Kilian Friedrich

Is PillCam COLON capsule endoscopy ready for colorectal cancer screening? A prospective feasibility study in a community gastroenterology practice.

OBJECTIVES:Colorectal cancer (CRC) screening with colonoscopy was introduced into the National Cancer Prevention Program in Germany in 2002. As compliance for screening is low (around 3% per year), colon capsule endoscopy (CCE) could be an alternative approach. In this study, feasibility and performance of CCE were evaluated in comparison with colonoscopy in ambulatory patients with special attention to a short colon transit time.METHODS:CCE was prospectively tested in ambulatory patients enrolled for colonoscopy who presented for screening or with positive fecal occult blood test. Study subjects underwent colon preparation and ingested the capsule in the morning. Colonoscopy was performed after excretion of the capsule. Colonoscopy and CCE were performed by independent physicians who were blinded to the results.RESULTS:In total, 38 patients were included. One patient was excluded because the capsule remained in the stomach during the entire period of examination. Another patient had limited time and the procedure had to be stopped when the capsule was still in the transverse colon. We therefore report the results of 36 patients (30 men and 6 women; mean age 56 years, range 23–73 years) who successfully completed CCE and the conventional colonoscopy examination. The capsule was excreted within 6 h in 84% of the patients (median transit time 4.5 h). If oral sodium phosphate was excluded from the preparation, the colon transit time increased to a median of 8.25 h. In total, 7 of 11 small polyps (<6 mm) detected by colonoscopy were identified by CCE. One small polyp detected by CCE was not identified by colonoscopy. In this series, no large polyps were found. One CRC was detected by both methods. The mean rates of colon cleanliness (range from 1=excellent to 4=poor) in the cecum (2.1), transverse colon (1.6), and in the descending colon (1.5) were significantly better than in the rectosigmoid colon (2.6), and the overall mean rate during colonoscopy was significantly better than during CCE. No adverse effects occurred.CONCLUSIONS:CCE appears to be a promising new modality for colonic evaluation and may increase compliance with CRC screening. To achieve a short colon transit time, sodium phosphate seems to be a necessary adjunct during preparation. The short transit time is a prerequisite to abandon the delay mode of the capsule. With an undelayed PillCam COLON capsule, a “pan-enteric” examination of the gastrointestinal tract would be possible. Further studies are needed to improve the cleanliness, especially in the rectum and to evaluate the method as a potential screening tool.

Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis

Alkaline phosphatase (ALP) is an important serum marker in primary sclerosing cholangitis (PSC). Patients with obstruction of the large bile ducts due to dominant strictures (DS) are a special, clinically important phenotype.

FUT2 and FUT3 genotype determines CA19-9 cut-off values for detection of cholangiocarcinoma in patients with primary sclerosing cholangitis.

BACKGROUND & AIMS Allelic variants of fucosyltransferases 2 and 3 (FUT2/3) influence serum levels of CA19-9, a screening parameter commonly used for detection of biliary malignancy in PSC. We aimed at improving diagnostic accuracy of CA19-9 by determining the impact of FUT2/3 genotypes. METHODS CA19-9 levels were measured in 433 PSC patients, 41 of whom had biliary malignancy. Genotypes for FUT3 and FUT2 were used to assign patients to one of three groups: A, no FUT3 activity regardless of FUT2 activity; B, both FUT2 and FUT3 activity and C, no FUT2 activity without loss of FUT3 activity. Group-specific cut-off values were determined by Youdens index. RESULTS The median CA19-9 values of cancer-free patients were significantly different (p<0.001) in Groups A (2.0U/ml), B (17.0U/ml), and C (37.0U/ml). Biliary malignancy patients in Groups B and C had significantly higher CA19-9 values than cancer-free patients (p<0.001). The optimal cut-off, as determined by ROC analysis, for all patients was 88.5U/ml. Optimal cut-off values in Groups A, B, and C were 4.0U/ml, 74.5U/ml, and 106.8U/ml, respectively. Use of these values improved sensitivity of CA19-9 in Groups B and C. Further, use of group-dependent cut-off values with 90% sensitivity resulted in a 42.9% reduction of false positive results. CONCLUSIONS Use of FUT2/3 genotype-dependent cut-off values for CA19-9 improved sensitivity and reduced the number of false positive results.

First clinical trial of a newly developed capsule endoscope with panoramic side view for small bowel: A pilot study

Capsule endoscopy is the first‐line diagnostic technique for the small bowel. However, the inability to visualize the duodenal papilla is an inherent limitation of this method. In the present study, we evaluated feasibility of a newly developed CapsoCam SV1 capsule.

Safety analysis of endoscopist‐directed propofol sedation: A prospective, national multicenter study of 24 441 patients in German outpatient practices

Since 2008, there exists a German S3‐guideline allowing non‐anesthesiological administration of propofol for gastrointestinal endoscopy. In this prospective, national, multicenter study, we evaluated the safety of endoscopist‐administered propofol sedation (EDP) in German outpatient practices of Gastroenterology.

PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity

Diabetes is a multi‐organ disease and diabetic cardiomyopathy can result in heart failure, which is a leading cause of morbidity and mortality in diabetic patients. In the liver, insulin resistance contributes to hyperglycaemia and hyperlipidaemia, which further worsens the metabolic profile. Defects in mTOR signalling are believed to contribute to metabolic dysfunctions in diabetic liver and hearts, but evidence is missing that mTOR activation is causal to the development of diabetic cardiomyopathy. This study shows that specific mTORC1 inhibition by PRAS40 prevents the development of diabetic cardiomyopathy. This phenotype was associated with improved metabolic function, blunted hypertrophic growth and preserved cardiac function. In addition PRAS40 treatment improves hepatic insulin sensitivity and reduces systemic hyperglycaemia in obese mice. Thus, unlike rapamycin, mTORC1 inhibition with PRAS40 improves metabolic profile in diabetic mice. These findings may open novel avenues for therapeutic strategies using PRAS40 directed against diabetic‐related diseases.

TSC22D4 is a molecular output of hepatic wasting metabolism

In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. Here, we show that tumour growth triggers hepatic metabolic dysfunction as part of the cancer cachectic phenotype, particularly by reduced hepatic very‐low‐density‐lipoprotein (VLDL) secretion and hypobetalipoproteinemia. As a molecular cachexia output pathway, hepatic levels of the transcription factor transforming growth factor beta 1‐stimulated clone (TSC) 22 D4 were increased in cancer cachexia. Mimicking high cachectic levels of TSC22D4 in healthy livers led to the inhibition of hepatic VLDL release and lipogenic genes, and diminished systemic VLDL levels under both normal and high fat dietary conditions. Liver‐specific ablation of TSC22D4 triggered hypertriglyceridemia through the induction of hepatic VLDL secretion. Furthermore, hepatic TSC22D4 expression levels were correlated with the degree of body weight loss and VLDL hypo‐secretion in cancer cachexia, and TSC22D4 deficiency rescued tumour cell‐induced metabolic dysfunction in hepatocytes. Therefore, hepatic TSC22D4 activity may represent a molecular rationale for peripheral energy deprivation in subjects with metabolic wasting diseases, including cancer cachexia.

A Frequent PNPLA3 Variant Is a Sex Specific Disease Modifier in PSC Patients with Bile Duct Stenosis

Background & Aims Primary sclerosing cholangitis predominantly affects males and is an important indication for liver transplantation. The rs738409 variant (I148M) of the PNPLA3 gene is associated with alcoholic and non-alcoholic liver disease and we evaluated its impact on the disease course of PSC. Methods The I148M polymorphism was genotyped in 121 German PSC patients of a long-term prospective cohort and 347 Norwegian PSC patients. Results In the prospective German cohort, actuarial survival free of liver transplantation was significantly reduced for I148M carriers (p = 0.011) compared to wildtype patients. This effect was restricted to patients with severe disease, as defined by development of dominant stenosis (DS) requiring endoscopic intervention. DS patients showed markedly decreased survival (p = 0.004) when carrying the I148M variant (I148M: mean 13.8 years; 95% confidence interval: 11.6–16.0 vs. wildtype: mean 18.6 years; 95% confidence interval: 16.3–20.9) while there was no impact on survival in patients without a DS (p = 0.87). In line with previous observations of sex specific effects of the I148M polymorphism, the effect on survival was further restricted to male patients (mean survival 11.9 years; 95% confidence interval: 10.0–14.0 in I148M carriers vs. 18.8 years; 95% confidence interval: 16.2–21.5 in wildtype; p<0.001) while female patients were unaffected by the polymorphism (p = 0.65). These sex specific findings were validated in the Norwegian cohort (p = 0.013). Conclusions In male PSC patients with severe disease with bile duct stenosis requiring intervention, the common I148M variant of the PNPLA3 gene is a risk factor for reduced survival.

PNPLA3 in end-stage liver disease: Alcohol consumption, hepatocellular carcinoma development, and transplantation-free survival

The rs738409 variant (I148M) of the patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) gene is associated with several liver malfunctions. Its impact on end‐stage liver disease has not been addressed yet.

Fut2 genotype is a risk factor for dominant stenosis and biliary candida infections in primary sclerosing cholangitis

A recent genome‐wide association study identified the FUT2 secretor status and genotype defined by the single‐nucleotide polymorphism rs601338 as potential genetic risk factor in primary sclerosing cholangitis (PSC), which significantly influences biliary bacterial composition.