multicenter studies. METHODS: Data from patients recruited at eight centers across Europe and the United States were analyzed. MHE was detected using the psychometric hepatic encephalopathy score (PHES). A subset was also tested with the simplified animal naming test (S-ANT1). Patients were followed for OHE development and death/liver transplantation (LTx). RESULTS: A total of 1462 patients with a median model of end-stage liver disease of 11 were included (Child-Pugh (CP) stages: A 47%/B 41%/C 12%). Median follow-up time was 19 months, during which 336 (23%) patients developed an OHE episode and 464 (32%) reached the composite end point of death/LTx (369 deaths, 95 LTx). In multivariable analyses, MHE (defined by PHES) was associated with the development of OHE (subdistribution hazard ratio 1.74, p < 0.001) and poorer LTx-free survival (hazard ratio 1.53, p < 0.001) in the total cohort as well as in the subgroup of patients without a history of OHE. In subgroup analyses, MHE (defined by PHES) was associated with OHE development in patients with CP B, whereas there was no association in patients with CP A or C. In the subgroup of patients with available S-ANT1, MHE (defined by S-ANT1) was independently associated with OHE development. Combined testing (PHES+S-ANT1) was superior to single testing for predicting OHE and poorer LTx-free survival. CONCLUSIONS: This large multicenter study demonstrates that screening for MHE is a useful tool for predicting OHE and poorer survival.

Prevalence of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Multicenter Study.

INTRODUCTION: The prevalence of minimal hepatic encephalopathy (MHE), in particular in different subgroups, remains unknown. This study aimed to analyze the prevalence of MHE in different subgroups to identify patients at high risk and to pave the way for personalized screening approaches. METHODS: In this study, data of patients recruited at 10 centers across Europe and the United States were analyzed. Only patients without clinical signs of hepatic encephalopathy were included. MHE was detected using the Psychometric Hepatic Encephalopathy Score (PHES, cut-off < or ≤-4 depending on local norms). Clinical and demographic characteristics of the patients were assessed and analyzed. RESULTS: In total, 1,868 patients with cirrhosis with a median model for end-stage liver disease (MELD) of 11 were analyzed (Child-Pugh [CP] stages: A 46%, B 42%, and C 12%). In the total cohort, MHE was detected by PHES in 650 patients (35%). After excluding patients with a history of overt hepatic encephalopathy, the prevalence of MHE was 29%. In subgroup analyses, the prevalence of MHE in patients with CP A was low (25%), whereas it was high in CP B or C (42% and 52%). In patients with a MELD score <10, the prevalence of MHE was only 25%, but it was 48% in patients with a MELD score ≥20. Standardized ammonia levels (ammonia level/upper limit of normal of each center) correlated significantly, albeit weakly with PHES (Spearman ρ = -0.16, P < 0.001). DISCUSSION: The prevalence of MHE in patients with cirrhosis was high but varied substantially between diseases stages. These data may pave the way for more individualized MHE screening approaches.

Emerging immunotherapy for HCC: A guide for hepatologists.

HCC is one of the most common cancers worldwide, and the third leading cause of cancer-related death globally. HCC comprises nearly 90% of all cases of primary liver cancer. Approximately half of all patients with HCC receive systemic therapy during their disease course, particularly in the advanced stages of disease. Immuno-oncology has been paradigm shifting for the treatment of human cancers, with strong and durable antitumor activity in a subset of patients across a variety of malignancies including HCC. Immune checkpoint inhibition with atezolizumab and bevacizumab, an antivascular endothelial growth factor neutralizing antibody, has become first-line therapy for patients with advanced HCC. Beyond immune checkpoint inhibition, immunotherapeutic strategies such as oncolytic viroimmunotherapy and adoptive T-cell transfer are currently under investigation. The tumor immune microenvironment of HCC has significant immunosuppressive elements that may affect response to immunotherapy. Major unmet challenges include defining the role of immunotherapy in earlier stages of HCC, evaluating combinatorial strategies that use targeting of the immune microenvironment plus immune checkpoint inhibition, and identifying treatment strategies for patients who do not respond to the currently available immunotherapies. Herein, we review the rationale, mechanistic basis and supporting preclinical evidence, and available clinical evidence for immunotherapies in HCC as well as ongoing clinical trials of immunotherapy.

Costs of a structured early detection program for advanced liver fibrosis and cirrhosis: insights on the "plus" of Check-up 35.

BACKGROUND: The implementation of an early detection program for liver cirrhosis in a general population has been discussed for some time. Recently, the effectiveness of a structured screening procedure, called SEAL (Structured Early detection of Asymptomatic Liver cirrhosis), using liver function tests (AST and ALT) and APRI to early detect advanced fibrosis and cirrhosis in participants of the German "Check-up 35" was investigated. METHODS: This study identifies the expected diagnostic costs of SEAL in routine care and their drivers and reports on prevailing CLD etiologies in this check-up population. The analysis is based on theoretical unit costs, as well as on the empirical billing and diagnostic data of SEAL participants. RESULTS: Screening costs are mainly driven by liver biopsies, which are performed in a final step in some patients. Depending on the assumed biopsy rates and the diagnostic procedure, the average diagnostic costs are between EUR 5.99 and 13.74 per Check-up 35 participant and between EUR 1,577.06 and 3,620.52 per patient diagnosed with fibrosis/cirrhosis (F3/F4). The prevailing underlying etiology in 60% of cases is non-alcoholic fatty liver disease. DISCUSSION: A liver screening following the SEAL algorithm could be performed at moderate costs. Screening costs in routine care depend on actual biopsy rates and procedures, attendance rates at liver specialists, and the prevalence of fibrosis in the Check-up 35 population. The test for viral hepatitis newly introduced to Check-up 35 as once-in-a-lifetime part of Check-up 35 is no alternative to SEAL.

Bevacizumab in combination with octreotide rescues a patient with liver cirrhosis, GAVE syndrome and refractory hemorrhage - a case report.

Gastric antral vascular ectasia (GAVE) syndrome is a rare but often challenging etiology of upper gastrointestinal bleeding (UGIB).We report on a 60-year-old patient with liver cirrhosis, GAVE syndrome and recurrent and refractory GAVE-related UGIB. During a 5-month hospital stay, the patient required a total of 82 packed red blood cells (pRBCs) and 23 gastroscopies. All endoscopic approaches, including multiple argon plasma coagulation and band ligation sessions, remained unsuccessful. Antrectomy was waived because of the high perioperative mortality risk in Child-Pugh B liver cirrhosis. TIPS insertion also failed to control the bleeding. Only continuous intravenous octreotide infusion slowed the bleeding, but this forced the patient to be hospitalized. After 144 inpatient days, administration of subcutaneous octreotide allowed the patient to be discharged. However, the patient continued to require two pRBCs every 2-3 weeks. Based on recently published data, we treated the patient with bevacizumab (anti-VEGF antibody) off-label at a dose of 7.5 mg/kg body weight every three weeks in nine single doses over six months. Since the first administration, the patient has remained transfusion-free, has not required hospitalization, and leads an active life, working full-time. He remains on octreotide, which has been reduced but not yet discontinued. Additionally, no adverse events were observed.Thus, in patients with liver cirrhosis and refractory GAVE-related hemorrhage, bevacizumab combined with subcutaneous octreotide should be considered as an effective and durable pharmacological treatment option.

NAFLD-driven HCC: Safety and efficacy of current and emerging treatment options.

In light of a global rise in obesity and type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) represent an increasingly important underlying aetiology of hepatocellular carcinoma (HCC). HCCs arising from lipotoxicity-mediated chronic inflammation are characterised by several unique features: in contrast to virally driven HCC, up to 50% of NAFLD-HCC occurs in patients without cirrhosis and annual HCC incidence is comparatively low, complicating current surveillance strategies. On average, patients are older and are more frequently diagnosed at an advanced stage. While locoregional treatments are probably equally effective regardless of HCC aetiology, the picture is less clear for systemic therapy. Tyrosine kinase inhibitors are probably equally effective, while there have been initial signals that immune checkpoint inhibitors may be less effective in NAFLD-HCC than in viral HCC. Current international clinical practice guidelines for HCC do not consider aetiology, as there are insufficient data to draw specific conclusions or to recommend aetiology-specific modifications to the current management of patients with HCC. However, in light of the growing relevance of NAFLD-HCC, future clinical trials should assess whether HCC aetiology - and NAFLD/NASH in particular - influence the safety and efficacy of a given treatment.

Fully automated AI-based splenic segmentation for predicting survival and estimating the risk of hepatic decompensation in TACE patients with HCC.

OBJECTIVES: Splenic volume (SV) was proposed as a relevant prognostic factor for patients with hepatocellular carcinoma (HCC). We trained a deep-learning algorithm to fully automatically assess SV based on computed tomography (CT) scans. Then, we investigated SV as a prognostic factor for patients with HCC undergoing transarterial chemoembolization (TACE). METHODS: This retrospective study included 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020. A convolutional neural network was trained and validated on the first 100 consecutive cases for spleen segmentation. Then, we used the algorithm to evaluate SV in all 327 patients. Subsequently, we evaluated correlations between SV and survival as well as the risk of hepatic decompensation during TACE. RESULTS: The algorithm showed Sørensen Dice Scores of 0.96 during both training and validation. In the remaining 227 patients assessed with the algorithm, spleen segmentation was visually approved in 223 patients (98.2%) and failed in four patients (1.8%), which required manual re-assessments. Mean SV was 551 ml. Survival was significantly lower in patients with high SV (10.9 months), compared to low SV (22.0 months, p = 0.001). In contrast, overall survival was not significantly predicted by axial and craniocaudal spleen diameter. Furthermore, patients with a hepatic decompensation after TACE had significantly higher SV (p < 0.001). CONCLUSION: Automated SV assessments showed superior survival predictions in patients with HCC undergoing TACE compared to two-dimensional spleen size estimates and identified patients at risk of hepatic decompensation. Thus, SV could serve as an automatically available, currently underappreciated imaging biomarker. KEY POINTS: • Splenic volume is a relevant prognostic factor for prediction of survival in patients with HCC undergoing TACE, and should be preferred over two-dimensional surrogates for splenic size. • Besides overall survival, progression-free survival and hepatic decompensation were significantly associated with splenic volume, making splenic volume a currently underappreciated prognostic factor prior to TACE. • Splenic volume can be fully automatically assessed using deep-learning methods; thus, it is a promising imaging biomarker easily integrable into daily radiological routine.

Prescription rates of common medications in patients with decompensated cirrhosis in Germany.

BACKGROUND: Adequate pharmacological treatment is of pivotal importance to improve prognosis in patients with decompensated liver cirrhosis. We studied the adherence to recommended pharmacological treatments as secondary prevention in cirrhotic patients following a first decompensation in German primary care. METHODS: Using the Disease Analyzer Database, the current study sample included patients with liver cirrhosis who had an initial diagnosis of a first decompensation event between 2015 and 2018 (index date) and a follow-up time of at least 6 months after the index date. Pharmacological treatments following the 6 months after the index date were studied. RESULTS: The study included 1538 patients with a first decompensation event. The frequency of first-time complications of cirrhosis was 60% new onset of ascites, 25% overt hepatic encephalopathy (HE), 3% spontaneous bacterial peritonitis (SBP), and 12% acute variceal bleeding. The adherence to guideline-recommended treatment following the initial decompensation was highest for ascites, with 91.3% of patients receiving diuretics. Non-selective beta-blockers following an event of variceal bleeding were prescribed in 69.1% and lactulose and/or rifaximin in 59.1% after a bout of HE. The frequency of prescriptions of antibiotics after SBP was 60.4%. Potenzially harmful prescribed medications included non-steroidal anti-inflammatory drugs in 15.5%, benzodiazepines in 12.8%, opioids in 9.5%, and proton pump inhibitors in 73.7%. CONCLUSION: Our findings underline the need for intensified efforts to distribute practice guidelines for liver cirrhosis and increase awareness of over-prescribing of potentially harmful medication.

Urinary ethyl glucuronide (uEtG) as a marker for alcohol consumption in liver transplant candidates: a real-world cohort.

