Victor Moreno

An urgent referral strategy for symptomatic patients with suspected colorectal cancer based on a quantitative immunochemical faecal occult blood test

BACKGROUND European health systems have developed referral guidelines for the selection of patients for the urgent investigation of suspected colorectal cancer. AIM To evaluate whether quantitative faecal immunochemical testing performs better than commonly used high-risk symptoms based strategies for fast-tracking cancer referrals. METHODS We prospectively studied 1054 symptomatic patients referred for a colonoscopy who provided a sample for faecal immunochemical testing. The usefulness of faecal immunochemical testing and two current guidelines for urgent referral were compared for their efficacy in the detection of colorectal cancer and advanced neoplasia. RESULTS The guidelines detected 46.7% and 43.3% of cases of colorectal cancer while faecal haemoglobin concentration ≥15μg Hb/g detected 96.7% of cases. The diagnostic accuracy of both the guidelines and faecal haemoglobin concentration ≥15μg Hb/g for the detection of advanced neoplasia was: sensitivity 38.3%, 36.1%, 57.1% and specificity 71.8%, 69.5%, 86.6%, respectively. Male gender (OR 2.35; p<0.001), age (1.34; p=0.002), and faecal haemoglobin concentration ≥10μg Hb/g (7.81; p<0.001) were independent predictive factors of advanced neoplasia. CONCLUSIONS A faecal immunochemical test based-strategy performs better than current high-risk symptoms based strategies for fast-tracking cancer referrals. A score that combines gender, age and a faecal immunochemical test could accurately estimate the risk of advanced neoplasia.

Association of Streptococcus gallolyticus subspecies gallolyticus with colorectal cancer: Serological evidence

The colonic opportunist Streptococcus gallolyticus subspecies gallolyticus (SGG) is potentially associated with colorectal cancer (CRC). Large‐scale seroepidemiological data for SGG antibodies and their possible association with CRC is currently missing. Associations between CRC and antibody responses to SGG were examined in 576 CRC cases and 576 controls matched by sex, age and province from a population‐based multicase–control project (MCC‐Spain). MCC‐Spain was conducted between 2008 and 2013 in 12 Spanish provinces. Antibody responses to recombinant affinity‐purified SGG pilus proteins Gallo1569, 2039, 2178 and 2179 were analysed by multiplex serology. Polyomavirus (PyV) JC VP1 and PyV 6 VP1 proteins served as disease‐specificity controls. In the control population, antibody responses to pilus proteins were mostly weak. Antibody responses to individual pilus proteins Gallo2039 (OR: 1.58, 95% CI: 1.09–2.28), Gallo2178 (OR: 1.58, 95% CI: 1.09–2.30) and Gallo2179 (OR: 1.45, 95% CI: 1.00–2.11) were significantly associated with CRC risk. The association was stronger for positivity to two or more pilus proteins of Gallo1569, Gallo2178 and Gallo2179 (OR:1.93, 95% CI: 1.04–3.56) and for double‐positivity to Gallo2178 and Gallo2179 (OR: 3.54, 95% CI: 1.49–8.44). The association between SGG infection and CRC risk was stronger among individuals younger than 65 years. For the first time we demonstrated a statistically significant association of exposure to SGG antigens and CRC in a large seroepidemiological study. These results should stimulate further studies on the role of SGG in CRC pathogenesis.

Type 2 Diabetes, Antidiabetic Medications, and Colorectal Cancer Risk: Two Case-Control Studies from Italy and Spain.

