Smoking Cessation and Short- and Longer-Term Mortality.

BACKGROUND: Smoking cessation reduces mortality and morbidity. However, the extent and rapidity at which cessation reduces contemporary death rates from smoking-related illnesses remain uncertain. METHODS: We pooled current or former versus never cigarette smoker hazard ratios from four national cohorts with linkage to death registries in the United States, United Kingdom, Norway, and Canada among adults 20 to 79 years of age from 1974 to 2018. We calculated excess risk differences and survival, comparing current or never smokers with age-specific cessation and cessation fewer than 3, 3 to 9, or 10 or more years earlier. RESULTS: Among 1.48 million adults followed for 15 years, 122,697 deaths occurred. Adjusting for age, education, alcohol use, and obesity, current smokers had higher hazard ratios for death compared with never smokers (2.8 for women, 2.7 for men). Survival between 40 and 79 years of age was 12 and 13 years less in women and men, respectively, who smoked compared with never smokers (about 24 to 26 years of life lost for smokers who died from smoking combined with zero loss for smokers who did not die from smoking). Former smokers showed lower hazard ratios (1.3 in both women and men). Short-term cessation for fewer than 3 years was associated with a lower excess risk of 95% in women and 90% in men younger than 40 years of age, with notable beneficial associations also in women and men 40 to 49 years of age (81% and 61%, respectively) and 50 to 59 years of age (63% and 54%, respectively). Cessation at every age was associated with longer survival, particularly cessation before 40 years of age. Among all ages and compared with continued smoking, cessation of fewer than 3 years potentially averted 5 years of life lost and cessation for 10 or more years averted about 10 years of life lost, yielding survival similar to that of never smokers. CONCLUSIONS: Quitting smoking at any age, but particularly in younger years, was associated with lower excess mortality overall and from vascular, respiratory, and neoplastic diseases. Beneficial associations were evident as early as 3 years after cessation. (Funded by Canadian Institutes of Health Research [FDN-154277].)

1,3-Butadiene, styrene and selected outcomes among synthetic rubber polymer workers: Updated exposure-response analyses.

OBJECTIVE: - To evaluate exposure-response relationships between 1,3-butadiene and styrene and selected diseases among synthetic rubber polymer workers. METHODS: - 21,087 workers (16,579 men; 4508 women) were followed from 1943 through 2009 to determine mortality outcomes. Cox regression models estimated rate ratios (RRs) and 95% confidence intervals (CIs) by quartile of cumulative exposure to butadiene or styrene and exposure-response trends for cancers of the bladder, lung, kidney, esophagus and pancreas, and for all nonmalignant respiratory disease (NMRD), chronic obstructive pulmonary disease (COPD) and pneumonia. RESULTS: - Bladder cancer RRs were 2.13 (95% CI = 1.03 to 4.41) and 1.64 (95% CI = 0.76 to 3.54) in the highest quartiles of cumulative exposure to butadiene and styrene, respectively, and exposure-response trends were positive for both monomers (butadiene, trend p = 0.001; styrene, trend p = 0.004). Further analyses indicated that the exposure-response effect of each monomer on bladder cancer was demonstrated clearly only in the subgroup with high cumulative exposure (at or above the median) to the other monomer. Lung cancer was not associated with either monomer among men. Among women, lung cancer RRs were above 1.0 in each quartile of cumulative exposure to each monomer, but exposure-response was not seen for either monomer. Male workers had COPD RRs slightly above 1.0 in each quartile of cumulative exposure to each monomer, but there was no evidence of exposure-response among the exposed. Monomer exposure was not consistently associated with COPD in women or with the other cancer outcomes. CONCLUSIONS: - This study found a positive exposure-response relationship between monomer exposures and bladder cancer. The independent effects of butadiene and styrene on this cancer could not be delineated. In some analyses, monomer exposure was associated with lung cancer in women and with COPD in men, but inconsistent exposure-response trends and divergent results by sex do not support a causal interpretation of the isolated positive associations.

1,3-Butadiene, styrene and lymphohaematopoietic cancers among North American synthetic rubber polymer workers: exposure-response analyses.

OBJECTIVE: To evaluate exposure-response between 1,3-butadiene, styrene and lymphohaematopoietic cancers in an updated cohort of workers at six North American plants that made synthetic rubber polymers. METHODS: Employees were followed from 1943 through 2009 to determine mortality outcomes. Cox regression analyses estimated rate ratios (RRs) and 95% CIs by quartile of cumulative exposure to butadiene or styrene, measured in parts per million-years (ppm-years), and exposure-response trends for all leukaemia, lymphoid leukaemia, myeloid leukaemia, acute myeloid leukaemia, non-Hodgkin's lymphoma (NHL), multiple myeloma and all B-cell malignancies. RESULTS: Among 21 087 workers, adjusted RRs for butadiene and all leukaemia (132 deaths) rose with increasing exposure, with an RR of 2.53 (95% CI 1.37 to 4.67) in the highest exposure quartile (≥363.64 ppm-years), and the exposure-response trend was statistically significant for all leukaemia (p=0.014) and for lymphoid leukaemia (52 deaths, p=0.007). Styrene exposure-response trends for all leukaemia and lymphoid leukaemia were less consistent than those for butadiene. Cumulative exposures to butadiene and styrene were not associated consistently with myeloid leukaemias or the B-cell malignancies, NHL and multiple myeloma. CONCLUSIONS: We confirmed a positive exposure-response relationship between butadiene and all leukaemia among workers, most of whom had coexposure to styrene. Results supported an association between butadiene and lymphoid leukaemia, but not myeloid leukaemia, and provided little evidence of any association of butadiene or styrene exposures with major subtypes of B-cell malignancies other than lymphoid leukaemia, including NHL and multiple myeloma.

Mortality Among Men and Women in the North American Synthetic Rubber Industry, 1943 to 2009.

OBJECTIVE: To evaluate 1943 to 2009 mortality among 22,785 synthetic rubber industry employees. METHODS: Standardized mortality ratio (SMR) and internal Cox regression analyses. RESULTS: Among hourly employees with more than or equal to 10 years worked and more than or equal to 20 years since hire, SMRs were elevated for leukemia (SMR = 139, 95% confidence interval [CI] = 106 to 179), non-Hodgkin lymphoma (NHL) (SMR = 136, CI = 102 to 177), bladder cancer (SMR = 148, CI = 110 to 195) and, for women only, lung cancer (SMR = 225, CI = 103 to 427). Butadiene and styrene exposure-response trends were positive for leukemia and bladder cancer but not for NHL or for lung cancer among women. CONCLUSIONS: Results support a causal relationship between butadiene and leukemia. Interpretation of results for lung cancer among women and for bladder cancer is uncertain because of inability to control for smoking and inadequate or inconsistent support from other studies for an association between butadiene or styrene and the latter cancers.

Schistosomiasis is associated with incident HIV transmission and death in Zambia.

BACKGROUND: We examined relationships between schistosome infection, HIV transmission or acquisition, and all-cause death. METHODS: We retrospectively tested baseline sera from a heterosexual HIV-discordant couple cohort in Lusaka, Zambia with follow-up from 1994-2012 in a nested case-control design. Schistosome-specific antibody levels were measured by ELISA. Associations between baseline antibody response to schistosome antigens and incident HIV transmission, acquisition, and all-cause death stratified by gender and HIV status were assessed. In a subset of HIV- women and HIV+ men, we performed immunoblots to evaluate associations between Schistosoma haematobium or Schistosoma mansoni infection history and HIV incidence. RESULTS: Of 2,145 individuals, 59% had positive baseline schistosome-specific antibody responses. In HIV+ women and men, baseline schistosome-specific antibodies were associated with HIV transmission to partners (adjusted hazard ratio [aHR] = 1.8, p<0.005 and aHR = 1.4, p<0.05, respectively) and death in HIV+ women (aHR = 2.2, p<0.001). In 250 HIV- women, presence of S. haematobium-specific antibodies was associated with increased risk of HIV acquisition (aHR = 1.4, p<0.05). CONCLUSION: Schistosome infections were associated with increased transmission of HIV from both sexes, acquisition of HIV in women, and increased progression to death in HIV+ women. Establishing effective prevention and treatment strategies for schistosomiasis, including in urban adults, may reduce HIV incidence and death in HIV+ persons living in endemic areas.

Prostate-specific antigen concentration in vaginal fluid after exposure to semen.

OBJECTIVE: Prostate-specific antigen (PSA) is the best established biomarker of semen exposure. PSA in vaginal fluid returns to pre-exposure concentrations within 24-48 h, but the speed of decay during the first 10 h is unknown. We sought to determine how fast PSA concentrations decline during the first 10 h after exposure to semen. STUDY DESIGN: Women in the 50 enrolled couples were intravaginally inoculated with 10, 20, 100 and 200 µl of their partner's semen and then collected vaginal swabs immediately after, 30 min, 4 h and 10 h after exposure. Forty-seven sets of samples were tested for PSA. Mixed linear models for repeated measures examined the association between log-transformed PSA values and sampling time and semen exposure volume. Sensitivity analyses excluded data from nonabstainers. Fixed-effect estimates from the statistical models were graphed. RESULTS: PSA values were highest at 200 µl inoculation volumes and at earlier post-exposure time points, then decline steadily. The lowest inoculation volume (10 µl) corresponded to the smallest concentration of PSA throughout the post-inoculation time points. Average PSA levels return to clinically non-detectable levels within 10 h only at the lowest semen exposures. The PSA decay curve assumes a very similar profile across all time points and semen amounts. CONCLUSIONS: The PSA decay curve is similar for varying semen exposure volumes, with average PSA concentrations remaining above clinical thresholds 10 h after exposure at all except the very smallest semen exposure levels. PSA is an objective marker of recent exposure to semen, permitting such detection with high accuracy. IMPLICATIONS: This study clarifies how PSA values vary at different semen exposure levels and time points during the first 10 h post-exposure. Future contraceptive studies that use PSA as a semen biomarker will be better informed about PSA concentrations at different sampling times and exposure amounts.

Risk of heterosexual HIV transmission attributable to sexually transmitted infections and non-specific genital inflammation in Zambian discordant couples, 1994-2012.

Background: Studies have demonstrated the role of ulcerative and non-ulcerative sexually transmitted infections (STI) in HIV transmission/acquisition risk; less is understood about the role of non-specific inflammatory genital abnormalities. Methods: HIV-discordant heterosexual Zambian couples were enrolled into longitudinal follow-up (1994-2012). Multivariable models estimated the effect of genital ulcers and inflammation in both partners on time-to-HIV transmission within the couple. Population-attributable fractions (PAFs) were calculated. Results: A total of 207 linked infections in women occurred over 2756 couple-years (7.5/100 CY) and 171 in men over 3216 CY (5.3/100 CY). Incident HIV among women was associated with a woman's non-STI genital inflammation (adjusted hazard ratio (aHR) = 1.55; PAF = 8%), bilateral inguinal adenopathy (BIA; aHR = 2.33; PAF = 8%), genital ulceration (aHR = 2.08; PAF = 7%) and the man's STI genital inflammation (aHR = 3.33; PAF = 5%), BIA (aHR = 3.35; PAF = 33%) and genital ulceration (aHR = 1.49; PAF = 9%). Infection among men was associated with a man's BIA (aHR = 4.11; PAF = 22%) and genital ulceration (aHR = 3.44; PAF = 15%) as well as with the woman's non-STI genital inflammation (aHR = 1.92; PAF = 13%) and BIA (aHR = 2.76; PAF = 14%). In HIV-M+F- couples, the man being uncircumcised. with foreskin smegma. was associated with the woman's seroconversion (aHR = 3.16) relative to being circumcised. In F+M- couples, uncircumcised men with BIA had an increased hazard of seroconversion (aHR = 13.03 with smegma and 4.95 without) relative to being circumcised. Self-reporting of symptoms was low for ulcerative and non-ulcerative STIs. Conclusions: Our findings confirm the role of STIs and highlight the contribution of non-specific genital inflammation to both male-to-female and female-to-male HIV transmission/acquisition risk. Studies are needed to characterize pathogenesis of non-specific inflammation including inguinal adenopathy. A better understanding of genital practices could inform interventions.

Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States.

Prior improvements in multiple myeloma (MM) survival were not fully observed in racial and ethnic minorities and older individuals. We hypothesized that improvements in MM management in recent years have reduced these disparities. We used the Surveillance, Epidemiology, and End Results registries to calculate the incidence and relative survival rates (RSRs) of MM in the United States for patients diagnosed from 1993 to 1997 (prethalidomide), 1998 to 2002 (introduction of thalidomide), 2003 to 2007 (bortezomib and lenalidomide), and 2008 to 2012 (upfront bortezomib and lenalidomide, early availability of carfilzomib and pomalidomide). MM incidence increased significantly among non-Hispanic whites (NHWs) and non-Hispanic black (NHB) men, but not among NHB women and Hispanics. Improvement in 5-year RSRs (1993-1997 vs 2008-2012) was seen among patients of all age and race/ethnicity groups. Ten-year RSRs (1993-1997 vs 2003-2007) improved for patients <65 years of age (19.6%-35%; P < .001), but not for patients ≥75 years of age (7.8%-9.3%; P = .3). Among patients 65 to 74 years of age, 10-year RSRs improved for NHWs (11.3% vs 20.5%; P < .001) and Hispanics (10.6% vs 20.2%; P = .02), but not for NHBs (12.6% vs 19.5%; P = .06.). These findings confirm consistent improvement in survival for MM patients and point to the challenge of further extending these improvements to older and minority patients.

Impact of marital status, insurance status, income, and race/ethnicity on the survival of younger patients diagnosed with multiple myeloma in the United States.

BACKGROUND: Recent advances in the treatment of multiple myeloma (MM) have been associated with improved survival, predominantly among young and white patients. The authors hypothesized that sociodemographic factors, adjusted for race/ethnicity, influence the survival of younger patients with MM. METHODS: Overall survival (OS) data were obtained for individuals included in the Surveillance, Epidemiology, and End Results (SEER-18) program who were diagnosed with MM before the age of 65 years between 2007 and 2012. The sociodemographic variables addressed were marital status, insurance status, median household income, and educational achievement in the county of residence. Race/ethnicity was defined as a self-reported construct including Hispanic (regardless of race), non-Hispanic black, non-Hispanic white, and other. RESULTS: There were 10,161 cases of MM included with a median follow-up of 27 months (range, 0-71 months; 22,179 person-years). Using multivariable Cox proportional hazards analysis, SEER registry; age; male sex; and 3 sociodemographic factors including marital status (other than married), insurance status (uninsured or Medicaid), and county-level income (lowest 2 quartiles), but not race/ethnicity, were found to be associated with an increased risk of death. The 4-year estimated OS rate was 71.1%, 63.2%, 53.4%, and 46.5% (P<.001), respectively, for patients with 0, 1, 2, or 3 adverse sociodemographic factors. Hispanic and non-Hispanic black individuals were found to have more adverse sociodemographic factors and worse OS. However, when the population was stratified by the cumulative number of sociodemographic factors, no consistent association between race/ethnicity and OS was observed after adjustment for confounders. CONCLUSIONS: Sociodemographic factors that potentially affect care, but not race/ethnicity, were found to influence the survival of younger patients with MM. Cancer 2016;122:3183-90. © 2016 American Cancer Society.

Accuracy of urinary human papillomavirus testing for the presence of cervical human papillomaviruses and higher grades of cervical intraepithelial neoplasia.

BACKGROUND: Although urine-based testing for human papillomavirus (HPV) is being explored as a practical approach for cervical cancer screening, whether the results differ by age, race, or indicators of excess body weight or in populations exposed to HPV vaccines has not been documented by previous studies. The purpose of this study was to determine the accuracy of urinary HPV testing for the presence of cervical HPVs and high-grade cervical intraepithelial lesions (grade 2 and 3 cervical intraepithelial neoplasia [CIN]) by the aforementioned population characteristics. METHODS: The study population consisted of 502 women diagnosed with different grades of CIN. HPV testing was performed with paired urine and cervical cell DNA with the Roche Diagnostics Linear Array test. Agreement coefficient 1 and probabilities were calculated to determine the accuracy of urinary HPV testing for the presence of cervical HPVs and CIN lesions. RESULTS: Substantial to almost perfect agreement (0.66-0.83) was observed in the detection of any HPV genotype in urine specimens versus cervical specimens, regardless of the population characteristics. Although the positive predictive value for the detection of CIN lesions was relatively low, the negative predictive value for CIN-3 was high (≥90%) among women positive for any of the urinary or cervical high-risk human papillomavirus (HR-HPV) genotypes or HPV genotypes not included in currently available HPV vaccines. CONCLUSIONS: The results demonstrate that urinary HPV testing provides highly satisfactory results for excluding the possibility of any cervical HPV infections, including HPV types not included in vaccines and CIN lesions associated with any HR-HPV, regardless of a woman's age, race, or excess body weight. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2836-2844. © 2016 American Cancer Society.

Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features.

PURPOSE: Multiple myeloma (MM) is the most common hematologic malignancy affecting Blacks in the USA, with standardized incidence rates that are twofold to threefold higher than Whites. The rationale for the disparity is unclear. METHODS: Using participants enrolled in the Molecular And Genetic Epidemiology study of myeloma (259 MM cases; 461 controls), we examined the risk of MM associated with family history of cancer, differences by race and among cases, defining clinical features. Risk estimates were calculated using odds ratios and corresponding 95% confidence intervals from logistic regression adjusted for confounders. RESULTS: Overall, MM risk in cases with relatives affected with any hematologic malignancy was significantly elevated compared to controls (OR 1.89, 95% CI 1.25-2.86). Myeloma risk associated with a family history of MM was higher than the risk associated with any hematologic malignancy (OR 3.75, 95% CI 1.75-8.05), and the effect was greater for Blacks (OR 20.9, 95% CI 2.59-168) than Whites (OR 2.04, 95% 0.83-5.04), among cases with early onset (≤60 years; OR 4.58, 95% CI 1.21-17.3) and with increasing numbers of affected relatives (p trend = 0.001). Overall, frequencies of end organ damage differed in cases with relatives affected with any hematologic malignancy and significantly more cases exhibited κ light chain restriction (OR 3.23, 95% CI 1.13-9.26). CONCLUSIONS: The excess risk of MM observed in Blacks and the variation in clinical features observed in MM patients according to family history of hematologic malignancy may be attributed to a shared germline and environmental susceptibility.

1,3-Butadiene, styrene and lymphohematopoietic cancer among male synthetic rubber industry workers--Preliminary exposure-response analyses.

We updated the mortality experience of North American synthetic rubber industry workers to include follow-up from 1944 through 2009, adding 11 years of mortality data to previous investigations. The present analysis used Cox regression to examine the exposure-response relationship between 1,3-butadiene (BD) and styrene (STY) parts per million (ppm)-years and leukemia (N = 114 deaths), non-Hodgkin lymphoma (NHL) (N = 89) and multiple myeloma (MM) (N = 48). A pattern of largely monotonically increasing rate ratios across deciles of BD ppm-years and a positive, statistically significant exposure-response trend were observed for BD ppm-years and leukemia. Using continuous, untransformed BD ppm-years the regression coefficient (ß) adjusted only for age was 2.6 × 10(-4) (p < 0.01); the regression coefficient adjusted for age, year of birth, race and plant was 2.9 × 10(-4) (p < 0.01). STY ppm-years also displayed a positive exposure-response association with leukemia. STY and BD were strongly correlated, and the separate effects of these two agents could not be estimated. For NHL, a pattern of approximately monotonically increasing rate ratios across deciles of exposure was seen for STY but not for BD; the test of trend was statistically significant in one of five models that used different STY exposure metrics and adjusted for age and other covariates. BD ppm-years and STY ppm-years were not associated with MM. The present analyses indicated a positive exposure-response relationship between BD cumulative exposure and leukemia. This result along with other research and biological information support an interpretation that BD causes leukemia in humans. STY exposure also was positively associated with leukemia, but its independent effect could not be delineated because of its strong correlation with BD, and there is no external support for a STY-leukemia association. STY, but not BD, was associated positively with NHL. The interpretation of this result is uncertain because the exposure-response data were statistically imprecise and because consistent support for causality from other studies is lacking. The current study provides no support for an association between BD or STY and MM.