BACKGROUND: In order to reduce alcohol relapse after liver transplantation (LT), the German national guidelines for waiting-list maintenance and organ allocation demand a minimum 6-month period of alcohol abstinence pre-LT, confirmed by measuring urinary ethyl glucuronide (uEtG). METHODS: Between January 2015 and June 2016, uEtG was measured at least once in 339 cirrhotic patients with an indication for LT at the University Medical Center Mainz. uEtG was measured with an enzyme-linked immunosorbent assay (ELISA) screening test (cutoff value: 500 µg/L). For uEtG values ≥ 500 µg/L, liquid chromatography-mass spectrometry (LC-MS/MS) was performed as a confirmatory assay. Data were collected prospectively in a transplant database. RESULTS: Of the 339 potential liver transplant candidates, uEtG was negative in 86.4 %. Most patients were male (64.3 %), with an average age of 56.42 ±â€Š10.1 years. In the multivariate analysis, mean corpuscular volume (p = 0.001), urinary creatinine (p = 0.001), gamma-glutamyl transferase (p = 0.001), and hemoglobin (p = 0.003) were significantly associated with a positive uEtG test result. The sensitivity of the ELISA screening test was 100 % for uEtG values > 2000 µg/L, as confirmed by LC-MS/MS. CONCLUSION: uEtG is an effective parameter to reveal alcohol consumption by patients on the waiting list for LT. The sensitivity of the ELISA is excellent for uEtG values > 2000 µg/L, for which LC-MS/MS confirmation could be omitted.

Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program.

BACKGROUND: To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with advanced CCA in conjunction with an extensive biomarker program. METHODS: Afatinib was administered continuously p. o. as add-on in patients with advanced CCA who received conventional chemotherapy with gemcitabine/cisplatin. A classical 3 + 3 phase I study was employed, while the maximum tolerated dose (MTD) of oral afatinib was determined in a 2 step dose escalation. Safety, overall survival (OS) and progression free survival (PFS) were evaluated for all patients. Finally, a translational biomarker analysis was conducted for the EGFR and VEGF signalling cascades. RESULTS: Overall, 9 patients were enrolled. Further recruitment was discontinued due to lack of efficacy results of the tested drug in other indications. 30 mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0 months, respectively. Diarrhoea and haematological disorders were the most common observed AEs. Almost all patients overexpressed EGFR on their tumour tissues, whereas none of them expressed mutations in Exons 18, 19 and 21. Non-responders showed a higher variation of VEGF-C, -D, leptin and sEGFR in their sera. CONCLUSIONS: Afatinib failed to show survival benefits in combination with gemcitabine/cisplatin in patients with advanced CCA. Mutational analysis of EGFR and pathways associated with VEGF-C, -D and leptin might show promising results in future studies. CLINICAL TRIALS REGISTRATION: NCT01679405 August, 2012.

Cytokeratin-18 fragments predict treatment response and overall survival in gastric cancer in a randomized controlled trial.

BACKGROUND: Gastric cancer is common malignancy and exhibits a poor prognosis. At the time of diagnosis, the majority of patients present with metastatic disease which precludes curative treatment. Non-invasive biomarkers which discriminate early from advanced stages or predict the response to treatment are urgently required. This study explored the cytokeratin-18 fragment M30 and full-length cytokeratin-18 M65 in predicting treatment response and survival in a randomized, placebo-controlled trial of advanced gastric cancer. METHODS: Patients enrolled in the SUN-CASE study received sunitinib or placebo as an adjunct to standard therapy with leucovorin (Ca-folinate), 5-fluorouracil, and irinotecan in second or third line. Treatment response rates, progression-free survival and overall survival were assessed during a follow-up period of 12 months. Cytokeratin-18 fragments were analyzed in 52 patients at baseline and day 14 of therapy. RESULTS: Levels of M30 correlated with the presence of metastasis and lymph node involvement and decreased significantly during chemotherapy. Importantly, baseline levels of M30 were significantly higher in patients who failed therapy. In addition, patients who did not respond to treatment were also identifiable at day 14 based on elevated M30 levels. By stepwise regression analysis, M30 at day 14 was identified as independent predictor of treatment response. Likewise, serum levels of full-length cytokeratin-18 M65 at baseline also correlated with treatment failure and progression-free survival. The addition of sunitinib did not exert any effects on serum levels of M30 or M65. CONCLUSION: The cytokeratin-18 fragment M30 at day 14 identifies patients that fail to second- or third-line therapy for advanced gastric cancer. Validation of this non-invasive biomarker in gastric cancer is warranted.

