Risk Of Rectal Cancer Research Articles

Common dietary patterns and risk of cancers of the colon and rectum: Analysis from the United Kingdom Women's Cohort Study (UKWCS).

Few prospective cohort studies in the UK have specifically focused on the associations between commonly consumed dietary patterns and colorectal cancer (CRC). The aim of our study was to assess whether red meat, poultry, fish and vegetarian dietary patterns are associated with differences in the incidence of cancers of colon and rectum in the UKWCS. Four common dietary patterns were defined based on a hierarchy of consumption of red meat, poultry and fish for each cohort participant, using a 217‐item food frequency questionnaire. Cox proportional hazards regression was used to provide adjusted hazard ratios (HR) and 95% confidence intervals (CI) for CRC. A total of 32,147 women recruited and surveyed between 1995 and 1998 were followed up for a mean of 17.2 years (426,798 person‐years). A total of 462 incident CRC cases were documented; 335 colon cancers (172 proximal and 119 distal) and 152 in the rectum. In multivariable‐adjusted models, there was no evidence of a reduction in risk of overall CRC (HR = 0.86, 95% CI: 0.66–1.12), colon cancer (HR = 0.77, 95% CI: 0.56–1.05) or rectal cancer (HR = 1.04, 95% CI: 0.66–1.63) when comparing grouped red meat free diets with diets containing red meat. Exploratory analysis suggested a reduced risk of distal colon cancer in grouped red meat free diets (HR = 0.56, 95% CI: 0.34–0.95), though numbers with this outcome were small. These results indicate that a protective association of red meat free diets specifically on distal colon cancer merits confirmation in a larger study.

EP-1463: Phase II study of adaptive high-dose neoadjuvant radiotherapy in high risk rectal cancer

EP-1463: Phase II study of adaptive high-dose neoadjuvant radiotherapy in high risk rectal cancer

Coffee drinking and colorectal cancer and its subsites: A pooled analysis of 8 cohort studies in Japan.

Coffee is a rich source of bioactive compounds that have potential anticarcinogenic effects. However, it remains unclear whether coffee drinking is associated with colorectal cancer. Also, despite different etiological factors involved in gut physiology, few studies have investigated this association by anatomical site of the lesion. To address these issues, this study examined the association between coffee drinking and colorectal cancer in a pooled analysis from 8 cohort studies conducted in Japan. Among 320,322 participants followed up for 4,503,274 person-years, 6,711 incident colorectal cancer cases were identified. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using the random effects model. Coffee drinking was not materially associated with colorectal cancer risk in men or women (pooled HR 0.92, 95% CI 0.82-1.03 in men and pooled HR 0.90, 95% CI 0.76-1.07 in women). Analysis by subsite showed a lower risk of colon cancer among female drinkers of ≥3 cups coffee/day (pooled HR 0.80, 95% CI 0.64-0.99). There was no such association in men. Coffee drinking was not associated with risk of rectal cancer in men or women. Results were virtually the same among never smokers except for an increased risk of rectal cancer associated with frequent coffee consumption. Coffee drinking may be associated with lower risk of colon cancer in Japanese women.

Tooth loss and risk of colorectal cancer: a dose-response meta-analysis of prospective cohort studies.

BackgroundPrevious studies have indicated that tooth loss is associated with colorectal cancer risk but have presented controversial results.MethodsWe conducted a dose–response meta-analysis in order to investigate the correlation between tooth loss and colorectal cancer risk. Up to August 2017, six eligible studies were included in this meta-analysis.ResultsOur results showed statistically significant association between tooth loss and colorectal cancer (OR =1.08, 95% CI: 1.03–1.15, P<0.001). In addition, we obtained the best fit at an inflection point of every two tooth loss in piecewise regression analysis, and the summary relative risk (RR) of colorectal cancer for an increase of every two tooth loss was 1.06 (95% CI: 1.02–1.11, P<0.001). Furthermore, tooth loss was significantly associated with colorectal cancer risk in Caucasia (RR: 1.18; 95% CI: 1.09–1.28; P<0.001) and Asia (RR: 1.06; 95% CI: 1.02–1.10; P<0.001). Moreover, tooth loss was significantly associated with a higher risk of colon cancer (RR: 1.09; 95% CI: 1.02–1.17; P<0.001) and rectal cancer (RR: 1.08; 95% CI: 1.01–1.17; P<0.001).ConclusionSubgroup meta-analyses showed consistency with the primary findings. Considering these promising results, increasing tooth loss may be harmful to our health, and maintenance of our oral health is essential.

