This review gives an account of recent advances in our knowledge of the molecular mechanisms in colorectal cancer. Genetic changes in the germ line, combined with somatic mutations, occur in familial syndromes of colorectal cancer, whereas somatic mutations are the outstanding feature of sporadic colorectal cancer. Genetic changes drive the progression from adenoma to carcinoma and probably influence individual susceptibility and response to treatment.

/pdf/molecular-basis-of-colorectal-cancer-7rro5tgxde.pdf

Molecular Basis of Colorectal Cancer

https://www.gastrojournal.org/article/S0016-5085(10)00176-9/pdf

Inflammation and Colon Cancer

http://www.bccancer.bc.ca/screening/Documents/COLON_GuidelinesManual-AGAGuidelinesColonoscopySurveillance.pdf

Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)61543-7.pdf

Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials.

It is widely accepted that alterations to cyclooxygenase-2 (COX-2) expression and the abundance of its enzymatic product prostaglandin E2 (PGE2) have key roles in influencing the development of colorectal cancer. Deregulation of the COX-2/PGE2 pathway appears to affect colorectal tumorigenesis via a number of distinct mechanisms: promoting tumour maintenance and progression, encouraging metastatic spread, and perhaps even participating in tumour initiation. Here, we review the role of COX-2/ PGE2 signalling in colorectal tumorigenesis and highlight its ability to influence the hallmarks of cancer-attributes defined by Hanahan and Weinberg as being requisite for tumorigenesis. In addition, we consider components of the COX-prostaglandin pathway emerging as important regulators of tumorigenesis; namely, the prostanoid (EP) receptors, 15-hydroxyprostaglandin dehydrogenase and the prostaglandin transporter. Finally, based on recent findings, we propose a model for the cellular adaptation to the hypoxic tumour microenvironment that encompasses the interplay between COX-2, hypoxia-inducible factor 1 and dynamic switches in β-catenin function that fine-tune signalling networks to meet the ever-changing demands of a tumour. © The Author 2009. Published by Oxford University Press. All rights reserved.

The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment.

Background Overexpression of cyclooxygenase 2 (COX-2) has been associated with colorectal adenomatous polyps and cancer, prompting researchers to propose its inhibition as a chemopreventive intervention. Methods The Prevention of Colorectal Sporadic Adenomatous Polyps trial was a randomized, placebo-controlled, double-blind study of the COX-2 inhibitor celecoxib given daily in a single 400-mg dose. At 107 centers in 32 countries, we randomly assigned 1561 subjects who had had adenomas removed before enrollment to receive celecoxib (933 subjects) or placebo (628 subjects) daily, after stratification according to the use or nonuse of low-dose aspirin. The primary outcome was detection of adenomas at either year 1 or year 3 by colonoscopy and was compared among the groups with the use of the Mantel–Cox test. Results Colonoscopies were performed at year 1 on 88.7 percent of the subjects who had undergone randomization and at year 3 on 79.2 percent. Of the 557 subjects in the placebo group and the 840 subjects in the celecoxib group who were included in the efficacy analysis, 264 and 270, respectively, were found to have at least one adenoma at year 1, at year 3, or both. The cumulative rate of adenomas detected through year 3 was 33.6 percent in the celecoxib group and 49.3 percent in the placebo group (relative risk, 0.64; 95 percent confidence interval, 0.56 to 0.75; P<0.001). The cumulative rate of advanced adenomas detected through year 3 was 5.3 percent in the celecoxib group and 10.4 percent in the placebo group (relative risk, 0.49; 95 percent confidence interval, 0.33 to 0.73; P<0.001). Adjudicated serious cardiovascular events occurred in 2.5 percent of subjects in the celecoxib group and 1.9 percent of those in the placebo group (relative risk, 1.30; 95 percent confidence interval, 0.65 to 2.62). Conclusions The use of 400 mg of celecoxib once daily significantly reduced the occurrence of colorectal adenomas within three years after polypectomy. (ClinicalTrials.gov number, NCT00141193.)

/pdf/celecoxib-for-the-prevention-of-colorectal-adenomatous-2vlkkeylbl.pdf

Celecoxib for the Prevention of Colorectal Adenomatous Polyps

Objective: Patients with fibromyalgia demonstrate high rates of comorbid somatic and psychiatric disorders. The current post hoc study analyzed the prevalence of comorbid conditions and their relationship to pregabalin efficacy in patients with fibromyalgia pooled from four Phase III clinical trials. Methods: Patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria, randomized to placebo or 300, 450, or 600 mg/day pregabalin, and with ≥ 1 postbaseline pain score were included. The frequency of comorbid conditions was obtained from patient-reported, voluntary medical histories. Patients were categorized based on the presence of a medical condition (e.g., irritable bowel syndrome) or a group of medical conditions (e.g., neurological disorders). Two efficacy variables were examined within each comorbid category: endpoint changes from baseline in weekly mean pain diary scores (11-point numeric rating scale) and Patient Global Impression of Change. Results: A large propor...

Medical conditions in fibromyalgia patients and their relationship to pregabalin efficacy: pooled analysis of Phase III clinical trials.

Pregabalin improves fibromyalgia related sleep disturbance

Effect of pregabalin on quantitative electroencephalography (qeeg) during non-rem sleep in patients with fibromyalgia and sleep maintenance difficulties

Objective
To assess the effect of pregabalin on polysomnographic (PSG) measures of sleep and patient-rated sleep, tiredness, and pain in fibromyalgia patients.

Methods
We performed a randomized, double-blind, placebo-controlled, 2-period crossover PSG study. Patients ages ≥18 years with fibromyalgia satisfied subjective and objective sleep disturbance criteria prior to randomization. Eligible patients were randomized (1:1) to pregabalin (300–450 mg/day) or placebo for crossover period 1, and vice versa for period 2. Each crossover period comprised a dose-adjustment and dose-maintenance phase, with a 2-week taper/washout between periods. In-laboratory PSGs were recorded during 2 consecutive nights at screening and at the end of each crossover period. The primary end point was the difference in sleep maintenance defined by PSG-recorded wake after sleep onset (WASO; minutes) between 4 weeks of treatment with pregabalin and with placebo. Other PSG measures; patient-rated sleep, tiredness, and pain; and tolerability were assessed.

Results
Of 119 patients randomized (103 women [86.6%], mean age 48.4 years), 102 (85.7%) completed both periods. Patients treated with pregabalin showed a reduction in PSG-determined WASO versus treatment with placebo (week 4 difference: −19.2 minutes [95% confidence interval (95% CI) −26.7, −11.6]; P < 0.0001). Pain score improved (decreased) with pregabalin versus placebo treatment at all 4 weeks (week 4 difference: −0.52 [95% CI −0.90, −0.14]; P = 0.0084). Modest (ρ = <0.3) but significant correlations were found between PSG sleep assessments and ratings of pain and sleep quality. Frequently reported all-causality adverse events (pregabalin versus placebo) were: dizziness (30.4% versus 9.9%), somnolence (20.5% versus 4.5%), and headache (8.9% versus 8.1%).

Conclusion
Patients with fibromyalgia treated with pregabalin had statistically significant and meaningful improvements in sleep, as assessed by PSG. Patients with fibromyalgia also reported decreased daily pain. Pregabalin was well tolerated.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/acr.21595

Effect of pregabalin on sleep in patients with fibromyalgia and sleep maintenance disturbance: a randomized, placebo-controlled, 2-way crossover polysomnography study.

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