Advances in Fecal Tests for Colorectal Cancer Screening

textabstractColorectal cancer (CRC) forms an important public health problem, especially in developed countries. CRC screening tests can be used to identify asymptomatic individuals with CRC precursors and (early) cancer. Removal of these lesions reduces CRC incidence and prevents CRC-related mortality. There are a range of screening tests available, each with advantages and disadvantages. Stool screening tests can broadly be divided into fecal occult blood tests (FOBTs) and molecular biomarker test, such as DNA/RNA marker tests, protein markers, and fecal microbiome marker tests. Guaiac fecal occult blood tests (gFOBT) have been demonstrated in large randomized screening trials to reduce CRC mortality. Fecal immunochemical tests (FIT) have superior adherence, usability, and accuracy as compared to gFOBT. Advantage of the use of quantitative FITs in CRC screening programs is the cut-off level that can be adjusted. Molecular biomarker DNA tests have shown to detect significantly more cancers than FIT. By combining biomarker DNA tests with FIT, sensitivity for advanced adenomas can be increased significantly. However, it has lower specificity thus demands more colonoscopy resources, is more cumbersome, and costly. The adherence has not been assessed in population screening trials. For these reasons, FIT is therefore at present regarded as the preferred method of non-invasive CRC screening. This chapter will review the current status of fecal test-based CRC screening

Does Routine Endoscopy or Contrast Swallow Study After Esophagectomy and Gastric Tube Reconstruction Change Patient Management?

Background: Anastomotic leakage is a severe complication after esophagectomy. The objective was to investigate the diagnostic and predictive value of routine contrast swallow study and endoscopy for the detection of anastomotic dehiscence in patients after esophagectomy. Methods: All patients who underwent contrast swallow and/or endoscopy within 7 days after oesophagectomy for cancer between January 2005 and December 2009 were selected from an institutional database. Results: Some 173 patients underwent endoscopy, and 184 patients underwent a contrast swallow study. The sensitivity of endoscopy for anastomotic leakage requiring intervention is 56 %, specificity 41 %, positive predictive value (PPV) 8 %, and negative predictive value (NPV) 95 %. The sensitivity of contrast swallow study for detecting leakage requiring intervention in patients without signs of leakage was 20 %, specificity 20 %, PPV 3 %, and NPV 97 %. Conclusions: In patients without clinical suspicion of leakage, there is no benefit to perform routine examinations

Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity

Lynch syndrome (LS) is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR) genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS) must be defined. We present an oligonucleotide-directed mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, the MSH6 variant of interest is introduced into mouse embryonic stem cells by site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the DNA damaging agent 6-thioguanine (6TG) allows the identification of MMR abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We demonstrate the efficacy of the genetic screen, investigate the phenotype of 26 MSH6 VUS and compare our screening results to clinical data from suspected-LS patients carrying these variant alleles

Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis

OBJECTIVE: Serrated polyposis syndrome (SPS) is accompanied by an increased risk of colorectal cancer (CRC). Patients fulfilling the clinical criteria, as defined by the WHO, have a wide variation in CRC risk. We aimed to assess risk factors for CRC in a large cohort of patients with SPS and to evaluate the risk of CRC during surveillance. DESIGN: In this retrospective cohort analysis, all patients with SPS from seven centres in the Netherlands and two in the UK were enrolled. WHO criteria were used to diagnose SPS. Patients who only fulfilled WHO criterion-2, with IBD and/or a known hereditary CRC syndrome were excluded. RESULTS: In total, 434 patients with SPS were included for analysis; 127 (29.3%) were diagnosed with CRC. In a per-patient analysis ≥1 serrated polyp (SP) with dysplasia (OR 2.07; 95% CI 1.28 to 3.33), ≥1 advanced adenoma (OR 2.30; 95% CI 1.47 to 3.67) and the fulfilment of both WHO criteria 1 and 3 (OR 1.60; 95% CI 1.04 to 2.51) were associated with CRC, while a history of smoking was inversely associated with CRC (OR 0.36; 95% CI 0.23 to 0.56). Overall, 260 patients underwent surveillance after clearing of all relevant lesions, during which two patients were diagnosed with CRC, corresponding to 1.9 events/1000 person-years surveillance (95% CI 0.3 to 6.4). CONCLUSION: The presence of SPs containing dysplasia, advanced adenomas and/or combined WHO criteria 1 and 3 phenotype is associated with CRC in patients with SPS. Patients with a history of smoking show a lower risk of CRC, possibly due to a different pathogenesis of disease. The risk of developing CRC during surveillance is lower than previously reported in literature, which may reflect a more mature multicentre cohort with less selection bias

Pediatric Gastrointestinal Endoscopy: European Society of Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and European Society of Gastrointestinal Endoscopy (ESGE) Guidelines

ABSTRACT: This Guideline refers to infants, children and adolescents aged 0–18 years. The areas covered include: indications for diagnostic and therapeutic esophagogastroduodenoscopy and ileo-colonoscopy; endoscopy for foreign body ingestion; corrosive ingestion and stricture/stenosis endoscopic management; upper and lower gastrointestinal bleeding; endoscopic retrograde cholangio-pancreatography and endoscopic ultrasonography. Percutaneous endoscopic gastrostomy and endoscopy specific to inflammatory bowel disease (IBD) has been dealt with in other Guidelines [1–3] and are therefore not mentioned in this Guideline. Training and ongoing skill maintenance are to be dealt with in an imminent sister publication to this

Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: A stepped-wedge cluster randomised trial

Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. Methods: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. Discussion: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care

Predictors of Gastrointestinal Transit Times in Colon Capsule Endoscopy

Optimizing the accuracy of colon capsule endoscopy (CCE) requires high completion rates. To prevent incomplete CCE, we aimed to identify predictors associated with slow CCE transit times. METHODS: In this population-based study, participants received CCE with a split-dose polyethylene glycol bowel preparation and booster regimen (0.5 L oral sulfate solution and 10 mg metoclopramide if capsule remained in stomach for > 1 hour). The following predictors were assessed: age, sex, body mass index (BMI), smoking, coffee and fiber intake, diet quality, physical activity, dyspeptic complaints, stool pattern, history of abdominal surgery, medication use, and CCE findings. Multivariable logistic and linear regressions with backward elimination were performed. RESULTS: We analyzed 451 CCE procedures with a completion rate of 51.9%. The completion rate was higher among older participants (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.04–2.28, P = 0.03) and participants with a changed stool pattern (OR 2.27, 95% CI 1.20–4.30, P = 0.01). Participants with a history of abdominal surgery had a lower completion rate (OR 0.54, 95% CI 0.36–0.80, P = 0.003). Participants with higher BMI had faster stomach, small bowel, and total transit times (β = −0.10, P = 0.01; β = −0.14, P = 0.001; β = −0.12, P = 0.01). A faster small bowel transit was found in participants with a changed stool pattern (β = −0.08, P = 0.049) and the use of metoclopramide (β = −0.14, P = 0.001). Participants with high fiber intake had a slower colonic transit (β = 0.11, P = 0.03). DISCUSSION: Younger age, unchanged stool pattern, history of abdominal surgery, low BMI, and high fiber intake resulted in slower CCE transit times and lower completion rates. In future practice, these factors can be considered to adjust preparation protocols

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting

Optimization of detection of residual disease after neoadjuvant therapy in patients with esophageal cancer

Current treatments for locally advanced esophageal cancer consist of neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) followed by surgery. Nearly one-third of patients obtain a pathologically complete response (pCR) after nCRT. Patients with a complete (clinical) response to nCRT might therefore be candidates for active surveillance, which entails postponement of surgery until recurrence of tumor is detected during clinical response evaluations (CREs). CREs should be performed with accurate diagnostic modalities to timely detect locoregional and distant disease after nCRT. The combination of endoscopy with bite-on-bite biopsies, endoscopic ultrasound with fine-needle aspiration (EUS-FNA) of suspected lymph nodes, and positron emission tomography/computed tomography (PET/CT) has shown 90% sensitivity for detecting substantial (i.e., >10%) residual disease. In this literature review, we address the current state of diagnostic modalities used in CREs and how accuracy for detection of residual tumor after nCRT could be improved. With regard to the currently adopted bite-on-bite biopsy technique, sufficient bite-on-bite biopsies should be taken over larger mucosal areas within the initial tumor site to reduce sampling errors. Detection of positive lymph nodes with EUS-FNA could be improved by sampling all visible lymph nodes. Developments in the field of PET/CT and magnetic resonance imaging (MRI) with simultaneous PET (PET/MRI) have potential to improve CREs by qualitative and quantitative assessment. Other promising techniques require further determination. With wide-area transepithelial sampling (WATS) larger mucosal areas could be sampled compared to regular biopsies, although data in patients treated with nCRT are to be awaited. The detection of positive lymph nodes might be improved by EUS elastography or contrast-enhanced harmonic EUS (CEH-EUS), but these techniques still require further investigation in a setting after nCRT. Finally, image analysis with radiomics, novel biomarkers derived from breath [volatile organic compounds (VOCs)] and liquid biopsies [circulating tumor DNA (ctDNA) as detected in blood samples] might be of complementary value to current diagnostics