Appointments timed in proximity to annual milestones and compliance with screening: randomised controlled trial

Objective To investigate whether appointments for screening timed in proximity to annual milestones (birthdays, Christmas and New Year) may be used as a strategy to improve attendance for screening for colorectal cancer

Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomised controlled trial

Objective To determine the risk of colorectal cancer after screening with flexible sigmoidoscopy

Methods to Estimate the Comparative Effectiveness of Clinical Strategies that Administer the Same Intervention at Different Times

Clinical guidelines that rely on observational data due to the absence of data from randomized trials benefit when the observational data or its analysis emulates trial data or its analysis. In this paper, we review a methodology for emulating trials that compare the effects of different timing strategies, that is, strategies that vary the frequency of delivery of a medical intervention or procedure. We review trial emulation for comparing (i) single applications of the procedure at different times, (ii) fixed schedules of application, and (iii) schedules adapted to the evolving clinical characteristics of the patients. For illustration, we describe an application in which we estimate the effect of surveillance colonoscopies in patients who had an adenoma detected during the Norwegian Colorectal Cancer Prevention (NORCCAP) trial

Long-term follow-up of colorectal cancer screening attendees identifies differences in Phascolarctobacterium spp. using 16S rRNA and metagenome sequencing

BackgroundThe microbiome has been implicated in the initiation and progression of colorectal cancer (CRC) in cross-sectional studies. However, there is a lack of studies using prospectively collected samples.MethodsFrom the Norwegian Colorectal Cancer Prevention (NORCCAP) trial, we analyzed 144 archived fecal samples from participants who were diagnosed with CRC or high-risk adenoma (HRA) at screening and from participants who remained cancer-free during 17 years of follow-up. We performed 16S rRNA sequencing of all the samples and metagenome sequencing on a subset of 47 samples. Differences in taxonomy and gene content between outcome groups were assessed for alpha and beta diversity and differential abundance.ResultsDiversity and composition analyses showed no significant differences between CRC, HRA, and healthy controls. Phascolarctobacterium succinatutens was more abundant in CRC compared with healthy controls in both the 16S and metagenome data. The abundance of Bifidobacterium and Lachnospiraceae spp. was associated with time to CRC diagnosis.ConclusionUsing a longitudinal study design, we identified three taxa as being potentially associated with CRC. These should be the focus of further studies of microbial changes occurring prior to CRC diagnosis

Colorectal cancer - Demand for a joint Nordic study on the value of colonoscopic screening

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A highly selective purine-based inhibitor of CSF1R potently inhibits osteoclast differentiation

The colony-stimulating factor 1 receptor (CSF1R) plays an important role in the regulation of many inflammatory processes, and overexpression of the kinase is implicated in several disease states. Identifying selective, smallmolecule inhibitors of CSF1R may be a crucial step toward treating these disorders. Through modelling, synthesis, and a systematic structure-activity relationship study, we have identified a number of potent and highly selective purine-based inhibitors of CSF1R. The optimized 6,8-disubstituted antagonist, compound 9, has enzymatic IC50 of 0.2 nM, and displays a strong affinity toward the autoinhibited form of CSF1R, contrasting that of other previously reported inhibitors. As a result of its binding mode, the inhibitor shows excellent selectivity (Selectivity score: 0.06), evidenced by profiling towards a panel of 468 kinases. In cell-based assays, this inhibitor shows dose-dependent blockade of CSF1-mediated downstream signalling in murine bone marrow-derived macrophages (IC50 = 106 nM) as well as disruption of osteoclast differentiation at nanomolar levels. In vivo experiments, however, indicate that improve metabolic stability is needed in order to further progress this compound class

Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers

<p>Abstract</p> <p>Background</p> <p>Multiple epigenetic and genetic changes have been reported in colorectal tumors, but few of these have clinical impact. This study aims to pinpoint epigenetic markers that can discriminate between non-malignant and malignant tissue from the large bowel, i.e. markers with diagnostic potential.</p> <p>The methylation status of eleven genes (<it>ADAMTS1</it>, <it>CDKN2A</it>, <it>CRABP1</it>, <it>HOXA9</it>, <it>MAL</it>, <it>MGMT</it>, <it>MLH1</it>, <it>NR3C1</it>, <it>PTEN</it>, <it>RUNX3</it>, and <it>SCGB3A1</it>) was determined in 154 tissue samples including normal mucosa, adenomas, and carcinomas of the colorectum. The gene-specific and widespread methylation status among the carcinomas was related to patient gender and age, and microsatellite instability status. Possible CIMP tumors were identified by comparing the methylation profile with microsatellite instability (MSI), <it>BRAF</it>-, <it>KRAS</it>-, and <it>TP53 </it>mutation status.</p> <p>Results</p> <p>The mean number of methylated genes per sample was 0.4 in normal colon mucosa from tumor-free individuals, 1.2 in mucosa from cancerous bowels, 2.2 in adenomas, and 3.9 in carcinomas. Widespread methylation was found in both adenomas and carcinomas. The promoters of <it>ADAMTS1</it>, <it>MAL</it>, and <it>MGMT </it>were frequently methylated in benign samples as well as in malignant tumors, independent of microsatellite instability. In contrast, normal mucosa samples taken from bowels without tumor were rarely methylated for the same genes. Hypermethylated <it>CRABP1, MLH1</it>, <it>NR3C1</it>, <it>RUNX3</it>, and <it>SCGB3A1 </it>were shown to be identifiers of carcinomas with microsatellite instability. In agreement with the CIMP concept, MSI and mutated <it>BRAF </it>were associated with samples harboring hypermethylation of several target genes.</p> <p>Conclusion</p> <p>Methylated <it>ADAMTS1</it>, <it>MGMT</it>, and <it>MAL </it>are suitable as markers for early tumor detection.</p

"Drop in" gastroscopy outpatient clinic - experience after 9 months

<p>Abstract</p> <p>Background</p> <p>Logistics handling referrals for gastroscopy may be more time consuming than the examination itself. For the patient, "drop in" gastroscopy may reduce uncertainty, inadequate therapy and time off work.</p> <p>Methods</p> <p>After an 8-9 month run-in period we asked patients, hospital staff and GPs to fill in a questionnaire to evaluate their experience with "drop in" gastroscopy and gastroscopy by appointment, respectively. The diagnostic gain was evaluated.</p> <p>Results</p> <p>112 patients had "drop in" gastroscopy and 101 gastroscopy by appointment. The number of "drop in" patients varied between 3 and 12 per day (mean 6.5). Mean time from first GP consultation to gastroscopy was 3.6 weeks in the "drop in" group and 14 weeks in the appointment group. The half-yearly number of outpatient gastroscopies increased from 696 before introducing "drop in" to 1022 after (47% increase) and the proportion of examinations with pathological findings increased from 42% to 58%. Patients and GPs expressed great satisfaction with "drop in". Hospital staff also acclaimed although it caused more unpredictable working days with no additional staff.</p> <p>Conclusions</p> <p>"Drop in" gastroscopy was introduced without increase in staff. The observed increase in gastroscopies was paralleled by a similar increase in pathological findings without any apparent disadvantages for other groups of patients. This should legitimise "drop in" outpatient gastroscopies, but it requires meticulous observation of possible unwanted effects when implemented.</p

Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas

Background The presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma. This study investigates a panel of epigenetic markers for the detection of colorectal cancer and adenomas. Methods Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the biomarker panel. Results Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94%) and adenomas (35-91%), whereas normal mucosa samples were rarely (0-5%) methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa. Conclusions The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection