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.

Markers of cell death predict therapy response in patients with cirrhosis and hepatorenal syndrome.

BACKGROUND AND AIMS: Hepatorenal syndrome is a major complication in patients with cirrhosis and associated with high mortality. Predictive biomarkers for therapy response are largely missing. Cytokeratin18-based cell death markers are significantly elevated in patients with complications of chronic liver disease, but the role of these markers in patients with HRS treated with vasoconstrictors and albumin is unknown. METHODS: We prospectively analyzed a total of 138 patients with HRS, liver cirrhosis without HRS and acute kidney injury treated at the University Medical Center Mainz between April 2013 and July 2018. Serum levels of M30 and M65 were analyzed by ELISA and clinical data were collected. Predictive ability was assessed by Kaplan-Meier curves, logistic regression and c-statistic. Primary endpoint was response to therapy. RESULTS: M30 and M65 were significantly increased in patients with HRS compared to non-HRS controls (M30: p < 0.0001; M65: p < 0.0001). Both serum markers showed predictive ability for dialysis- and LTX-free survival but not overall survival. Logistic regression confirmed M30 and M65 as independent prognostic factors for response to therapy. A novel predictive score comprising bilirubin and M65 showed highest predictive ability to predict therapy response. CONCLUSIONS: Serum levels of M30 and M65 can robustly discriminate patients into responders and non-responders to terlipressin therapy with a good predictive ability for dialysis- and LTX-free survival in cirrhotic patients. Cell death parameters might possess clinical relevance in patients with liver cirrhosis and HRS.

Structured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL.

BACKGROUND & AIMS: Detection of patients with early cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. The SEAL program aimed at evaluating the usefulness of a structured screening procedure to detect cirrhosis as early as possible. METHODS: SEAL was a prospective cohort study with a control cohort from routine care data. Individuals participating in the general German health check-up after the age of 35 ("Check-up 35") at their primary care physicians were offered a questionnaire, liver function tests (aspartate and alanine aminotransferase [AST and ALT]), and follow-up. If AST/ALT levels were elevated, the AST-to-platelet ratio index (APRI) score was calculated, and patients with a score >0.5 were referred to a liver expert in secondary and/or tertiary care. RESULTS: A total of 11,859 participants were enrolled and available for final analysis. The control group comprised 349,570 participants of the regular Check-up 35. SEAL detected 488 individuals with elevated APRI scores (4.12%) and 45 incident cases of advanced fibrosis/cirrhosis. The standardized incidence of advanced fibrosis/cirrhosis in the screening program was slightly higher than in controls (3.83‰ vs. 3.36‰). The comparison of the chance of fibrosis/cirrhosis diagnosis in SEAL vs. in standard care was inconclusive (marginal odds ratio 1.141, one-sided 95% CI 0.801, +Inf). Of note, when patients with decompensated cirrhosis at initial diagnosis were excluded from both cohorts in a post hoc analysis, SEAL was associated with a 59% higher chance of early cirrhosis detection on average than routine care (marginal odds ratio 1.590, one-sided 95% CI 1.080, +Inf; SEAL 3.51‰, controls: 2.21‰). CONCLUSIONS: The implementation of a structured screening program may increase the early detection rate of cirrhosis in the general population. In this context, the SEAL pathway represents a feasible and potentially cost-effective screening program. REGISTRATION: DRKS00013460 LAY SUMMARY: Detection of patients with early liver cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. This study demonstrates that the implementation of a structured screening program using easily obtainable measures of liver function may increase the early detection rate of cirrhosis in the general population. In this context, the 'SEAL' pathway represents a feasible and potentially cost-effective screening program.

Continued alcohol consumption and hepatic encephalopathy determine quality of life and psychosocial burden of caregivers in patients with liver cirrhosis.

BACKGROUND: Patients with liver cirrhosis suffer from significantly reduced health-related quality of life and are often dependent on support from caregivers. In this context, caregivers often suffer from impaired quality of life (QoL) as well as psychosocial burden (PB). The aim of the present study was to identify factors influencing QoL and PB of caregivers in order to improve the social care of patients and caregivers. METHODS: In this cross-sectional study, 106 patients with liver cirrhosis and their caregivers were included. (Health-related) QoL was surveyed in patients (CLDQ) and caregivers (SF-36) and PB was determined by Zarit Burden Interview. RESULTS: Alcohol related liver cirrhosis (55%) was the predominant etiology of liver cirrhosis and the median MELD of the cohort was 14. QoL did not differ between patients with and without alcohol-related liver cirrhosis (p = 0.6). In multivariable analysis, continued alcohol consumption (p = 0.020), a history of hepatic encephalopathy (HE) (p = 0.010), poorer QoL of patients (p = 0.030) and poorer QoL of caregivers (p = 0.005) were associated with a higher PB of caregivers. Factors independently associated with poorer QoL of caregivers were continued alcohol consumption (p = 0.003) and a higher PB of caregivers (p = 0.030). CONCLUSION: Caregivers of patients with liver cirrhosis suffer from impaired QoL and PB, especially in case of continued alcohol consumption or the occurrence of HE.

Impact of acute-on-chronic liver failure and decompensated liver cirrhosis on psychosocial burden and quality of life of patients and their close relatives.

BACKGROUND: Patients with liver cirrhosis often suffer from complications such as ascites, gastrointestinal bleeding, and infections, resulting in impaired quality of life. Frequently, the close relatives of patients also suffer from a lower quality of life in chronic diseases. In recent years, acute-to-chronic liver failure has been defined as a separate entity with high mortality. Often several organs are affected which makes intensive care therapy necessary. Little is known about the influence of acute-on-chronic-liver failure (ACLF) on the quality of life of patients and the psychosocial burden on close relatives. AIM: The purpose of this prospective study is to investigate the influence of decompensated liver cirrhosis and the onset of ACLF of the patient's' quality of life and the psychosocial burden of close relatives. METHOD: In this non - randomized prospective cohort study a total of 63 patients with acute decompensation of liver cirrhosis and hospital admission were enrolled in the study. To assess the quality of life of patients, the disease specific CLDQ questionnaire was assessed. In addition. Quality of life and psychosocial burden of first degree relatives was measured using the generic SF-36 questionnaire as well as the Zarit Burden Score. RESULTS: 21 of the 63 patients suffered from ACLF. Patients with ACLF showed a lower quality of life in terms of worries compared to patients with only decompensated liver cirrhosis (3,57 ± 1,17 vs. 4,48 ± 1,27; p value: 0,008) and increased systemic symptoms (3,29 ± 1,19 vs. 4,48 ± 1,58; p value: 0,004). The univariate analysis confirmed the link between the existence of an ACLF and the concerns of patients. (p value: 0,001). The organ failure score was significantly associated with overall CLDQ scores, especially with worries and systemic symptoms of patients. Interestingly the psychosocial burden and quality of life of close relative correlates with patient's quality of life and was influenced by the onset of an acute-on-chronic liver failure. CONCLUSION: Patients with decompensated liver cirrhosis suffer from impaired quality of life. In particular, patients with ACLF have a significantly reduced quality of life. The extent of the psychosocial burden on close relative correlates with poor quality of life in patients with decompensated liver disease and is influenced by the existence of ACLF.

Terlipressin and albumin combination treatment in patients with hepatorenal syndrome type 2.

Background: Hepatorenal syndrome (HRS) is associated with a poor prognosis. In HRS type 1, loss of renal function is rapidly progressive, while HRS type 2 is characterised by chronic ascites and more moderately elevated renal parameters. While treatment with terlipressin/albumin is well established in type 1, its effectiveness in chronic HRS is less clear. Objective: The aim of this study was to evaluate the effectiveness of terlipressin/albumin treatment in patients with HRS type 2. Methods: All patients with a first episode of HRS between April 2013 and February 2016 were included in this observational study. Relevant clinical and laboratory parameters were recorded and patients were followed. Results: A total of 106 patients with HRS were included. With terlipressin therapy reversal of HRS types 1 and 2 was achieved in 48% and 46% of patients (p = 0.84) with relapse rates of 8% vs 50% (p = 0.001). Overall survival (OS) and survival free of liver transplantation (LTx) were similar in HRS types 1 and 2 (p = 0.69; p = 0.64). In multivariate analysis response to treatment was independently associated with better OS in HRS type 2, in addition to established risk factors such as lower Model for End-Stage Liver Disease score, absence of hepatic encephalopathy and eligibility for LTx. Conclusion: A terlipressin treatment course seems to be justified in selected patients with HRS type 2, especially in countries and settings with long transplant waiting lists. In addition treatment response might also help to identify HRS type 2 patients with a more favourable outcome.

Validation of the simplified Animal Naming Test as primary screening tool for the diagnosis of covert hepatic encephalopathy.

BACKGROUND: Diagnosis of covert hepatic encephalopathy (CHE) is time consuming in clinical practice. Recently, a new diagnostic tool - the simplified Animal Naming Test (S-ANT1) - was presented with promising results in an Italian cohort. The aim of the present study was to validate S-ANT1 in a cohort of cirrhotic patients from a German tertiary referral centre. METHODS: 143 cirrhotic patients and 37 healthy controls were enrolled. Hepatic encephalopathy (HE) grade 1 (HE1) was clinically diagnosed according to the West-Haven Criteria. Critical flicker frequency and Psychometric Hepatic Encephalopathy Score were used to detect minimal HE (MHE). All participants were additionally examined by S-ANT1. RESULTS: 58 (40.6%) patients presented with CHE (40 MHE, 18 HE1). S-ANT1 was lowest in patients with HE1, followed by patients with MHE, patients without CHE, and healthy controls, respectively (each p < 0.05). Naming <20 animals discriminated best between patients with and without CHE in ROC analysis (with Youden's index). With a cut-off value of ≥23 mentioned animal names further testing for CHE could be avoided in 38.5% of patients with a negative predictive value of 84%. CONCLUSIONS: S-ANT1 may become an important first screening tool for the assessment of CHE in clinical practice.

Clinical Predictors for Poor Quality of Life in Patients With Covert Hepatic Encephalopathy.

BACKGROUND: Current EASL/AASLD guidelines recommend treatment of covert hepatic encephalopathy (HE) only in symptomatic patients, for example, in those with impaired quality of life or with affected driving abilities. GOALS: Because testing for impaired quality of life is time consuming, the aim of the present study was to identify simple clinical predictors for poor quality of life in patients with covert HE (CHE). STUDY: In total, 139 cirrhotic in- and outpatients without a history of overt hepatic encephalopathy were enrolled. Diagnosis of HE grade 1 (HE1) was diagnosed clinically according to the West-Haven Criteria. Critical flicker frequency and the Psychometric Hepatic Encephalopathy Score were used to detect minimal HE (MHE). Chronic Liver Disease Questionnaire was used to assess health-related quality of life (HrQoL). RESULTS: CHE was detected in 51 (36.7%) patients. Multivariate analysis identified a history of falls in the previous year (P=0.003) and female gender (P=0.030) as independent predictors of reduced HRQoL in patients with CHE. Comparison of patients with and without a history of falls revealed relevant differences in the subdomains-abdominal symptoms, fatigue, systemic symptoms, emotional functions and worries. CONCLUSIONS: A history of falls and female gender are associated with impaired HRQoL in patients with CHE. These data indicate that a history of falls should be considered as a treatment indication in patients with CHE to improve HRQoL and ultimately prognosis.

Endoscopic and angiographic management of lower gastrointestinal bleeding: Review of the published literature.

Lower gastrointestinal bleeding is common and occurs often in elderly patients. In rare cases it is associated with hemorrhagic shock. A large number of such bleedings, which are often caused by colon diverticula, subside spontaneously. Alternatively they can be treated by endoscopic procedures successfully. Given the aging population of our society, the rising incidence of lower gastrointestinal tract bleeding and new anticoagulant therapies, some of the bleedings tend to be severe. Colonoscopy is the established standard procedure for the diagnosis and treatment of lower gastrointestinal bleeding. However, a small number of patients experience re-bleeding or shock; their bleeding does not resolve spontaneously and cannot be treated successfully by endoscopic procedures. In such patients, interventional radiology is very useful for the detection of bleeding and the achievement of hemostasis. Against this background we performed a literature search using PubMed to identify all relevant studies focused on the endoscopic and radiological management of lower gastrointestinal bleeding and present recent conclusions on the subject.

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.

[Evaluation of Abnormal Liver Chemistries in General Practitioner Care - The Reality of Primary Care in Germany]. / Abklärung von Leberwerterhöhungen in der hausärztlichen Praxis ­ Versorgungsrealität in Deutschland.

BACKGROUND: In general practitioner care, abnormal liver chemistries are often being diagnosed unintentionally. So far, there is no evidence-based, structured diagnostic pathway for classifying and evaluating elevated liver enzymes, especially with regard to the early detection of patients at increased risk for liver fibrosis or liver cirrhosis. Accordingly, dealing with elevated liver values which are noticed in the course of a general blood examination is a diagnostic challenge that strongly depends on the doctor's approach. METHODS AND PARTICIPANTS: In the course of a survey, 391 general practitioners in Rhineland-Palatinate and Saarland were interviewed between March and June 2017. The focus was on behavior and strategies with regard to the clarification of elevated liver values as well as the identification of challenges and training interests. In addition to the descriptive analysis, a factor analysis was performed. RESULTS: The determination of liver values such as γ-GT, AST and ALT is frequently performed in general practitioner care without the existence of any particular cause. There are strongly different clusters of liver values that are being analyzed in the course of a liver function test. In the case of increased liver values, a majority of the physicians surveyed generally prefer a controlled waiting (58 %). Due to the absence of an established diagnosis and treatment pathway, challenges arise in everyday practice which relate to controlled waiting, cooperation with gastroenterological specialists, as well as orientation to predefined laboratory value portfolios. DISCUSSION: In addition to the introduction of an evidence-based diagnosis and treatment pathway, it should be considered to optimize the flow of information between general practitioners and gastroenterological specialists. Last but not least, it would be desirable if more training courses for general practitioners could be offered in this subject area.

Surveillance of Hepatocellular Carcinoma and Diagnostic Algorithms in Patients with Liver Cirrhosis.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most deadly complication of all major chronic liver diseases. Since early detection is the most significant determinant of overall survival, intense screening is of major importance. METHODS: This overview is based on a systematic review of the available literature on HCC screening and surveillance in the PubMed database. RESULTS: Over the last decades, major etiological risk factors were identified and the population at highest risk for the development of HCC was clearly defined. Screening in these patients has been repeatedly demonstrated to detect early tumor stages and to be cost-effective. Therefore, screening is recommended by all current guidelines and usually comprises a bi-annual ultrasound examination in Western countries. In some Asian countries biomarkers are also used; however, their efficiency for Western HCCs remains to be determined. The detection of lesions >1 cm during routine screening requires subsequent confirmation of HCC. The diagnosis can be accurately established by modern imaging techniques, i.e. computed tomography or magnetic resonance imaging, in the majority of patients. In ambiguous cases and if radiological criteria are not met by two imaging techniques, biopsies remain the gold standard for diagnosis. Furthermore, histology is of key importance for the development of new diagnostic and predictive biomarkers. CONCLUSION: Screening and detection algorithms for patients at risk for HCC are effective and should be rigorously implemented in clinical routine.

Acute gastrointestinal bleeding - a new approach to clinical and endoscopic management.

Overt or occult gastrointestinal bleeding is a frequently observed condition in routine gastroenterological practice. Occult gastrointestinal bleeding is usually a purely incidental finding, based on the discovery of iron deficiency anemia in the laboratory or blood in stool (a positive Hemoccult test). However, overt bleeding accompanied by the clinical features of tarry stool, hematemesis, or hematochezia may be a life-threatening condition, calling for immediate emergency management. In contrast to traumatology, algorithms of emergency and intensive medicine are not sufficiently validated yet for acute life-threatening bleeding. The purpose of this review was to present all established and new endoscopic hemostasis techniques and to evaluate their efficacy, as well as to provide the treating endoscopist with practical advice on how he/she could incorporate these procedures into acute medical management. The recommendations are based on inspection of the study results in the recent published literature, as well as emergency medicine algorithms in traumatology.

[Response to Terlipressin and albumin is associated with improved outcome in patients with cirrhosis and hepatorenal syndrome]. / Leberzirrhose und hepatorenales Syndrom: Das Ansprechen auf Terlipressin und Albumin ist mit besserem Überleben assoziiert.

BACKGROUND AND AIM: Hepatorenal syndrome (HRS) is a severe but potentially reversible complication in patients with cirrhosis. Untreated it is associated with a poor prognosis. Several randomized controlled trials (RCT) demonstrated that treatment with terlipressin and albumin improves renal function. However the effect on overall survival is unclear. Aim of the study was to gain further insight into the effect of terlipressin treatment in patients with HRS on renal function, overall survival and survival without liver transplantation or renal replacement. METHODS: All patients presenting with HRS and treated with terlipressin in our tertiary referral liver and transplantation center between April 2013 and April 2014 were included. Clinically relevant parameters such as response to therapy, overall survival and transplant- and renal-replacement-free-survival were prospectively investigated. RESULTS: Overall 57 patients were prospectively followed over a median of 65 days. In the majority of patients cirrhosis was in an advanced stage (Child-Pugh C: 46; 81%). Median cumulative terlipressin dosage and treatment duration were 20 mg and 5 days, respectively. Complete or partial response to terlipressin with recovery from HRS was observed in 20 and 3 out of 57 patients (51%; 5%). Median overall survival was significantly better in patients with response to terlipressin than in patients with non-response (167 vs. 27 days; p > 0.0001), as well as median survival free of liver transplantation and renal-replacement-therapy (81 vs. 4 days; p > 0.0001). In uni- and multivariate analysis, non-response was associated with a high baseline serum-bilirubin-concentration. CONCLUSION: Terlipressin in combination with albumin is effective in the majority of patients with HRS. Response to therapy is associated with improved survival.

The impact of patient and tumour baseline characteristics on the overall survival of patients with advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND: Impact of patient and tumour baseline characteristics on the overall survival is not well characterized in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. AIMS/METHODS: Univariate/multivariate analyses were conducted to identify retrospectively the impact of baseline characteristics on the survival of 110 patients with advanced HCC treated with sorafenib. RESULTS: Median survival of the whole cohort was 6.7 months, median survival in Child-Pugh A, B, C patients was 10.5, 6.1 and 3.0 months and median survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C/D was 6.8/2.6 months. Presence of ascites, presence of macrovascular invasion and BCLC stage D (mainly determined by Child-Pugh C status and Eastern Cooperative Oncology Group Performance Status>2) remained independent prognostic factors for the survival on multivariate analysis. Particularly, the presence of macrovascular invasion significantly influenced survival both in patients with liver cirrhosis Child-Pugh A and Child-Pugh B. CONCLUSION: Well maintained liver function and performance status are prerequisites for sorafenib treatment in patients with advanced HCC. Our findings do not support routine clinical use of sorafenib in Child-Pugh B patients. Evaluation of ascites and particularly macrovascular invasion might help to identify patients more likely to benefit from sorafenib treatment.

Clinicopathologic features and prognosis of young patients with hepatocellular carcinoma in a large German cohort.