Contraceptive discontinuation and switching among couples receiving integrated HIV and family planning services in Lusaka, Zambia.

OBJECTIVE: To describe predictors of contraceptive method discontinuation and switching behaviours among HIV-positive couples receiving couples' voluntary HIV counselling and testing services in Lusaka, Zambia. DESIGN: Couples were randomized in a factorial design to two-family planning educational intervention videos, received comprehensive family planning services and were assessed every 3 months for contraceptive initiation, discontinuation and switching. METHODS: We modelled factors associated with contraceptive method upgrading and downgrading via multivariate Andersen-Gill models. RESULTS: Most women continued the initial method selected after randomization. The highest rates of discontinuation/switching were observed for injectable contraceptive and intrauterine device users. Time to discontinuing the more effective contraceptive methods or downgrading to oral contraceptives or condoms was associated with the women's younger age, desire for more children within the next year, heavy menstrual bleeding, bleeding between periods and cystitis/dysuria. Health concerns among women about contraceptive implants and male partners not wanting more children were associated with upgrading from oral contraceptives or condoms. HIV status of the woman or the couple was not predictive of switching or stopping. CONCLUSION: We found complicated patterns of contraceptive use. The predictors of contraception switching indicate that interventions targeted to younger couples that address common contraception-related misconceptions could improve effective family planning utilization. We recommend these findings be used to increase the uptake and continuation of contraception, especially long-acting reversible contraceptive (LARC) methods, and that fertility goal based, LARC-focused family planning be offered as an integral part of HIV prevention services.

Mortality following bone metastasis and skeletal-related events among women with breast cancer: a population-based analysis of U.S. Medicare beneficiaries, 1999-2006.

The aim of the study is to quantify the impact of bone metastasis and skeletal-related events (SREs) on mortality in older breast cancer patients. Using the linked Surveillance, Epidemiology and End Results-Medicare database, we identified women aged 65 years or older diagnosed with breast cancer between July 1, 1999 and December 31, 2005 and followed them to determine deaths occurring through December 31, 2006. We classified patients as having possible bone metastasis and SREs using discharge diagnoses from inpatient claims and diagnoses paired with procedure codes from outpatient claims. We used Cox regression to estimate mortality hazards ratios (HR) among women with bone metastasis with or without SRE, compared with women without bone metastasis. Among 98,260 women with breast cancer (median follow-up, 3.3 years), 7,189 (7.3%) had bone metastasis either at breast cancer diagnosis (1.5%) or during follow-up (5.8%). SREs occurred in 3,319 (46%) of women with bone metastasis. HRs for risk of death were 4.9 (95% CI 4.7-5.1) and 6.2 (95% CI 5.9-6.5), respectively, for women with bone metastasis but no SRE and for women with bone metastasis plus SRE, compared with women without bone metastasis. In analyses restricted to women with bone metastasis, the adjusted HR was 1.5 (95% CI 1.4-1.6) for women with bone metastasis plus SRE, compared with women with bone metastasis but without SRE. Having a bone metastasis, as indicated by Medicare claims, was associated strongly with mortality among women with breast cancer. This association was stronger for bone metastasis complicated by SRE than for bone metastasis without SRE.

Cigarette smoking and risk of histological subtypes of epithelial ovarian cancer in the EPIC cohort study.

New data regarding a positive association between smoking and risk of epithelial ovarian cancer (EOC), especially the mucinous tumor type, has started to emerge. The purpose of this study was to examine the association between different measures of smoking exposures and subtypes of EOC in a large cohort of women from 10 European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort is a multicenter prospective study initiated in 1992. The questionnaires included data about dietary, lifestyle, and health factors. Information about cigarette smoking was collected from individuals in all participating countries. We used Cox proportional hazard regression models to estimate hazard ratio (HR) of EOC overall and serous, mucinous, and endometroid histological subtypes, with 95% confidence intervals (CIs) associated with different measures of smoking exposures adjusting for confounding variables. Altogether 836 incident EOC cases were identified among 326,831 women. The tumors were classified as 400 serous, 83 mucinous, 80 endometroid, 35 clear cell, and 238 unspecified. Compared with never smokers, current smokers had a significantly increased risk for mucinous tumors [HR = 1.85 (95% CI 1.08-3.16)] and those smoking more than 10 cigarettes per day had a doubling in risk [HR = 2.25(95% CI 1.26-4.03)] as did those who had smoked less than 15 pack-years of cigarettes [HR = 2.18 (95% CI 1.07-4.43)]. The results from the EPIC study add further evidence that smoking increases risk of mucinous ovarian cancer and support the notion that the effect of smoking varies according to histological subtype.

Genotypes and haplotypes in the insulin-like growth factors, their receptors and binding proteins in relation to plasma metabolic levels and mammographic density.

BACKGROUND: Increased mammographic density is one of the strongest independent risk factors for breast cancer. It is believed that one third of breast cancers are derived from breasts with more than 50% density. Mammographic density is affected by age, BMI, parity, and genetic predisposition. It is also greatly influenced by hormonal and growth factor changes in a woman's life cycle, spanning from puberty through adult to menopause. Genetic variations in genes coding for hormones and growth factors involved in development of the breast are therefore of great interest. The associations between genetic polymorphisms in genes from the IGF pathway on mammographic density and circulating levels of IGF1, its binding protein IGFBP3, and their ratio in postmenopausal women are reported here. METHODS: Samples from 964 postmenopausal Norwegian women aged 55-71 years were collected as a part of the Tromsø Mammography and Breast Cancer Study. All samples were genotyped for 25 SNPs in IGF1, IGF2, IGF1R, IGF2R, IGFALS and IGFBP3 using Taqman (ABI). The main statistical analyses were conducted with the PROC HAPLOTYPE procedure within SAS/GENETICS (SAS 9.1.3). RESULTS: The haplotype analysis revealed six haploblocks within the studied genes. Of those, four had significant associations with circulating levels of IGF1 or IGFBP3 and/or mammographic density. One haplotype variant in the IGF1 gene was found to be associated with mammographic density. Within the IGF2 gene one haplotype variant was associated with levels of both IGF1 and IGFBP3. Two haplotype variants in the IGF2R were associated with the level of IGF1. Both variants of the IGFBP3 haplotype were associated with the IGFBP3 level and indicate regulation in cis. CONCLUSION: Polymorphisms within the IGF1 gene and related genes were associated with plasma levels of IGF1, IGFBP3 and mammographic density in this study of postmenopausal women.

1,3-butadiene, styrene and lung cancer among synthetic rubber industry workers.

OBJECTIVE: To evaluate the association between cumulative exposure to 1,3-butadiene (BD) or styrene (STY) and lung cancer among synthetic rubber industry workers. METHODS: Internal Cox regression analyses were performed both with and without natural logarithm transformation of exposure variables and both with and without the inclusion of those unexposed to monomers. RESULTS: Among women, analyses using untransformed BD exposure showed no trend. Analyses using natural logarithm-transformed BD exposure indicated a positive trend when the unexposed were included (P < 0.05) and an inverse trend when the unexposed were excluded (P < 0.05). No exposure-response trends were seen for BD among men or for STY among women or men. CONCLUSIONS: These results suggest that the association between BD and lung cancer, seen in some analyses of female employees, is not causal. STY did not appear to be associated with lung cancer.

Lower red blood cell folate enhances the HPV-16-associated risk of cervical intraepithelial neoplasia.

