Gallbladder disease and pancreatic cancer risk: a multicentric case-control European study.

BACKGROUND AND AIMS: The overall evidence on the association between gallbladder conditions (GBC: gallstones and cholecystectomy) and pancreatic cancer (PC) is inconsistent. To our knowledge, no previous investigations considered the role of tumour characteristics on this association. Thus, we aimed to assess the association between self-reported GBC and PC risk, by focussing on timing to PC diagnosis and tumour features (stage, location, and resection). METHODS: Data derived from a European case-control study conducted between 2009 and 2014 including 1431 PC cases and 1090 controls. We used unconditional logistic regression models to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for recognized confounders. RESULTS: Overall, 298 (20.8%) cases and 127 (11.6%) controls reported to have had GBC, corresponding to an OR of 1.70 (95% CI 1.33-2.16). The ORs were 4.84 (95% CI 2.96-7.89) for GBC diagnosed <3 years before PC and 1.06 (95% CI 0.79-1.41) for ≥3 years. The risk was slightly higher for stage I/II (OR = 1.71, 95% CI 1.15-2.55) vs. stage III/IV tumours (OR = 1.23, 95% CI 0.87-1.76); for tumours sited in the head of the pancreas (OR = 1.59, 95% CI 1.13-2.24) vs. tumours located at the body/tail (OR = 1.02, 95% CI 0.62-1.68); and for tumours surgically resected (OR = 1.69, 95% CI 1.14-2.51) vs. non-resected tumours (OR = 1.25, 95% CI 0.88-1.78). The corresponding ORs for GBC diagnosed ≥3 years prior PC were close to unity. CONCLUSION: Our study supports the association between GBC and PC. Given the time-risk pattern observed, however, this relationship may be non-causal and, partly or largely, due to diagnostic attention and/or reverse causation.

Dissemination of health technologies: Trends in the use of diagnostic test in breast cancer screening.

OBJECTIVE: To analyse trends in the use of diagnostic test in breast cancer screening programs in Spain. MATERIALS AND METHODS: Retrospective study of 542,695 women who had undergone at least one screening mammogram in any of the screening centres of three administrative regions in Spain, between 1996 and 2011. Process measures were: overall recall rate, overall invasive test rate, and rates of each type of invasive test (fine-needle aspiration biopsy, core-needle biopsy and surgical biopsy). As results measures were included detection of benign lesions rate, ductal in situ cancer rate and invasive cancer rate. Adjusted by age rates were estimated year by year for each measure and, also, the annual percent of change and its corresponding joint points. RESULTS: Core-needle biopsy rates decreased between 1996 and 1999 and changed trends in 1999-2011 with an increase of 4.9% per year. Overall recall rate declined by 4.6% from 1999 to 2004, invasive test rate declined between 1996 and 2004 by 24.3%. Fine-needle aspiration biopsy rate changes were: a 22.4% declined per year (1996-1998), and 13.5% declined per year (1998-2005). Benign lesions rate decreased from 1996 to 2011, 21.4% per year (1996-2001) and 6.0% (2001-2011). Ductal carcinoma in situ and invasive cancer had no-statistically significant changes. CONCLUSION: The introduction of core-needle biopsy was slow and not concurrent with the reduction in the use of other diagnostic tests, but also represented a reduction in the rate of overall diagnostic tests and in the detection rate of benigns lesions without affecting the cancer detection rates.

Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives.

Background: Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Methods: Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. Results: FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. Conclusions: The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies.

A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. METHODS: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. RESULTS: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01-12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11-2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36-0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9-16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29-2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. CONCLUSIONS: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis between MP and PDAC points to a mechanistic link between these conditions.

Prediction of non-muscle invasive bladder cancer outcomes assessed by innovative multimarker prognostic models.

