Colorectal cancer risk following adenoma removal: a large prospective population-based cohort study

Background: Randomised controlled trials have demonstrated significant reductions in colorectal cancer (CRC) incidence and mortality associated with polypectomy. However, little is known about whether polypectomy is effective at reducing CRC risk in routine clinical practice. The aim of this investigation was to quantify CRC risk following polypectomy in a large prospective population-based cohort study.

Methods: Patients with incident colorectal polyps between 2000 and 2005 in Northern Ireland (NI) were identified via electronic pathology reports received to the NI Cancer Registry (NICR). Patients were matched to the NICR to detect CRC and deaths up to 31st December 2010. CRC standardised incidence ratios (SIRs) were calculated and Cox proportional hazards modelling applied to determine CRC risk.

Results: During 44,724 person-years of follow-up, 193 CRC cases were diagnosed amongst 6,972 adenoma patients, representing an annual progression rate of 0.43%. CRC risk was significantly elevated in patients who had an adenoma removed (SIR 2.85; 95% CI: 2.61 to 3.25) compared with the general population. Male sex, older age, rectal site and villous architecture were associated with an increased CRC risk in adenoma patients. Further analysis suggested that not having a full colonoscopy performed at, or following, incident polypectomy contributed to the excess CRC risk.

Conclusions: CRC risk was elevated in individuals following polypectomy for adenoma, outside of screening programmes.

Impact: This finding emphasises the need for full colonoscopy and adenoma clearance, and appropriate surveillance, after endoscopic diagnosis of adenoma.

A novel gene expression signature in peripheral blood mononuclear cells for early detection of colorectal cancer.

BACKGROUND: Early detection and treatment of colorectal adenomatous polyps (AP) and colorectal cancer (CRC) is associated with decreased mortality for CRC. However, accurate, non-invasive and compliant tests to screen for AP and early stages of CRC are not yet available. A blood-based screening test is highly attractive due to limited invasiveness and high acceptance rate among patients. AIM: To demonstrate whether gene expression signatures in the peripheral blood mononuclear cells (PBMC) were able to detect the presence of AP and early stages CRC. METHODS: A total of 85 PBMC samples derived from colonoscopy-verified subjects without lesion (controls) (n = 41), with AP (n = 21) or with CRC (n = 23) were used as training sets. A 42-gene panel for CRC and AP discrimination, including genes identified by Digital Gene Expression-tag profiling of PBMC, and genes previously characterised and reported in the literature, was validated on the training set by qPCR. Logistic regression analysis followed by bootstrap validation determined CRC- and AP-specific classifiers, which discriminate patients with CRC and AP from controls. RESULTS: The CRC and AP classifiers were able to detect CRC with a sensitivity of 78% and AP with a sensitivity of 46% respectively. Both classifiers had a specificity of 92% with very low false-positive detection when applied on subjects with inflammatory bowel disease (n = 23) or tumours other than CRC (n = 14). CONCLUSION: This pilot study demonstrates the potential of developing a minimally invasive, accurate test to screen patients at average risk for colorectal cancer, based on gene expression analysis of peripheral blood mononuclear cells obtained from a simple blood sample.

Decision analysis of the effectiveness of lung cancer screening using autofluorescence bronchoscopy and computed tomography