Background Type 2 diabetes mellitus has been associated with an excess risk of colorectal cancer, although the time–risk relationship is unclear, and there is limited information on the role of antidiabetic medications. Aim We examined the association between type 2 diabetes, antidiabetic medications, and the risk of colorectal cancer, considering also duration of exposures. Methods We analyzed data derived from two companion case–control studies conducted in Italy and Spain between 2007 and 2013 on 1,147 histologically confirmed colorectal cancer cases and 1,594 corresponding controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional multiple logistic regression models, adjusted for socioeconomic factors and major potential confounding factors. Results Overall, 14% of cases and 12% of controls reported a diagnosis of diabetes, corresponding to an OR of colorectal cancer of 1.21 (95% CI 0.95–1.55). The OR was 1.49 (95% CI 0.97–2.29) for a duration of diabetes of at least 15 years. The OR was 1.53 (95% CI 1.06–2.19) for proximal colon cancer, 0.94 (95% CI 0.66–1.36) for distal colon cancer, and 1.32 (95% CI 0.94–1.87) for rectal cancer. In comparison with no use, metformin use was associated with a decreased colorectal cancer risk (OR 0.47, 95% CI 0.24–0.92), while insulin use was associated with an increased risk (OR 2.20, 95% CI 1.12–4.33); these associations were stronger for longer use (OR 0.36 and 8.18 for ≥10 years of use of metformin and insulin, respectively). Conclusion This study shows evidence of a positive association between diabetes and colorectal cancer, mainly proximal colon cancer. Moreover, it indicates a negative association between colorectal cancer and metformin use and a positive association for insulin use.

Colorectal Cancer and Long-Term Exposure to Trihalomethanes in Drinking Water: A Multicenter Case-Control Study in Spain and Italy.

Background: Evidence on the association between colorectal cancer and exposure to disinfection by-products in drinking water is inconsistent. Objectives: We assessed long-term exposure to trihalomethanes (THMs), the most prevalent group of chlorination by-products, to evaluate the association with colorectal cancer. Methods: A multicenter case–control study was conducted in Spain and Italy in 2008–2013. Hospital-based incident cases and population-based (Spain) and hospital-based (Italy) controls were interviewed to ascertain residential histories, type of water consumed in each residence, frequency and duration of showering/bathing, and major recognized risk factors for colorectal cancer. We estimated adjusted odds ratios (OR) for colorectal cancer in association with quartiles of estimated average lifetime THM concentrations in each participant’s residential tap water (micrograms/liter; from age 18 to 2 years before the interview) and estimated average lifetime THM ingestion from drinking residential tap water (micrograms/day). Results: We analyzed 2,047 cases and 3,718 controls. Median values (ranges) for average lifetime residential tap water concentrations of total THMs, chloroform, and brominated THMs were 30 (0–174), 17 (0–63), and 9 (0–145) μg/L, respectively. Total THM concentration in residential tap water was not associated with colorectal cancer (OR = 0.92, 95% CI: 0.66, 1.28 for highest vs. lowest quartile), but chloroform concentrations were inversely associated (OR = 0.31, 95% CI: 0.24, 0.41 for highest vs. lowest quartile). Brominated THM concentrations showed a positive association among men in the highest versus the lowest quartile (OR = 1.43, 95% CI: 0.83, 2.46). Patterns of association were similar for estimated average THM ingestion through residential water consumption. Conclusions: We did not find clear evidence of an association between detailed estimates of lifetime total THM exposure and colorectal cancer in our large case–control study population. Negative associations with chloroform concentrations and ingestion suggest differences among specific THMs, but these findings should be confirmed in other study populations. Citation: Villanueva CM, Gracia-Lavedan E, Bosetti C, Righi E, Molina AJ, Martín V, Boldo E, Aragonés N, Perez-Gomez B, Pollan M, Gomez Acebo I, Altzibar JM, Jiménez Zabala A, Ardanaz E, Peiró R, Tardón A, Chirlaque MD, Tavani A, Polesel J, Serraino D, Pisa F, Castaño-Vinyals G, Espinosa A, Espejo-Herrera N, Palau M, Moreno V, La Vecchia C, Aggazzotti G, Nieuwenhuijsen MJ, Kogevinas M. 2017. Colorectal cancer and long-term exposure to trihalomethanes in drinking water: a multicenter case–––control study in Spain and Italy. Environ Health Perspect 125:56–65; http://dx.doi.org/10.1289/EHP155

Perinatal and childhood factors and risk of breast cancer subtypes in adulthood.

BACKGROUND Accumulated exposure to hormones and growth factors during early life may influence the future risk of breast cancer (BC). This study examines the influence of childhood-related, socio-demographic and anthropometric variables on BC risk, overall and by specific pathologic subtypes. METHODS This is a case-control study where 1539 histologically-confirmed BC cases (23-85 years) and 1621 population controls, frequency matched by age, were recruited in 10 Spanish provinces. Perinatal and childhood-related characteristics were directly surveyed by trained staff. The association with BC risk, globally and according to menopausal status and pathologic subtypes, was evaluated using logistic and multinomial regression models, adjusting for tumor specific risk factors. RESULTS Birth characteristics were not related with BC risk. However, women with high socioeconomic level at birth presented a decreased BC risk (OR=0.45; 95% CI=0.29-0.70), while those whose mothers were aged over 39 years at their birth showed an almost significant excess risk of hormone receptor positive tumors (HR+) (OR=1.35; 95% CI=0.99-1.84). Women who were taller than their girl mates before puberty showed increased postmenopausal BC risk (OR=1.26; 95% CI=1.03-1.54) and increased HR+ BC risk (OR=1.26; 95% CI=1.04-1.52). Regarding prepubertal weight, while those women who were thinner than average showed higher postmenopausal BC risk (OR=1.46; 95% CI=1.20-1.78), associated with HR+ tumors (OR=1.34; 95% CI=1.12-1.61) and with triple negative tumors (OR=1.56; 95% CI=1.03-2.35), those who were heavier than average presented lower premenopausal BC risk (OR=0.64; 95% CI=0.46-0.90) and lower risk of epidermal growth factor receptor positive tumors (OR=0.61; 95% CI=0.40-0.93). CONCLUSION These data reflect the importance of hormones and growth factors in the early stages of life, when the mammary gland is in development and therefore more vulnerable to proliferative stimuli.

0058 Colorectal cancer risk and shift work in a population-based case-control study in Spain (MCC-Spain)

Objectives Epidemiological cancer studies on shift work have focused on breast cancer while evidence on other tumours is limited. We evaluated colorectal cancer risk in relation to night and rotating shift work and genetic variation, in a population based case-control study in Spain. Method 1066 male and 592 female incident colorectal cancer cases and 3388 randomly selected population controls of both sexes, enrolled in 11 regions of Spain, were included. Information was collected on socio-demographic, lifestyle, medical history and other variables by face-to-face interviews. Lifetime occupational history on daily time schedule of each job, day/night/rotating shifts, light at night exposure, and duration of different jobs, was used for exposure assessment. We used unconditional logistic regression adjusting for potential confounders. Results Among controls 10% of males and 4% females had ever worked full time in permanent night shifts (working between midnight and 6am) and 24% of males and 14% of females in rotating shifts for ≥1 year. Having ever performed rotating shift work was associated with an increased risk for colorectal cancer (adjusted Odds Ratio 1.33, 95% CI 1.15–1.55) compared to permanent day workers. ORs increased with cumulative years of rotating shift work and the OR for more than 30 years work 1.54 (1.22–1.94). Having ever worked in permanent night shift was not associated with colorectal cancer risk. Analysis on gene-environment interactions with genes in circadian, melatonin and sleep pathways are ongoing and will be presented. Conclusions In this large population based study we found an increase in colorectal cancer risk associated with rotating shift work.

Menstrual and Reproductive Factors and Risk of Gastric and Colorectal Cancer in Spain

Background Sex hormones play a role in gastric cancer and colorectal cancer etiology, however, epidemiological evidence is inconsistent. This study examines the influence of menstrual and reproductive factors over the risk of both tumors. Methods In this case-control study 128 women with gastric cancer and 1293 controls, as well as 562 female and colorectal cancer cases and 1605 controls were recruited in 9 and 11 Spanish provinces, respectively. Population controls were frequency matched to cases by age and province. Demographic and reproductive data were directly surveyed by trained staff. The association with gastric, colon and rectal cancer was assessed using logistic and multinomial mixed regression models. Results Our results show an inverse association of age at first birth with gastric cancer risk (five-year trend: OR = 0.69; p-value = 0.006). Ever users of hormonal contraception presented a decreased risk of gastric (OR = 0.42; 95%CI = 0.26–0.69), colon (OR = 0.64; 95%CI = 0.48–0.86) and rectal cancer (OR = 0.61; 95%CI = 0.43–0.88). Postmenopausal women who used hormone replacement therapy showed a decreased risk of colon and rectal tumors. A significant interaction of educational level with parity and months of first child lactation was also observed. Conclusion These findings suggest a protective role of exogenous hormones in gastric and colorectal cancer risk. The role of endogenous hormones remains unclear.

Night shift work and stomach cancer risk in the MCC-Spain study

Objectives Night shift work has been classified as a probable human carcinogen by the International Agency for Research on Cancer, based on experimental studies and limited evidence on human breast cancer risk. Evidence at other cancer sites is scarce. We evaluated the association between night shift work and stomach cancer risk in a population-based case–control study. Methods A total of 374 incident stomach adenocarcinoma cases and 2481 population controls were included from the MCC-Spain study. Detailed data on lifetime night shift work were collected including permanent and rotating shifts, and their cumulative duration (years). Adjusted unconditional logistic regression models were used in analysis. Results A total of 25.7% of cases and 22.5% of controls reported ever being a night shift worker. There was a weak positive, non-significant association between ever having had worked for at least 1 year in permanent night shifts and stomach cancer risk compared to never having worked night shifts (OR=1.2, 95% CI 0.9 to 1.8). However, there was an inverse ‘U’ shaped relationship with cumulative duration of permanent night shifts, with the highest risk observed in the intermediate duration category (OR 10–20 years=2.0, 95% CI 1.1 to 3.6) (p for trend=0.19). There was no association with ever having had worked in rotating night shifts (OR=0.9, 95% CI 0.6 to 1.2) and no trend according to cumulative duration (p for trend=0.68). Conclusion We found no clear evidence concerning an association between night shift work and stomach cancer risk.

Risk Model for Prostate Cancer Using Environmental and Genetic Factors in the Spanish Multi-Case-Control (MCC) Study

Prostate cancer (PCa) is the second most common cancer among men worldwide. Its etiology remains largely unknown compared to other common cancers. We have developed a risk stratification model combining environmental factors with family history and genetic susceptibility. 818 PCa cases and 1,006 healthy controls were compared. Subjects were interviewed on major lifestyle factors and family history. Fifty-six PCa susceptibility SNPs were genotyped. Risk models based on logistic regression were developed to combine environmental factors, family history and a genetic risk score. In the whole model, compared with subjects with low risk (reference category, decile 1), those carrying an intermediate risk (decile 5) had a 265% increase in PCa risk (OR = 3.65, 95% CI 2.26 to 5.91). The genetic risk score had an area under the ROC curve (AUROC) of 0.66 (95% CI 0.63 to 0.68). When adding the environmental score and family history to the genetic risk score, the AUROC increased by 0.05, reaching 0.71 (95% CI 0.69 to 0.74). Genetic susceptibility has a stronger risk value of the prediction that modifiable risk factors. While the added value of each SNP is small, the combination of 56 SNPs adds to the predictive ability of the risk model.

Antibody reactivity against Helicobacter pylori proteins in a sample of the Spanish adult population in 2008‐2013

Differences in Helicobacter pylori protein expression have been related to the risk of severe gastric diseases. In Spain, a marked geographic pattern in gastric cancer mortality has long been reported. Objective: To characterize antibody reactivity patterns against 16 H. pylori proteins, by age, sex, and region of birth, in a large sample of the Spanish adult population.