Validation of the SNACOR clinical scoring system after transarterial chemoembolisation in patients with hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolisation is the standard of care for intermediate stage (BCLC B) hepatocellular carcinoma, but it is challenging to decide when to repeat or stop treatment. Here we performed the first external validation of the SNACOR (tumour Size and Number, baseline Alpha-fetoprotein, Child-Pugh and Objective radiological Response) risk prediction model. METHODS: A total of 1030 patients with hepatocellular carcinoma underwent transarterial chemoembolisation at our tertiary referral centre from January 2000 to December 2016. We determined the following variables that were needed to calculate the SNACOR at baseline: tumour size and number, alpha-fetoprotein level, Child-Pugh class, and objective radiological response after the first transarterial chemoembolisation. Overall survival, time-dependent area under receiver-operating characteristic curves, Harrell's C-index, and the integrated Brier score were calculated to assess predictive ability. Finally, multivariate analysis was performed to identify independent predictors of survival. RESULTS: The study included 268 patients. Low, intermediate, and high SNACOR scores predicted a median survival of 31.5, 19.9, and 9.2 months, respectively. The areas under the receiver-operating characteristic curve for overall survival were 0.641, 0.633, and 0.609 at 1, 3, and 6 years, respectively. Harrell's C-index was 0.59, and the integrated Brier Score was 0.175. Independent predictors of survival included tumour size (P < 0.001), baseline alpha-fetoprotein level (P < 0.001) and Child-Pugh class (P < 0.004). Objective radiological response (P = 0.821) and tumour number (P = 0.127) were not additional independent predictors of survival. CONCLUSIONS: The SNACOR risk prediction model can be used to identify patients with a dismal prognosis after the first transarterial chemoembolisation who are unlikely to benefit from further transarterial chemoembolisation. However, Harrell's C-index showed only moderate performance. Accordingly, this risk prediction model can only serve as one of several components used to make the decision about whether to repeat treatment.

The Manchester Triage System (MTS): a score for emergency management of patients with acute gastrointestinal bleeding.

BACKGROUND: Suspected gastrointestinal (GI) bleeding is a common initial diagnosis in emergency departments. Despite existing endoscopic scores to estimate the risk of GI bleeding, the primary clinical assessment of urgency can remain challenging. The 5-step Manchester Triage System (MTS) is a validated score that is often applied for the initial assessment of patients presenting in emergency departments. METHODS: All computer-based records of patients who were admitted between January 2014 and December 2014 to our emergency department in a tertiary referral hospital were analyzed retrospectively. The aim of our retrospective analysis was to determine if patient triage using the MTS is associated with rates of endoscopy and with presence of active GI bleeding. RESULTS: In summary, 5689 patients with a GI condition were treated at our emergency department. Two hundred eighty-four patients (4.9 %) presented with suspected GI bleeding, and 165 patients (58 %) received endoscopic diagnostic. Endoscopic intervention for hemostasis was needed in 34 patients (21 %). In patients who underwent emergency endoscopy, triage into MTS categories with higher urgency was associated with higher rates of endoscopic confirmation of suspected GI bleeding (79 % of patients with MTS priority levels 1 or 2, 53 % in level 3 patients, and 40 % in levels 4 or 5 patients; p = 0.024). CONCLUSIONS: The MTS is an established tool for triage in emergency departments and could have a potential to guide early clinical decision-making with regards to urgency of endoscopic evaluation in patients with suspected GI bleeding.

Treating Hepatobiliary Cancers: The Oncology Way.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. HCC represents more than 90% of primary liver cancers. There is growing incidence of HCC worldwide. In the western world, HCC arises in a cirrhotic background in up to 90% of cases, and cirrhosis itself is a progressive disease that affects patient survival. Thus, outcome in patients with HCC and the chances for anti-tumor treatment and it is results are dependent not only on tumor-associated factors but also on the liver function. Cholangio carcinoma is the second most common primary liver tumor with an estimated incidence of 1:100,000. Cholangiocarcinoma can be sub-classified as intrahepatic (iCCA), perihilar or distal where iCCA arises within the liver parenchyma. Overall, the incidence of iCCA seems to be increasing globally. This may be attributed to a global increase of risk factors shared between HCC and iCCA, such as viral hepatitis, liver cirrhosis, diabetes mellitus, obesity, NASH, and others.

Epidemiology of hepatic encephalopathy in german hospitals - the EpHE study.

Background Hepatic encephalopathy (HE) is a serious complication of liver cirrhosis. The proportion of patients with liver cirrhosis attending German hospitals suffering from HE is unknown. Methods In the first part of the study, data of 14 community hospitals and 5 university hospitals covering the years 2010 and 2011 were analyzed retrospectively for the DRG codes of liver cirrhosis and hepatic encephalopathy. In the second prospective part of the multicenter observational study, all patients with liver cirrhosis attending the departments of gastroenterology of 16 participating community hospitals within a study period of 3 months were included and screened for HE clinically according to the West Haven criteria (grades 1 - 4). Results A diagnosis of liver cirrhosis has been coded in 6366 cases in 2010 and in 7279 cases in 2011. In the vast majority of hospitals, less than 20 % of these cases had an additional DRG code for HE. Two hundred seventy-eight patients with liver cirrhosis were included into the prospective study. A clinically detectable HE was present in 36 % of the patients (n = 99). The majority was classified as West Haven 1 (n = 59, 59.6 %). Of the patients without clinical sings of HE, 48 % (n = 134) showed a pathological NCT. Conclusion Our data suggest that HE is underdiagnosed in German hospitals. Since treatment of HE may improve the prognosis of the patients as well as their quality of life, hospitalized patients with liver cirrhosis should be routinely screened for HE.

Extended Abstract: Management of Liver Cancer.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. HCC represents more than 90% of primary liver cancers. There is a growing incidence of HCC worldwide. In the Western world, HCC arises in a cirrhotic background in up to 90% of cases, and cirrhosis itself is a progressive disease that affects patient survival. Thus, outcome in patients with HCC and the chances for anti-tumor treatment and its results are dependent not only on tumor-associated factors but also on liver function.

Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1 secretion.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) associated macrophages accelerate tumor progression by growth factor release. Therefore, tumor-associated macrophages (TAM) and their initiated signaling cascades are potential therapeutic targets. Aiming at understanding anticancer effects of systemic HCC therapy, we investigated the impact of sorafenib on macrophage function, focusing on macrophage-related growth factor secretion. METHODS: Macrophage markers, cytokine and growth factor release were investigated in CSF-1 (M1) or GMCSF (M2) maturated monocyte-derived macrophages. Macrophages were treated with sorafenib (1.2-5.0 µg/ml) and culture supernatants were transferred to hepatoma cell cultures to assess growth propagation. Insulin-like growth factor (IGF) signaling was blocked with NVP-AEW541 to confirm the role of IGF-1 in macrophage-driven hepatoma cell propagation. Macrophage activation was followed by ELISA of serum soluble mCD163 in sorafenib-treated patients with HCC. RESULTS: Alternative macrophages (M2), which showed higher IGF-1 (p=0.022) and CD163 mRNA (p=0.032) expression compared to classical macrophages (M1), increased hepatoma growth. This effect was mediated by M2-conditioned culture media. In turn, sorafenib lowered mCD163 and IGF-1 release by M2 macrophages, which decelerated M2 macrophage driven HuH7 and HepG2 proliferation by 47% and 64%, respectively. IGF-receptor blockage with NVP-AEW541 reduced growth induction by M2-conditioned culture media in a dose dependent manner. A transient mCD163 reduction during sorafenib treatment indicated a coherent M2 macrophage inhibition in patients with HCC. CONCLUSIONS: Sorafenib alters macrophage polarization, reduces IGF-1-driven cancer growth in vitro and partially inhibits macrophage activation in vivo. Thus macrophage modulation might contribute to the anti-cancer activity of sorafenib. However, more efficient macrophage-directed therapies are required.