Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium.

BACKGROUND: Type 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time-risk relationship are unclear, and there is limited information on the role of antidiabetic medications. PATIENTS AND METHODS: We analyzed individual-level data from 15 case-control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates. RESULTS: Overall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72-2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03-1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14-0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75-8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53-1.70, for ≥15 years). CONCLUSION: This study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration-risk relationship.

Ulcer, gastric surgery and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Peptic ulcer and its treatments have been associated to pancreatic cancer risk, although the evidence is inconsistent. METHODS: We pooled 10 case-control studies within the Pancreatic Cancer Case-control Consortium (PanC4), including 4717 pancreatic cancer cases and 9374 controls, and estimated summary odds ratios (OR) using multivariable logistic regression models. RESULTS: The OR for pancreatic cancer was 1.10 [95% confidence interval (CI) 0.98-1.23] for history of ulcer (OR = 1.08 for gastric and 0.97 for duodenal ulcer). The association was stronger for a diagnosis within 2 years before cancer diagnosis (OR = 2.43 for peptic, 1.75 for gastric, and 1.98 for duodenal ulcer). The OR was 1.53 (95% CI 1.15-2.03) for history of gastrectomy; however, the excess risk was limited to a gastrectomy within 2 years before cancer diagnosis (OR = 6.18, 95% CI 1.82-20.96), while no significant increased risk was observed for longer time since gastrectomy. No associations were observed for pharmacological treatments for ulcer, such as antacids, H2-receptor antagonists, or proton-pump inhibitors. CONCLUSIONS: This uniquely large collaborative study does not support the hypothesis that peptic ulcer and its treatment materially affect pancreatic cancer risk. The increased risk for short-term history of ulcer and gastrectomy suggests that any such association is due to increased cancer surveillance.

Changing trends of diseases in Eastern Europe: closing the gap.

One of the greatest challenges in Europe at the beginning of the 21st Century is the wide east-west health gap. In 2008, the difference in life expectancy between men in some Western European countries and Russia was 20 years. Whilst trends for life expectancy at birth have improved in many areas around the world, those for Russia, as well as those for some other former Soviet Union countries, have fluctuated greatly and have not shown signs of growth since the middle of the 20th Century. This problem is most acute in Russia and former Soviet Union countries, but is also far from being solved in the states that have made significant progress since 1990 and joined the European Union in the 21st Century. One of the priorities of the Polish presidency of the European Union, which began in July 2011, is the call for a European solidarity for health that could help to close the health gap dividing Europe.

Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved. METHODS: To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case-control studies (5585 cases and 11,827 controls) participating in the International Pancreatic Cancer Case-Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models. RESULTS: Compared with abstainers and occasional drinkers (< 1 drink per day), we observed no association for light-to-moderate alcohol consumption (≤ 4 drinks per day) and pancreatic cancer risk; however, associations were above unity for higher consumption levels (OR = 1.6, 95% confidence interval 1.2-2.2 for subjects drinking ≥ 9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area. CONCLUSION: This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer.

Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4).

BACKGROUND: To evaluate the dose-response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables. METHODS: We analyzed data from 12 case-control studies within the International Pancreatic Cancer Case-Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models. RESULTS: Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0-1.3) for former smokers and 2.2 (95% CI 1.7-2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR=3.4 for ≥35 cigarettes per day, P for trend<0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR=2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years. CONCLUSIONS: This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ∼20 years after quitting.

Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Cigarette smoking is the best-characterized risk factor for pancreatic cancer. However, data are limited for other tobacco smoking products and smokeless tobacco. MATERIALS AND METHODS: We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk of pancreatic cancer using data from 11 case-control studies (6056 cases and 11,338 controls) within the International Pancreatic Cancer Case-Control Consortium (PanC4). Pooled odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models adjusted for study center and selected covariates. RESULTS: Compared with never tobacco users, the OR for cigar-only smokers was 1.6 (95% CI: 1.2-2.3), i.e. comparable to that of cigarette-only smokers (OR 1.5; 95% CI 1.4-1.6). The OR was 1.1 (95% CI 0.69-1.6) for pipe-only smokers. There was some evidence of increasing risk with increasing amount of cigar smoked per day (OR 1.82 for ≥ 10 grams of tobacco), although not with duration. The OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI 0.75-1.3). CONCLUSION: This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use.

Does drinking pattern modify the effect of alcohol on the risk of coronary heart disease? Evidence from a meta-analysis.