Background: Lung cancer (LC) is the leading cause of cancer death in the developed world. Most cancers are associated with tobacco smoking. A primary hope for reducing lung cancer has been prevention of smoking and successful smoking cessation programs. To date, these programs have not been as successful as anticipated. Objective: The aim of the current study was to evaluate whether lung cancer screening combining low dose computed tomography with autofluorescence bronchoscopy (combined CT & AFB) is superior to CT or AFB screening alone in improving lung cancer specific survival. In addition, the extent of improvement and ideal conditions for combined CT & AFB screening were evaluated. Methods: We applied decision analysis and Monte Carlo simulation modeling using TreeAge Software to evaluate our study aims. Histology- and stage specific probabilities of lung cancer 5-year survival proportions were taken from Surveillance and Epidemiologic End Results (SEER) Registry data. Screeningassociated data was taken from the US NCI Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), National Lung Screening Trial (NLST), and US NCI Lung Screening Study (LSS), other relevant published data and expert opinion. Results: Decision Analysis - Combined CT and AFB was the best approach at Improving 5-year survival (Overall Expected Survival (OES) in the entire screened population was 0.9863) and in lung cancer patients only (Lung Cancer Specific Expected Survival (LOSES) was 0.3256). Combined screening was slightly better than CT screening alone (OES = 0.9859; LCSES = 0.2966), and substantially better than AFB screening alone (OES = 0.9842; LCSES = 0.2124), which was considerably better than no screening (OES = 0.9829; LCSES = 0.1445). Monte Carlo simulation modeling revealed that expected survival in the screened population and lung cancer patients is highest when screened using CT and combined CT and AFB. CT alone and combined screening was substantially better than AFB screening alone or no screening. For LCSES, combined CT and AFB screening is significantly better than CT alone (0.3126 vs. 0.2938, p< 0.0001). Conclusions: Overall, these analyses suggest that combined CT and AFB is slightly better than CT alone at improving lung cancer survival, and both approaches are substantially better than AFB screening alone or no screening.

Psychosocial epidemiology of colorectal cancer

The research explored the role played by personality and stress in the development and progress of colorectal cancer. Personality type was related to health outcomes following diagnosis, and to participation in bowel cancer screening. The personality types also differed in terms of their capacity to deal with stress.

A preliminary analysis of the cost-effectiveness of the National Bowel Cancer Screening Program – demonstrating the potential value of comprehensive real world data

Background The complexity and cost of treating cancer patients is escalating rapidly and increasingly difficult decisions are being made regarding which interventions provide value for money. BioGrid Australia supports collection and analysis of comprehensive treatment and outcome data across multiple sites. Here we use preliminary data regarding the National Bowel Cancer Screening Program (NBCSP) and stage-specific treatment costs for colorectal cancer (CRC) to demonstrate the potential value of real world data for cost-effectiveness analyses (CEA).

Methods Data regarding the impact of NBCSP on stage at diagnosis was combined with stage-specific CRC treatment costs and existing literature. An incremental CEA was undertaken from a government healthcare perspective, comparing NBCSP to no-screening. The 2008 invited population (n=681,915) was modelled in both scenarios. Effectiveness was expressed as CRC-related life years saved (LYS). Costs and benefits were discounted at 3% per annum.

Results Over the lifetime and relative to no-screening, NBCSP was predicted to save 1,265 life-years, prevent 225 CRC cases and cost an additional $48.3 million, equivalent to a cost-effectiveness ratio of $38,217 per LYS. A scenario analysis assuming full participation improved this to $23,395.

Conclusions This preliminary CEA based largely on contemporary real world data suggests population-based FOBT screening for CRC is attractive. Planned ongoing data collection will enable repeated analyses over time, using the same methodology in the same patient populations, permitting an accurate analysis of the impact of new therapies and changing practice. Similar CEA using real world data related to other disease types and interventions appears desirable.

Decision support and the effectiveness of web-based delivery and information tailoring for bowel cancer screening : an exploratory study

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females throughout the developed world. Population screening using fecal occult blood tests (FOBTs) facilitates early detection and greater chance of survival, but participation rates are low. We developed a Web-based decision tool to provide information tailored to an individual’s decision stage for CRC screening and attitude toward screening utilizing the Preventive Health Model (PHM) and Precaution Adoption Process Model (PAPM) as theoretical frameworks for screening behavior. We describe the practical steps employed in the tool’s design and the subsequent conduct of an exploratory study.
Objective: To design a decision tool for CRC screening and conduct an exploratory study among average-risk men and women to (1) test the impact of message type (tailored vs non-tailored) and message delivery modality (Web-based vs paper-based) on attitudes toward screening and screening uptake, and (2) investigate the acceptability of the decision tool and relevance of materials.
Methods: Participants (n = 100), recruited from a population sample of men and women aged 50-76 residing in urban Adelaide, Australia, were randomly assigned to a control group or one of 4 interventions: (1) Web-based and tailored information, (2) paper-based and tailored information, (3) Web-based and non-tailored (generic) information, or (4) paper-based and non-tailored information. Participation was augmented by snowball recruitment (n = 19). Questionnaires based on PHM variables were administered pre- and post-intervention. Participants were given the opportunity to request an FOBT. Following the intervention, participants discussed the acceptability of the tool.
Results: Full data were available for 87.4% (104/119) of participants. Post-intervention, perceived susceptibility scores for individuals receiving tailored information increased from mean 10.6 (SD 2.1) to mean 11.8 (SD 2.2). Scores on self-efficacy increased in the tailored group from mean 11.7 (SD 2.0) to mean 12.6 (SD 1.8). There were significant time x modality x message effects for social influence and salience and coherence, reflecting an increase in these scores for tailored Web-based participants only; social influence scores increased from mean 11.7 (SD 2.6) to mean 14.9 (SD 2.3), and salience and coherence scores increased from mean 16.0 (SD 2.2) to mean 17.7 (SD 2.1). There was no greater influence of modality or message type on movement toward a decision to screen or screening uptake, indicating that neither tailored messages nor a Web modality had superior effect. Overall, participants regarded tailored messages positively, but thought that the Web tool lacked “media richness.”
Conclusions: This exploratory study confirms that tailoring on PHM predictors of CRC screening has the potential to positively address attitudes toward screening. However, tailoring on these variables did not result in significantly increased screening uptake. Future research should consider other possible psychosocial influences. Mode of delivery did not affect outcomes, but as a delivery medium, the Web has economic and logistical advantages over paper.

Cellular and Molecular Biomarkers for Risk Assessment of Colorectal cancer

The detection of Colorectal Cancer (CRC), at early stages, is one of the proven strategies resulting in a higher cure rate. In recent years, several studies have appeared identifying potential cancer markers in serum, plasma and stool in an attempt to improve actual screening procedures. Thus, the aim of the study was (1) Evaluate MN frequency, (2) Evaluate plasma ultrafiltrate capacity to induce MN formation, (3) Evaluate SEPT9 and NOTCH3 promoter methylation profile in peripheral blood lymphocytes from subjects resulted positive to fecal occult blood test and examined by colonoscopy. MN frequency was significantly higher in subjects with histological diagnosis of CRC and adenoma than control (p ≤ 0.001 and p ≤ 0.01, respectively). About, CF-MN analysis, a statistically significant difference was observed between CRC and control (p ≤ 0.05). On the other hand, SEPT9 and NOTCH3 promoter methylation status was significantly lower in CRC subjects than controls; additionally, NOTCH3 promoter methylation status was significantly lower in CRC subjects than adenoma subjects (p ≤ 0.01). The results obtained allow conclude that MN frequency varies according CRC pathologic status and, together with other variables, is a valid biomarker for adenoma and CRC risk. Additionally, the plasma of patients affected with CRC not only serve as a biomarker for oxidative stress but also as biomarker of genetic damage correlated with the carcinogenic process that verifies in colon-rectum. SEPT9 and NOTCH3 promoter methylation status, at peripheral blood level, varies according hystopathological changes observed in colon-rectum, suggesting that promoter methylation profile of these genes could be a reliable biomarker for CRC risk.

Serum amino acid profiles and their alterations in colorectal cancer

Mass spectrometry-based serum metabolic profiling is a promising tool to analyse complex cancer associated metabolic alterations, which may broaden our pathophysiological understanding of the disease and may function as a source of new cancer-associated biomarkers. Highly standardized serum samples of patients suffering from colon cancer (n = 59) and controls (n = 58) were collected at the University Hospital Leipzig. We based our investigations on amino acid screening profiles using electrospray tandem-mass spectrometry. Metabolic profiles were evaluated using the Analyst 1.4.2 software. General, comparative and equivalence statistics were performed by R 2.12.2. 11 out of 26 serum amino acid concentrations were significantly different between colorectal cancer patients and healthy controls. We found a model including CEA, glycine, and tyrosine as best discriminating and superior to CEA alone with an AUROC of 0.878 (95% CI 0.815-0.941). Our serum metabolic profiling in colon cancer revealed multiple significant disease-associated alterations in the amino acid profile with promising diagnostic power. Further large-scale studies are necessary to elucidate the potential of our model also to discriminate between cancer and potential differential diagnoses. In conclusion, serum glycine and tyrosine in combination with CEA are superior to CEA for the discrimination between colorectal cancer patients and controls.

Development and preliminary validation of the cancer family impact scale for colorectal cancer

This study aimed to develop and validate The Cancer Family Impact Scale (CFIS), an instrument for use in studies investigating relationships among family factors and colorectal cancer (CRC) screening when family history is a risk factor. We used existing data to develop the measure from 1,285 participants (637 families) across the United States who were in the Johns Hopkins Colon Cancer Genetic Testing study. Participants were 94% white with an average age of 50.1 years, and 60% were women. None had a personal CRC history, and eighty percent had 1 FDR with CRC and 20% had more than one FDR with CRC. The study had three aims: (1) to identify the latent factors underlying the CFIS via exploratory factor analysis (EFA); (2) to confirm the findings of the EFA via confirmatory factor analysis (CFA); and (3) to assess the reliability of the scale via Cronbach's alpha. Exploratory analyses were performed on a split half of the sample, and the final model was confirmed on the other half. The EFA suggested the CFIS was an 18-item measure with 5 latent constructs: (1) NEGATIVE: negative effects of cancer on the family; (2) POSITIVE: positive effects of cancer on the family; (3) COMMUNICATE: how families communicate about cancer; (4) FLOW: how information about cancer is conveyed in families; and (5) NORM: how individuals react to family norms about cancer. CFA on the holdout sample showed the CFIS to have a reasonably good fit (Chi-square = 389.977, df = 122, RMSEA= 0.058 (.052-.065), CFI=.902, TLI=.877, GF1=.939). The overall reliability of the scale was α=0.65. The reliability of the subscales was: (1) NEGATIVE α = 0.682; (2) POSITIVE α = 0.686; (3) COMMUNICATE α = 0.723; (4) FLOW α = 0.467; and (5) NORM α = 0.732. ^ We concluded the CFIS to be a good measure with most fit levels over 0.90. The CFIS could be used to compare theoretically driven hypotheses about the pathways through which family factors could influence health behavior among unaffected individuals at risk due to family history, and also aid in the development and evaluation of cancer prevention interventions including a family component. ^

NOD2 mutations and colorectal cancer - Where do we stand?

Due to the overwhelming burden of colorectal cancer (CRC), great effort has been placed on identifying genetic mutations that contribute to disease development and progression. One of the most studied polymorphisms that could potentially increase susceptibility to CRC involves the nucleotide-binding and oligomerization-domain containing 2 (NOD2) gene. There is growing evidence that the biological activity of NOD2 is far greater than previously thought and a link with intestinal microbiota and mucosal immunity is increasingly sought after. In fact, microbial composition may be an important contributor not only to inflammatory bowel diseases (IBD) but also to CRC. Recent studies have showed that deficient NOD2 function confers a communicable risk of colitis and CRC. Despite the evidence from experimental models, population-based studies that tried to link certain NOD2 polymorphisms and an increase in CRC risk have been described as conflicting. Significant geographic discrepancies in the frequency of such polymorphisms and different interpretations of the results may have limited the conclusions of those studies. Since being first associated to IBD and CRC, our understanding of the role of this gene has come a long way, and it is tempting to postulate that it may contribute to identify individuals with susceptible genetic background that may benefit from early CRC screening programs or in predicting response to current therapeutic tools. The aim of this review is to clarify the status quo of NOD2 mutations as genetic risk factors to chronic inflammation and ultimately to CRC. The use of NOD2 as a predictor of certain phenotypic characteristics of the disease will be analyzed as well.

NOD2 mutations and colorectal cancer - Where do we stand?

