Exposure to pesticides and risk of colorectal cancer: A systematic review and meta-analysis.

Colorectal cancer (CRC) is a widespread malignancy worldwide, and its relationship with pesticide exposure remains inconclusive. This study aims to elucidate the relationship between pesticide exposure and the risk of colon, rectal, or CRC, focusing on specific pesticide groups. We conducted an extensive literature search for peer-reviewed studies published up to March 31, 2023. Summary risk ratios (RR) and their corresponding 95% confidence intervals (CI) were calculated using stratified random-effects meta-analyses, taking into account different types of exposure and outcomes, and various exposed populations and pesticide subgroups. This approach aimed to address the substantial heterogeneity observed across the literature. We also assessed heterogeneity and potential small-study effects to ensure the robustness of our findings. From the 50 studies included in this review, 33 contributed to the meta-analysis. Our results indicate a significant association between herbicide exposure and colon cancer in both lifetime-days (LDs) (RR = 1.20; 95% CI = 1.01-1.42) and intensity-weighted lifetime-days (IWLDs) (RR = 1.29, 95% CI = 1.12-1.49) exposure. Similarly, insecticide exposure was associated with an increased risk of colon cancer in IWLDs (RR = 1.32; 95% CI = 1.02-1.70) exposure, and rectal cancer in any versus never exposure (RR = 1.21; 95% CI = 1.07-1.36), IDs (RR = 1.86; 95% CI = 1.30-2.67) and IWLDs (RR = 1.70; 95% CI = 1.03-2.83) exposure. While these findings suggest significant associations of herbicide and insecticide exposure with colon and rectal cancer, respectively, further research is needed to explore the impact of other pesticide groups and deepen our understanding of pesticide exposure. These results have important implications for policymakers and regulators, underscoring the need for stricter supervision and regulation of pesticide use to mitigate CRC risk.

A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer.

BACKGROUND: We assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC). METHODS: This phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1-21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D. RESULTS: In phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses. CONCLUSIONS: Nofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC. CLINICAL TRIAL REGISTR ATION: Clinicaltrials.gov (NCT03475251).

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial.

BACKGROUND: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC). METHODS: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33. RESULTS: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; Pnoninferiority = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%). CONCLUSIONS: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC. CLINICAL TRIAL REGISTRATION: JapicCTI-173618, jRCTs031180122.

Dipeptidyl peptidase 4-inhibitor treatment was associated with a reduced incidence of neoplasm in patients with type 2 diabetes: a meta-analysis of 115 randomized controlled trials with 121961 participants.

OBJECTIVE: To evaluate the association between dipeptidyl peptidase 4 inhibitor (DPP-4i) and the incidence of neoplasm in patients with type 2 diabetes (T2D). METHODS: Pubmed, Medline, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov website were searched from May 2002 to December 2021. Randomized controlled trials with reports of neoplasm events which compared DPP-4i versus non-DPP-4i users. RESULTS: Generally, DPP-4i was associated with a decreased incidence of overall neoplasm events in patients with T2D when compared with non-DPP-4i agents (OR = 0.91, 95%CI, 0.8 to 0.97). Moreover, the incidence of rectal neoplasm, especially rectal malignant neoplasm, and the incidence of skin neoplasm were significantly decreased in DPP-4i users. The overall neoplasm events were less frequent in DPP-4i users who were elderly, or male, or obese, or Caucasian, or with over 10 years of diabetes, or with follow-up duration over 52 weeks. CONCLUSIONS: DPP-4i was associated with decreased risks of overall neoplasm, rectal neoplasm, rectal malignant neoplasm and skin neoplasm in patients with T2D. The overall neoplasm events were less frequent in patient with DPP-4i treatment who were elderly, male, obese, Caucasian, with long diabetes durations and with long follow-up durations. Further investigations are still required. META-ANALYSIS REGISTRATION: CRD42021273627.

Understanding the Interaction Between Prostaglandins and Toll-Like Receptors in Nicotine-Induced Rectal Tumor in Animals.

