Smartphone Application to Reinforce Education Increases High-Quality Preparation for Colorectal Cancer Screening Colonoscopies in a Randomized Trial.

BACKGROUND & AIMS: Sufficient bowel preparation is crucial for successful screening and surveillance colonoscopy. However, rates of inadequate preparation are still high. We investigated the effects of reinforced patient education using a smartphone application software (APP) for colonoscopy preparation in participants in a CRC screening program. METHODS: We performed a prospective, endoscopist-blinded study of 500 patients undergoing split-dose bowel preparation for CRC screening or surveillance colonoscopies at multiple centers in Germany, from November 2017 through January 2019. Participants (n = 500) were given oral and written instructions during their initial appointment and then randomly assigned (1:1) to groups that received reinforced education starting 3 days before the colonoscopy (APP group) or no further education (controls). The primary outcome was quality of bowel preparation according to the Boston bowel preparation scale. Secondary outcomes included polyp and adenoma detection rates, compliance with low-fiber diet, split-dose laxative intake, perceived discomfort from the preparation procedure. RESULTS: The mean Boston bowel preparation scale score was significantly higher in the APP-group (7.6 ± 0.1) than in the control group (6.7 ± 0.1) (P < .0001). The percentage of patients with insufficient bowel preparation was significantly lower in the APP group (8%) than in the control group (17%) (P = .0023). The adenoma detection rate was significantly higher in the APP group (35% vs 27% in controls) (P = .0324). Use of the APP was accompanied by a lower level of non-compliance with correct laxative intake (P =.0080) and diet instructions (P = .0089). The APP group reported a lower level of discomfort during preparation (P < .0001). CONCLUSIONS: In a randomized trial, reinforcing patient education with a smartphone application optimized bowel preparation in the 3 days before colonoscopy, increasing bowel cleanliness, adenoma detection, and compliance in patients undergoing CRC screening or surveillance. ClinicalTrials.gov no: NCT03290157.

Improving the quality and acceptance of colonoscopy preparation by reinforced patient education with short message service: results from a randomized, multicenter study (PERICLES-II).

BACKGROUND AND AIMS: Sufficient bowel preparation is crucial for successful screening and surveillance colonoscopy. However, the rates of inadequate preparation are still high. We investigated the effects of reinforcing patient education and guidance by using the short message service (SMS). METHODS: In this prospective, endoscopist-blinded, multicenter study, standard instructions pertaining to split-dose preparation were provided in a verbal and written format to all patients during the initial appointment. Patients were randomly assigned (1:1) to a group that received reinforced education starting 4 days before the colonoscopy (SMS group) or to the control group which did not receive further education. The primary outcome was the percentage of insufficient preparation results (Boston Bowel Preparation Scale [BBPS] score <6). The secondary outcomes included quality of bowel preparation according to the BBPS, polyp and adenoma detection rates, and patients' perceived discomfort in the preparation procedure. RESULTS: The percentage of patients with insufficient bowel preparation was significantly lower in the SMS group (9%) than in the control group (19%) (P = .0013). The mean BBPS score was significantly higher in the SMS group (7.4 ± 0.1) than in the control group (6.5 ± 0.1) (P < .0001). Each colon segment had significantly higher BBPS scores in the SMS group. The adenoma detection rate and number of detected adenomas in the right segment of the colon were higher in the SMS group. SMS messages were accompanied by a lower level of discomfort during preparation (numeric rating scale) (5.2 SMS vs 5.8 controls) (P = .0042). CONCLUSIONS: Reinforced patient education by using SMS messages during the 4 days before colonoscopy increased bowel cleanliness, adenoma detection in the right segment of the colon, and reduced discomfort. (Clinical trial registration number: NCT02272036.).

Effect of a Single Aspirin Dose Prior to Fecal Immunochemical Testing on Test Sensitivity for Detecting Advanced Colorectal Neoplasms: A Randomized Clinical Trial.

