Study protocol: population screening for colorectal cancer by colonoscopy or CT colonography: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer (CRC) is the second most prevalent type of cancer in Europe. Early detection and removal of CRC or its precursor lesions by population screening can reduce mortality. Colonoscopy and computed tomography colonography (CT colonography) are highly accurate exams and screening options that examine the entire colon. The success of screening depends on the participation rate. We designed a randomized trial to compare the uptake, yield and costs of direct colonoscopy population screening, using either a telephone consultation or a consultation at the outpatient clinic, versus CT colonography first, with colonoscopy in CT colonography positives.</p> <p>Methods and design</p> <p>7,500 persons between 50 and 75 years will be randomly selected from the electronic database of the municipal administration registration and will receive an invitation to participate in either CT colonography (2,500 persons) or colonoscopy (5,000 persons) screening. Those invited for colonoscopy screening will be randomized to a prior consultation either by telephone or a visit at the outpatient clinic. All CT colonography invitees will have a prior consultation by telephone. Invitees are instructed to consult their general practitioner and not to participate in screening if they have symptoms suggestive for CRC. After providing informed consent, participants will be scheduled for the screening procedure. The primary outcome measure of this study is the participation rate. Secondary outcomes are the diagnostic yield, the expected and perceived burden of the screening test, level of informed choice and cost-effectiveness of both screening methods.</p> <p>Discussion</p> <p>This study will provide further evidence to enable decision making in population screening for colorectal cancer.</p> <p>Trial registration</p> <p>Dutch trial register: NTR1829</p

Colonoscopic surveillance improves survival after colorectal cancer diagnosis in inflammatory bowel disease

Item does not contain fulltextBACKGROUND: Colonoscopic surveillance provides the best practical means for preventing colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients. Strong evidence for improved survival from surveillance programmes is sparse. METHOD: The aim of this study was to compare tumour stage and survival of IBD patients with CRC who were a part of a surveillance programme with those who were not. A nationwide pathology database (PALGA (pathologisch anatomisch landelijk geautomatiseerd archief)) was consulted to identify IBD patients with CRC treated in all eight university hospitals in The Netherlands over a period of 15 years. Patients were assigned to the surveillance group when they had undergone one or more surveillance colonoscopies before a diagnosis of CRC. Patients who had not undergone surveillance served as controls. Tumour stage and survival were compared between the two groups. RESULTS: A total of 149 patients with IBD-associated CRC were identified. Twenty-three had had colonoscopic surveillance before CRC was discovered. The 5-year CRC-related survival rate of patients in the surveillance group was 100% compared with 74% in the non-surveillance group (P=0.042). In the surveillance group, only one patient died as a consequence of CRC compared with 29 patients in the control group (P=0.047). In addition, more early tumour stages were found in the surveillance group (P=0.004). CONCLUSIONS: These results provide evidence for improved survival from colonoscopic surveillance in IBD patients by detecting CRC at a more favourable tumour stage

Evaluating risk factor assumptions: a simulation-based approach

<p>Abstract</p> <p>Background</p> <p>Microsimulation models are an important tool for estimating the comparative effectiveness of interventions through prediction of individual-level disease outcomes for a hypothetical population. To estimate the effectiveness of interventions targeted toward high risk groups, the mechanism by which risk factors influence the natural history of disease must be specified. We propose a method for evaluating these risk factor assumptions as part of model-building.</p> <p>Methods</p> <p>We used simulation studies to examine the impact of risk factor assumptions on the relative rate (RR) of colorectal cancer (CRC) incidence and mortality for a cohort with a risk factor compared to a cohort without the risk factor using an extension of the CRC-SPIN model for colorectal cancer. We also compared the impact of changing age at initiation of screening colonoscopy for different risk mechanisms.</p> <p>Results</p> <p>Across CRC-specific risk factor mechanisms, the RR of CRC incidence and mortality decreased (towards one) with increasing age. The rate of change in RRs across age groups depended on both the risk factor mechanism and the strength of the risk factor effect. Increased non-CRC mortality attenuated the effect of CRC-specific risk factors on the RR of CRC when both were present. For each risk factor mechanism, earlier initiation of screening resulted in more life years gained, though the magnitude of life years gained varied across risk mechanisms.</p> <p>Conclusions</p> <p>Simulation studies can provide insight into both the effect of risk factor assumptions on model predictions and the type of data needed to calibrate risk factor models.</p

SMURF1 Amplification Promotes Invasiveness in Pancreatic Cancer

Pancreatic cancer is a deadly disease, and new therapeutic targets are urgently needed. We previously identified DNA amplification at 7q21-q22 in pancreatic cancer cell lines. Now, by high-resolution genomic profiling of human pancreatic cancer cell lines and human tumors (engrafted in immunodeficient mice to enrich the cancer epithelial fraction), we define a 325 Kb minimal amplicon spanning SMURF1, an E3 ubiquitin ligase and known negative regulator of transforming growth factor β (TGFβ) growth inhibitory signaling. SMURF1 amplification was confirmed in primary human pancreatic cancers by fluorescence in situ hybridization (FISH), where 4 of 95 cases (4.2%) exhibited amplification. By RNA interference (RNAi), knockdown of SMURF1 in a human pancreatic cancer line with focal amplification (AsPC-1) did not alter cell growth, but led to reduced cell invasion and anchorage-independent growth. Interestingly, this effect was not mediated through altered TGFβ signaling, assayed by transcriptional reporter. Finally, overexpression of SMURF1 (but not a catalytic mutant) led to loss of contact inhibition in NIH-3T3 mouse embryo fibroblast cells. Together, these findings identify SMURF1 as an amplified oncogene driving multiple tumorigenic phenotypes in pancreatic cancer, and provide a new druggable target for molecularly directed therapy

Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study)

Background: Recent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications. The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas. Methods/design. Multicenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma 3 cm, located between 115 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane i

Of monkeys and men:Impatience in perceptual decision-making

For decades sequential sampling models have successfully accounted for human and monkey decision-making, relying on the standard assumption that decision makers maintain a pre-set decision standard throughout the decision process. Based on the theoretical argument of reward rate maximization, some authors have recently suggested that decision makers become increasingly impatient as time passes and therefore lower their decision standard. Indeed, a number of studies show that computational models with an impatience component provide a good fit to human and monkey decision behavior. However, many of these studies lack quantitative model comparisons and systematic manipulations of rewards. Moreover, the often-cited evidence from single-cell recordings is not unequivocal and complimentary data from human subjects is largely missing. We conclude that, despite some enthusiastic calls for the abandonment of the standard model, the idea of an impatience component has yet to be fully established; we suggest a number of recently developed tools that will help bring the debate to a conclusive settlement

Phylogenetic and functional marker genes to study ammonia-oxidizing microorganisms (AOM) in the environment

The oxidation of ammonia plays a significant role in the transformation of fixed nitrogen in the global nitrogen cycle. Autotrophic ammonia oxidation is known in three groups of microorganisms. Aerobic ammonia-oxidizing bacteria and archaea convert ammonia into nitrite during nitrification. Anaerobic ammonia-oxidizing bacteria (anammox) oxidize ammonia using nitrite as electron acceptor and producing atmospheric dinitrogen. The isolation and cultivation of all three groups in the laboratory are quite problematic due to their slow growth rates, poor growth yields, unpredictable lag phases, and sensitivity to certain organic compounds. Culture-independent approaches have contributed importantly to our understanding of the diversity and distribution of these microorganisms in the environment. In this review, we present an overview of approaches that have been used for the molecular study of ammonia oxidizers and discuss their application in different environments

Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis

Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies