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1.  Investing in Prospective Cohorts for Etiologic Study of Occupational Exposures 
Prospective cohorts have played a major role in understanding the contribution of diet, physical activity, medical conditions, and genes to the development of many diseases, but have not been widely used for occupational exposures. Studies in agriculture are an exception. We draw upon our experience using this design to study agricultural workers to identify conditions that might foster use of prospective cohorts to study other occupational settings. Prospective cohort studies are perceived by many as the strongest epidemiologic design. It allows updating of information on exposure and other factors, collection of biologic samples before disease diagnosis for biomarker studies, assessment of effect modification by genes, lifestyle, and other occupational exposures, and evaluation of a wide range of health outcomes. Increased use of prospective cohorts would be beneficial in identifying hazardous exposures in the workplace. Occupational epidemiologists should seek opportunities to initiate prospective cohorts to investigate high priority, occupational exposures.
PMCID: PMC4516175  PMID: 25603935
prospective cohorts; agricultural exposures; occupational epidemiology
2.  Increased stomach cancer risk following radiotherapy for testicular cancer 
British Journal of Cancer  2014;112(1):44-51.
Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose–response relationship are sparse.
In a cohort of 22 269 5-year TC survivors diagnosed during 1959–1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression.
Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7–20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend<0.001), with an OR of 20.5 (3.7–114.3) for ⩾50.0 Gy compared with <10 Gy. Radiation-related risks remained elevated ⩾20 years after exposure (P<0.001). Risk after any chemotherapy was not elevated (OR=1.1; 95% CI 0.5–2.5; 14 cases and 23 controls).
Radiotherapy for TC involving parts of the stomach increased gastric cancer risk for several decades, with the highest risks after stomach doses of ⩾30 Gy. Clinicians should be aware of these excesses when previously irradiated TC survivors present with gastrointestinal symptoms and when any radiotherapy is considered in newly diagnosed TC patients.
PMCID: PMC4453604  PMID: 25349972
stomach cancer; testicular cancer; radiotherapy; chemotherapy
3.  Pancreatic cancer risk after treatment of Hodgkin lymphoma 
Annals of Oncology  2014;25(10):2073-2079.
Risk of subsequent pancreatic cancer among Hodgkin lymphoma survivors increased significantly with both increasing radiation dose to the pancreatic tumor location and increasing number of alkylating agent-containing cycles of chemotherapy. Especially high risks were observed among patients who received both subdiaphragmatic radiotherapy and ≥6 cycles of alkylating agent-containing chemotherapy.
Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to radiation dose and specific chemotherapeutic agents.
Patients and methods
We conducted an international case–control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls.
Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5–158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m2 of procarbazine with nitrogen mustard or ≥3900 mg/m2 of cyclophosphamide.
Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.
PMCID: PMC4176454  PMID: 25185241
Hodgkin lymphoma; pancreatic cancer; radiotherapy; chemotherapy; second cancer
4.  Preconception stress increases the risk of infertility: results from a couple-based prospective cohort study—the LIFE study 
Human Reproduction (Oxford, England)  2014;29(5):1067-1075.
Are women's stress levels prospectively associated with fecundity and infertility?
Higher levels of stress as measured by salivary alpha-amylase are associated with a longer time-to-pregnancy (TTP) and an increased risk of infertility.
Data suggest that stress and reproduction are interrelated; however, the directionality of that association is unclear.
In 2005–2009, we enrolled 501 couples in a prospective cohort study with preconception enrollment at two research sites (Michigan and Texas, USA). Couples were followed for up to 12 months as they tried to conceive and through pregnancy if it occurred. A total of 401 (80%) couples completed the study protocol and 373 (93%) had complete data available for this analysis.
Enrolled women collected saliva the morning following enrollment and then the morning following their first observed study menses for the measurement of cortisol and alpha-amylase, which are biomarkers of stress. TTP was measured in cycles. Covariate data were captured on both a baseline questionnaire and daily journals.
Among the 401 (80%) women who completed the protocol, 347 (87%) became pregnant and 54 (13%) did not. After adjustment for female age, race, income, and use of alcohol, caffeine and cigarettes while trying to conceive, women in the highest tertile of alpha-amylase exhibited a 29% reduction in fecundity (longer TTP) compared with women in the lowest tertile [fecundability odds ratios (FORs) = 0.71; 95% confidence interval (CI) = (0.51, 1.00); P < 0.05]. This reduction in fecundity translated into a >2-fold increased risk of infertility among these women [relative risk (RR) = 2.07; 95% CI = (1.04, 4.11)]. In contrast, we found no association between salivary cortisol and fecundability.
Due to fiscal and logistical concerns, we were unable to collect repeated saliva samples and perceived stress questionnaire data throughout the duration of follow-up. Therefore, we were unable to examine whether stress levels increased as women continued to fail to get pregnant. Our ability to control for potential confounders using time-varying data from the daily journals, however, minimizes residual confounding.
This is the first US study to demonstrate a prospective association between salivary stress biomarkers and TTP, and the first in the world to observe an association with infertility.
This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3358). There are no conflicts of interest to declare.
Not applicable.
PMCID: PMC3984126  PMID: 24664130
infertility; fecundity; stress; cortisol; alpha-amylase
5.  Using multi-country household surveys to understand who provides reproductive and maternal health services in low- and middle-income countries: a critical appraisal of the Demographic and Health Surveys 
The Demographic and Health Surveys (DHS) are a vital data resource for cross-country comparative analyses. This study is part of a set of analyses assessing the types of providers being used for reproductive and maternal health care across 57 countries. Here, we examine some of the challenges encountered using DHS data for this purpose, present the provider classification we used, and provide recommendations to enable more detailed and accurate cross-country comparisons of healthcare provision.
We used the most recent DHS surveys between 2000 and 2012; 57 countries had data on family planning and delivery care providers and 47 countries had data on antenatal care. Every possible response option across the 57 countries was listed and categorised. We then developed a classification to group provider response options according to two key dimensions: clinical nature and profit motive.
We classified the different types of maternal and reproductive healthcare providers, and the individuals providing care. Documented challenges encountered during this process were limitations inherent in household survey data based on respondents’ self-report; conflation of response options in the questionnaire or at the data processing stage; category errors of the place vs. professional for delivery; inability to determine whether care received at home is from the public or private sector; a large number of negligible response options; inconsistencies in coding and analysis of data sets; and the use of inconsistent headings.
To improve clarity, we recommend addressing issues such as conflation of response options, data on public vs. private provider, inconsistent coding and obtaining metadata. More systematic and standardised collection of data would aid international comparisons of progress towards improved financial protection, and allow us to better characterise the incentives and commercial nature of different providers.
Les enquêtes démographiques et de santé (EDS) sont une ressource vitale de données pour des analyses comparatives entre les pays. Cet article fait partie d'une série d'analyses évaluant les types de prestataires utilisés pour les soins de santé reproductive et maternelle dans 57 pays. Ici, nous examinons certains des défis rencontrés, en utilisant les données EDS à cette fin, présentons la classification que nous avons utilisée pour les prestataires et fournissons des recommandations pour permettre des comparaisons plus détaillées et précises entre les pays sur la prestation des soins de santé.
Nous avons utilisé les plus récents relevés EDS entre 2000 et 2012; 57 pays avaient des données sur la planification familiale et les prestataires de soins d'accouchement et 47 pays avaient des données sur les soins prénatals. Chaque option de réponse possible dans les 57 pays a été répertoriée et classée. Nous avons ensuite développé une classification pour grouper les options de réponses des prestataires selon deux dimensions clés: la nature clinique et la recherche du profit.
Nous avons classé les différents types de prestataires de soins de santé maternelle et reproductive, et les personnes qui fournissent des soins. Les défis documentées rencontrées durant ce processus étaient les limitations inhérentes aux données de l'enquête sur les ménages sur la base de l'auto-report des répondants, l'amalgame d'options de réponse dans le questionnaire ou à l’étape de traitement des données, les erreurs de catégories du lieu par rapport à la profession pour l'accouchement, l'incapacité à déterminer si les soins reçus à domicile étaient du secteur public ou privé, un grand nombre d'options de réponse négligeables, des incohérences dans le codage et l'analyse des ensembles de données, et l'utilisation de rubriques incompatibles.
Pour améliorer la clarté, nous recommandons de tacler les problèmes tels que l'amalgame d'options de réponses, les données sur les prestataires du public par rapport à ceux du privé, l'incohérence dans le codage et l'obtention de métadonnées. Plus de collecte systématique et standardisée des données aiderait les comparaisons internationales des progrès vers une meilleure protection financière et nous permettra de mieux caractériser les incitations et la nature commerciale des différents prestataires.
Las Encuestas Demográficas y de Salud (EDS) son una fuente de datos vitales para el análisis comparativo entre países. Este artículo es parte de un grupo de análisis que evalúan los tipos de proveedores de atención a la salud reproductiva y materna que están siendo utilizados en 57 países. Examinamos algunos de los retos encontrados al utilizar datos de EDS con este propósito, presentamos la clasificación de proveedores que hemos usado, y proveemos recomendaciones para permitir una comparación más detallada y más precisa de la prestación de servicios sanitarios en diferentes países.