Importance: Fecal immunochemical tests for hemoglobin are widely used for colorectal cancer (CRC) screening. Observational studies suggested that sensitivity of fecal immunochemical tests for detecting advanced neoplasms could be increased by acetylsalicylic acid (aspirin), especially among men. Objective: To evaluate the potential to increase sensitivity of fecal immunochemical tests by administering a single 300-mg oral aspirin dose 2 days before stool sampling. Design, Setting, and Participants: A randomized, placebo-controlled, double-blind trial was conducted in 14 gastroenterology practices and 4 hospitals in Germany, and included 2422 men and women aged 40 to 80 years scheduled for colonoscopy, with no recent use of aspirin or other drugs with antithrombotic effects (enrollment from June 2013 to November 2016, and final follow-up January 27, 2017). Interventions: Administration of a single tablet containing 300 mg of aspirin (n = 1208) or placebo (n = 1214) 2 days before fecal sampling for fecal immunochemical test. Main Outcome and Measures: The primary outcome was sensitivity of a quantitative fecal immunochemical test at 2 predefined cutoffs (10.2 and 17-µg Hb/g stool) for detecting advanced neoplasms (colorectal cancer or advanced adenoma). Results: Among 2422 randomized patients (mean [SD] age, 59.6 [7.9] years; 1219, 50%, men), 2134 were included in the analysis (78% for primary screening colonoscopy, 22% for diagnostic colonoscopy). Advanced neoplasms were identified in 224 participants (10.5%), including 8 participants (0.4%) with CRC and 216 participants (10.1%) with advanced adenoma. Sensitivity was 40.2% in the aspirin group and 30.4% in the placebo group (difference 9.8%, 95% CI, -3.1% to 22.2%, P = .14) at cutoff 10.2-µg Hb/g stool and 28.6% in the aspirin and 22.5% in the placebo group (difference 6.0%, 95% CI, -5.7% to 17.5%, P = .32) at cutoff 17-µg Hb/g stool. Conclusions and Relevance: Among adults aged 40 to 80 years not using aspirin or other antithrombotic medications, administration of a single dose of oral aspirin prior to fecal immunochemical testing, compared with placebo, did not significantly increase test sensitivity for detecting advanced colorectal neoplasms at 2 predefined cutoffs of a quantitative fecal immunochemical test. Trial registration: Deutsches Register Klinischer Studien Identifier: DRKS00003252; EudraCT Identifier: 2011-005603-32/DE.

Direct-acting antiviral agents in the treatment of chronic Hepatitis C - "Real-life" experience from an academic centre and two specialized clinical practices.

The introduction of the new direct antiviral agents has revolutionized the therapy of chronic hepatitis C. Today we are able to cure the vast majority of our patients with an 8- to 12-week therapy course of an antiviral combination therapy with an excellent safety profile. Real-life data are very important to further develop our experience with the new therapeutics and help us to improve the care of our patients in our everyday clinical practice.In our study, we present the retrospective analysis of a representative German cohort of 344 patients with chronic hepatitis C treated with the new direct antiviral agents. The patients were recruited in an academic center of southern Germany (University Clinic of Ulm, Clinic of Internal Medicine I) and in 2 highly specialized clinical practices in the city center and the near region of Ulm. Within this in-detail characterized study cohort, we analyzed the efficacy and safety of antiviral therapy under real-life conditions.In 322 patients, we could document SVR12 data and found an excellent overall SVR12 rate of 97.8 % across all genotypes. In more detail, we could show comparable SVR12 results of 99 % and 99.2 % in patients with the hepatitis C virus subtypes 1a and 1b of and an excellent SVR12 rate of 93.1 % in genotype 3 patients without liver cirrhosis. Nevertheless, SVR12 rates tend to be lower in patients with the presence of liver cirrhosis, especially in genotype 3 patients with the lowest SVR12 rate in the whole study group of only 80 %. In general, there were no major safety issues except of 1 patient treated with a protease-inhibitor-based regimen who developed a generalized skin reaction and needed hospitalization and premature end of antiviral therapy.In summary, our analysis of this well characterized representative cohort of 344 patients adds more information in the field of real-life experience with the new antiviral therapeutics and could therefore contribute to improve the care of our patients. Together with the existing real-life data, we now can proceed in achieving the aim of viral eradication of hepatitis C virus within our population.