BACKGROUND: We adapted Bayesian statistical learning strategies to the prognosis field to investigate if genome-wide common SNP improve the prediction ability of clinico-pathological prognosticators and applied it to non-muscle invasive bladder cancer (NMIBC) patients. METHODS: Adapted Bayesian sequential threshold models in combination with LASSO were applied to consider the time-to-event and the censoring nature of data. We studied 822 NMIBC patients followed-up >10 years. The study outcomes were time-to-first-recurrence and time-to-progression. The predictive ability of the models including up to 171,304 SNP and/or 6 clinico-pathological prognosticators was evaluated using AUC-ROC and determination coefficient. RESULTS: Clinico-pathological prognosticators explained a larger proportion of the time-to-first-recurrence (3.1 %) and time-to-progression (5.4 %) phenotypic variances than SNPs (1 and 0.01 %, respectively). Adding SNPs to the clinico-pathological-parameters model slightly improved the prediction of time-to-first-recurrence (up to 4 %). The prediction of time-to-progression using both clinico-pathological prognosticators and SNP did not improve. Heritability (h (2)) of both outcomes was <1 % in NMIBC. CONCLUSIONS: We adapted a Bayesian statistical learning method to deal with a large number of parameters in prognostic studies. Common SNPs showed a limited role in predicting NMIBC outcomes yielding a very low heritability for both outcomes. We report for the first time a heritability estimate for a disease outcome. Our method can be extended to other disease models.

Pre- and postnatal exposure to tobacco smoke and respiratory outcomes during the first year.

The different role of prenatal and postnatal exposure to tobacco smoke in respiratory outcomes in infants has not yet been clearly established. Our objective is to assess the effects of these exposures on the risk of respiratory outcomes during the first year of life of infants from a Spanish multicenter cohort study. A total of 2506 women were monitored until delivery. About 2039 infants made up the final population. The outcomes were caused by the occurrence of the following: otitis, cough persisting for more than 3 weeks, lower respiratory tract symptoms (wheezing or chestiness), and lower respiratory tract infections (bronchitis, bronchiolitis, or pneumonia). The relationship between prenatal and postnatal exposure and health outcomes was explored using logistic regression analysis. Maternal smoking during pregnancy increased the odds for wheezing (OR: 1.41, 95% CI: 0.99-2.01) and chestiness (OR: 1.46, 95% CI: 1.03-2.01). Postnatal exposure from fathers was associated with otitis (OR: 1.25, 95% CI: 1.01-1.54). Passive exposure at work of non-smoking mothers during pregnancy was related to cough (OR: 1.62, 95% CI: 1.05-2.51). Exposure to tobacco smoke was related to a higher risk of experiencing respiratory outcomes in young infants. Prenatal exposure was that most clearly associated with the respiratory outcomes analyzed.

LINE-1 methylation in leukocyte DNA, interaction with phosphatidylethanolamine N-methyltransferase variants and bladder cancer risk.

BACKGROUND: Aberrant global DNA methylation is shown to increase cancer risk. LINE-1 has been proven a measure of global DNA methylation. The objectives of this study were to assess the association between LINE-1 methylation level and bladder cancer risk and to evaluate effect modification by environmental and genetic factors. METHODS: Bisulphite-treated leukocyte DNA from 952 cases and 892 hospital controls was used to measure LINE-1 methylation level at four CpG sites by pyrosequencing. Logistic regression model was fitted to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Interactions between LINE-1 methylation levels and environmental and genetic factors were assessed. RESULTS: The risk of bladder cancer followed a nonlinear association with LINE-1 methylation. Compared with subjects in the middle tertile, the adjusted OR for subjects in the lower and the higher tertiles were 1.26 (95% CI 0.99-1.60, P=0.06) and 1.33 (95% CI 1.05-1.69, P=0.02), respectively. This association significantly increased among individuals homozygous for the major allele of five single-nucleotide polymorphisms located in the phosphatidylethanolamine N-methyltransferase gene (corrected P-interaction<0.05). CONCLUSIONS: The findings from this large-scale study suggest that both low and high levels of global DNA methylation are associated with the risk of bladder cancer.

Work in the textile industry in Spain and bladder cancer.