BACKGROUND: In the present study, we tried to understand the crosstalk between prostaglandins-COX-mediated rectal tumors and toll- like receptors in rats. METHODS: The tumor was induced using nicotine (100 µL/mL). Following the induction, the serum and rectal tissue were analyzed for Lipo-polysaccharides (LPS) and prostaglandin E2 in serum, and tissue expression of inflammatory mediators like TLR2,4, NFkB; cancer markers like Matrix metalloproteases 2 (MMP2), 9 and Cyclo-oxygenases 2 (COX-2) were estimated. The gut microflora analysis was carried out using the fresh fecal samples of both the study groups. RESULTS: In nicotine-induced group, there was a significant alteration in the gut microflora toward high Gram-negative strains and a decline in Gram-positive populations. All the inflammatory as well as cancer prognostic markers were significantly increased in the tumor-induced animals. CONCLUSION: From the present study, it could be concluded that nicotine significantly induced rectal cancer in the mice model by modu- lating gut microflora and increasing COX-2 and prostaglandin E2 levels.

Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP).

AIMS: Locally advanced rectal cancer (LARC) is an area of unmet medical need with one third of patients dying from their disease. With response to neoadjuvant chemo-radiotherapy being a major prognostic factor, trial SAKK 41/16 assessed potential benefits of adding regorafenib to capecitabine-amplified neoadjuvant radiotherapy in LARC patients. METHODS: Patients received regorafenib at three dose levels (40/80/120 mg once daily) combined with capecitabine 825 mg/m2 bidaily and local radiotherapy. We developed population pharmacokinetic models from plasma concentrations of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine as well as regorafenib and its metabolites M-2 and M-5 as implemented into SAKK 41/16 to assess potential drug-drug interactions (DDI). After establishing parent-metabolite base models, drug exposure parameters were tested as covariates within the respective models to investigate for potential DDI. Simulation analyses were conducted to quantify their impact. RESULTS: Plasma concentrations of capecitabine, regorafenib and metabolites were characterized by one and two compartment models and absorption was described by parallel first- and zero-order processes and transit compartments, respectively. Apparent capecitabine clearance was 286 L/h (relative standard error [RSE] 14.9%, interindividual variability [IIV] 40.1%) and was reduced by regorafenib cumulative area under the plasma concentration curve (median reduction of 45.6%) as exponential covariate (estimate -4.10 × 10-4 , RSE 17.8%). Apparent regorafenib clearance was 1.94 L/h (RSE 12.1%, IIV 38.1%). Simulation analyses revealed significantly negative associations between capecitabine clearance and regorafenib exposure. CONCLUSIONS: This work informs the clinical development of regorafenib and capecitabine combination treatment and underlines the importance of studying potential DDI with new anticancer drug combinations.

Benefit from upfront FOLFOXIRI and bevacizumab in BRAFV600E-mutated metastatic colorectal cancer patients: does primary tumour location matter?

BACKGROUND: Recent data suggest that BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients with right-sided tumours and ECOG-PS = 0 may achieve benefit from the triplet regimen differently than those with left-sided tumours and ECOG-PS > 0. METHODS: The predictive impact of primary sidedness and ECOG-PS was evaluated in a large real-life dataset of 296 BRAFV600E-mutated mCRC patients treated with upfront triplet or doublet ± bevacizumab. Biological differences between right- and left-sided BRAFV600E-mutated CRCs were further investigated in an independent cohort of 1162 samples. RESULTS: A significant interaction effect between primary sidedness and treatment intensity was reported in terms of both PFS (p = 0.010) and OS (p = 0.003), with a beneficial effect of the triplet in the right-sided group and a possible detrimental effect in the left-sided. No interaction effect was observed between ECOG-PS and chemo-backbone. In the MSS/pMMR population, a consistent trend for a side-related subgroup effect was observed when FOLFOXIRI ± bevacizumab was compared to oxaliplatin-based doublets±bevacizumab (p = 0.097 and 0.16 for PFS and OS, respectively). Among MSS/pMMR tumours, the BM1 subtype was more prevalent in the right-sided group (p = 0.0019, q = 0.0139). No significant differences were observed according to sidedness in the MSI-H/dMMR population. CONCLUSIONS: Real-life data support the use of FOLFOXIRI ± bevacizumab only in BRAFV600E-mutated mCRC patients with right-sided tumours.

[The TAILOR study establishes, in patients mCRC wt, the first line use of FOLFOX in combination with cetuximab]. / Lo studio TAILOR sancisce, nei pazienti con mCRC RAS wild-type, l'impiego in first line di FOLFOX in associazione a cetuximab.