Nitrate in drinking water and colorectal cancer risk: A nationwide population-based cohort study.

Nitrate in drinking water may increase risk of colorectal cancer due to endogenous transformation into carcinogenic N-nitroso compounds. Epidemiological studies are few and often challenged by their limited ability of estimating long-term exposure on a detailed individual level. We exploited population-based health register data, linked in time and space with longitudinal drinking water quality data, on an individual level to study the association between long-term drinking water nitrate exposure and colorectal cancer (CRC) risk. Individual nitrate exposure was calculated for 2.7 million adults based on drinking water quality analyses at public waterworks and private wells between 1978 and 2011. For the main analyses, 1.7 million individuals with highest exposure assessment quality were included. Follow-up started at age 35. We identified 5,944 incident CRC cases during 23 million person-years at risk. We used Cox proportional hazards models to estimate hazard ratios (HRs) of nitrate exposure on the risk of CRC, colon and rectal cancer. Persons exposed to the highest level of drinking water nitrate had an HR of 1.16 (95% CI: 1.08-1.25) for CRC compared with persons exposed to the lowest level. We found statistically significant increased risks at drinking water levels above 3.87 mg/L, well below the current drinking water standard of 50 mg/L. Our results add to the existing evidence suggesting increased CRC risk at drinking water nitrate concentrations below the current drinking water standard. A discussion on the adequacy of the drinking water standard in regards to chronic effects is warranted.

Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer.

Constitutive activation of interferon signaling pathways has been reported in colorectal cancer (CRC), leading to a strong CD8+ T cell response through stimulation of NLRC5 expression. Primed CD8+ T cell expansion, however, may be negatively regulated by PD-L1 expression. Additionally, aberrant PD-L1 expression enables cancer cells to escape the immune attack. Our study aimed to select potential regulatory variants in the NLRC5 and PD-L1 genes by using several online in silico tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, microRNA and transcription factor binding site prediction tools and to investigate their influence on CRC risk in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Logistic regression analysis adjusted for age and gender reported a moderate association between rectal cancer risk and two NLRC5 SNPs, rs1684575 T>G (OR: 1.60, 95% CI: 1.13–2.27, recessive model) and rs3751710 (OR: 0.70, 95% CI: 0.51–0.96, dominant model). Given that a combination of genetic variants, rather than a single polymorphism, may explain better the genetic etiology of CRC, we studied the interplay between the variants within NLRC5, PD-L1 and the previously genotyped IFNGR1 and IFNGR2 variants, to evaluate their involvement in the risk of CRC development. Overall we obtained 18 pair-wise interactions within and between the NLRC5 ad PD-L1 genes and 6 more when IFNGR variants were added. Thirteen out of the 24 interactions were below the threshold for the FDR calculated and controlled at an arbitrary level q*<0.10. Furthermore, the interaction IFNGR2 rs1059293 C>T—NLRC5 rs289747 G>A (P<0.0001) remained statistically significant even after Bonferroni correction. Our data suggest that not only a single genetic variant but also an interaction between two or more variants within genes involved in immune regulation may play important roles in the onset of CRC, providing therefore novel biological information, which could eventually improve CRC risk management but also PD-1-based immunotherapy in CRC.

INNOVA: A phase II randomized study comparing INterval versus NeOadjuVAnt chemotherapy in magnetic resonance imaging-defined high risk rectal cancer.