GOALS AND BACKGROUND: Hepatocellular carcinoma in non-hepatitis B virus endemic areas is rare in patients younger than 40 years of age. The aim of this study was to characterize young patients in a large German cohort in comparison with older patients with regard to underlying liver disease, clinical management, and survival. STUDY: We analyzed the clinical data and medical records of 1108 consecutive patients with confirmed hepatocellular carcinoma. Twenty-five patients (2%) were younger than 40 years of age. We compared this subgroup with patients older than 40 years of age. RESULTS: Underlying chronic liver disease was less common in young patients and detectable in only 56% of patients. Fibrolamellar carcinoma was more frequent in young versus old patients (20% vs. 0.7%; P<0.001). There was a trend toward more potentially curative treatment options in young patients, and overall survival was longer in the young group compared with older patients (56.0 vs. 15.2 mo; P=0.048). CONCLUSIONS: This western cohort of young patients is distinctly different from described Asian cohorts, especially with regard to a lower rate of underlying liver disease and particularly hepatitis B virus. Young patients had a better overall survival than older patients.

Computed virtual chromoendoscopy for classification of small colorectal lesions: a prospective comparative study.

OBJECTIVES: Standard colonoscopy offers no reliable discrimination between neoplastic and nonneoplastic colorectal lesions. Computed virtual chromoendoscopy with the Fujinon intelligent color enhancement (FICE) system is a new dyeless imaging technique that enhances mucosal and vascular patterns. This prospective trial compared the feasibility of FICE, standard colonoscopy, and conventional chromoendoscopy with indigo carmine in low- and high-magnification modes for determination of colonic lesion histology. METHODS: Sixty-three patients with 150 flat or sessile lesions less than 20 mm in diameter were enrolled. At colonoscopy, each lesion was observed with six different endoscopic modalities: standard colonoscopy, FICE, and conventional chromoendoscopy with indigo carmine (0.2%) dye spraying in both low- and high-magnification modes. Histopathology of all lesions was confirmed by evaluation of endoscopic resection or biopsy specimens. Endoscopic images were stored electronically and randomly allocated to a blinded reader. RESULTS: Of the 150 polyps, 89 were adenomas and 61 were hyperplastic polyps with an average size of 7 mm. For identifying adenomas, the FICE system with low and high magnifications revealed a sensitivity of 89.9% and 96.6%, specificity of 73.8% and 80.3%, and diagnostic accuracy of 83% and 90%, respectively. Compared with standard colonoscopy, the sensitivity and diagnostic accuracy achieved by FICE were significantly better under both low (P < 0.02) and high (P < 0.03) magnification and were comparable to that of conventional chromoendoscopy. CONCLUSIONS: The FICE system identified morphological details that efficiently predict adenomatous histology. For distinguishing neoplastic from nonneoplastic lesions, FICE was superior to standard colonoscopy and equivalent to conventional chromoendoscopy.

TGFbeta-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN.

Transforming growth factor beta (TGFbeta) has profound growth-suppressive effects on normal epithelial cells, but supports metastasis formation in many tumour types. In most epithelial tumour cells TGFbeta(1) treatment results in epithelial dedifferentiation with reduced cell aggregation and enhanced cellular migration. Here we show that the epithelial dedifferentiation, accompanied by dissociation of the E-cadherin adhesion complex, induced by TGFbeta(1) depended on phosphatidylinositol 3-kinase (PI3-kinase) and the phosphatase PTEN as analysed in PANC-1 and Smad4-deficient BxPC-3 pancreatic carcinoma cells. TGFbeta(1) treatment enhanced tyrosine phosphorylation of alpha- and beta-catenin, which resulted in dissociation of the E-cadherin/catenin complex from the actin cytoskeleton and reduced cell-cell adhesion. The PI3-kinase and PTEN were found associated with the E-cadherin/catenin complex via beta-catenin. TGFbeta(1) treatment reduced the amount of PTEN bound to beta-catenin and markedly increased the tyrosine phosphorylation of beta-catenin. By contrast, forced expression of PTEN clearly reduced the TGFbeta(1)-induced phosphorylation of beta-catenin. The TGFbeta(1)-induced beta-catenin phosphorylation was also dependent on PI3-kinase and Ras activity. The described effects of TGFbeta(1) were independent of Smad4, which is homozygous deleted in BxPC-3 cells. Collectively, these data show that the TGFbeta(1)-induced destabilisation of E-cadherin-mediated cell-cell adhesion involves phosphorylation of beta-catenin, which is regulated by E-cadherin adhesion complex-associated PI3-kinase and PTEN.