OBJECTIVE: To evaluate the strength of the evidence provided by epidemiological literature investigating drinking pattern as effect modifier of alcohol intake on the risk of coronary heart disease (CHD). DESIGN: Meta-analysis of observational studies. DATA SOURCES: Medline, citation tracking, from 1966 to 2006. REVIEW METHODS: Original studies investigating the amount of alcohol intake, combined with the frequency of alcohol consumption and/or pattern of alcohol drinking affecting the risk of CHD were extracted. Among them, cohort and case-control studies reporting sufficient data to perform statistical analyses and using people who abstained from alcohol as the reference were included. RESULTS: Six (4 cohort and 2 case-control) out of 118 studies reviewed met the inclusion criteria. Compared with those who abstained from alcohol, regular heavy drinkers and heavy irregular or binge drinkers showed significantly different pooled relative risks of 0.75 (95% confidence interval 0.64 to 0.89) and 1.10 (1.03 to 1.17) respectively. The dose-response relation between the amount of alcohol intake and CHD risk was significantly different in regular and irregular drinkers. A J-shaped curve, with nadir around 28 grams of alcohol per week, and last protective dose of 131 grams per week, was obtained including drinkers who consumed alcohol for 2 days a week or less. Conversely, in people who consumed alcohol for more than 2 days a week a significant protective effect was seen even when drinking high amounts of alcohol. CONCLUSION: This meta-analysis suggests that binge and heavy irregular drinking modify the favourable effect of alcohol intake on the CHD risk. However, this conclusion should be taken with caution because of the small number of studies considered.

Human papillomavirus infection in women with and without cervical cancer in Warsaw, Poland.

Cervical cancer incidence and mortality in Poland is among the highest in Europe. To investigate infection with different human papillomaviruses (HPV) in Warsaw, Poland, we obtained cervical cell specimens from 834 women aged 18-59 years from the general population, and 88 cervical cancers. DNA of 44 HPV types was detected using a GP5+/6+-based PCR assay. HPV prevalence was 16.6% in the general female population, being highest (24.2%) in women aged 25-34 years, notably among unmarried women (37.3%). HPV prevalence fell to 8.6% at ages 55-59. High-risk HPV prevalence was 11.3%, with HPV16 being the most common type (3.7%). All but one cervical cancer were high-risk HPV-positive, although the importance of HPV16 (73%) was much greater, and multiple infections fewer (1%), than among HPV-positive women in the general female population. In summary, we report a relatively high burden of HPV infection in Warsaw, Poland, where 79% of cervical cancers are theoretically preventable by HPV16/18 vaccines.

Genetic variation in five genes important in telomere biology and risk for breast cancer.

Telomeres, consisting of TTAGGG nucleotide repeats and a protein complex at chromosome ends, are critical for maintaining chromosomal stability. Genomic instability, following telomere crisis, may contribute to breast cancer pathogenesis. Many genes critical in telomere biology have limited nucleotide diversity, thus, single nucleotide polymorphisms (SNPs) in this pathway could contribute to breast cancer risk. In a population-based study of 1995 breast cancer cases and 2296 controls from Poland, 24 SNPs representing common variation in POT1, TEP1, TERF1, TERF2 and TERT were genotyped. We did not identify any significant associations between individual SNPs or haplotypes and breast cancer risk; however, data suggested that three correlated SNPs in TERT (-1381C>T, -244C>T, and Ex2-659G>A) may be associated with reduced risk of breast cancer among individuals with a family history of breast cancer (odds ratios 0.73, 0.66, and 0.57, 95% confidence intervals 0.53-1.00, 0.46-0.95 and 0.39-0.84, respectively). In conclusion, our data do not support substantial overall associations between SNPs in telomere pathway genes and breast cancer risk. Intriguing associations with variants in TERT among women with a family history of breast cancer warrant follow-up in independent studies.

Reproductive risk factors for endometrial cancer among Polish women.

We conducted a population-based case-control study of reproductive factors in Warsaw and Lódz, Poland, in 551 incident endometrial cancer cases and 1925 controls. The reproductive variable most strongly related to risk was multiparity, with subjects with three or more births having a 70% lower risk than the nulliparous women. The reduced risk was particularly strong below 55 years of age. Subjects with older ages at a first birth were also at reduced risk even after adjustment for number of births. Ages at last birth or intervals since last birth were not strongly related to risk. Spontaneous abortions were unrelated to risk, but induced abortions were associated with slight risk increases (odds ratios=1.28, 95% confidence intervals 0.8-2.1 for 3+ vs no abortions). The absence of effects on risk of later ages at, or short intervals since, a last birth fails to support the view that endometrial cancer is influenced by mechanical clearance of initiated cells. Alternative explanations for reproductive effects should be sought, including alterations in endogenous hormones.

Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer.

Helicobacter pylori infection, the dominant risk factor for gastric cancers, has been shown to elicit T helper type 1 (Th1) polarized immunological responses. We conducted a population-based study of 305 gastric cancer cases and 427 age- and gender-matched controls in Warsaw, Poland, to evaluate the association with several variants in genes responsible for Th1-cell-mediated response. Genotyping was performed on genomic DNA by TaqMan(TM) assays to determine TNFA (-308 G>A, -417 G>A, -555 G>A, -1036 C>T, -1042 C>A, -1210 T>C), IL1A (-889 C>T), IFNGR2 (Ex7-128 T>C, Ex2-34 C>G and Ex2-16 A>G) and IL12A (IVS2-798 T>A, IVS2-701 C>A and Ex7+277 G>A) polymorphisms. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for sex, age, education and smoking status. Out of six single nucleotide polymorphisms (SNPs) tested in TNFA, gastric cancer risk was significantly associated with the TNFA (-308 G>A) polymorphism, with ORs of 1.4 (95% CI: 1.0-2.0) for the G/A and 2.5 (95% CI: 1.3-4.9) for the A/A genotype carriers, when compared with the more frequent genotype (G/G) (P-trend < 0.001). Among the three tested SNPs in the IFNGR2 gene, only the Ex7-128C>T polymorphism was associated with increased risk, with ORs of 1.5 (95% CI: 1.0-2.3) for T/C and 1.7 (95% CI: 1.1-2.7) for C/C carriers when compared with T/T carriers (P-trend = 0.01). Subjects carrying both IFNGR2 Ex7-128 C/C and TNFA -308 A/A genotypes had the highest risk (OR = 5.5, 95% CI: 1.5-19.4), although the interaction was not statistically significant. IL1A (-889 C>T) and the three examined IL12A variants were unrelated to gastric cancer risk. Our findings suggest that two Th1-related polymorphisms (TNFA -308 A>G and IFNGR2 Ex7-128 C>T) may increase the risk of gastric cancer.

Established breast cancer risk factors by clinically important tumour characteristics.

Breast cancer is a morphologically and clinically heterogeneous disease; however, it is less clear how risk factors relate to tumour features. We evaluated risk factors by tumour characteristics (histopathologic type, grade, size, and nodal status) in a population-based case-control of 2386 breast cancers and 2502 controls in Poland. Use of a novel extension of the polytomous logistic regression permitted simultaneous modelling of multiple tumour characteristics. Late age at first full-term birth was associated with increased risk of large (> 2 cm) tumours (odds ratios (95% confidence intervals) 1.19 (1.07-1.33) for a 5-year increase in age), but not smaller tumours (P for heterogeneity adjusting for other tumour features (Phet) = 0.007). On the other hand, multiparity was associated with reduced risk for small tumours (0.76 (0.68-0.86) per additional birth; Phet = 0.004). Consideration of all tumour characteristics simultaneously revealed that current or recent use of combined hormone replacement therapy was associated with risk of small (2.29 (1.66-3.15)) and grade 1 (3.36 (2.22-5.08)) tumours (Phet = 0.05 for size and 0.0008 for grade 1 vs 3), rather than specific histopathologic types (Phet = 0.63 for ductal vs lobular). Finally, elevated body mass index was associated with larger tumour size among both pre- and postmenopausal women (Phet = 0.05 and 0.0001, respectively). None of these relationships were explained by hormone receptor status of the tumours. In conclusion, these data support distinctive risk factor relationships by tumour characteristics of prognostic relevance. These findings might be useful in developing targeted prevention efforts.

Occupation and risk of stomach cancer in Poland.

