Van Hoof TJ, Ho SY, Kelvey-Albert M, et al.
Opportunities to improve colorectal and breast cancer screening in Connecticut.
Conn Med. 2013; 77(1):5-10 [PubMed]

Colorectal and breast cancer represent serious and common public-health problems in the United States. While effective screening tests exist for both types of cancer, Connecticut lacks a consistent source of data about screening rates to guide improvement efforts. Beginning in 2011, the Connecticut Department of Public Health commissioned Qualidigm, the state's Medicare Quality Improvement Organization, to conduct an analysis of the most recent fee-for-service Medicare claims data to determine screening rates for colorectal cancer (2000-2009) and breast cancer (2008-2009). This article highlights key findings of this analysis in order to increase awareness of opportunities for improvement in colorectal and breast cancer screening. The article also offers recommendations about next steps that primary care clinicians can consider to improve cancer screening among their patient populations.

Grulich AE, Hillman R, Brotherton JM, Fairley CK
Time for a strategic research response to anal cancer.
Sex Health. 2012; 9(6):628-31 [PubMed]

Anal cancer was until recently regarded as a rare cancer of little consequence. The articles in this special edition of Sexual Health clearly demonstrate that anal cancer is increasing in incidence and, in some populations, it has become an urgent public health priority. In this summary paper, we will review the data presented in this issue and elsewhere on the magnitude of the issue, the means of prevention and treatment, and suggest a way forward.

Fairley CK, Brotherton JM, Hillman R, Grulich AE
Why a special issue on anal cancer and what is in it?
Sex Health. 2012; 9(6):501-3 [PubMed]

This editorial describes the contents of this special issue of Sexual Health devoted to anal cancer. The aim of the issue is to provide readers with information to assist them in making decisions about what to do about detecting anal cancer early in men who have sex with men with HIV. Should they be advocating screening? It discusses the epidemiology of HPV infection, anal intraepithelial neoplasia, and anal cancer in MSM, heterosexual men and women; anal cancer screening and treatment of anal cancer. And most importantly, what should be done about vaccinating boys with the HPV vaccine.

Kodela R, Chattopadhyay M, Goswami S, et al.
Positional isomers of aspirin are equally potent in inhibiting colon cancer cell growth: differences in mode of cyclooxygenase inhibition.
J Pharmacol Exp Ther. 2013; 345(1):85-94 [PubMed] Article available free on PMC after 01/04/2014

We compared the differential effects of positional isomers of acetylsalicylic acid (o-ASA, m-ASA, and p-ASA) on cyclooxygenase (COX) inhibition, gastric prostaglandin E2 (PGE2), malondialdehyde, tumor necrosis factor-alpha (TNF-α) levels, superoxide dismutase (SOD) activity, human adenocarcinoma colon cancer cell growth inhibition, cell proliferation, apoptosis, and cell-cycle progression. We also evaluated the gastric toxicity exerted by ASA isomers. All ASA isomers inhibit COX enzymes, but only the o-ASA exerted an irreversible inhibitory profile. We did not observe a significant difference between ASA isomers in their ability to decrease the in vivo synthesis of PGE2 and SOD activity. Furthermore, all isomers increased the levels of gastric and TNF-α when administered orally at equimolar doses. We observed a dose-dependent cell growth inhibitory effect; the order of potency was p-ASA > m-ASA ≈ o-ASA. There was a dose-dependent decrease in cell proliferation and an increase in apoptosis, with a concomitant Go/G1 arrest. The ulcerogenic profile of the three ASA isomers showed a significant difference between o-ASA (aspirin) and its two positional isomers when administered orally at equimolar doses (1 mmol/kg); the ulcer index (UI) for o-ASA indicated extensive mucosal injury (UI = 38), whereas m-ASA and p-ASA produced a significantly decreased toxic response (UI = 12 and 8, respectively) under the same experimental conditions. These results suggest that the three positional isomers of ASA exert practically the same biologic profile in vitro and in vivo but showed different safety profiles. The mechanism of gastric ulcer formation exerted by aspirin and its two isomers warrants a more detailed and thorough investigation.

Raj KP, Zell JA, Rock CL, et al.
Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas.
Br J Cancer. 2013; 108(3):512-8 [PubMed] Article available free on PMC after 19/02/2014

BACKGROUND: The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial.
METHODS: Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75-100%) vs the lower three quartiles (0-25, 25-50 and 50-75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation.
RESULTS: A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1-3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08-0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53-4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates.
CONCLUSION: These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled.

Lee SJ, Boscardin WJ, Stijacic-Cenzer I, et al.
Time lag to benefit after screening for breast and colorectal cancer: meta-analysis of survival data from the United States, Sweden, United Kingdom, and Denmark.
BMJ. 2013; 346:e8441 [PubMed]