Hepatitis C virus impairs the induction of cytoprotective Nrf2 target genes by delocalization of small Maf proteins.

The expression of a variety of cytoprotective genes is regulated by short cis-acting elements in their promoters, called antioxidant response elements (AREs). A central regulator of ARE-mediated gene expression is the NF-E2-related factor 2 (Nrf2). Nrf2/ARE-regulated genes are crucial for the maintenance of cellular integrity. Hepatitis C virus inhibits the induction of ARE-regulated genes, but neither induction nor inhibition of ARE-regulated gene expression affects HCV replication directly. In HCV-replicating cells the core protein triggers the delocalization of sMaf proteins from the nucleus to the replicon complex. Here sMafs bind to NS3. The extranuclear sMaf proteins prevent Nrf2 from entry in the nucleus and thereby inhibit the induction of Nrf2/ARE-regulated genes. This results in the decreased expression of cytoprotective genes. Consistent with this finding, the elimination of ROI is impaired in HCV-replicating cells as demonstrated by elevated protein oxidation or 8-OH-dG formation, reflecting DNA damage. In conclusion, these data identified a novel mechanism of Nrf2 regulation and suggest that the HCV-dependent inhibition of Nrf2/ARE-regulated genes confers to the HCV-associated pathogenesis by elevation of intracellular ROI that affect integrity of the host genome and regenerative processes.

Effect of Various Invitation Schemes on the Use of Fecal Immunochemical Tests for Colorectal Cancer Screening: Protocol for a Randomized Controlled Trial.

BACKGROUND: Fecal occult blood testing has been offered for many years in the German health care system, but participation rates have been notoriously low. OBJECTIVE: The aim of this study is to evaluate the effect of various personal invitation schemes on the use of fecal immunochemical tests (FITs) in persons aged 50-54 years. METHODS: This study consists of a three-armed randomized controlled trial: (1) arm A: an invitation letter from a health insurance plan including a FIT test kit, (2) arm B: an invitation letter from a health insurance plan including an offer to receive a free FIT test kit by mail upon easy-to-handle request (ie, by internet, fax, or reply mail), and (3) arm C: an information letter on an existing colonoscopy offer (ie, control). Within arms A and B, a random selection of 50% of the study population will receive reminder letters, the effects of which are to be evaluated in a substudy. RESULTS: A total of 17,532 persons aged 50-54 years in a statutory health insurance plan in the southwest of Germany-AOK Baden-Wuerttemberg-were sent an initial invitation, and 5825 reminder letters were sent out. The primary end point is FIT usage within 1 year from receipt of invitation or information letter. The main secondary end points include gender-specific FIT usage within 1 year, rates of positive test results, rates of colonoscopies following a positive test result, and detection rates of advanced neoplasms. The study was launched in September 2017. Data collection and workup were completed in fall 2019. CONCLUSIONS: This randomized controlled trial will provide important empirical evidence for enhancing colorectal cancer screening offers in the German health care system. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00011858; https://bit.ly/2UBTIdt. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16413.

The Effects of Differing Invitation Models on the Uptake of Immunological Fecal Occult Blood Testing.