Hemos utilizado datos de las EDS más recientes, entre el 2000 y 2012; 57 países tenían datos sobre planeación familiar y proveedores de servicios durante el parto y 47 países tenían datos sobre cuidados prenatales. Cada opción posible de respuesta en los 57 países fue listada y categorizada. Después se desarrolló una clasificación para agrupar las opciones de respuesta según proveedor, siguiendo dos dimensiones clave: naturaleza clínica y afán de lucro.
Hemos clasificado los diferentes tipos de proveedores de cuidados sanitarios en salud materna y reproductiva, y a los individuos que ofrecían los servicios. Los retos documentados durante este proceso fueron las limitaciones inherentes a los datos en las encuestas realizadas en los hogares basados en las auto-respuestas de los encuestados; fusión de las opciones de respuesta en el cuestionario o durante la etapa de procesamiento de datos; errores de categoría sobre el lugar versus profesional que atendió el parto; incapacidad para determinar si los cuidados recibidos en el hogar eran del sector público o privado; un gran número de opciones de respuesta insignificantes; inconsistencias en la codificación y el análisis del conjunto de datos; y uso de encabezamientos inconsistentes.
Para mejorar la claridad, recomendamos abordar cuestiones tales como la fusión de opciones de respuesta, datos sobre el proveedor público versus privado, codificación inconsistente, y la obtención de metadatos. Una recolección de datos más sistemática y estandarizada facilitaría las comparaciones internacionales del progreso hacia una protección financiera mejorada, y nos permitiría una mejor caracterización de las iniciativas y de la naturaleza comercial de los diferentes proveedores.
PMCID: PMC4409817  PMID: 25641212
demographic and health surveys; reproductive health; maternal health; private sector; methods; healthcare providers
6.  HPV-Related Cancers after Solid Organ Transplantation in the US 
Transplant recipients have elevated cancer risk including risk of human papillomavirus (HPV)-associated cancers of the cervix, anus, penis, vagina, vulva, and oropharynx. We examined the incidence of HPV-related cancers in 187,649 U.S. recipients in the Transplant Cancer Match Study. Standardized incidence ratios (SIRs) compared incidence rates to the general population, and incidence rate ratios (IRR) compared rates across transplant subgroups. We observed elevated incidence of HPV-related cancers (SIRs: in situ 3.3–20.3, invasive 2.2–7.3), except for invasive cervical cancer (SIR 1.0). Incidence increased with time since transplant for vulvar, anal, and penile cancers (IRRs 2.1–4.6 for 5+ vs. <2 years). Immunophenotype, characterized by decreased incidence with HLA DRB1:13 and increased incidence with B:44, contributed to susceptibility at several sites. Use of specific immunosuppressive medications was variably associated with incidence; for example, tacrolimus, was associated with reduced incidence for some anogenital cancers (IRRs 0.4–0.7) but increased incidence of oropharyngeal cancer (IRR 2.1). Thus, specific features associated with recipient characteristics, transplanted organs, and medications are associated with incidence of HPV-related cancers after transplant. The absence of increased incidence of invasive cervical cancer highlights the success of cervical screening in this population and suggests a need for screening of other HPV-related cancers.
PMCID: PMC4049182  PMID: 24119294
HPV-related cancer; organ transplant cohort; Transplant Cancer Match study; immunosuppression
7.  Risk of lymphoma subtypes after solid organ transplantation in the United States 
British Journal of Cancer  2013;109(1):280-288.
Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes.
We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987–2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation.
The risk varied widely across subtypes, with strong elevations (SIRs 10–100) for hepatosplenic T-cell lymphoma, Burkitt's lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2–4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (<20 years) and those receiving organs other than kidneys.
Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma.
PMCID: PMC3708563  PMID: 23756857
non-Hodgkin's lymphoma; Hodgkin's lymphoma; transplantation; immunosuppression; Burkitt's lymphoma; T-cell lymphoma
8.  Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma 
Journal of medical genetics  2007;45(3):142-146.
Background and objective
Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position −93, rs1800734) modifies the risk of cancer after methylating chemotherapy.
133 patients who developed cancer following chemotherapy and/or radiotherapy (n=133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 −93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 −93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression.
Carrier frequency of the MLH1 −93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n=12) or breast cancer (53.3%. n=15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n=69; breast cancer patients, 27.2%, n=22). The MLH1 −93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n=420) and healthy controls (36.3%, n=952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent.
These data support the hypothesis that the common polymorphism at position −93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.
PMCID: PMC4022773  PMID: 17959715
9.  Risk of treatment-related esophageal cancer among breast cancer survivors 
Annals of Oncology  2012;23(12):3081-3091.
Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use.
Nested case–control study of esophageal cancer among 289 748 ≥5-year survivors of female breast cancer from five population-based cancer registries (252 cases, 488 individually matched controls), with individualized radiation dosimetry and information abstracted from medical records.
The largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location (Ptrend < 0.001), with doses of ≥35 Gy associated with an odds ratio (OR) of 8.3 [95% confidence interval (CI) 2.7–28]. Patients with hormonal therapy ≤5 years preceding esophageal cancer diagnosis had lower risk (OR = 0.4, 95% CI 0.2–0.8). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. Our data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g. smoking).
Esophageal cancer is a radiation dose-related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up.
PMCID: PMC3501231  PMID: 22745217
breast cancer; esophageal cancer; radiotherapy; second cancer
10.  Hospital Episode Statistics data analysis of postoperative venous thromboembolus in patients undergoing urological surgery: a review of 126,891 cases 
Current guidelines on venous thromboembolism (VTE) prevention do not reflect the potential varying risk for patients undergoing different urological procedures. Our study aimed to establish the procedure specific rate of postoperative VTE in patients undergoing urological surgery.
Hospital Episode Statistics were obtained for all patients undergoing common urological procedures between April 2009 and April 2010. This cohort was followed up to identify all patients reattending with either deep vein thrombosis (DVT) or pulmonary embolism (PE) within 12 months.
A total of 126,891 individuals underwent urological surgery during the study period. This included 89,628 men (70.6%) and 37,236 women (29.3%) with a mean age of 65.2 years. At the 12-month follow-up, 839 patients (0.66%) were readmitted with VTE. Of these, 373 (0.29%) were admitted with DVT and 466 (0.37%) with PE. The procedure-specific rate of VTE varied significantly between 2.86% following cystectomy and 0.23% following urethral dilatation. Procedures performed in the lithotomy position carried a significantly lower risk of VTE than those performed in the supine position (0.60% vs 1.28%, p<0.0001). Furthermore, of all procedures performed in the lithotomy position, those performed on benign conditions carried a significantly lower risk than those performed on malignant disease (0.52% vs 0.79%, p<0.0001).
Procedure specific rates of postoperative VTE vary widely among patients undergoing urological procedures. These findings suggest the potential benefit of prolonging the use of thromboprophylaxis in high-risk patients but also exploring the apparent lack of need for routine thromboprophylaxis in patients undergoing low-risk procedures.
PMCID: PMC3964643  PMID: 23317732
Urology; Venous thromboembolism; Pulmonary embolism; Deep vein thrombosis
11.  FDG-PET metabolic response predicts outcomes in anal cancer managed with chemoradiotherapy 
British Journal of Cancer  2011;105(4):498-504.
The aim was to investigate the correlation between 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus.
A total of 48 patients with biopsy-proven anal SCC underwent FDG-PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin). Kaplan–Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response.
In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression-free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P<0.0001). The 5-year overall survival (OS) was 88% in CMR, 69% in PMR and 0% in NR (P<0.0001). Cox proportional hazards regression analyses for PFS and OS found significant associations for incomplete (PMR+NR) vs complete FDG-PET response to treatment only, (HR 4.1 (95% CI: 1.5–11.5, P=0.013) and 6.7 (95% CI: 2.1–21.6, P=0.002), respectively).
FDG-PET metabolic response to chemoradiotherapy in anal cancer is significantly associated with PFS and OS, and in this cohort incomplete FDG-PET response was a stronger predictor than T or N stage.
PMCID: PMC3170972  PMID: 21792197
anal cancer; chemoradiotherapy; metabolic response; FDG-PET
13.  Polychlorinated biphenyl serum concentrations, lifestyle and time-to-pregnancy 
Consumption of fish contaminated with polychlorinated biphenyls (PCBs) and prenatal PCB serum concentrations have been associated with a longer time-to-pregnancy (TTP). However, the relationship between preconception serum PCBs concentrations and TTP has not been previously studied.