OBJECTIVES: To determine a pooled, quantitative estimate of the length of time needed after breast or colorectal cancer screening before a survival benefit is observed.
DESIGN: Meta-analysis of survival data from population based, randomized controlled trials comparing populations screened and not screened for breast or colorectal cancer. Trials were identified as high quality by reviews from the Cochrane Collaboration and United States Preventive Services Task Force.
SETTING: Trials undertaken in the United States, Denmark, United Kingdom, and Sweden.
POPULATION: Screened patients older than 40 years.
PRIMARY OUTCOME MEASURES: Time to death from breast or colorectal cancer in screened and control populations.
INTERVENTIONS: Fecal occult blood testing for colorectal cancer screening, mammography for breast cancer screening.
RESULTS: Our study included five and four eligible trials of breast and colorectal cancer screening, respectively. For breast cancer screening, 3.0 years (95% confidence interval 1.1 to 6.3) passed before one death from breast cancer was prevented for every 5000 women screened. On average across included studies, it took 10.7 years (4.4 to 21.6) before one death from breast cancer was prevented for 1000 women screened. For colorectal cancer screening, 4.8 years (2.0 to 9.7) passed before one death from colorectal cancer was prevented for 5000 patients screened. On average across included studies, it took 10.3 years (6.0 to 16.4) before one death from colorectal cancer was prevented for 1000 patients screened.
CONCLUSIONS: Our results suggest that screening for breast and colorectal cancer is most appropriate for patients with a life expectancy greater than 10 years. Incorporating time lag estimates into screening guidelines would encourage a more explicit consideration of the risks and benefits of screening for breast and colorectal cancer.

Kumar M, Nagpal R, Verma V, et al.
Probiotic metabolites as epigenetic targets in the prevention of colon cancer.
Nutr Rev. 2013; 71(1):23-34 [PubMed]

Dietary interventions for preventing colon cancer have recently attracted increased attention from researchers and clinicians. The probiotics have emerged as potential therapeutic agents but are also regarded as healthy dietary supplements for nutrition and health applications. The probiotic metabolome may interfere with various cellular and molecular processes, including the onset and progression of colon cancer. Probiotic metabolites may lead to the modulation of diverse cellular signal transduction and metabolic pathways. The gut microbial metabolites (organic acids, bacteriocins, peptides, etc.) have been noted to interact with multiple key targets in various metabolic pathways that regulate cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis, and metastasis. Progress in this field suggests that epigenetic alterations will be widely used in the near future to manage colon cancer. The present review provides insights into the molecular basis of the therapeutic applications and the chemopreventive activities of certain probiotic metabolites, with emphasis on the interaction between these metabolites and the molecular signaling cascades that are considered to be epigenetic targets in preventing colon cancer.

Thosani N, Thosani SN, Kumar S, et al.
Reduced risk of colorectal cancer with use of oral bisphosphonates: a systematic review and meta-analysis.
J Clin Oncol. 2013; 31(5):623-30 [PubMed]

PURPOSE: The association between oral bisphosphonate (BP) intake and colorectal cancer (CRC) risk has been investigated in several recent studies with conflicting results. We summarized the evidence from the published studies in a categorical, dose-response meta-analysis.
METHODS: Relevant studies were identified by a search of MEDLINE and EMBASE databases through January 15, 2012. We included studies that reported effect size estimates with 95% CIs for the association between exposure to oral BPs and risk of CRC.
RESULTS: Three case-control studies with a total of 16,998 CRC cases and 108,197 controls and one cohort study with 94,405 individuals exposed to BPs and 283,181 unexposed to BPs were included in meta-analysis. The random effect model meta-analysis suggested reduced risk of CRC with exposure to oral BPs with pooled odds ratio (OR) of 0.87 (95% CI, 0.78 to 0.97). Significant inverse relationship was noted for 10 or more prescriptions categories, with pooled ORs of 0.71 (95% CI, 0.58 to 0.87). Similarly, the analysis for 1 to 3 years of use and more than 3 years of use of BPs suggested a significant inverse relationship, with pooled ORs of 0.76 (95% CI, 0.68 to 0.85) and 0.78 (95% CI, 0.61 to 0.99), respectively.
CONCLUSION: This meta-analysis suggests that the use of oral BPs at a dose of 10 or more prescriptions or 1 or more years of duration is associated with reduced risk of CRC. Further randomized controlled trials are needed to prove this association.

Sharaf RN, Ladabaum U
Comparative effectiveness and cost-effectiveness of screening colonoscopy vs. sigmoidoscopy and alternative strategies.
Am J Gastroenterol. 2013; 108(1):120-32 [PubMed]

OBJECTIVES: Fecal occult blood testing (FOBT) and sigmoidoscopy are proven to decrease colorectal cancer (CRC) incidence and mortality. Sigmoidoscopy's benefit is limited to the distal colon. Observational data are conflicting regarding the degree to which colonoscopy affords protection against proximal CRC. Our aim was to explore the comparative effectiveness and cost-effectiveness of colonoscopy vs. sigmoidoscopy and alternative CRC screening strategies in light of the latest published data.
METHODS: We performed a contemporary cost-utility analysis using a Markov model validated against data from randomized controlled trials of FOBT and sigmoidoscopy. Persons at average CRC risk within the general US population were modeled. Screening strategies included those recommended by the United States (US) Preventive Services Task Force, including colonoscopy every 10 years (COLO), flexible sigmoidoscopy every 5 years (FS), annual fecal occult blood testing, annual fecal immunochemical testing (FIT), and the combination FS/FIT. The main outcome measures were quality-adjusted life-years (QALYs) and costs.
RESULTS: In the base case, FIT dominated other strategies. The advantage of FIT over FS and COLO was contingent on rates of uptake and adherence that are well above current US rates. Compared with FIT, FS and COLO both cost <$50,000/QALY gained when FIT per-cycle adherence was <50%. COLO cost $56,800/QALY gained vs. FS in the base case. COLO cost <$100,000/QALY gained vs. FS when COLO yielded a relative risk of proximal CRC of <0.5 vs. no screening. In probabilistic analyses, COLO was cost-effective vs. FS at a willingness-to-pay threshold of $100,000/QALY gained in 84% of iterations.
CONCLUSIONS: Screening colonoscopy may be cost-effective compared with FIT and sigmoidoscopy, depending on the relative rates of screening uptake and adherence and the protective benefit of colonoscopy in the proximal colon. Colonoscopy's cost-effectiveness compared with sigmoidoscopy is contingent on the ability to deliver ~50% protection against CRC in the proximal colon.