BACKGROUND: Participation rates in colorectal cancer screening in Germany are low. We therefore investigated the effectiveness of different invitation models for immunological stool blood tests (fecal immunological tests, FITs). METHODS: A randomized controlled trial in 50- to 54-year-old clients of the health insurance provider AOK Baden-Wuerttemberg. A total of 17 532 insured persons were randomized to receive: (A) an invitation letter including a FIT (n = 5850); (B) an invitation letter including an option to request a FIT (n = 5844); or (C) an invitation letter only (n = 5838; control group, routine practice). Reminder letters were sent to half the members of groups A and B, selected at random, after 4 weeks. The primary endpoint was the use of a FIT within 1 year of the date of the invitation letter. IRRID: RR2-10.2196/16413. Registration: DRKS00011858. RESULTS: The invitation letter with a FIT enclosed (A) increased usage from 10% to 29.7% compared with the control group (+19.7% points, p < 0.0001; men: +19.4%, women: +18.8%). The invitation letter with a FIT request option (B) increased usage from 10% to 27.7% (+17.7% points, p < 0.0001; men: +17.7%, women: +17.4%). Reminders increased usage in group A by 7.5% points and in group B by 8.5% points. Participation among women was higher than among men in all groups. The FIT positivity rate was 6.9%. A subsequent colonoscopy was reported for 64.3% of FIT-positive participants, and advanced neoplasia was found in 21.3% of these cases. CONCLUSION: Letters of invitation that include a FIT and those that offer low-threshold access to a FIT achieve strong, comparable increases in the usage of FIT in the context of colorectal cancer screening.

Validation of the X-Vision ERCP Training System and technical challenges during early training of sphincterotomy.

BACKGROUND & AIMS: A new fluoroscopy-free training system for endoscopic retrograde cholangiopancreatography (ERCP) with different model subtypes recently was developed. This study aimed to establish construct validity by investigating whether the X-Vision ERCP Training System could distinguish experienced endoscopists from beginners and to reveal characteristic mistakes during sphincterotomy. METHODS: Six staff gastroenterologists that practice ERCP, 10 trainees that perform esophagogastroduodenoscopy and colonoscopy, and 12 residents without endoscopic experience each sequentially attempted 4 different models, simulating selective cannulation of the pancreatic or bile duct, intubation of differently arranged rubber papillas, stent placement, and sphincterotomy of a biopapilla. Performance parameters were recorded and participants' expectations were compared before and after training to determine whether the simulator was a credible tool for ERCP training. Staff gastroenterologists graded the realism and utility of the simulation. The quality of sphincterotomy was assessed by an expert endoscopist. RESULTS: Participants with ERCP experience had significantly shorter procedure times compared with those with intermediate (P < .001) or no endoscopic experience (P < .001). Total and single credibility scores significantly increased after simulator practice. The faculty found the X-Vision ERCP Training System to be realistic and useful for training. In the less-experienced groups, common mistakes made during sphincterotomy included inadequate positioning of the duodenoscope, traumatic intubation of the papilla, and continued cutting despite insufficient endoscopic view. CONCLUSIONS: The X-Vision ERCP Training System distinguished subjects with different levels of experience and was regarded as realistic and useful for ERCP training. Common mistakes during sphincterotomy could be assessed objectively.

Auditory evoked potentials compared with bispectral index for monitoring of midazolam and propofol sedation during colonoscopy.

OBJECTIVES: The purpose of this study was to evaluate and compare Bispectral index (BIS) and A-line auditory evoked potential index (AAI) for monitoring depth of low-dose midazolam and propofol sedation during colonoscopy. METHODS: A total of 115 consecutive patients (ASA I-IV), receiving low-dose midazolam and propofol sedation for colonoscopy, were evaluated. BIS and AAI levels, Observer's Assessment of Alertness/Sedation (OAA/S) scores, blood pressure, heart rate, oxygen saturation, as well as the presence or absence of eyelash reflex, patient reaction to an external noxious stimulus and to procedure-related pain were recorded every 1-3 min by a single trained observer. RESULTS: There was a positive correlation between BIS and OAA/S scores (correlation coefficient=0.77) and to a lesser extent AAI and OAA/S scores (correlation coefficient=0.47). BIS and AAI showed significant differences between subsequent levels of sedation (P<0.001). The clustered receiver operating characteristic curve estimate of BIS for the detection of deep sedation was significantly better than that of AAI (P<0.001). Regarding the presence or absence of eyelash reflex and patient reaction to an external noxious stimulus and to procedure-related pain, significant different levels were found for BIS as well as AAI, respectively. Only small changes were observed in hemodynamic variables and oxygen saturation. Overall, our data suggest target BIS levels of slightly above 73 for moderate sedation (defined as OAA/S scores 2 and 3). CONCLUSIONS: BIS and AAI correlated with the level of sedation. Hemodynamic variables were poor indicators of the hypnotic-anesthetic status of the patient. BIS discriminated best between moderate and deep sedation and could complement clinical observation for guidance of moderate sedation.