TPS879 Background: Patients with rectal cancers treated with neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy are not exposed to systemic doses of chemotherapy until very late in the treatment schedule. Preoperative chemotherapy, either in the neoadjuvant or interval setting can lead to early treatment of micrometastasis, improve the tumor response and possibly the overall survival. Phase II studies of neoadjuvant chemotherapy in rectal cancer have shown good response to chemotherapy with no tumor progression and good compliance. A phase II study evaluating the effect of giving chemotherapy in the interval waiting period between chemoradiation and surgery has shown acceptable toxicity and high pathological complete response rates. Methods: This single centre, randomized, open label, phase II trial compares the safety and efficacy of two pre-operative regimens in locally advanced MRI defined high-risk rectal cancers. Based on the Simon optimal two-stage design, 94 patients will be randomised to either Arm A [3 cycles of neoadjuvant chemotherapy (capecitabine and oxaliplatin) followed by chemoradiation (50.4 Gy with capecitabine) and then surgery] or Arm B [neoadjuvant chemoradiation followed by 3 cycles of interval chemotherapy and then surgery]. Patients in both arms receive 3 cycles of adjuvant chemotherapy. The primary end-point is the pathological complete response rate. Secondary end-points include frequency and severity of adverse events, RO resection rates, tumor regression grading and compliance to treatment. The inclusion criteria: age 18 to 70 years; ECOG performance status 0-2; non-metastatic, locally advanced rectal cancer with any one of the following features on high-resolution thin slice MRI: any T3/T4 tumor in the lower rectum, T3c/T3d/T4 tumor in the mid rectum, N2 disease, threatened mesorectal fascia, or extramural vascular invasion. Patients are randomly assigned to one of the two intervention arms in a 1:1 ratio. Prespecified activity goal for the first stage of accrual was met; second stage accrual began in July 2017. Clinical trial information: CTRI/2015/01/005385.

Does adherence to the World Cancer Research Fund/American Institute of Cancer Research cancer prevention guidelines reduce risk of colorectal cancer in the UK Women's Cohort Study?

Evidence on adherence to diet-related cancer prevention guidelines and associations with colorectal cancer (CRC) risk is limited and conflicting. The aim of this cohort analysis is to evaluate associations between adherence to the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) 2007 recommendations and incident CRC. The UK Women's Cohort Study comprises over 35 372 women who filled in a FFQ at baseline in 1995. They were followed up for CRC incidence for a median of 17·4 years, an individual score linking adherence to eight of the WCRF/AICR recommendations was constructed. Cox proportional hazards regression provided hazard ratios (HR) and 95 % CI for the estimation of CRC risk, adjusting for confounders. Following exclusions, 444 CRC cases were identified. In the multivariate-adjusted model, women within the second and third (highest) categories of the WRCF/AICR score had HR of 0·79 (95 % CI 0·62, 1·00) and 0·73 (95 % CI 0·48, 1·10), respectively, for CRC compared with those in the lowest, reference category. The overall linear trend across the categories was not significant (P=0·17). No significant associations were observed between the WCRF/AICR score and proximal colon, distal colon and rectal cancers separately. Of the individual score components, a BMI within the normal weight range was borderline significantly protective only for rectal cancer in the fully adjusted model. In view of the likely different causes of CRC subtypes, further research is needed to identify the optimal dietary patterns associated with reducing colon and rectal cancer risk, respectively.

Oral Antibiotic Use and Risk of Colorectal Cancer in the United Kingdom, 1989-2012: A Matched Case-Control Study