Yogosawa S, Yamada Y, Yasuda S, et al.
Dehydrozingerone, a structural analogue of curcumin, induces cell-cycle arrest at the G2/M phase and accumulates intracellular ROS in HT-29 human colon cancer cells.
J Nat Prod. 2012; 75(12):2088-93 [PubMed]

Dehydrozingerone (1) is a pungent constituent present in the rhizomes of ginger (Zingiber officinale) and belongs structurally to the vanillyl ketone class. It is a representative of half the chemical structure of curcumin (2), which is an antioxidative yellow pigment obtained from the rhizomes of turmeric (Curcuma longa). Numerous studies have suggested that 2 is a promising phytochemical for the inhibition of malignant tumors, including colon cancer. On the other hand, there have been few studies on the potential antineoplastic properties of 1, and its mode of action based on a molecular mechanism is little known. Therefore, the antiproliferative effects of 1 were evaluated against HT-29 human colon cancer cells, and it was found that 1 dose-dependently inhibited growth at the G2/M phase with up-regulation of p21. Dehydrozingerone additionally led to the accumulation of intracellular ROS, although most radical scavengers could not clearly repress the cell-cycle arrest at the G2/M phase. Furthermore, two synthetic isomers of 1 (iso-dehydrozingerone, 3, and ortho-dehydrozingerone, 4) were also examined. On comparing of their activities, accumulation of intracellular ROS was found to be interrelated with growth-inhibitory effects. These results suggest that analogues of 1 may be potential chemotherapeutic agents for colon cancer.

Giraldi G, De Luca d'Alessandro E
The HPV infection in males: an update.
Ann Ig. 2012 Nov-Dec; 24(6):497-506 [PubMed]

The role of Human papillomavirus (HPV) in malignant and non-malignant genital diseases in females is well known and the corresponding epidemiological burden has been widely described, in males instead, less is known about the role of the virus in anal, penile and head and neck cancer, and the burden of malignant and non-malignant HPV-related diseases. There are many types of HPV that can infect the epithelium: some types can cause genital warts (low risk genotype), other types (high risk genotypes) can cause cancers of the penis, anus or oropharynx. Relative to females, males tend to be less knowledgeable about the infection: some may view its consequences as less likely and severe for themselves than for females, and thus could perceive vaccination as unnecessary. Including boys in the vaccination program generally exceeded conventional thresholds of good value for money, even under favorable conditions of vaccine protection and health benefits; however, uncertainty still exists in many areas that can either strengthen or attenuate the findings achieved.

de Wijkerslooth TR, de Haan MC, Stoop EM, et al.
Reasons for participation and nonparticipation in colorectal cancer screening: a randomized trial of colonoscopy and CT colonography.
Am J Gastroenterol. 2012; 107(12):1777-83 [PubMed]

OBJECTIVES: We compared reported reasons for participation and nonparticipation in colorectal cancer (CRC) screening between colonoscopy and computed tomographic (CT) colonography in a randomized controlled trial.
METHODS: We randomly invited 8,844 people for screening by colonoscopy or CT colonography. On a questionnaire, invitees indicated reasons for participation or nonparticipation and indicated the most decisive reason.
RESULTS: The most frequently cited reasons to accept screening were early detection of precursor lesions and CRC, and contribution to science. The most frequently cited reasons to decline were the unpleasantness of the examination, the inconvenience of the preparation, a lack of symptoms, and "no time/too much effort." Among colonoscopy nonparticipants, elderly invitees cited inconvenience less often, and absence of symptoms more often, than did the group overall. The reason reported most frequently as the most decisive reason not to participate was the unpleasantness of the examination among colonoscopy nonparticipants, and "no time/too much effort" and lack of symptoms among CT colonography nonparticipants.
CONCLUSIONS: In light of these results, future screening programs could tailor the information provided to invitees.

Stubbins RE, Hakeem A, Núñez NP
Using components of the vitamin D pathway to prevent and treat colon cancer.
Nutr Rev. 2012; 70(12):721-9 [PubMed] Article available free on PMC after 01/12/2013

The objective of this review was to analyze the components of vitamin D and their potential usefulness in preventing and treating colorectal cancer. The active form of vitamin D, 1α,25(OH(2) )D(3) , targets the wnt/β-catenin pathway by upregulating key tumor suppressor genes such as E-cadherin, which promotes an epithelial phenotype, but this is only possible when the vitamin D receptor (VDR) is present. Colorectal cell lines have shown that VDR expression levels decrease in the later stages of colon cancer. In colorectal cancers with low VDR expression, treatments to increase VDR expression could target alterations at the genomic and epigenomic levels by modulating transcription factors such as SNAIL1 and by utilizing histone deacetyltransferase inhibitors, respectively. Finally, epidemiological studies suggest that the current US Recommended Dietary Allowance should be increased to 2,000 IU in order to raise serum 25(OH)D(3) levels above 30 ng/mL. This increase in vitamin D status can be obtained most efficiently from sun exposure or vitamin D supplementation. In summary, vitamin D and its metabolites could be utilized in strategies to treat and prevent colon cancer.

Waller J, Macedo A, von Wagner C, et al.
Communication about colorectal cancer screening in Britain: public preferences for an expert recommendation.
Br J Cancer. 2012; 107(12):1938-43 [PubMed] Article available free on PMC after 04/12/2013

BACKGROUND: Informed decision-making approaches to cancer screening emphasise the importance of decisions being determined by individuals' own values and preferences. However, advice from a trusted source may also contribute to autonomous decision-making. This study examined preferences regarding a recommendation from the NHS and information provision in the context of colorectal cancer (CRC) screening.
METHODS: In face-to-face interviews, a population-based sample of adults across Britain (n=1964; age 50-80 years) indicated their preference between: (1) a strong recommendation to participate in CRC screening, (2) a recommendation alongside advice to make an individual decision, and (3) no recommendation but advice to make an individual decision. Other measures included trust in the NHS and preferences for information on benefits and risks.
RESULTS: Most respondents (84%) preferred a recommendation (47% strong recommendation, 37% recommendation plus individual decision-making advice), but the majority also wanted full information on risks (77%) and benefits (78%). Men were more in favour of a recommendation than women (86% vs 81%). Trust in the NHS was high overall, but the minority who expressed low trust were less likely to want a recommendation.
CONCLUSION: Most British adults want full information on risks and benefits of screening but they also want a recommendation from an authoritative source. An 'expert' view may be an important part of autonomous health decision-making.

Wang ZH, Gao QY, Fang JY
Green tea and incidence of colorectal cancer: evidence from prospective cohort studies.
Nutr Cancer. 2012; 64(8):1143-52 [PubMed]

A systematic meta-analysis of prospective cohort studies on green tea consumption and colorectal cancer was performed to determine whether green tea has a chemopreventive effect against colorectal cancer. Six eligible cohort studies involving 352,275 participants and 1675 cases of colorectal cancer were identified. Combined relative risk (RR) ratios for the highest vs. lowest and increment of 1 cup/day green tea consumption levels were calculated. The combined RR of 0.90 (95% CI: 0.72-1.08) was found comparing highest vs. lowest green tea consumption levels for colorectal cancer. No significant differences by cancer-site were found, but an inverse association between green tea and incidence of colorectal cancer (RR: 0.70; 95% CI: 0.55-0.85) and colon cancer (RR: 0.69; 95% CI: 0.48-0.98) was demonstrated in Shanghai population. Singapore men had a higher risk of colorectal cancer (RR: 1.36; 95% CI: 1.06-1.74). Furthermore, an increase in green tea consumption of 1 cup/day was not associated with incidence of colorectal cancer (RR: 0.97; 95% CI: 0.91-1.03). Despite the limited evidence from Shanghai studies in support of green tea as potential chemopreventive agents against colorectal cancer, available data from prospective cohort studies are insufficient to conclude that green tea may protect against colorectal cancer.

Carey EJ, Lindor KD
Chemoprevention of colorectal cancer with ursodeoxycholic acid: cons.
Clin Res Hepatol Gastroenterol. 2012; 36 Suppl 1:S61-4 [PubMed]

Animal and human data suggest a relationship between bile acids, especially secondary bile acids, and colorectal cancer. Ursodeoxycholic acid, a synthetic bile acid, has been shown in animal and in vitro studies to reduce the risk of colonic dysplasia and cancer development. Human trials have focused on patients with history of adenoma, inflammatory bowel disease, primary sclerosing cholangitis, and primary biliary cirrhosis. Some studies suggest that ursodeoxycholic may reduce the colorectal cancer risk, but to date the studies are small, mostly retrospective, and lacking in solid evidence to support use of UDCA for colorectal cancer chemoprophylaxis.

Serfaty L
Chemoprevention of colorectal cancer with ursodeoxycholic acid: pro.
Clin Res Hepatol Gastroenterol. 2012; 36 Suppl 1:S53-60 [PubMed]

Colorectal cancer is the third and second most common cancer among men and women, respectively, in France. Interest in the chemoprevention of colorectal cancer has increased over the last two decades. Experimental data strongly suggest that ursodeoxycholic acid (UDCA) may have chemopreventative actions in colorectal cancer. UDCA is able to inhibit tumor development in azoxymethane and in dextran-related colitis models. In high-risk populations such as subjects with previous colorectal adenoma removal or inflammatory bowel disease, five out of 10 published studies suggested beneficial effects with UDCA on colonic carcinogenesis. In the azoxymethane model, UDCA inhibited tumor development by counteracting the tumor-promoting effects of secondary bile acids such as deoxycholic acid (DCA). The opposing effects of UDCA and DCA on lipid raft composition may be central to their effects on colonic tumorigenesis. Differential effects of DCA and UDCA on growth factor and inflammatory signals involved in colorectal carcinogenesis, such as epidermal growth factor receptor (EGFR) signaling and COX-2 expression, very likely mediate their opposing effects on colonic tumor promotion and tumor inhibition, respectively.

Mathers JC, Movahedi M, Macrae F, et al.
Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.
Lancet Oncol. 2012; 13(12):1242-9 [PubMed]

BACKGROUND: Observational studies report that higher intake of dietary fibre (a heterogeneous mix including non-starch polysaccharides and resistant starches) is associated with reduced risk of colorectal cancer, but no randomised trials with prevention of colorectal cancer as a primary endpoint have been done. We assessed the effect of resistant starch on the incidence of colorectal cancer.
METHODS: In the CAPP2 study, individuals with Lynch syndrome were randomly assigned in a two-by-two factorial design to receive 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was done with a block size of 16. Post-intervention, patients entered into double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint for this analysis was development of colorectal cancer in participants randomly assigned to resistant starch or resistant-starch placebo with both intention-to-treat and per-protocol analyses. This study is registered, ISRCTN 59521990.
FINDINGS: 463 patients were randomly assigned to receive resistant starch and 455 to receive resistant-starch placebo. At a median follow-up 52·7 months (IQR 28·9-78·4), 53 participants developed 61 primary colorectal cancers (27 of 463 participants randomly assigned to resistant starch, 26 of 455 participants assigned to resistant-starch placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 1·40 (95% CI 0·78-2·56; p=0·26) and Poisson regression accounting for multiple primary events gave an incidence rate ratio (IRR) of 1·15 (95% CI 0·66-2·00; p=0·61). For those completing 2 years of intervention, per-protocol analysis yielded a HR of 1·09 (0·55-2·19, p=0·80) and an IRR of 0·98 (0·51-1·88, p=0·95). No information on adverse events was gathered during post-intervention follow-up.
INTERPRETATION: Resistant starch had no detectable effect on cancer development in carriers of hereditary colorectal cancer. Dietary supplementation with resistant starch does not emulate the apparently protective effect of diets rich in dietary fibre against colorectal cancer.
FUNDING: European Union, Cancer Research UK, Bayer Corporation, National Starch and Chemical Co, UK Medical Research Council, Newcastle Hospitals Trustees, Cancer Council of Victoria Australia, THRIPP South Africa, The Finnish Cancer Foundation, SIAK Switzerland, and Bayer Pharma.

Knudsen AB, Hur C, Gazelle GS, et al.
Rescreening of persons with a negative colonoscopy result: results from a microsimulation model.
Ann Intern Med. 2012; 157(9):611-20 [PubMed] Article available free on PMC after 04/12/2013

BACKGROUND: Persons with a negative result on screening colonoscopy are recommended to repeat the procedure in 10 years.
OBJECTIVE: To assess the effectiveness and costs of colonoscopy versus other rescreening strategies after an initial negative colonoscopy result.
DESIGN: Microsimulation model.
DATA SOURCES: Literature and data from the Surveillance, Epidemiology, and End Results program.
TARGET POPULATION: Persons aged 50 years who had no adenomas or cancer detected on screening colonoscopy.
TIME HORIZON: Lifetime.
PERSPECTIVE: Societal.
INTERVENTION: No further screening or rescreening starting at age 60 years with colonoscopy every 10 years, annual highly sensitive guaiac fecal occult blood testing (HSFOBT), annual fecal immunochemical testing (FIT), or computed tomographic colonography (CTC) every 5 years.
OUTCOME MEASURES: Lifetime cases of colorectal cancer, life expectancy, and lifetime costs per 1000 persons, assuming either perfect or imperfect adherence.
RESULTS OF BASE-CASE ANALYSIS: Rescreening with any method substantially reduced the risk for colorectal cancer compared with no further screening (range, 7.7 to 12.6 lifetime cases per 1000 persons [perfect adherence] and 17.7 to 20.9 lifetime cases per 1000 persons [imperfect adherence] vs. 31.3 lifetime cases per 1000 persons with no further screening). In both adherence scenarios, the differences in life-years across rescreening strategies were small (range, 30 893 to 30 902 life-years per 1000 persons [perfect adherence] vs. 30 865 to 30 869 life-years per 1000 persons [imperfect adherence]). Rescreening with HSFOBT, FIT, or CTC had fewer complications and was less costly than continuing colonoscopy.
RESULTS OF SENSITIVITY ANALYSIS: Results were sensitive to test-specific adherence rates.
LIMITATION: Data on adherence to rescreening were limited.
CONCLUSION: Compared with the currently recommended strategy of continuing colonoscopy every 10 years after an initial negative examination, rescreening at age 60 years with annual HSFOBT, annual FIT, or CTC every 5 years provides approximately the same benefit in life-years with fewer complications at a lower cost. Therefore, it is reasonable to use other methods to rescreen persons with negative colonoscopy results.
PRIMARY FUNDING SOURCE: National Cancer Institute.

Kuno T, Hatano Y, Tomita H, et al.
Organomagnesium suppresses inflammation-associated colon carcinogenesis in male Crj: CD-1 mice.
Carcinogenesis. 2013; 34(2):361-9 [PubMed]

Magnesium (Mg) deficiency increases genomic instability and Mg intake has been reported to be inversely associated with a risk of colorectal cancer (CRC). This study was designed to determine whether organo-Mg in drinking water suppresses inflammation-associated colon carcinogenesis in mice. Male Crj: CD-1 mice were initiated with a single i.p. injection of azoxymethane (AOM, 10mg/kg body weight) and followed by a 1 week exposure to dextran sulfate sodium (DSS, 1.5%, w/v) in drinking water to induce colonic neoplasms. They were then given the drinking water containing 7, 35 or 175 p.p.m. organo-Mg for 13 weeks. The chemopreventive efficacy of organo-Mg was determined 16 weeks after the AOM exposure. Administration with organo-Mg at all doses caused a significant inhibition of CRC development (P < 0.01 and P < 0.001). Especially, the highest dose of organo-Mg significantly suppressed the occurrence of all the colonic pathological lesions (mucosal ulcer, dysplasia, adenoma and adenocarcinoma). Organo-Mg also significantly reduced the number of mitoses/anaphase bridging, as well as proliferation of CRC. Additionally, at week 4, organo-Mg lowered the messenger RNA expression of certain proinflammatory cytokines, such as interleukin-1β, interleukin-6, interferon-γ and inducible nitric oxide synthase in the lesion-free colorectal mucosa at week 4 but increased the Nrf-2 messenger RNA expression. Our findings that organo-Mg inhibits inflammation-related mouse colon carcinogenesis by modulating the proliferative activities and chromosomal instability of CRC and suppressing colonic inflammation may suggest potential use of organo-Mg for clinical chemoprevention trials of CRC in the inflamed colon.

Ren SX, Cheng AS, To KF, et al.
Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer.
Cancer Res. 2012; 72(24):6512-23 [PubMed]

Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells.

Waly MI, Ali A, Guizani N, et al.
Pomegranate (Punica granatum) peel extract efficacy as a dietary antioxidant against azoxymethane-induced colon cancer in rat.
Asian Pac J Cancer Prev. 2012; 13(8):4051-5 [PubMed]

Functional foods include antioxidant nutrients which may protect against many human chronic diseases by combating reactive oxygen species (ROS) generation. The purpose of the present study was to investigate the protective effect of pomegranate peel extract (PPE) on azoxymethane (AOM)-induced colon tumors in rats as an in vivo experimental model. Forty Sprague-Dawley rats (4 weeks old) were randomly divided into 4 groups containing 10 rats per group, and were treated with either AOM, PPE, or PPE plus AOM or injected with 0.9% physiological saline solution as a control. At 8 weeks of age, the rats in the AOM and PPE plus AOM groups were injected with 15 mg AOM/kg body weight, once a week for two weeks. After the last AOM injection, the rats were continuously fed ad-libitum their specific diets for another 6 weeks. At the end of the experiment (i.e. at the age of 4 months), all rats were killed and the colon tissues were examined microscopically for lesions suspected of being preneoplastic lesions or tumors as well as for biochemical measurement of oxidative stress indices. The results revealed a lower incidence of aberrant crypt foci in the PPE plus AOM administered group as compared to the AOM group. In addition, PPE blocked the AOM-induced impairment of biochemical indicators of oxidative stress in the examined colonic tissue homogenates. The results suggest that PPE can partially inhibit the development of colonic premalignant lesions in an AOM-induced colorectal carcinogenesis model, by abrogating oxidative stress and improving the redox status of colonic cells.

Duncan A, Turnbull D, Gregory T, et al.
Using the Transtheoretical Model of Behaviour Change to describe readiness to rescreen for colorectal cancer with faecal occult blood testing.
Health Promot J Austr. 2012; 23(2):122-8 [PubMed]

ISSUE ADDRESSED: This study used the Transtheoretical Model of Behaviour Change (TTM) to describe reparticipation in colorectal cancer (CRC) screening according to social cognitive and background variables.
METHODS: A random sample of men and women aged 50-74 years living in South Australia completed a questionnaire measuring TTM stage and attitudes toward screening using a faecal occult blood test (FOBT). Participants were categorised according to four stages of readiness to rescreen: action, maintenance, relapse and inconsistent. Multivariate techniques were used to determine predictors of lower readiness stages compared with maintenance.
RESULTS: Of the 849 study participants, 29.9% were either non-adherent or had no intentions to maintain adherence (inconsistent and relapse). Compared with maintenance rescreeners, relapse participants reported less: social influences to screen (RR=0.86, p<0.001); satisfaction with prior screening (RR=0.87, p=0.03), self-efficacy (RR=0.96, p=0.01); and screening benefits (RR=0.84, p<0.001). Relapse participants were also more likely to not have private health insurance (RR=1.33, p=0.04) and be unaware of the need to repeat screening (RR=1.41, p=0.02). Inconsistent screeners were less likely to have planned when they will next rescreen (RR= 0.84, p=0.04) and reported greater barriers to rescreening (RR=1.05, p=0.05). Action participants were younger (RR= 0.98, p=<0.001), reported less social influences to screen (RR=0.94, p<0.001) and were less likely to have known someone who has had CRC (RR=0.82, p=0.01).
CONCLUSIONS: Social cognitive, demographic and background variables significantly differentiated screening maintenance from lower readiness stages.

Bian J, Bennett CL, Fisher DA, et al.
Unintended consequences of health information technology: evidence from veterans affairs colorectal cancer oncology watch intervention.
J Clin Oncol. 2012; 30(32):3947-52 [PubMed] Article available free on PMC after 10/11/2013

PURPOSE: We evaluated the Colorectal Cancer (CRC) Oncology Watch intervention, a clinical reminder implemented in Veterans Integrated Service Network 7 (including eight hospitals) to improve CRC screening rates in 2008.
PATIENTS AND METHODS: Veterans Affairs (VA) administrative data were used to construct four cross-sectional groups of veterans at average risk, age 50 to 64 years; one group was created for each of the following years: 2006, 2007, 2009, and 2010. We applied hospital fixed effects for estimation, using a difference-in-differences model in which the eight hospitals served as the intervention sites, and the other 121 hospitals served as controls, with 2006 to 2007 as the preintervention period and 2009 to 2010 as the postintervention period.
RESULTS: The sample included 4,352,082 veteran-years in the 4 years. The adherence rates were 37.6%, 31.6%, 34.4%, and 33.2% in the intervention sites in 2006, 2007, 2009, and 2010, respectively, and the corresponding rates in the controls were 31.0%, 30.3%, 32.3%, and 30.9%. Regression analysis showed that among those eligible for screening, the intervention was associated with a 2.2-percentage point decrease in likelihood of adherence (P < .001). Additional analyses showed that the intervention was associated with a 5.6-percentage point decrease in likelihood of screening colonoscopy among the adherent, but with increased total colonoscopies (all indicators) of 3.6 per 100 veterans age 50 to 64 years.
CONCLUSION: The intervention had little impact on CRC screening rates for the studied population. This absence of favorable impact may have been caused by an unintentional shift of limited VA colonoscopy capacity from average-risk screening to higher-risk screening and to CRC surveillance, or by physician fatigue resulting from the large number of clinical reminders implemented in the VA.

Smartt HJ, Greenhough A, Ordóñez-Morán P, et al.
β-catenin negatively regulates expression of the prostaglandin transporter PGT in the normal intestinal epithelium and colorectal tumour cells: a role in the chemopreventive efficacy of aspirin?
Br J Cancer. 2012; 107(9):1514-7 [PubMed] Article available free on PMC after 23/10/2013

BACKGROUND: Levels of the pro-tumorigenic prostaglandin PGE(2) are increased in colorectal cancer, previously attributed to increased synthesis through COX-2 upregulation and, more recently, to decreased catabolism. The functionally linked genes 15-prostaglandin dehydrogenase (15-PGDH) and the prostaglandin transporter PGT co-operate in prostaglandin degradation and are downregulated in colorectal cancer. We previously reported repression of 15-PGDH expression by the Wnt/β-catenin pathway, commonly deregulated during early colorectal neoplasia. Here we asked whether β-catenin also regulates PGT expression.
METHODS: The effect of β-catenin deletion in vivo was addressed by PGT immunostaining of β-catenin(-/lox)-villin-cre-ERT2 mouse tissue. The effect of siRNA-mediated β-catenin knockdown and dnTCF4 induction in vitro was addressed by semi-quantitative and quantitative real-time RT-PCR and immunoblotting.
RESULTS: This study shows for the first time that deletion of β-catenin in murine intestinal epithelium in vivo upregulates PGT protein, especially in the crypt epithelium. Furthermore, β-catenin knockdown in vitro increases PGT expression in both colorectal adenoma- and carcinoma-derived cell lines, as does dnTCF4 induction in LS174T cells.
CONCLUSIONS: These data suggest that β-catenin employs a two-pronged approach to inhibiting prostaglandin turnover during colorectal neoplasia by repressing PGT expression in addition to 15-PGDH. Furthermore, our data highlight a potential mechanism that may contribute to the non-selective NSAID aspirin's chemopreventive efficacy.

Chen GC, Pang Z, Liu QF
Magnesium intake and risk of colorectal cancer: a meta-analysis of prospective studies.
Eur J Clin Nutr. 2012; 66(11):1182-6 [PubMed]

Epidemiologic studies have suggested that magnesium intake may be associated with a decreased risk of colorectal cancer (CRC), but the findings have been inconsistent. We aimed to assess this association by conducting a meta-analysis of prospective studies. We performed a literature search on PubMed database through July 2012 to identify prospective studies of magnesium intake in relation to CRC risk. Reference lists of the retrieved articles were also reviewed. A random-effects model was used to compute the summary risk estimates. Eight prospective studies containing 338,979 participants and 8000 CRC cases met the inclusion criteria. The summary relative risk (RR) for the highest vs lowest category of magnesium intake for CRC was 0.89 (95% CI, 0.79-1.00), with little evidence of heterogeneity. Restricting the analysis to six studies that have adjusted for calcium intake yielded a similar result. For colon and rectal cancer, the pooled RR was 0.81 (95% CI, 0.70-0.93) and 0.94 (95% CI, 0.72-1.24), respectively. In the dose-response analyses, the summary RRs for an increment of magnesium intake of 50 mg/day for colorectal, colon and rectal cancer were, respectively, 0.95 (95% CI, 0.89-1.00), 0.93 (95% CI, 0.88-0.99) and 0.93 (95% CI, 0.83-1.04), and there was some evidence of heterogeneity; omitting one study that substantially contributed to the heterogeneity yielded generally similar results, but with low heterogeneity. We detected no indication of publication bias. On the basis of the findings of this meta-analysis, a higher magnesium intake seems to be associated with a modest reduction in the risk of CRC, in particular, colon cancer.

Littlejohn C, Hilton S, Macfarlane GJ, Phull P
Systematic review and meta-analysis of the evidence for flexible sigmoidoscopy as a screening method for the prevention of colorectal cancer.
Br J Surg. 2012; 99(11):1488-500 [PubMed]

BACKGROUND: Colorectal cancer is a significant cause of death. Removal of precancerous adenomas, and early detection and treatment of cancer, has been shown to reduce the risk of death. The aim of this review and meta-analysis was to determine whether flexible sigmoidoscopy (FS) is an effective population screening method for reducing mortality from colorectal cancer.
METHODS: MEDLINE (1946 to December 2012) and Embase (1980-2012, week 15) were searched for randomized clinical trials in which FS was used to screen non-symptomatic adults from a general population, and FS was compared with either no screening or any other alternative screening methods. Meta-analysis was carried out using a random-effects Mantel-Haenzsel model.
RESULTS: Twenty-four papers met the inclusion criteria, reporting results from 14 trials. Uptake of FS was usually lower than that for stool-based tests, although FS was more effective at detecting advanced adenoma and carcinoma. FS reduced the incidence of colorectal cancer after screening, and long-term mortality from colorectal cancer, compared with no screening in a selected population. Compared with stool-based tests in a general population, FS was associated with fewer interval cancers.
CONCLUSION: FS is efficacious at reducing colorectal cancer mortality compared with no screening. It is more effective at detecting advanced adenoma and carcinoma than stool-based tests. FS may be compromised by poorer uptake. Introduction of FS as a screening method should be done on a pilot basis in populations in which it is not currently used, and close attention should be paid to maximizing uptake. The relative risk of adverse events with FS compared with stool-based tests should be quantified, and its real-world effectiveness evaluated against the most effective stool-based tests.

Grulich AE, Poynten IM, Machalek DA, et al.
The epidemiology of anal cancer.
Sex Health. 2012; 9(6):504-8 [PubMed]

Anal cancer comprises malignancies of the anal canal principally of two morphologic variants: squamous cell carcinoma (SCC) and adenocarcinoma. In most settings, SCC compromises more than 70% of cases. In the general population, anal cancer is uncommon, with age-standardised incidence rates mostly between 1 and 2 per 100000 per year. However, incidence of anal SCC is increasing by 1-3% per year in developed country settings. High-risk human papillomavirus (HPV) types can be detected in 80-90% of all anal SCC cases, making it second only to cervical cancer in the closeness of its association with this virus. HPV-16 can be detected in ~90% of HPV-positive cases of anal SCC. Case-control studies have demonstrated that sexual risk factors (homosexuality in men and multiple sexual partners in women) are strongly associated with anal cancer risk. Other risk factors include immune deficiency and tobacco exposure. Anal cancer rates are highest in homosexual men, particularly in those who are HIV-positive, in whom anal cancer is among the most common of all cancers. Vaccination against HPV holds great promise for anal cancer prevention for those not already HPV-infected. For the current generation of adult high-risk populations, screening programs to allow early detection and treatment are under investigation.

Kilickap S, Arslan C, Rama D, Yalcin S
Screening colonoscopy participation in Turkish colorectal cancer patients and their first degree relatives.
Asian Pac J Cancer Prev. 2012; 13(6):2829-32 [PubMed]

BACKGROUND: This study aimed to research the awareness of screening colonoscopy (SC) among patients with colorectal cancer (CRC) and their relatives.
METHODOLOGY: A questionnaire form including information and behavior about colonoscopic screening for CRCs of patients and their first-degree relatives (FDRs) was prepared.
RESULTS: A total of 406 CRC patients were enrolled into the study, with 1534 FDRs (siblings n: 1381 and parents n: 153) . Positive family history for CRC was found in 12% of the study population. Previous SC was performed in 11% of patients with CRC. Mean age of the patients whose FDRs underwent SC was lower than the patients whose FDRs did not (52 vs 57 years; p<0,001). The frequency of SC in FDRs was 64% in patients diagnosed CRC under 35 years of age. Persons having a positive family history of CRC had SC more often (51 vs 22%, p<0,001). FDRs of patients having a higher educational level and income had SC more frequently.
CONCLUSIONS: When screening for CRC is planned, elderly subjects, those with family history for CRC, and those with low educational and lower income should be given especial attention in order that they be convinced to undergo screening for CRC.

Rial NS, Zell JA, Cohen AM, Gerner EW
Clinical end points for developing pharmaceuticals to manage patients with a sporadic or genetic risk of colorectal cancer.
Expert Rev Gastroenterol Hepatol. 2012; 6(4):507-17 [PubMed] Article available free on PMC after 23/10/2013

To reduce the morbidity and mortality from colorectal cancer (CRC), current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients at risk for CRC. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with a sporadic or genetic risk of CRC. It will also discuss therapeutic end points under evaluation in current efforts to develop drugs for treating CRC risk factors.