Cetuximab in combination with chemotherapy is a standard first-line treatment regimen for patients with metastatic colorectal cancer (mCRC) RAS wild-type (wt); however, the efficacy of cetuximab plus leucovorin, fluorouracil and oxaliplatin (FOLFOX) had never been demonstrated in a prospective, randomized, controlled phase III study. The TAILOR study is the first randomized, multicenter, prospective Phase III study evaluating the addition of cetuximab to FOLFOX in a RAS wt Chinese population and thus providing confirmatory data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone.

Experimental Model of Rectal Carcinogenesis Induced by N-Methyl-N-Nitrosoguanidine in Mice with Endoscopic Evaluation.

Background and purpose: The discovery of chemical substances with carcinogenic properties has allowed the development of several experimental models of colorectal cancer (CRC). Classically, experimental models of CRC in mice have been evaluated through clinical or serial euthanasia. The present study aims to investigate the role of low endoscopy in the analysis of carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Methods: Thirty C57BL6 mice were divided into two groups: a control group with fifteen animals that underwent rectal instillation of saline solution on day 0 and a carcinogen group with fifteen animals that underwent a 100 mg/kg MNNG rectal instillation on day 0. In both groups, low endoscopies were performed on weeks 4 and 8. We used a validated endoscopic scoring system to evaluate the severity of colitis and colorectal tumor. Euthanasia was carried out at week 12. Results: We observed higher inflammation scores (p <0.001) and a higher number of tumors (p <0.05) in the MNNG group than the control group, both at weeks 4 and 8. A worsening of inflammation scores from the first to the second endoscopy was also noticeable in the MNNG group. There were no bowel perforations related to the procedure, and there was one death in the control group. Conclusion: Low endoscopy in experimental animals allows safe macroscopic evaluation of colorectal carcinogenesis without the need for euthanasia.

Antibiotic use and risk of colorectal cancer: a systematic review and dose-response meta-analysis.

BACKGROUND: It is understudied whether the posed association of oral antibiotics with colorectal cancer (CRC) varies between antibiotic spectrums, colorectal continuum, and if a non-linear dose-dependent relationship is present. DESIGN: Three electronic databases and a trial platform were searched for all relevant studies, from inception until February 2020, without restrictions. Random-effects meta-analyses provided pooled effect-sizes (ES) with 95% confidence intervals (CI). Dose-response analyses modelling the relationship between number of days exposed to antibiotics and CRC risk were extended to non-linear multivariable random-effects models. RESULTS: Of 6483 identified publications ten were eligible, including 4.1 million individuals and over 73,550 CRC cases. The pooled CRC risk was increased among individuals who ever-used antibiotics (ES = 1.17, 95%CI 1.05-1.30), particularly for broad-spectrum antibiotics (ES = 1.70, 95%CI 1.26-2.30), but not for narrow-spectrum antibiotic (ES = 1.11, 95% 0.93-1.32). The dose-response analysis did not provide strong evidence of any particular dose-response association, and the risk patterns were rather similar for colon and rectal cancer. DISCUSSION: The antibiotic use associated CRC risk seemingly differs between broad- and narrow-spectrum antibiotics, and possibly within the colorectal continuum. It remains unclear whether this association is causal, requiring more mechanistic studies and further clarification of drug-microbiome interactions.

Long-term observational study on 6223 survivors of arsenic poisoning due to contaminated milk powder during infancy.

In 1955, an outbreak of arsenic poisoning caused by the ingestion of arsenic-contaminated Morinaga Dry Milk occurred in western Japan. This study aimed to assess the mortality and cancer incidence risk among Japanese individuals who were poisoned during this time as infants. In total, 6223 survivors (mean age at enrollment, 27.5 y) who had ingested contaminated milk when they were aged ≤ 2 y participated in this study. Follow-up was conducted from 1982 to 2018 (mean follow-up duration, 30.3 y). Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) were used to compare mortality and cancer incidence rates of subjects with the respective Japanese population rates, and 95% confidence intervals (95% CIs) of the SMR and SIR were also calculated. In total, 561 deaths and 524 new cancer cases were observed. A statistically significant increase in mortality rate was observed for all causes (SMR, 1.15; 1.01-1.19), nervous system disease (2.83, 1.62-4.19), respiratory disease (2.02, 1.37-2.62), genitourinary system disease (2.25, 1.10-3.73), and traffic accident (2.03, 1.14-3.04). In contrast, a significant decrease in cancer incidence rate was observed for all cancers (SIR, 0.96; 0.84-0.99), stomach cancer (0.77, 0.57-0.92), colon cancer (0.63, 0.41-0.85), rectum cancer (0.69, 0.43-0.95), and breast cancer (0.72, 0.52-0.89). Liver cancer showed a high mortality rate (SMR, 1.68; 1.06-2.31). In this study, after the long-term follow-up we revealed overall and cause-specific mortality and cancer incidence risk among survivors who ingested arsenic-contaminated dry milk as infants.

Rectal adenocarcinoma with rectoprostatic fistula following prostate brachytherapy.

An 80-year-old man with history of prostate cancer successfully treated with brachytherapy was initially thought to have Fournier's gangrene until imaging detected a rectoprostatic fistula. Although this is known to be a rare complication of prostate brachytherapy, in this case the aetiology was a new primary rectal adenocarcinoma. It was not possible to catheterise per urethra owing to the fistula, so he was fitted with suprapubic catheter, and underwent palliative loop colostomy. Brachytherapy carries a low risk of second primary cancers, although two previous cases reported such cancers as radiation induced. This is, to our knowledge, the first case of rectal adenocarcinoma following prostate brachytherapy in the literature.

Laparoscopic rectal tumor surgery after administration of a new sclerosing therapy (aluminum potassium sulfate and tannic acid injection) for internal hemorrhoids: A report of three cases.

Aluminum potassium sulfate and tannic acid (ALTA) injection is a new sclerosing therapy for internal hemorrhoids that has been gaining widespread use. However, there have been few reports about rectal cancer after ALTA injection. We performed laparoscopic surgery for three patients who had underwent ALTA therapy 6 months or 1 year earlier: (i) a 51-year-old man with neuroendocrine tumor; (ii) a 44-year-old woman with rectal cancer; and (iii) 77-year-old man with rectal cancer. All three patients had sclerosis of the resected rectal wall stump, making transection of the rectum difficult. Histological examination of the specimens also showed an inflammatory reaction and/or fibrosis of the resection stump. Although laparoscopic low anterior resection was planned for all three patients, we had to construct a diverting stoma for two patients and could not perform sphincter-preserving surgery for the other. We must be well prepared for laparoscopic rectal surgeries after ALTA therapy, and these cases suggest sigmoidoscopy before ALTA therapy should be recommended.

[Effect and mechanism of antimicrobial peptide cathelicidin secreted by tumor associated macrophage on the growth of colorectal cancer in mice].

Objective: To investigate the effect and mechanism of the antibacterial peptide cathelicidin secreted by tumor associated macrophages on the growth of colorectal cancer in mice. Methods: Azoxymethane (AOM)/ dextran sodium sulfate (DSS) method was used to establish a mouse model of colitis associated colon cancer. To induce tumor formation, cathelicidin antibody, IgG antibody (positive control) or PBS (negative control) was respectively injected into mice once every 3 days and lasted one month. Then the pictures of mice colon were taken, and the numbers of tumor were counted and evaluated. Expressions of cathelicidin in tumor associated macrophages isolated from tumor and adjacent normal tissues of mice were examined by quantitative RT-PCR (qRT-PCR) and Western blot. Expressions of the tumor proliferating antigen Ki-67, macrophage marker CD68 and cathelicidin in tumor and non-tumor tissues were determined by immunohistochemistry analysis. Apoptosis of cells from tumor tissues was analyzed by using TdT-mediated dUTP nick-end labeling (TUNEL). Results: In colon tumor tissues, cathlicidin strongly expressed in inflammatory cells (macrophages), but weakly expressed in tumor cells. The tumor number and size in mice injected with cathelicidin neutralizing antibody were 4.50±1.18 and (1.74±0.18) mm, respectively, significantly lower than 13.88±1.98 and (3.74±0.38) mm of mice injected with PBS (t=4.07, t=4.72; P< 0.01) and 15.25±1.82 and (3.40±0.36) mm of mice injected with IgG antibody (t=4.96, t=4.08; P<0.01). The Ki-67 positive rate of cells in tumor tissues of mice injected with cathelicidin neutralizing antibody was (28.20±3.44) %, significantly lower than (68.20±3.51) % of mice injected with PBS (t=8.135, P<0.01) and (69.20±3.41) % of mice injected with IgG antibody (t=8.461, P<0.01). Immunohistochemistry analyses showed that the expression of CD68 in tumor tissues of mice injected with cathelicidin antibody was significantly lower than that of mice injected with IgG antibody or PBS. TUNEL result showed that treatment with cathelicidin neutralizing antibody had negligible effect on the apoptosis of tumor cells. Conclusions: Cathelicidin secreted by tumor associated macrophages can promote the growth of colorectal cancer in mice, and neutralizing cathelicidin activity can inhibit the growth and proliferation of colorectal cancer. Cathelicidin mediated promotion of colon cancer proliferation may mainly be exerted by recruiting inflammatory cells such as macrophages into the tumor microenvironment.

Hipervitaminosis B12 y cáncer de recto / B12 hypervitaminosis and rectum cancer

Niveles elevados de vitamina B12 pueden ser relacionados con un alto riesgo de desarrollo de cáncer debido a una alteración de la integridad del ADN, como consecuencia del metabolismo anómalo de la cobalamina. Esto es importante para tener en cuenta la vitamina B12 como marcador tumoral inespecífico en el desarrollo de neoplasias sólidas, una vez descartadas otras patologías serias como enfermedades hematológicas, hepáticas y renales. Se presenta el caso de un paciente con hipervitaminosis B12 y cáncer de recto (AU)

High extreme values of B12 vitamin could be linked with high risk cáncer development throughout the DNA integrity distress because a cobalamine disfunctional metabolism. It's vital to understand the role of B12 vitamin as inespecific tumoral marker in the development of solid neoplasm when other many serious diseases as blood, liver and kidney diseases are rejected. We report a patient case about B12 hypervitaminosis and rectum cáncer (AU)

Ulcerative colitis associated with nephrotic syndrome after treatment with mesalazine developed into rectal carcinoma: a case study.

BACKGROUND: Previous studies reported that nephrotic syndrome is associated with ulcerative colitis (UC) patients treated with mesalazine. Dysplasia associated with UC often develops into colorectal carcinoma. CASE PRESENTATION: A 17-year-old man was referred to our hospital, complaining of diarrhea and bloody stool. Total colonoscopy (TC) was performed and total-type UC was diagnosed. After treatment with mesalazine for 5 years, a low-grade dysplasia (LGD) was detected in the rectum by histological analysis of a biopsy sample. One month later, he complained of dyspnea and edema. He was diagnosed with nephrotic syndrome and administered steroid and immunosuppressant treatment: cyclosporine and mizoribine. Eight years after LGD was detected, he complained of abdominal distension and pain. Stenosis of the upper rectum by an advanced rectal carcinoma was detected. Abdominal computed tomography showed a rectal tumor with multiple lymph node metastases. Transverse colostomy was performed surgically, followed by two cycles of modified FOLFOX6 and panitumumab. He safely underwent a total proctocolectomy with a stapled ileal pouch anal-canal anastomosis, total mesorectal and bilateral pelvic lymph node dissection, and temporary loop ileostomy. Metastases were observed in 25 lymph nodes microscopically. The pathological stage of rectal carcinoma was pT3N2bM1a. After one cycle of modified FOLFOX6 postoperatively, he was discharged from the hospital. CONCLUSIONS: A patient with UC associated with nephrotic syndrome was treated with mesalazine. LGD developed into an advanced rectal carcinoma after an 8-year interval. The use of immunosuppressants for the treatment of nephrotic syndrome might affect the development of rectal carcinoma. TRIAL REGISTRATION: Case report registration #1626.

The influence of hormone therapies on colon and rectal cancer.

Exogenous sex hormones seem to play a role in colorectal carcinogenesis. Little is known about the influence of different types or durations of postmenopausal hormone therapy (HT) on colorectal cancer risk. A nationwide cohort of women 50-79 years old without previous cancer (n = 1,006,219) were followed 1995-2009. Information on HT exposures was from the National Prescription Register and updated daily, while information on colon (n = 8377) and rectal cancers (n = 4742) were from the National Cancer Registry. Potential confounders were obtained from other national registers. Poisson regression analyses with 5-year age bands included hormone exposures as time-dependent covariates. Use of estrogen-only therapy and combined therapy were associated with decreased risks of colon cancer (adjusted incidence rate ratio 0.77, 95 % confidence interval 0.68-0.86 and 0.88, 0.80-0.96) and rectal cancer (0.83, 0.72-0.96 and 0.89, 0.80-1.00), compared to never users. Transdermal estrogen-only therapy implied more protection than oral administration, while no significant influence was found of regimen, progestin type, nor of tibolone. The benefit of HT was stronger for long-term hormone users; and hormone users were at lower risk of advanced stage of colorectal cancer, which seems supportive for a causal association between hormone therapy and colorectal cancer.

Dietary N-nitroso compounds and risk of colorectal cancer: a case-control study in Newfoundland and Labrador and Ontario, Canada.

Several N-nitroso compounds (NOC) have been shown to be carcinogenic in a variety of laboratory animals, but evidence of their carcinogenicity in humans is lacking. We aimed to examine the association between NOC intake and colorectal cancer (CRC) risk and possible effect modification by vitamins C and E and protein in a large case-control study carried out in Newfoundland and Labrador and Ontario, Canada. A total of 1760 case patients with pathologically confirmed adenocarcinoma and 2481 population controls were asked to complete a self-administered FFQ to evaluate their dietary intakes 1 year before diagnosis (for cases) or interview (for controls). Adjusted OR and 95 % CI were calculated across the quintiles of NOC (measured by N-nitrosodimethylamine (NDMA)) intake and relevant food items using unconditional logistic regression. NDMA intake was found to be associated with a higher risk of CRC (highest v. lowest quintiles: OR 1·42, 95 % CI 1·03, 1·96; P for trend = 0·005), specifically for rectal carcinoma (OR 1·61, 95 % CI 1·11, 2·35; P for trend = 0·01). CRC risk also increased with the consumption of NDMA-containing meats when the highest tertile was compared with the lowest tertile (OR 1·47, 95 % CI 1·03, 2·10; P for trend = 0·20). There was evidence of effect modification between dietary vitamin E and NDMA. Individuals with high NDMA and low vitamin E intakes had a significantly increased risk than those with both low NDMA and low vitamin E intakes (OR 3·01, 95 % CI 1·43, 6·51; P for interaction = 0·017). The present results support the hypothesis that NOC intake may be positively associated with CRC risk in humans. Vitamin E, which inhibits nitrosation, could modify the effect of NDMA on CRC risk.

N-Nitroso compounds and cancer incidence: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study.

BACKGROUND: Humans are exposed to preformed N-nitroso compounds (NOCs) and endogenous NOCs. Several NOCs are potential human carcinogens, including N-nitrosodimethylamine (NDMA), but evidence from population studies is inconsistent. OBJECTIVE: We examined the relation between dietary NOCs (NDMA), the endogenous NOC index, and dietary nitrite and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, United Kingdom, study. DESIGN: This was a prospective study of 23,363 men and women, aged 40-79 y, who were recruited in 1993-1997 and followed up to 2008. The baseline diet was assessed with food-frequency questionnaires. RESULTS: There were 3268 incident cancers after a mean follow-up of 11.4 y. Dietary NDMA intake was significantly associated with increased cancer risk in men and women [hazard ratio (HR): 1.14; 95% CI: 1.03, 1.27; P for trend = 0.03] and in men (HR: 1.24; 95% CI: 1.07, 1.44; P for trend = 0.005) when the highest quartile was compared with the lowest quartile in age- and sex-adjusted analyses but not in multivariate analyses (HR: 1.10; 95% CI: 0.97, 1.24; HR for men: 1.18; 95% CI: 1.00, 1.40; P for trend ≥ 0.05). When continuously analyzed, NDMA was associated with increased risk of gastrointestinal cancers (HR: 1.13; 95% CI: 1.00, 1.28), specifically of rectal cancer (HR: 1.46; 95% CI: 1.16, 1.84) per 1-SD increase after adjustment for age, sex, body mass index, cigarette smoking status, alcohol intake, energy intake, physical activity, education, and menopausal status (in women). The endogenous NOC index and dietary nitrite were not significantly associated with cancer risk. There was a significant interaction between plasma vitamin C concentrations and dietary NDMA intake on cancer incidence (P for interaction < 0.00001). CONCLUSIONS: Dietary NOC (NDMA) was associated with a higher gastrointestinal cancer incidence, specifically of rectal cancer. Plasma vitamin C may modify the relation between NDMA exposure and cancer risk.