Faculty Bibliography

BACKGROUND:Previous studies investigating associations between occupational history and risk of exocrine pancreatic cancer (EPC) did not use biomarkers of exposure. The only two studies that measured internal concentrations of organochlorine compounds (OCs) in EPC did not analyse their relationship with occupation. OBJECTIVE:To analyse the relationship between occupational history and blood concentrations of seven OCs in patients with EPC. METHODS:Incident cases of EPC were prospectively identified, and during hospital admission were interviewed face-to-face on occupational history and life-style factors (n = 135). Occupations were coded according to the International Standard of Occupations 1988. Some occupational exposures were also assessed with the Finnish job-exposure matrix (Finjem). Serum concentrations of OCs were analysed by high-resolution gas chromatography with electron-capture detection. RESULTS:Craftsmen and related trades workers had significantly higher concentrations of polychlorinated biphenyl (PCB) congeners 138, 153 and 180. Years worked in agriculture did not influence concentrations of p,p'-DDT, p,p'-DDE, hexachlorobenzene or β-hexachlorocyclohexane. Subjects who ever worked in agriculture had lower concentrations of PCBs (all p < 0.05). Occupational exposure to lead, nickel and low frequency magnetic fields was significantly associated with higher concentrations of PCBs. CONCLUSIONS:Certain occupations were associated with higher concentrations of PCBs, suggesting that these compounds may account for some increased risks found in previous studies. The lack of association between work in agriculture and concentrations of OC pesticides is consistent with occupation playing a lesser role than diet in influencing OC concentrations. Occupational studies on the relationships among exposure to industrial agents and EPC risk may need to consider adjusting for exposure to PCBs.

The diagnostic utility of detecting K-ras mutations for the diagnosis of exocrine pancreatic cancer (EPC) has not been properly studied, and few reports have analysed a clinically relevant spectrum of patients. The objective was to evaluate the clinical validity of detecting K-ras mutations in the diagnosis of EPC in a large sample of clinically relevant patients. We prospectively identified 374 patients in whom one of the following diagnoses was suspected at hospital admission: EPC, chronic pancreatitis, pancreatic cysts, and cancer of the extrahepatic biliary system. Mutations in the K-ras oncogene were analysed by PCR and artificial RFLP in 212 patients. The sensitivity and specificity of the K-ras mutational status for the diagnosis of EPC were 77.7% (95% CI: 69.2-84.8) and 78.0% (68.1-86.0), respectively. The diagnostic accuracy was hardly modified by sex and age. In patients with either mutated K-ras or CEA > 5 ng/ml, the sensitivity and specificity were 81.0% (72.9-87.6) and 62.6% (72.9-87.6), respectively. In patients with mutated K-ras and CEA > 5 ng/ml the sensitivity was markedly reduced. In comparisons with a variety of non-EPC patient groups sensitivity and specificity were both always greater than 75%. In this clinically relevant sample of patients the sensitivity and specificity of K-ras mutations were not sufficiently high for independent diagnostic use. However, it seems premature to rule out the utility of K-ras analysis in conjunction with other genetic and 'omics' technologies.

The objective was to analyze the relationship between occupation (and specific occupational exposures) and risk of exocrine pancreatic cancer (EPC). We conducted a multicenter hospital-based case-control study in Eastern Spain. We included 161 incident cases of EPC (59.6% men, 94 with histological confirmation, of whom 80% had ductal adenocarcinoma). Cases were frequency-matched with 455 controls by sex, age and province of residence. Information was elicited using structured questionnaires. Occupations were coded according to the Spanish version of the International Standard Classification of Occupations 1988. Occupational exposure to a selection of carcinogenic substances was assessed with the Finnish Job-Exposure Matrix (FINJEM). Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multiple logistic regression, adjusting for sex, age, province, education, alcohol and smoking. A higher risk of EPC was associated with having worked as 'Miners, shotfirers, stone cutters and carvers', 'Machinery mechanics and fitters', 'Building trades workers' and 'Motor vehicle drivers' in men, 'Office Clerks' in women, and 'Waiters' in both sexes. Cases with ductal adenocarcinomas were more likely to have been exposed to chlorinated hydrocarbon solvents (OR = 4.1, 95% CI: 1.1-15.2, p-trend = 0.04). We also observed significant associations with exposure to 'synthetic polymer dust exposure' and 'ionizing radiation'. Suggestive increases in risk were observed for 'pesticides', 'diesel and gasoline engine exhaust', and 'hydrocarbon solvents'. Results support the hypothesis that occupational exposure to chlorinated hydrocarbon solvents is associated with exocrine pancreatic cancer.

The use of Polychlorinated biphenyls (PCBs) has been severely restricted due to their high toxicity and persistency in the environment. However, the presence of PCBs in human tissues nowadays is still been reported worldwide. Background exposure predictors of the human PCB body burden require more precise understanding. In the present study, PCB congeners 138, 153, and 180 were quantified in adult adipose tissue samples (n=387) from Granada Province (Southern Spain) and data on potential predictors of PCB concentrations were gathered by questionnaire. Chemical analysis of the selected congeners was done by gas chromatography and mass spectrometry, and multivariate analyses were performed stratifying by gender. PCB residues were quantified in 92% (PCB 153), 90% (PCB 180), and 86% (PCB 138) of the population. Geometric mean concentrations were 161.65+/-4.41 ng/g lipid for PCB 153, 111.62+/-6.27 ng/g lipid for PCB 180, and 38.41+/-8.61 ng/g lipid for PCB 138. Multivariate models explained 30-36% of the variability in PCB concentrations. Age and body mass index (BMI) predicted exposure in both males and females and were positively correlated with the concentration of the three PCB congeners. Occupation and diet predicted exposure in the males, whereas only dietary predictors were observed in the females. Further in-depth studies are required to investigate the influence of dietary habits on the bioaccumulation of PCBs and to evaluate the impact of policies aimed at reducing human exposure.