Due to the overwhelming burden of colorectal cancer (CRC), great effort has been placed on identifying genetic mutations that contribute to disease development and progression. One of the most studied polymorphisms that could potentially increase susceptibility to CRC involves the nucleotide-binding and oligomerization-domain containing 2 (NOD2) gene. There is growing evidence that the biological activity of NOD2 is far greater than previously thought and a link with intestinal microbiota and mucosal immunity is increasingly sought after. In fact, microbial composition may be an important contributor not only to inflammatory bowel diseases (IBD) but also to CRC. Recent studies have showed that deficient NOD2 function confers a communicable risk of colitis and CRC. Despite the evidence from experimental models, population-based studies that tried to link certain NOD2 polymorphisms and an increase in CRC risk have been described as conflicting. Significant geographic discrepancies in the frequency of such polymorphisms and different interpretations of the results may have limited the conclusions of those studies. Since being first associated to IBD and CRC, our understanding of the role of this gene has come a long way, and it is tempting to postulate that it may contribute to identify individuals with susceptible genetic background that may benefit from early CRC screening programs or in predicting response to current therapeutic tools. The aim of this review is to clarify the status quo of NOD2 mutations as genetic risk factors to chronic inflammation and ultimately to CRC. The use of NOD2 as a predictor of certain phenotypic characteristics of the disease will be analyzed as well.

Relationship over time between psychological distress and physical activity in colorectal cancer survivors

Purpose Increased physical activity in colorectal cancer patients is related to improved recurrence free and overall survival. Psychological distress after cancer may place patients at risk of reduced physical activity; but paradoxically also act as a motivator for positive lifestyle change. The relationship between psychological distress and physical activity after cancer over time has not been described. Methods A prospective survey of 1966 (57% response) colorectal cancer survivors assessed the psychological distress variables of anxiety, depression, somatisation, cancer threat appraisal as predictors of physical activity five, 12, 24 and 36 months post-diagnosis 978 respondents had valid data for all time points. Results Higher somatisation was associated with greater physical inactivity (Relative risk ratio (RRR) =1.12; 95% CI=[1.1, 1.2]) and insufficient physical activity (RRR=1.05; [0.90, 1.0]). Respondents with a more positive appraisal of their cancer were significantly (p=0.031) less likely to be inactive (RRR=0.95; [0.90, 1.0]) or insufficiently active (RRR=0.96). Fatigued and obese respondents and current smokers were more inactive. Respondents whose somatisation increased between two time periods were less likely to increase their physical activity over the same period (p<0.001). Respondents with higher anxiety at one time period were less likely to have increased their activity at the next assessment (p=0.004). There was no association between depression and physical activity. Conclusions Cancer survivors who experience somatisation and anxiety are at greater risk of physical inactivity. The lack of a clear relationship between higher psychological distress and increasing physical activity argues against distress as a motivator to exercise in these patients.

A randomised controlled trial of a tele-based lifestyle intervention for colorectal cancer survivors ('CanChange') : Study protocol

Background Colorectal cancer survivors may suffer from a range of ongoing psychosocial and physical problems that negatively impact on quality of life. This paper presents the study protocol for a novel telephone-delivered intervention to improve lifestyle factors and health outcomes for colorectal cancer survivors. Methods/Design Approximately 350 recently diagnosed colorectal cancer survivors will be recruited through the Queensland Cancer Registry and randomised to the intervention or control condition. The intervention focuses on symptom management, lifestyle and psychosocial support to assist participants to make improvements in lifestyle factors (physical activity, healthy diet, weight management, and smoking cessation) and health outcomes. Participants will receive up to 11 telephone-delivered sessions over a 6 month period from a qualified health professional or 'health coach'. Data collection will occur at baseline (Time 1), post-intervention or six months follow-up (Time 2), and at 12 months follow-up for longer term effects (Time 3). Primary outcome measures will include physical activity, cancer-related fatigue and quality of life. A cost-effective analysis of the costs and outcomes for survivors in the intervention and control conditions will be conducted from the perspective of health care costs to the government. Discussion The study will provide valuable information about an innovative intervention to improve lifestyle factors and health outcomes for colorectal cancer survivors.