Optimizing Screening for Colorectal Cancer: An Algorithm Combining Fecal Immunochemical Test, Blood-Based Cancer-Associated Proteins and Demographics to Reduce Colonoscopy Burden.

BACKGROUND: Fecal Immunochemical Test (FIT) is widely used in population-based screening for colorectal cancer (CRC). This had led to major challenges regarding colonoscopy capacity. Methods to maintain high sensitivity without compromising the colonoscopy capacity are needed. This study investigates an algorithm that combines FIT result, blood-based biomarkers associated with CRC, and individual demographics, to triage subjects sent for colonoscopy among a FIT positive (FIT+) screening population and thereby reduce the colonoscopy burden. MATERIALS AND METHODS: From the Danish National Colorectal Cancer Screening Program, 4048 FIT+ (≥100 ng/mL Hemoglobin) subjects were included and analyzed for a panel of 9 cancer-associated biomarkers using the ARCHITECT i2000. Two algorithms were developed: 1) a predefined algorithm based on clinically available biomarkers: FIT, age, CEA, hsCRP and Ferritin; and 2) an exploratory algorithm adding additional biomarkers: TIMP-1, Pepsinogen-2, HE4, CyFra21-1, Galectin-3, B2M and sex to the predefined algorithm. The diagnostic performances for discriminating subjects with or without CRC in the 2 models were benchmarked against the FIT alone using logistic regression modeling. RESULTS: The discrimination of CRC showed an area under the curve (AUC) of 73.7 (70.5-76.9) for the predefined model, 75.3 (72.1-78.4) for the exploratory model, and 68.9 (65.5-72.2) for FIT alone. Both models performed significantly better (P < .001) than the FIT model. The models were benchmarked vs. FIT at cutoffs of 100, 200, 300, 400, and 500 ng/mL Hemoglobin using corresponding numbers of true positives and false positives. All performance metrics were improved at all cutoffs. CONCLUSION: A screening algorithm including a combination of FIT result, blood-based biomarkers and demographics outperforms FIT in discriminating subjects with or without CRC in a screening population with FIT results above 100 ng/mL Hemoglobin.

Early detection of colorectal neoplasia: application of a blood-based serological protein test on subjects undergoing population-based screening.

BACKGROUND: Blood-based biomarkers used for colorectal cancer screening need to be developed and validated in appropriate screening populations. We aimed to develop a cancer-associated protein biomarker test for the detection of colorectal cancer in a screening population. METHODS: Participants from the Danish Colorectal Cancer Screening Program were recruited. Blood samples were collected prior to colonoscopy. The cohort was divided into training and validation sets. We present the results of model development using the training set. Age, sex, and the serological proteins CEA, hsCRP, TIMP-1, Pepsinogen-2, HE4, CyFra21-1, Galectin-3, ferritin and B2M were used to develop a signature test to discriminate between participants with colorectal cancer versus all other findings at colonoscopy. RESULTS: The training set included 4048 FIT-positive participants of whom 242 had a colorectal cancer. The final model for discriminating colorectal cancer versus all other findings at colonoscopy had an AUC of 0.70 (95% CI: 0.66-0.74) and included age, sex, CEA, hsCRP, HE4 and ferritin. CONCLUSION: The performance of the biomarker signature in this FIT-positive screening population did not reflect the positive performance of biomarker signatures seen in symptomatic populations. Additional biomarkers are needed if the serological biomarkers are to be used as a frontline screening test.

Danish Society for Gastroenterology and Hepatology's clinical recommendations for colonoscopic surveillance for colorectal dysplasia and cancer in patients with inflammatory bowel disease.

OBJECTIVES: We aimed to produce clinical recommendations for colonoscopic surveillance for dysplasia and colorectal cancer in patients with inflammatory bowel diseases. MATERIALS AND METHODS: The Danish Society for Gastroenterology and Hepatology convened a committee to assess the literature on colorectal cancer in inflammatory bowel diseases and the effectiveness of colonoscopy surveillance, according to the Oxford Centre for Evidence Based Medicine levels of evidence. RESULTS: Clinical recommendations for the colonoscopic surveillance for dysplasia and colorectal cancer in patients with inflammatory bowel diseases were produced. These guidelines cover the risk stratification, entry, and follow-up of patients in the colonoscopy programme, the choice of image-enhanced colonoscopy modality, the investigation and treatment of lesions, and the management of special patient populations in the colonoscopy programme. CONCLUSIONS: Colonoscopic surveillance of inflammatory bowel disease is thought to be associated with a decreased risk of colorectal cancer and colorectal cancer-related mortality. Further evidence regarding the effectiveness of colonoscopic surveillance will contribute to understanding its role in the management of inflammatory bowel diseases. The Danish Society for Gastroenterology and Hepatology clinical guideline will aid gastroenterologists in the risk stratification of patients with inflammatory bowel disease, and the management of colorectal lesions. Gastroenterologists must inform and support patients with inflammatory bowel disease to decide whether to participate in the colonoscopic surveillance programme.

Enteroendocrine K and L cells in healthy and type 2 diabetic individuals.

AIMS/HYPOTHESIS: Enteroendocrine K and L cells are pivotal in regulating appetite and glucose homeostasis. Knowledge of their distribution in humans is sparse and it is unknown whether alterations occur in type 2 diabetes. We aimed to evaluate the distribution of enteroendocrine K and L cells and relevant prohormone-processing enzymes (using immunohistochemical staining), and to evaluate the mRNA expression of the corresponding genes along the entire intestinal tract in individuals with type 2 diabetes and healthy participants. METHODS: In this cross-sectional study, 12 individuals with type 2 diabetes and 12 age- and BMI-matched healthy individuals underwent upper and lower double-balloon enteroscopy with mucosal biopsy retrieval from approximately every 30 cm of the small intestine and from seven specific anatomical locations in the large intestine. RESULTS: Significantly different densities for cells positive for chromogranin A (CgA), glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, peptide YY, prohormone convertase (PC) 1/3 and PC2 were observed along the intestinal tract. The expression of CHGA did not vary along the intestinal tract, but the mRNA expression of GCG, GIP, PYY, PCSK1 and PCSK2 differed along the intestinal tract. Lower counts of CgA-positive and PC1/3-positive cells, respectively, were observed in the small intestine of individuals with type 2 diabetes compared with healthy participants. In individuals with type 2 diabetes compared with healthy participants, the expression of GCG and PYY was greater in the colon, while the expression of GIP and PCSK1 was greater in the small intestine and colon, and the expression of PCSK2 was greater in the small intestine. CONCLUSIONS/INTERPRETATION: Our findings provide a detailed description of the distribution of enteroendocrine K and L cells and the expression of their products in the human intestinal tract and demonstrate significant differences between individuals with type 2 diabetes and healthy participants. TRIAL REGISTRATION: NCT03044860.

Protocol Outlines for Parts 1 and 2 of the Prospective Endoscopy III Study for the Early Detection of Colorectal Cancer: Validation of a Concept Based on Blood Biomarkers.

BACKGROUND: Programs for population screening of colorectal cancer (CRC) have been implemented in several countries with fecal immunochemical testing (FIT) as the preferred platform. However, the major obstacle for a feces-based testing method is the limited compliance that reduces the clinical sensitivity for detection of participants with non-symptomatic CRC. Therefore, research approaches have been initiated to develop screening concepts based on biomarkers in blood. Preliminary results show that protein, genetic, epigenetic, and metabolomic components may be valuable in blood-based screening concepts, particularly when combinations of the various components appear to lead to significant improvements. OBJECTIVES: The protocol described in this paper focuses on the validation of concepts based on biomarkers in blood in a major population screened by FIT. METHODS: In Part 1, participants will be identified and included through the Danish CRC Screening Program comprising initial FIT and subsequent colonoscopy to those with a positive result. Blood samples will be collected from 8000 FIT-positive participants, who are offered subsequent colonoscopy. Findings and interventions at colonoscopy together with personal data including co-morbidity will be recorded. Blood samples and data will also be collected from 6000 arbitrarily chosen participants with negative FIT. In Part 2, blood samples and data will be collected from 30,000 FIT-negative participants three times within 4 years. The blood samples will be analyzed using various in-house and commercially available manual and automated analysis platforms. RESULTS: We anticipate Part 1 to terminate late August 2016 and Part 2 to terminate late September 2022. The results from Parts 1 and 2 will be presented within 12 to 18 months from termination. CONCLUSIONS: The purpose of this study is to improve the efficacy of identifying participants with neoplastic bowel lesions, to identify false negative participants, to identify participants at risk of interval neoplastic lesions, to improve the compliance in screening sessions, and to establish guidelines for out-patient follow-up of at-risk participants based on combinations of blood-based biomarkers.

[Modest risk of phosphate nephropathy by bowel cleansing]. / Beskeden risiko for fosfatnefropati ved colonudrensning.

Acute phosphate nephropathy is a rare, but serious adverse event associated with the use of sodium phosphate for bowel cleansing. It may lead to permanent renal impairment and a need for dialysis. The aetiology is hyperphosphataemia caused by intestinal absorption of the cleanser. Risk factors include: advanced age, existing kidney disease, decreased intravascular volume, and medications affecting renal perfusion or function such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and possibly nonsteroidal anti-inflammatory drugs.

[Double-balloon endoscopy for diagnosis and treatment of small bowel diseases. The first Danish experiences with 31 patients]. / Dobbeltballonendoskopi til diagnostik og behandling af sygdomme i tyndtarmen. De første danske erfaringer fra 31 patienter.

INTRODUCTION: Double-balloon endoscopy (DBE) is a novel technique for diagnosis and treatment of small bowel diseases. This study describes the first Danish experiences with DBE. MATERIALS AND METHODS: Retrospective study of 31 consecutive patients examined with DBE at Gentofte Hospital from March 2004 to September 2006. RESULTS: A total of 42 DBE (32 oral, ten anal) were performed. Insertion-length for the oral and anal DBE was 206 cm (range 40-500 cm) beyond the Ligament of Treitz and 141 cm (range 10-200 cm) beyond the ileo-cecal valve, respectively. Duration was 128 min/124 min (range 55-285 min/60-155 min), respectively. In two patients a total inspection of the small bowel was possible. The diagnostic yield was 74% (CI: 57%-86%) with a therapeutic yield in 21 patients (68% CI: 50%-81%). One major complication with perforation occurred due to improper handling of the endoscope. CONCLUSION: DBE is a new effective method for the diagnosis and treatment of small bowel diseases. If used correctly, DBE is safe with few complications. DBE is expected to become an essential endoscopic method for handling small bowel diseases in close conjunction with capsule endoscopy. DBE demands considerable resources and requires experience with advanced endoscopic techniques and hence should be limited to only a few national centres.

[Double balloon endoscopy: a new method for diagnosis and treatment of small bowel diseases]. / Dobbeltballonendoskopi: en ny metode til diagnostik og behandling af sygdomme i tyndtarmen.

Double balloon endoscopy (DBE) is a new method that enables endoscopy of the entire small intestine. The indications are primarily diagnosis and therapy of obscure gastrointestinal bleeding, Crohn's disease, tumours and polyps. The endoscope and procedure is described and an overview of the indications and experience with DBE is given based on a literature review. The method is a significant advance in gastrointestinal endoscopy.

Double-balloon endoscopy: who needs it?

OBJECTIVE: Double-balloon endoscopy (DBE) made the small bowel accessible to inspection and therapy in its entirety. However, DBE is a time-consuming procedure that requires a highly skilled endoscopist, several nurses and--more often than not--anesthesiological support. This makes the selection of patients for DBE a pivotal point. The mainstay of this screening examination of the small bowel is capsule endoscopy (CE). The aim of this study was to describe the results of this screening procedure and the subsequent DBE in patients with suspected mid-gastrointestinal bleeding (MGIB). MATERIAL AND METHODS: Patients referred for CE from March 2004 to September 2006 were evaluated retrospectively. If CE revealed pathology suitable for DBE, the procedure was then carried out. All referred patients were followed-up at the end of the period with regard to final diagnosis and symptom resolution. RESULTS: A total of 83 patients were referred for suspected MGIB. Indications for DBE were found in 26 patients (31%). A total of 34 DBEs (27 oral, 7 anal) were performed. Insertion length for the oral and anal DBE was 200 cm (range 40-500 cm) beyond the ligament of Treitz and 137 cm (range 10-200 cm) beyond the ileocecal valve, respectively. In 2 out of 4 patients where insertion was attempted, a total inspection of the small bowel was possible (50%). The diagnostic yield was 77% (CI: 58-89%) with a therapeutic yield of 73% (CI: 54-86%). None of the 57 patients for whom there was no indication for DBE required DBE within the next 12 months. CONCLUSIONS: CE can be applied as a screening procedure for DBE and allows for an approximately two-thirds reduction in the need for DBE as well as enabling a choice to be made between the oral and anal route.