BACKGROUND:Although virtually all populations worldwide are commonly exposed to numerous persistent organic pollutants (POPs) and human concentrations vary widely, only a few countries conduct nationwide surveillance programs of POP concentrations in representative samples of the general population. OBJECTIVE:To evaluate the distribution of serum concentrations of nineteen POPs and their main predictors in a representative sample of the general population of Catalonia. METHODS:Participants in the Catalan Health Interview Survey aged 18-74 years were interviewed face-to-face, gave blood, and underwent a physical exam. Graphs (including "POP Geoffrey Rose curves") were used to represent the full population distribution of each POP in the 919 participants. Through multivariate statistical models we analyzed the influence on POP concentrations of sex, age, body mass index (BMI), socioeconomic status and, in women, parity. RESULTS:We detected dichlorodiphenyltrichloroethane (p,p'-DDT), dichlorodiphenyldichloroethane (p,p'-DDE), polychlorinated biphenyls (PCBs) congeners 118, 138, 153 and 180, hexachlorobenzene (HCB) and beta-hexachlorocyclohexane (beta-HCH) in more than 85% of the subjects. p,p'-DDE, HCB and beta-HCH showed the highest concentrations (median=399, 159 and 92 ng/g lipid, respectively). Distributions were highly skewed and interindividual differences were up to 7700-fold. POP levels differed significantly by gender, age, BMI, educational level, and parity. CONCLUSIONS:In Catalonia, an advanced European society, exposure to POPs remains common, a vast majority of the population has much lower blood concentrations than a relative minority, and the population distributions of POP are hence highly skewed to the right. Shifting distributions towards lower concentrations requires more energetic policies and population strategies.

BACKGROUND:QUADOMICS is an adaptation of QUADAS (a quality assessment tool for use in systematic reviews of diagnostic accuracy studies), which takes into account the particular challenges presented by '-omics' based technologies. Our primary objective was to evaluate the applicability and consistency of QUADOMICS. Subsequently we evaluated and describe the methodological quality of a sample of recently published studies using the tool. METHODOLOGY/PRINCIPAL FINDINGS/RESULTS:45'-omics'-based diagnostic studies were identified by systematic search of Pubmed using suitable MeSH terms ("Genomics", "Sensitivity and specificity", "Diagnosis"). Three investigators independently assessed the quality of the articles using QUADOMICS and met to compare observations and generate a consensus. Consistency and applicability was assessed by comparing each reviewer's original rating with the consensus. Methodological quality was described using the consensus rating. Agreement was above 80% for all three reviewers. Four items presented difficulties with application, mostly due to the lack of a clearly defined gold standard. Methodological quality of our sample was poor; studies met roughly half of the applied criteria (mean +/- sd, 54.7+/-18.4%). Few studies were carried out in a population that mirrored the clinical situation in which the test would be used in practice, (6, 13.3%); none described patient recruitment sufficiently; and less than half described clinical and physiological factors that might influence the biomarker profile (20, 44.4%). CONCLUSIONS:The QUADOMICS tool can consistently be applied to diagnostic '-omics' studies presently published in biomedical journals. A substantial proportion of reports in this research field fail to address design issues that are fundamental to make inferences relevant for patient care.

BACKGROUND:In exocrine pancreatic cancer (EPC) mechanistic relationships may exist among some organochlorine compounds (OCs) and mutations in the K-ras oncogene, as well as among the latter and dietary factors. OBJECTIVE:To analyze (1) the relationship between food intake and serum concentrations of OCs in EPC patients and (2) the relative influence of food and OCs on the frequency of K-ras mutations in EPC. PATIENTS AND METHODS/METHODS:Incident cases of EPC were prospectively identified, and interviewed face-to-face during hospital admission (N=135 patients with data on OCs and diet, and N=97 with additional information on K-ras status). OCs were measured by high-resolution gas chromatography with electron-capture detection. RESULTS:Consumption of milk and other dairy products was positively associated with concentrations of p,p'-DDT, PCB 138 and PCB 153 (log-transformed betas=0.652, 0.588 and 0.317, respectively; all p<0.05). When adjusted by OCs, dairy products were no longer associated with K-ras. By contrast, after adjusting by consumption of dairy products, patients with the highest concentrations of p,p'-DDT and some PCBs remained more likely to have a K-ras-mutated EPC than patients with lower concentrations (OR for upper tertile of PCB 138=5.5, 95% CI: 1.3-23.4). CONCLUSIONS:Dairy products were a source of OCs. The association between dairy products and K-ras mutations was not independent of OCs. By contrast, the association between OCs and K-ras was not confounded by dairy products. OCs may be more likely to contribute to the occurrence of K-ras mutations than nutrients contained in dairy products.