Background: Microbiome dysbiosis predisposes to colorectal cancer (CRC), but a population-based study of antibiotic exposure and risk patterns is lacking. In this study, oral antibiotic use on CRC incidence was assessed. Methods: A matched case-control study (incident CRC cases and up to 5 matched controls) was performed using the Clinical Practice Research Datalink (CPRD; January 1, 1989 to December 31, 2012). Conditional logistic regression was used to assess CRC association with oral antibiotic use, adjusting for potential confounders. Antibiotic exposure in categorical and continuous terms (spline) was investigated for pattern of risk, stratified by specific tumour location. Findings: 28,980 CRC cases and 137,077 controls were identified. Oral antibiotic use was associated with CRC risk, but effects differed by anatomic location. Antibiotic use was found to be associated with excess risk of colon cancer in a dose-dependent fashion (Ptrend 60 days (Adjusted Odds Ratio [AOR], 0·85, 95% CI 0·79-0·93) as compared with no antibiotic exposure. Penicillins were associated with increased risk of colon cancer (AOR,1·09, [1·05-1·13]) whereas tetracyclines were associated with risk reduction for rectal cancer (AOR, 0·90, [0·84- 0·97]). Significant interactions were detected between antibiotic use and tumour location (colon vs rectum, Pinteraction ten years before diagnosis (AOR, 1·17, [1·06-1·31]). Interpretation: Oral antibiotic use is associated with an increased risk of colon cancer risk but a reduced risk for rectal cancer. This effect heterogeneity may suggest differences in gut microbiota and carcinogenesis mechanisms along the lower intestine tract. Funding Statement: This project was funded by Johns Hopkins Fisher Center Discovery Program and Bloomberg~Kimmel Institute for Cancer Immunotherapy. Declaration of Interests: All authors have no directly relevant conflicts of interest to disclose. DP reports grant and patent royalties through institution from Bristol Myers Squibb, grant from Compugen, stock from Trieza Therapeutics and Dracen Pharmaceuticals, and founder 22 equity from Potenza; being consultant for Aduro Biotech, Amgen, Astra Zeneca (Medimmune/Amplimmune), Bayer, DNAtrix, Dynavax Technologies Corporation, Ervaxx, FLX Bio, Rock Springs Capital, Janssen, Merck, Tizona, and ImmunomicTherapeutics; being scientific advisory board of Five Prime Therapeutics, Camden Nexus II, WindMil; being board of director for Dracen Pharmaceuticals outside the submitted work. SC reports being consultant for Novartis and Theravance outside the submitted work. CS reports grants from Bristol Myers Squibb for microbiome research outside the submitted work. All other authors have nothing to declare. Ethics Approval Statement: This study was approved by the Institutional Review Board of the Johns Hopkins University

Abdominal obesity and colorectal cancer risk: systematic review and meta-analysis of prospective studies.

The association between abdominal obesity (as measured by waist circumference (WC) and waist-to-hip ratio (WHR)) and colorectal cancer (CRC) has not been fully quantified, and the magnitude of CRC risk associated with abdominal obesity is still unclear. A meta-analysis of prospective studies was performed to elucidate the CRC risk associated with abdominal obesity. Pubmed and Embase were searched for studies assessing the association between abdominal obesity and CRC risk. Relative risks (RRs) with 95% confidence intervals (95% CIs) were pooled using random-effects model of meta-analysis. Nineteen prospective cohort studies from eighteen publications were included in this meta-analysis. A total of 12,837 CRC cases were identified among 1,343,560 participants. Greater WC and WHR were significantly associated with increased risk of total colorectal cancer (WC: RR 1.42, 95% CI 1.30, 1.55; WHR: RR 1.39, 95% CI 1.25, 1.53), colon cancer (WC: RR 1.53, 95% CI 1.36, 1.72; WHR: 1.39, 95% CI 1.18, 1.63), and rectal cancer (WC: RR 1.20, 95% CI 1.03, 1.39; WHR: RR 1.22, 95% CI 1.05, 1.42). Subgroup analyses further identified the robustness of the association above. No obvious risk of publication bias was observed. In summary, abdominal obesity may play an important role in the development of CRC.

High Risk of Anal and Rectal Cancer in Patients With Anal and/or Perianal Crohn’s Disease

Little is known about the magnitude of the risk of anal and rectal cancer in patients with anal and/or perineal Crohn's disease. We aimed to assess the risk of anal and rectal cancer in patients with Crohn's perianal disease followed up in the Cancers Et Surrisque Associé aux Maladies Inflammatoires Intestinales En France (CESAME) cohort. We collected data from 19,486 patients with inflammatory bowel disease (IBD) enrolled in the observational CESAME study in France, from May 2004 through June 2005; 14.9% of participants had past or current anal and/or perianal Crohn's disease. Subjects were followed up for a median time of 35 months (interquartile range, 29-40 mo). To identify risk factors for anal cancer in the total CESAME population, we performed a case-control study in which participants were matched for age and sex. Among the total IBD population, 8 patients developed anal cancer and 14 patients developed rectal cancer. In the subgroup of 2911 patients with past or current anal and/or perianal Crohn's lesions at cohort entry, 2 developed anal squamous-cell carcinoma, 3 developed perianal fistula-related adenocarcinoma, and 6 developed rectal cancer. The corresponding incidence rates were 0.26 per 1000 patient-years for anal squamous-cell carcinoma, 0.38 per 1000 patient-years for perianal fistula-related adenocarcinoma, and 0.77 per 1000 patient-years for rectal cancer. Among the 16,575 patients with ulcerative colitis or Crohn's disease without anal or perianal lesions, the incidence rate of anal cancer was 0.08 per 1000 patient-years and of rectal cancer was 0.21 per 1000 patient-years. Among factors tested by univariate conditional regression (IBD subtype, disease duration, exposure to immune-suppressive therapy, presence of past or current anal and/or perianal lesions), the presence of past or current anal and/or perianal lesions at cohort entry was the only factor significantly associated with development of anal cancer (odds ratio, 11.2; 95% CI, 1.18-551.51; P= .03). In an analysis of data from the CESAME cohort in France, patients with anal and/or perianal Crohn's disease have a high risk of anal cancer, including perianal fistula-related cancer, and a high risk of rectal cancer.

Synergistic antitumor interaction between valproic acid, capecitabine and radiotherapy in colorectal cancer: critical role of p53

BackgroundRecurrence with distant metastases has become the predominant pattern of failure in locally advanced rectal cancer (LARC), thus the integration of new antineoplastic agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to implement an intensified therapeutic strategy.The present study examined the combination of the histone deacetylase inhibitor (HDACi) valproic acid (VPA) with fluoropyrimidine-based chemo-radiotherapy on colorectal cancer (CRC) cells.MethodsHCT-116 (p53-wild type), HCT-116 p53−/− (p53-null), SW620 and HT29 (p53-mutant) CRC cell lines were used to assess the antitumor interaction between VPA and capecitabine metabolite 5′-deoxy-5-fluorouridine (5′-DFUR) in combination with radiotherapy and to evaluate the role of p53 in the combination treatment. Effects on proliferation, clonogenicity and apoptosis were evaluated, along with γH2AX foci formation as an indicator for DNA damage.ResultsCombined treatment with equipotent doses of VPA and 5′-DFUR resulted in synergistic effects in CRC lines expressing p53 (wild-type or mutant). In HCT-116 p53−/− cells we observed antagonist effects. Radiotherapy further potentiated the antiproliferative, pro-apoptotic and DNA damage effects induced by 5′-DFUR/VPA combination in p53 expressing cells.ConclusionsThese results highlighted the role of VPA as valuable candidate to be added to preoperative chemo-radiotherapy in LARC. On these bases we launched the ongoing phase I/II study of VPA and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer (V-shoRT-R3).

Plasma fatty acids and risk of colon and rectal cancers in the Singapore Chinese Health Study

Fatty acid composition in plasma captures both dietary intake and endogenous synthesis. Prospective analyses of plasma fatty acid composition are needed to establish the role of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) on risk of developing colorectal cancer. To evaluate associations between plasma fatty acid composition and colon or rectal cancer risk separately, a nested case-control study of 350 colorectal (211 colon and 139 rectal) cancer cases and an equal number of individually matched control subjects was conducted within the Singapore Chinese Health Study, a cohort of 63,257 men and women recruited between 1993 and 1998. Fatty acids in pre-diagnostic plasma were quantified using gas chromatography–tandem mass spectrometry. Conditional odds ratios (ORs) and 95% confidence intervals (CIs) comparing highest to lowest quartiles are presented. For colon cancer, inverse associations were reported with higher essential PUFAs, α-linolenic acid (OR = 0.41; 95% CI: 0.23, 0.73; Ptrend = 0.005) and linoleic acid (OR = 0.43; 95% CI: 0.23, 0.82; Ptrend = 0.008). Higher desaturase activity in the n-6 PUFA synthesis pathway estimated by the arachidonic:linoleic acid ratio was associated with increased colon cancer risk (OR = 3.53; 95% CI: 1.82, 6.85; Ptrend = 0.006), whereas higher desaturase activity in the MUFA synthesis pathway estimated by the oleic:stearic acid ratio was associated with decreased colon cancer risk (OR = 0.42; 95% CI: 0.19, 0.92; Ptrend = 0.024). There was no significant association between the essential fatty acids or the desaturase indices and rectal cancer risk. Endogenous synthesis of arachidonic and oleic acids has an impact on colon cancer development.

Association of mitochondrial copy number variation and T16189C polymorphism with colorectal cancer in North Indian population.

Globally, colorectal cancer is the third most common type of cancer. Genetic instability leading to cancer development is one of the major causes for development of cancer. Alterations in mitochondrial genome, that is, mutations, single-nucleotide polymorphisms, and copy number variations are known to contribute in cancer development. The aim of our study was to investigate association of mitochondrial T16189C polymorphism and copy number variation with colorectal cancer in North Indian population. DNA isolated from peripheral blood of 126 colorectal cancer patients and 114 healthy North Indian subjects was analyzed for T16189C polymorphism and half of them for mitochondrial copy number variation. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism, and copy number variation was estimated using real-time polymerase chain reaction, numbers of mitochondrial copies and found to be significantly higher in colorectal cancer patients than healthy controls (88 (58-154), p = 0.001). In the regression analysis, increased mitochondrial copy number variation was associated with risk of colorectal cancer (odds ratio = 2.885, 95% confidence interval = 1.3-6.358). However, T16189C polymorphism was found to be significantly associated with the risk of rectal cancer (odds ratio = 5.213, p = 0.001) and non-significantly with colon cancer (odds ratio = 0.867, p = 0.791). Also, false-positive report probability analysis was done to validate the significant findings. Our results here indicate that mitochondrial copy number variation may be playing an important role in the development of colorectal cancer, and detection of mitochondrial copy number variation can be used as a biomarker for predicting the risk of colorectal cancer in North Indian subjects.

MicroRNA-binding site polymorphisms in genes involved in colorectal cancer etiopathogenesis and their impact on disease prognosis.

According to the Vogelstein's model of colorectal carcinogenesis, genetic variations in highly penetrant genes may be involved in the colorectal cancer (CRC) pathogenesis. Similarly, aberrant function and/or altered expression of microRNAs (miRNAs) often occur in CRC. In this context, polymorphisms in miRNA-binding sites (miRSNPs) may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and increased susceptibility to common diseases. To explore this phenomenon, we have mined the 3' untranslated regions (3'UTRs) of genes known to be frequently mutated in CRC to search for miRSNPs and tested their association with CRC risk and clinical outcome. Eight miRSNPs (rs1804191, rs397768, rs41116 in APC; rs1137918, s227091, rs4585 in ATM; rs712, rs1137282, rs61764370 in KRAS; rs8674 in PARP1 and rs16950113 in SMAD7) were tested for their association with CRC risk in a case-control study (1111 cases and 1469 healthy controls). The role of these miRSNPs was also investigated in relation to clinical outcome on a subset of patients with complete follow-up. rs8679 within PARP1 was associated with CRC risk and patients' survival. In the dominant model, carriers of at least one C allele were at a decreased risk of cancer (P = 0.05). The CC genotype in rs8679 was also associated with an increased risk of recurrence/progression in patients that received 5-FU-based chemotherapy (log-rank test P = 0.03). Carriers of the homozygous variant genotype TT for rs712 in KRAS gene were associated with a decreased risk of rectal cancer (odds ratio (OR) = 0.65, 95% confidence intervals (CI) 0.43-1.00, P = 0.05) while individuals with colon cancer carrying the heterozygous GT genotype showed a longer overall survival (OS) (P = 0.04). We provide the first evidence that variations in potential miRNA-binding target sites in the 3' UTR of PARP1 gene may modulate CRC risk and prognosis after therapy. Further studies are needed to replicate our finding and assess miRSNPs as predictive biomarkers in independent populations.

Smokeless tobacco (snus) use and colorectal cancer incidence and survival: Results from nine pooled cohorts.

Although smoking is considered to be an established risk factor for colorectal cancer, the current evidence on the association between smokeless tobacco and colorectal cancer is scant and inconclusive. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess this association. A total of 417,872 male participants from nine cohort studies across Sweden were followed up for incidence of colorectal cancer and death. Outcomes were ascertained through linkage to health registers. We used shared frailty models with random effects at the study level to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During 7,135,504 person-years of observation, 4170 men developed colorectal cancer. There was no clear association between snus use and colorectal cancer overall. Exclusive current snus users, however, had an increased risk of rectal cancer (HR 1.40: 95% CI 1.09, 1.79). There were no statistically significant associations between snus use and either all-cause or colorectal cancer-specific mortality after colorectal cancer diagnosis. Our findings, from a large sample, do not support any strong relationships between snus use and colorectal cancer risk and survival among men. However, the observed increased risk of rectal cancer is noteworthy, and in merit of further attention.

Importance of Early Detection of Colorectal Cancer in Young Adults With GI Symptoms

Introduction: Colorectal cancer (CRC) diagnosed under age 50 is on the rise and is no longer unusual. Research suggests that someone born after 1990 has double the risk of colon cancer than those born in 1950. They also have four times the risk for early rectal cancer. We sought to determine the characteristics of early CRC diagnoses treated at our local facility. Patients referred to other facilities were excluded. Methods: Data was collected from 2006 to 2016 on patients diagnosed with CRC younger than age 50. We reviewed the age of diagnosis, stage of cancer, location, type and onset of symptoms. Common risk factors for CRC were also reviewed such as Body Mass Index (BMI), smoking status and family history of CRC. Results: Thirty three patients under the age of 50 were diagnosed with CRC. Ages ranged from 24 to 49 with 20 males and 13 females. Fifteen patients (45%) had rectal cancer and 18 patients (54%) were diagnosed with colon cancer. Almost half (48%) of patients were diagnosed with stage 3 or 4 cancer. Twenty eight patients (85%) had rectal bleeding as the major presenting symptom. Fourteen patients (42%) had symptom duration of more than 4 months prior to diagnosis. Twenty four patients (72%) had a BMI above 25. Fourteen patients (42%) were known smokers. Eight patients (24%) had a positive first or second degree relative with CRC. Conclusion: Advanced stage CRC was noted in our younger patients. Rectal bleeding was the primary presenting symptom. In our population, an elevated BMI over 25 was noted. Other risk factors such as smoking and family history of CRC were not overly represented. No genetic risk factor was identified although part of this cohort predated universal testing for hereditary CRC predisposition. Family history needs to be continually updated to assist the physician in determining the age to initiate CRC screening. Considering that almost half had advanced stage cancer and 85% presented with rectal bleeding, such symptoms should be evaluated in a timely manner as to achieve early diagnosis and treatment. Initiatives to increase awareness with patients and primary care providers are crucial.

Late toxicities and clinical outcome at 5 years of the ACCORD 12/0405-PRODIGE 02 trial comparing two neoadjuvant chemoradiotherapy regimens for intermediate-risk rectal cancer.

Outcome of intermediate risk rectal cancer may be improved by the addition of oxaliplatin during 5-fluoruracil concomitant neoadjuvant chemoradiotherapy. The purpose of this study is to analyze the main clinical results of the ACCORD12 trial (NCT00227747) in rectal cancer after 5 years of follow-up. Inclusion criteria were as follows: rectal adenocarcinoma accessible to digital examination staged T3-T4 Nx M0 (or T2 Nx distal anterior rectum). Two neoadjuvant chemoradiotherapy regimens were randomized: CAP45 (RT 45 Gy + capecitabine) and CAPOX50 (RT 50 Gy + capecitabine and oxaliplatin). Main end point was sterilization of the operative specimen. Acute and late toxicities were prospectively analyzed with dedicated questionnaires. Between November 2005 and July 2008, 598 patients were included in the trial. After a median follow-up of 60.2 months, there was no difference between treatment arms in multivariate analysis either for disease-free survival or overall survival (OS) [P = 0.9, hazard ratio (HR)=1.02; 95% confidence interval (CI), 0.76-1.36 and P = 0.3, HR = 0.87; 95% CI, 0.66-1.15, respectively]. There was also no difference of local control in univariate analysis (P = 0.7, HR = 0.92; 95% CI, 0.51-1.66). Late toxicities were acceptable with 1.6% G3 anal incontinence, and <1% G3 diarrhea, G3 rectal bleeding, G3 stenosis, G3-4 pain, G3 urinary incontinence, G3 urinary retention and G3 skeletal toxicity. There was a slight increase of erectile dysfunction over time with a 63% rate of erectile dysfunction at 5 years. There was no significant statistical difference for these toxicities between treatment arms. The CAPOX50 regimen did not improve local control, disease-free survival and overall survival in the ACCORD12 trial. Late toxicities did not differ between treatment arms.

Multiple Gene-Environment Interactions on the Angiogenesis Gene-Pathway Impact Rectal Cancer Risk and Survival.

Characterization of gene-environment interactions (GEIs) in cancer is limited. We aimed at identifying GEIs in rectal cancer focusing on a relevant biologic process involving the angiogenesis pathway and relevant environmental exposures: cigarette smoking, alcohol consumption, and animal protein intake. We analyzed data from 747 rectal cancer cases and 956 controls from the Diet, Activity and Lifestyle as a Risk Factor for Rectal Cancer study. We applied a 3-step analysis approach: first, we searched for interactions among single nucleotide polymorphisms on the pathway genes; second, we searched for interactions among the genes, both steps using Logic regression; third, we examined the GEIs significant at the 5% level using logistic regression for cancer risk and Cox proportional hazards models for survival. Permutation-based test was used for multiple testing adjustment. We identified 8 significant GEIs associated with risk among 6 genes adjusting for multiple testing: TNF (OR = 1.85, 95% CI: 1.10, 3.11), TLR4 (OR = 2.34, 95% CI: 1.38, 3.98), and EGR2 (OR = 2.23, 95% CI: 1.04, 4.78) with smoking; IGF1R (OR = 1.69, 95% CI: 1.04, 2.72), TLR4 (OR = 2.10, 95% CI: 1.22, 3.60) and EGR2 (OR = 2.12, 95% CI: 1.01, 4.46) with alcohol; and PDGFB (OR = 1.75, 95% CI: 1.04, 2.92) and MMP1 (OR = 2.44, 95% CI: 1.24, 4.81) with protein. Five GEIs were associated with survival at the 5% significance level but not after multiple testing adjustment: CXCR1 (HR = 2.06, 95% CI: 1.13, 3.75) with smoking; and KDR (HR = 4.36, 95% CI: 1.62, 11.73), TLR2 (HR = 9.06, 95% CI: 1.14, 72.11), EGR2 (HR = 2.45, 95% CI: 1.42, 4.22), and EGFR (HR = 6.33, 95% CI: 1.95, 20.54) with protein. GEIs between angiogenesis genes and smoking, alcohol, and animal protein impact rectal cancer risk. Our results support the importance of considering the biologic hypothesis to characterize GEIs associated with cancer outcomes.

Association between polymorphisms of TAS2R16 and susceptibility to colorectal cancer

BackgroundGenetics plays an important role in the susceptibility to sporadic colorectal cancer (CRC). In the last 10 years genome-wide association studies (GWAS) have identified over 40 independent low penetrance polymorphic variants. However, these loci only explain around 1‑4% of CRC heritability, highlighting the dire need of identifying novel risk loci. In this study, we focused our attention on the genetic variability of the TAS2R16 gene, encoding for one of the bitter taste receptors that selectively binds to salicin, a natural antipyretic that resembles aspirin. Given the importance of inflammation in CRC, we tested whether polymorphic variants in this gene could affect the risk of developing this neoplasia hypothesizing a role of TAS2R16 in modulating chronic inflammation within the gut.MethodsWe performed an association study using 6 tagging SNPs, (rs860170, rs978739, rs1357949, rs1525489, rs6466849, rs10268496) that cover all TAS2R16 genetic variability. The study was carried out on 1902 CRC cases and 1532 control individuals from four European countries.ResultsWe did not find any statistically significant association between risk of developing CRC and selected SNPs. However, after stratification by histology (colon vs. rectum) we found that rs1525489 was associated with increased risk of rectal cancer with a (Ptrend of = 0.0071).ConclusionsOur data suggest that polymorphisms within TAS2R16 gene do not have a strong influence on colon cancer susceptibility, but a possible role in rectal cancer should be further evaluated in larger cohorts.