Genetic Biopsy for Prediction of Surveillance Intervals after Endoscopic Resection of Colonic Polyps: Results of the GENESIS Study.

BACKGROUND AND OBJECTIVE: Current surveillance strategies for colorectal cancer following polypectomy are determined by endoscopic and histopathological factors. Such a distinction has been challenged. The present study was designed to identify molecular parameters in colonic polyps potentially defining new sub-groups at risk. METHODS: One hundred patients were enrolled in this multicentre study. Polyps biopsies underwent formalin-free processing (PAXgene, PreAnalytiX) and targeted next generation sequencing (38 genes (QIAGEN), NextSeq 500 platform (Illumina)). Genetic and histopathological analyses were done blinded to other data. RESULTS: In 100 patients, 224 polyps were removed. Significant associations of genetic alterations with endoscopic or histological polyp characteristics were observed for BRAF, KRAS, TCF7L2, FBXW7 and CTNNB1 mutations. Multivariate analysis revealed that polyps ≥ 10 mm have a significant higher relative risk for harbouring oncogene mutations (relative risk 3.467 (1.742-6.933)). Adenomas and right-sided polyps are independent risk factors for CTNNB1 mutations (relative risk 18.559 (2.371-145.245) and 12.987 (1.637-100.00)). CONCLUSIONS: Assessment of the mutational landscape of polyps can be integrated in the workflow of current colonoscopy practice. There are distinct genetic patterns related to polyp size and location. These results suffice to optimise individual risk calculation and may help to better define surveillance intervals.

Should Screening Colonoscopy Be Offered From Age 50?

BACKGROUND: The introduction of colonoscopic screening in 2002 for persons aged 55 and older was followed by a marked decline in the incidence of colon cancer in the corresponding age groups in Germany. The prevalence of colorectal neoplasia among persons aged 50 to 54 has remained unknown until now. Expert committees currently recommend colonoscopic screening for persons aged 50 and older. This option has been offered since 2014 by the AOK Baden-Württemberg and by Bosch BKK in the framework of their specialized medical care program. METHODS: In April 2014 and 2015, 84 726 insurees aged 50-54 were invited by mail to participate in colonoscopic screening. The utilization and results of colonoscopic screening were studied. A questionnaire about risks was additionally sent to half of the participants, who were selected at random (study registration: DRKS00006268). RESULTS: Within one year, 1.9% of persons to whom invitations had been sent took up the offer of colonoscopic screening; these persons included 3.3% of those already enrolled in the specialized medical care program. The 1396 colonoscopies that were performed revealed advanced neoplasia (colon cancer or advanced adenoma) in 6.8% of cases. The prevalence of advanced neoplasia among men aged 50 to 54 was nearly twice as high as that among women in the same age group (8.6% vs. 4.5%, p = 0.0027). It was also higher than the prevalences documented in the German nationwide cancer registry for women aged 55 to 79. The additional sending of a risk questionnaire along with the invitation had no effect on the rate of detection of relevant findings or on the rate of participation in colonoscopic screening. CONCLUSION: These findings lend support to the demand that the offer of colonoscopic screening should be extended at least to men aged 50 and above.

Grap-2, a novel RET binding protein, is involved in RET mitogenic signaling.