OBJECTIVE: We previously reported that higher circulating concentrations of folate are independently associated with a lower likelihood of becoming positive for high-risk human papillomaviruses (HR-HPVs) and of having a persistent HR-HPV infection and a greater likelihood of becoming HR-HPV negative (Cancer Res 2004;64:8788-93). In the present study conducted in the same study population, we tested whether circulating folate concentrations modify the risk of cervical intraepithelial neoplasia (CIN) > or =2 associated with specific types of HR-HPV. METHODS: Multiple logistic regression models were used to assess associations (odds ratio with 95% confidence intervals) across HR-HPV, folate, and rigorously reviewed cervical histology of each subject. RESULTS: HPV-16-positive women with low red blood cell folate were significantly more likely to be diagnosed with CIN > or =2 than were HPV-16-negative women with higher red blood cell folate (odds ratio 9, 95% confidence interval 3.3-24.8). CONCLUSION: To our knowledge, this is the first study reporting an independent association of folate with risk of having CIN > or =2 in a population tested extensively for HR-HPV and CIN that also adequately controlled for several other micronutrients and known risk factors for CIN. Our findings suggest that improving the folate status in HR-HPV-infected women may reduce the risk of CIN and thus the risk of cervical cancer. Folate supplementation should be tested as a means of reducing the risk of developing CIN > or =2 in women exposed to HR-HPV, especially HPV-16.

Mandatory fortification with folic acid in the United States is not associated with changes in the degree or the pattern of global DNA methylation in cells involved in cervical carcinogenesis.

The purpose of this study was to evaluate whether mandatory fortification of grain products with folic acid in the USA is associated with changes in global DNA methylation in cells involved in cervical carcinogenesis. Archived specimens of cervical intraepithelial neoplasia (CIN) diagnosed before (1990-92) and after mandatory folic acid fortification (2000-02) were used to examine for global DNA methylation in specific lesions involved in cervical carcinogenesis by using a monoclonal antibody specific for 5 methyl cytosine (5-mc). The total number of lesions examined was 152 in the pre-fortification period and 172 in the post-fortification period. Immunohistochemical staining for 5-mc, the assessment of methylation status and data entry were blinded with regard to the fortification status. Age- and race-adjusted mean percentage of cells positive for 5-mc or the 5-mc score was not significantly different (P>0.05) between the pre- and post fortification periods in any of the individual lesions evaluated (i.e., normal cervical epithelium, reactive cervical epithelium, metaplastic cervical epithelium, CIN or carcinoma in situ). The degree of global DNA methylation was significantly higher (P<0.0001) in >or= CIN 2 lesions compared to

Mortality among workers at a talc mining and milling facility.

BACKGROUND: This study evaluated mortality among workers at a talc mining and milling facility. METHODS: Subjects were white men actively employed between 1948 and 1989 and known to have been alive in or after 1950. Analyses assessed cancer mortality during the period 1950-89 (809 subjects) and non-cancer mortality during 1960-89 (782 subjects). RESULTS: Comparisons with regional general population death rates for 1960-89 indicated that the workers had more than expected deaths from all causes combined [209 observed/160 expected, standardized mortality ratio (SMR) = 131, 95% confidence interval (CI) = 114-150], due mainly to increased mortality from lung cancer (31/13, SMR = 232, CI = 157-329) and non-malignant respiratory disease (NMRD) (28/13, SMR = 221, CI = 147-320). The lung cancer excess was concentrated in miners (18/4.6, SMR = 394, CI = 233-622); millers had only a small increase (7/5.5, SMR = 128, CI = 51-263). An excess of NMRD occurred both in miners (10/4.2, SMR = 241, CI = 116-444) and in millers (11/4.8, SMR = 227, CI = 113-407). The median estimated exposure to respirable dust was 511 mg/m(3)-days for all exposed employees, 739 mg/m(3)-days for mine workers and 683 mg/m(3)-days for mill workers. Employees with high, compared with low, estimated exposure to dust had a rate ratio of 0.5 (CI = 0.2-1.3) for lung cancer and of 11.8 (CI = 3.1-44.9) for pulmonary fibrosis. CONCLUSIONS: Exposure to talc ore dust may not have been responsible for the lung cancer excess among these workers but probably contributed to the elevated rate of NMRD, particularly pulmonary fibrosis.