BACKGROUND/OBJECTIVE: Textile manufacturing is a complex industry that has frequently been associated with bladder cancer. However, results have not been consistent. This study investigated the risk of bladder cancer in Spanish textile workers. METHODS: We analysed data from a multicentre hospital-based case-control study carried out in Spain (1998-2001) including 1219 cases of bladder cancer and 1271 controls. Of those, 126 cases and 122 controls reported a history of employment in the textile industry. Lifetime occupational history was obtained using a computer-assisted personal interview. Occupations, locations and materials used in the textile industry were assessed using a detailed questionnaire and expert assessment. RESULTS: Overall, no increased risk of bladder cancer was found for textile workers, including duration of employment analysis. Increased risks were observed for weavers (OR = 1.82, 95% CI 0.95 to 3.47), for workers in winding/warping/sizing (OR 4.11, 95% CI 1.58 to 10.71) and for those exposed to synthetic materials (OR 1.89, 95% CI 1.00 to 3.56). Working for more than 10 years appeared to be associated with an increased risk for weavers (OR 2.27, 95% CI 0.97 to 5.34), for those who had ever worked in winding/warping/sizing (OR 11.03, 95% CI 1.37, 88.89), for workers in the weaving room (OR 2.94, 95% CI 1.24 to 7.01) and for those exposed to synthetic (OR 2.62, 95% CI 1.14 to 6.01) or cotton (OR 2.00, 95% CI 1.04 to 3.87) materials. Statistically significant higher risks were also found for specific combinations of occupations or locations with exposure to synthetics and cotton. CONCLUSIONS: There was no overall increased risk for textile workers, but increased risks were found for specific groups of workers. Our findings indicate that observed risks in previous studies may be better evaluated by analysis of materials used or section worked within the industry and occupation.

Occupation and bladder cancer in a hospital-based case-control study in Spain.

OBJECTIVES: We investigated the association between occupation and bladder cancer in a hospital-based case-control study conducted in Spain. METHODS: 1219 patients with transitional cell carcinoma of the urinary bladder and 1271 controls selected from 18 hospitals in Spain between June 1998 and September 2000 provided detailed information on life-time occupational history, smoking habits, medical history, and other factors. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for each occupation and industry, adjusting for age, hospital region, smoking duration, and employment in a high-risk occupation for bladder cancer. RESULTS: Statistically significant increased risks were observed among men employed as machine operators in the printing industry (OR 5.4; 95% CI 1.6 to 17.7), among men employed in the transportation equipment industry (OR 1.6; 95% CI 1.1 to 2.6) and among those who had worked for >/=10 years in the electrical/gas/sanitary services (OR 3.9; 95% CI 1.5 to 10.4) and in hotels and other lodgings (OR 3.1; 95% CI 1.3 to 7.3). Men who worked as miscellaneous mechanics and repairers (OR 2.0; 95% CI 1.1 to 3.6) and as supervisors in production occupations (OR 2.1; 95% CI 1.2 to 3.6) also had excess risks for bladder cancer. Male farmers and those who worked in crop and livestock production had decreased risks for bladder cancer. We found no significant associations between occupation or industry and bladder cancer risk among women. CONCLUSIONS: We did not observe excess bladder cancer risk for many of the occupations identified as being a priori at high risk. Examination of more detailed job exposure information should help clarify these associations.

Assessment of lifetime exposure to trihalomethanes through different routes.

OBJECTIVES: To evaluate lifetime exposure to trihalomethanes (THM) through ingestion, inhalation, and dermal absorption in a hospital based case-control study of bladder cancer conducted between 1998 and 2001 in five areas of Spain. The study base was comprised of subjects living in the catchment areas of the participating hospitals. METHODS: Individual information on water related habits was obtained from personal interviews of 1219 cases and 1271 controls: residential and occupational history, drinking water source at each residence and job, amount of water consumption, frequency and duration of showering, bathing, and swimming pool attendance. THM levels, water source history, and year when chlorination started in study areas were ascertained through measurements in drinking water samples and questionnaires to water companies and local authorities. Estimates of THM levels covered 79% of the subjects' person-years of exposure. RESULTS: Current and historical average THM levels in water were correlated. Control subjects reported that drinking water source in the last residence was municipal for 63%, bottled for 22%, private well for 2%, and other sources for 13%. For the time window between age 15 and the time of interview, average residential THM level was 32.2 mug/l. THM exposure through ingestion was 23.7 mug/day on average, and was correlated with the ingestion THM level in the workplace. Overall, 79% usually took showers, 16% usually took baths, and 13% had ever attended a swimming pool. Between 21% and 45% of controls unexposed to THM through ingestion were evaluated as moderately or highly exposed through showering or bathing, and 5-10% were exposed through swimming in pools. CONCLUSION: The importance of evaluating different routes is underscored by findings from experimental studies showing substantial differences in THM uptake and internal distribution by route.