Signal transduction of the RET receptor tyrosine kinase is involved in developmental processes as well as in neoplastic transformation. Activation of RET initiates receptor autophosphorylation on specific tyrosines that act as docking sites for downstream signaling molecules. Using the cytoplasmatic part of RET as bait in a yeast two-hybrid screen, we identified a novel SH2 and SH3 domain containing adaptor protein previously termed Grap-2/Grf40/GrpL/GRID and its murine homologue as Gads/Mona, respectively. This protein, predominantly expressed in cells of hematopoietic origin, is involved in signaling downstream of the T-cell receptor and the receptor for monocyte colony-stimulating factor. Here, we show that Grap-2 is also expressed in neuroendocrine tumors and cell lines known to bear mutated forms of RET. Endogenously expressed RET and Grap-2 coimmunoprecipitate from lysates of a medullary thyroid carcinoma cell line. Grap-2 directly associates with RET in pull-down experiments using in vitro translated proteins. Overexpression of Grap-2 inhibits RET-induced NF-kappaB activation, and cotransfection of Grap-2 significantly reduces focus formation induced by oncogenic RET in NIH 3T3 cells. Taken together, these results suggest that besides being involved in tyrosine kinase signaling in hematopoietic cells, Grap-2 plays a tissue-specific role as an inhibitor of RET mitogenic signaling.

Mutation Ala(171)Thr stabilizes the gonadotropin-releasing hormone receptor in its inactive conformation, causing familial hypogonadotropic hypogonadism.

Mutations of the GnRH receptor have been recognized as a cause of familial gonadotropin deficiency. We here identify and functionally characterize a novel human GnRH receptor variant bearing an Ala(171)Thr substitution located at transmembrane helix 4 (TMH4). The affected kindred displays severe hypogonadotropic hypogonadism. After in vitro expression in human embryonic kidney 293T cells, the Ala(171)Thr mutant GnRH receptor exhibited a lack of phospholipase C activity in signal transduction. Specific receptor binding of (125)I-labeled GnRH ligand was undetectable in Ala(171)Thr GnRH receptor-transfected cells. Molecular modeling and dynamic simulation of the Ala(171)Thr GnRH receptor suggests the introduction of a stable hydrogen bond between residue Thr(171) and Tyr(119) side-chains at a distance of 2 A. Although spatially distant from the GnRH ligand-binding site, this hydrogen bond impedes conformational mobility of the TMH3 and TMH4 domains required for sequential ligand binding and receptor activation, thus stabilizing the GnRH receptor in its inactive conformation. Receptor structure modeling and functional data provide a comprehensive molecular view of how mutation Ala(171)Thr causes a complete loss of GnRH receptor function.

Bi-allelic inactivation of the MEN1 tumor suppressor gene in human grade II astrocytoma.

In humans and gene-targeted mice, loss of multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene function causes neuroendocrine tumors, frequently of the parathyroid and pituitary glands and the pancreas. The MEN1 gene product interacts with glial fibrillary acidic protein (GFAP) in the brain. We here demonstrate bi-allelic MEN1 inactivation in a grade II astrocytoma in an individual carrying a heterozygous MEN1 germ line deletion mutation (788del6). This tumor represents a novel, non-endocrine MEN1-phenotype, compatible with a role of MEN1-GFAP in glial oncogenesis. Clinically, a genetic predisposition to variant neoplasias should be considered in the management of MEN1 patients.

Autoimmune pancreatitis complicated by carcinoma of the pancreatobiliary system: a case report and review of the literature.

We present the case of a 67-year-old woman who developed a metastatic adenocarcinoma of the pancreatobiliary system shortly after the histologically confirmed diagnosis of autoimmune pancreatitis (AIP). This case highlights the need for increased alertness not only in differentiating AIP from pancreatic cancer at the time of diagnosis, but also to exclude concomitant malignancies of the pancreatobiliary system in the management of histologically confirmed AIP.

Expression of the Grb2-related RET adapter protein Grap-2 in human medullary thyroid carcinoma.

Inappropriate signaling of the RET receptor tyrosine kinase causes different forms of human thyroid malignancy. We have previously identified the adaptor Grap-2 as RET binding protein. To verify involvement of Grap-2 in RET oncogenic signaling we performed sequence and expression analysis of Grap-2 in 15 human MTC samples. All tumors displayed marked Grap-2 mRNA and protein expression without a linear correlation. Beyond one conservative base pair substitution we detected no further alteration in genomic Grap-2 sequence. Consistent Grap-2 expression suggests a specific role for this adaptor in human MTC, while qualitative alterations do not appear to influence RET signaling.