BACKGROUND: In spite of the dramatic decline in the incidence of stomach cancer in the twentieth century, Poland has one of the highest rates in the world. AIMS: To evaluate the risk of stomach cancer by grouped occupations and industries, as well as by some specific occupational exposures. METHODS: Cases (n = 443) were newly diagnosed with stomach adenocarcinomas between 1994 and 1996. Controls (n = 479) were randomly selected from the general population in Warsaw. RESULTS: Only a few occupations and industries were associated with significantly increased risks of stomach cancer. The most suggestive finding was for work in the leather goods industry. Risk was also significantly increased among men working in fabricated metal production and among women ever employed as managers and governmental officials. Men ever employed as teaching professionals and women employed as technical and science professionals had significantly decreased risks of stomach cancer. Among men, a significant positive trend in risk with duration of employment was observed for work in the leather industry and special trade construction. No significantly increased risks were observed for specific exposures assessed by a job-exposure matrix or by self-reports. However among men there were non-significantly increased risks with 10 or more years exposure to asbestos, metal dust, and nitrosamines assessed by a job-exposure matrix. CONCLUSIONS: Employment in the leather goods industry, special trade construction, and metal fabrication was associated with an increased risk of stomach cancer among men. However, there were only weak associations with specific exposures. Occupational exposures do not contribute substantially to the high rates of stomach cancer in Poland.

Trends in cancer mortality in the European Union and accession countries, 1980-2000.

Cancer mortality rates and trends over the period 1980-2000 for accession countries to the European Union (EU) in May 2004, which include a total of 75 million inhabitants, were abstracted from the World Health Organization (WHO) database, together with, for comparative purposes, those of the current EU. Total cancer mortality for men was 166/100,000 in the EU, but ranged between 195 (Lithuania) and 269/100,000 (Hungary) in central and eastern European accession countries. This excess related to most cancer sites, including lung and other tobacco-related neoplasms, but also stomach, intestines and liver, and a few neoplasms amenable to treatment, such as testis, Hodgkin's disease and leukaemias. Overall cancer mortality for women was 95/100,000 in the EU, and ranged between 100 and 110/100,000 in several central and eastern European countries, and up to 120/100,000 in the Czech Republic and 138/100,000 in Hungary. The latter two countries had a substantial excess in female mortality for lung cancer, but also for several other sites. Furthermore, for stomach and especially (cervix) uteri, female rates were substantially higher in central and eastern European accession countries. Over the last two decades, trends in mortality were systematically less favourable in accession countries than in the EU. Most of the unfavourable patterns and trends in cancer mortality in accession countries are due to recognised, and hence potentially avoidable, causes of cancer, including tobacco, alcohol, dietary habits, pollution and hepatitis B, plus inadequate screening, diagnosis and treatment. Consequently, the application of available knowledge on cancer prevention, diagnosis and treatment may substantially reduce the disadvantage now registered in the cancer mortality of central and eastern European accession countries.

Smoking, alcohol, diet, dentition and sexual practices in the epidemiology of oral cancer in Poland.

The effect of smoking, drinking, diet, dental care and sexual habits on the risk of oral and pharyngeal cancer was investigated in a case-control study conducted in Warsaw, Poland. The study comprised 122 patients (including 44 females) aged 23-80 years with histologically confirmed cancer of oral cavity and pharynx. Controls were 124 subjects (including 52 females) admitted to the hospital for different non-neoplastic conditions unrelated to tobacco and alcohol consumption, with frequency matched to cases by age and sex. Smoking and drinking were strongly associated with an increased risk of oral cancer. Among consumers of both products, risks of oral cancer tended to combine in a multiplicative fashion and were increased more than 14-fold among those who consumed more than 15 cigarettes and seven or more drinks per day. Cessation of smoking was associated with reduced risk of this cancer. The risks varied by type of cigarettes smoked, being lower among those consuming filtered cigarettes only (OR = 1.6) than nonfilter (OR = 6.5) or mixed (OR = 4.2) cigarettes. High fruit intake was associated with significantly decreased risk (OR = 0.4) with the strongest significant inverse association found for fruit juices and citrus fruits ( < 0.01). After adjustment for tobacco smoking and alcohol drinking, poor dentition as evidenced by missing teeth, frequency of dental check-ups and frequency of teeth brushing emerged as a strong risk factor. Number of missing teeth and frequency of dental check-ups and frequency of tooth brushing showed increased ORs of 9.8, 11.9 and 3.2, respectively. Denture wearing did not affect oral cancer risk. No differences were detected in sexual practices (including oral sex and intercourse with prostitutes). In terms of attributable risk, smoking accounted for 57% of oral cancer cases in Poland, alcohol for 31% and low fruit intake for 12%. Attributable risks for low frequency of tooth brushing and dental check-ups were 56% and 47%, respectively. In conclusion, smoking and drinking cessation and increase of fresh fruit intake are likely to be effective preventive measures against oral cancer. These findings indicate also that poor oral hygiene may be an independent risk factor.