Gender-related differences in clinical and pathological characteristics and therapy of bladder cancer.

OBJECTIVE: To confirm the very high male:female ratios previously observed among Spanish bladder cancer patients and to assess gender differences in tumoral characteristics, diagnostic procedures, and treatment in a large series of consecutive bladder cancer patients. PATIENTS AND METHODS: All newly diagnosed bladder cancer patients (n=615) in 17 Spanish hospitals, between 1997-2000, were included. Information was collected both through personal interviews to patients and from medical records using a structured form. RESULTS: Seventy-six percent of tumours were superficial. The male:female ratio was 6.7 and it was similar for superficial and infiltrating tumours. Women were older than men at the diagnosis of bladder cancer (68.2+/-9.4 years versus 65.7+/-9.7 years, p=0.01). Ten percent of superficial tumours in women, versus 3% in men, were classified as "other histological types" (p=0.008). T1GIII tumours were more frequent among men (17% versus 7%, p=0.047). On the other hand, women were more likely to present with 0a-stage tumours (48.6% versus 35.5%, p=0.04), multiple tumours (50% versus 29%, trend test: 0.005), multi-centric tumours (54% versus 38%, p=0.019), and larger infiltrating masses (5.2 cm versus 3.8 cm, p=0.03) than men. Among 0a-stage tumours, only 23% of women compared to 54% of men received transurethral resection (TUR) alone (p=0.002). Women were almost five-fold more likely to receive additional therapies to TUR (p=0.004) after adjusting for age, geographical area, stage, tumoral size, nuclear grade, and multiplicity. CONCLUSION: The study confirms the very high male:female ratio of bladder cancer in Spain. We found substantial differences in the pathological characteristics of tumours from men and women. There was a tendency for women to receive more frequently non-standard, more aggressive, therapy than men.

[Characteristics of lung cancer in patients exposed to silica at work. A comparison of exposed and non-exposed individuals]. / Características del cáncer de pulmón en pacientes con exposición laboral a la sílice. Estudio comparativo entre individuos expuestos y no expuestos.

INTRODUCTION: In 1977 silica was listed as a group 1 carcinogen (demonstrated in humans) by the International Agency for Research on Cancer. However, conflicting results from various studies have kept debate alive as to its carcinogenic capacity. The interest of this debate lies in the large number of workers exposed to silica. OBJECTIVE: To analyze the differential characteristics of lung cancer among silica exposed and silica non-exposed individuals, to identify indirectly a possible carcinogenic effect of silica. METHODS: For all males with a diagnosis of lung cancer over a period of 22 consecutive months at the National Silicosis Institute (Oviedo, Spain), we recorded work history, age, smoking habits, spirometry, the presence of pneumoconiosis and histology. RESULTS: Comparing the results for silica exposed and non-exposed individuals, we found significant differences for age (63.7 8.8 and 66.7 8.6 y, respectively; p < 0.05), smoking (44.1 22.4 and 48.9 22.3 packs/year; p < 0.05) and a Tiffeneau index under 70% (in 78% of exposed vs. 55% of non-exposed patients; p < 0.05). No significant differences in histology, signs and symptoms or radiographs were observed between the two groups. In the multifactorial analysis in function of age of onset, exposure to silica continued to be an independent predictor. CONCLUSION: Our results show that the clinical and radiological signs and histology of patients exposed or non-exposed to silica did not differ. However, lung cancer appears earlier among individuals with work-related exposure to silica and lower rates of tobacco smoking, suggesting some carcinogenic effect for silica.

Lung cancer risk in iron and steel foundry workers: a nested case control study in Asturias, Spain.

BACKGROUND: Workers of iron and steel foundries have a high lung cancer risk but the findings on specific processes associated with this risk are inconsistent. We examined the risk of lung cancer among workers in the main industrial processes of a large iron and steel foundry in Asturias, Spain. METHODS: We conducted a nested case-control study comprised of 144 male lung cancer cases and 558 controls, selected from a study base of about 24,400 workers employed in the industry between 1952 and 1995. Cases were identified through linkage of industry records with those of two cancer registries. Controls were selected through industry records using incidence density sampling, were matched to cases by age and date of birth and had to be alive and without lung cancer at the time of selection. Smoking history was obtained through company medical records. Unconditional logistic regression was applied and all ORs were adjusted for age and tobacco consumption. RESULTS: Workers were, on an average, heavy smokers and a very strong relation was observed for smoking (OR for "ever smoker" = 32.4). Workers having ever been employed in the blast furnace had an excess lung cancer risk (OR = 2.55, 95% CI 1.25-5.21) compared to a reference group of workers not employed in metal producing departments. A similar excess was observed for workers having as their longest held job employment in the blast furnace. A two-fold risk was also observed for workers in the main foundry. For subgroups of workers, tobacco smoking appeared to be an important positive or negative confounder. CONCLUSIONS: In this large Spanish foundry, a high risk was observed for workers employed in departments with high exposure to crystalline silica, PAHs, and various other carcinogenic chemicals. Although comparisons were made between workers of the same industry, smoking habits differed and adjustment by smoking modified considerably the risk estimates.

[Bladder cancer in Asturias, Spain: incidence and trends (1982-1993)]. / Cáncer de vejiga en Asturias: incidencia y evolución (1982-1993).

OBJECTIVES: To assess epidemiological aspects of bladder cancer in Asturias, as a preliminary step before undertaking epidemiological and genetic research of the etiology and survival of bladder neoplasm. METHODS: cases from the Asturias Regional Cancer Registry, Spain were used to calculated annual incidence rates between 1982 and 1993 for Asturias and all its health areas. It has been Standardized incidence ratios with the indirect method for the Asturian areas and other Spanish regions were obtained our results are also compared with other european countries. RESULTS: The trend in bladder cancer in Asturias has been increasing significantly in the last twelve years (11.03 to 15.10 age standardized rate per 100,000). For the different health areas no differences have been identified, while there were not significant differences between our region and other Spanish regions. Standardized rates for Asturian men are in the highest group among European countries, while women rates are at an intermediate level. CONCLUSIONS: Between 1982 and 1993, bladder cancer incidence has been increasing in Asturias. The different behaviour of incidence ratios between men and women and the similar epidemiological factors between Asturias and other parts of Spain point at the need for further epidemiological research to look at the different occupational factors existing in an industrial area like Asturias.

[Lung cancer mortality trends in Asturias (1976-1989)]. / Tendencia de la mortalidad por cáncer de pulmón en Asturias (1976-1989).

BACKGROUND: The Trend of lung cancer mortality rates in Asturias during 14 years is studied in order to know whether it shows the same change pattern described for other countries. METHODS: With this purpose, a graphic study of adjusted and age specific rates, including and analysis of birth cohorts, is carried out, and the change average percentage per year and the sex ratio are calculated. RESULTS: In men, the continuous increase of mortality stands out (change average percentage per year of age adjusted rates of 4.83%) with the only exception of the age group of 45-54 years, which had a variation per year of 1.90%, whereas in women, an overall decrease (-1.18 %) was observed, with the exception of women older than 74 years, who showed an increase of 1.73% per year. In men, the cohorts analysis showed on increasing cohort effect in all generations and a decreasing effect in some women. CONCLUSIONS: Lung cancer will probably go on increasing in Asturias in the next years, among men, whereas in women, it seems that a generalized decrease has been initiated, mainly in the youngest ones and the, increase, observed in other countries in previous years, is not evident. Additional studies, focused on the reasons for these trends, will be necessary and basically the following up of the evolution in men of 45-54 years, whose incipient decrease may indicate a change of trend, which facilitates hypothesis generation and verification.