Eighty-three women (contributing 442 menstrual cycles) planning pregnancies completed daily diaries regarding menstruation, intercourse, home pregnancy test results, and reported use of alcohol and cigarettes. TTP denoted the number of observed menstrual cycles required for pregnancy. Preconception blood specimens underwent toxicologic analysis for 76 PCB congeners via gas chromatography with electron capture; serum lipids were quantified with enzymatic methods. A priori, PCB congeners were summed into a total and three groupings—estrogenic, anti-estrogenic and other—and entered into discrete analogs of Cox models with time-varying covariates to estimate fecundability odds ratios (FOR) and corresponding 95% confidence intervals (CIs).
Estrogenic and anti-estrogenic PCB concentrations (ng/g serum) conferred reduced FORs in fully adjusted models (0.32; 95% CI 0.03, 3.90 and 0.01: 95% CI < 0.00, 1.99, respectively). Reduced FORs (0.96) were observed for alcohol consumption standardized to a 28-day menstrual cycle in the same adjusted model (FOR = 0.96; 95% CI 0.93, 1.00).
These data suggest that environmental exposures including those amenable to change, such as alcohol consumption, may impact female fecundity. The findings are sensitive to model specification and PCB groupings, underscoring the need to further assess the impact of chemical mixtures on sensitive reproductive outcomes, such as TTP, especially in the context of lifestyle factors which are amenable to change, thereby improving reproductive health.
PMCID: PMC2628447  PMID: 18940895
time-to-pregnancy; polychlorinated biphenyls; fecundity; lifestyle; environment
14.  Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study 
British Journal of Cancer  2008;98(4):728-733.
The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985–1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6–5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8–8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.
PMCID: PMC2259175  PMID: 18253122
asynchronous contralateral breast cancer; CHEK2*1100delC mutation; genes; radiation therapy; chemotherapy
15.  Polychlorinated biphenyl serum concentrations, lifestyle and time-to-pregnancy 
Consumption of fish contaminated with polychlorinated biphenyls (PCBs) and prenatal PCB serum concentrations have been associated with a longer time-to-pregnancy (TTP). However, the relationship between preconception serum PCBs concentrations and TTP has not been previously studied.
Eighty-three women (contributing 442 menstrual cycles) planning pregnancies completed daily diaries regarding menstruation, intercourse, home pregnancy test results, and reported use of alcohol and cigarettes. TTP denoted the number of observed menstrual cycles required for pregnancy. Preconception blood specimens underwent toxicologic analysis for 76 PCB congeners via gas chromatography with electron capture; serum lipids were quantified with enzymatic methods. A priori, PCB congeners were summed into a total and three groupings—estrogenic, anti-estrogenic and other— and entered into discrete analogs of Cox models with time-varying covariates to estimate fecundability odds ratios (FOR) and corresponding 95% confidence intervals (CIs).
Estrogenic and anti-estrogenic PCB concentrations (ng/g serum) conferred reduced FORs in fully adjusted models (0.32; 95% CI 0.03, 3.90 and 0.01: 95% CI < 0.00, 1.99, respectively). Reduced FORs (0.96) were observed for alcohol consumption standardized to a 28-day menstrual cycle in the same adjusted model (FOR = 0.96; 95% CI 0.93, 1.00).
These data suggest that environmental exposures including those amenable to change, such as alcohol consumption, may impact female fecundity. The findings are sensitive to model specification and PCB groupings, underscoring the need to further assess the impact of chemical mixtures on sensitive reproductive outcomes, such as TTP, especially in the context of lifestyle factors which are amenable to change, thereby improving reproductive health.
PMCID: PMC2628447  PMID: 18940895
time-to-pregnancy; polychlorinated biphenyls; fecundity; lifestyle; environment
16.  New approaches for genotyping paraffin wax embedded breast tissue from patients with cancer: the Iowa women’s health study 
Journal of Clinical Pathology  2005;58(9):955-961.
Background: The use of paraffin wax embedded tissue samples as a source of DNA for genotype analysis has been limited because of difficulties in DNA extraction and single nucleotide polymorphism (SNP) analysis.
Aims: To test the feasibility of applying the combination of a commonly used DNA isolation procedure, PureGene, and a high throughput SNP analysis method, the polymerase chain reaction (PCR)-INVADER assay, to genotype several types of paraffin wax embedded breast tissues.
Methods: Twenty formalin fixed, paraffin wax blocks were obtained from five participants in the Iowa women’s health study. Each participant provided several types of tissue including normal lymph node, normal nipple/areola tissue, inflammatory/fibrotic breast tissue, or normal breast tissue, and tumour tissue.
Results: Good quality DNA (260/280 ratio >1.6) was obtained from all tissues. Normal lymph nodes yielded the largest amount of DNA (97.1 μg). DNA obtained from the samples was tested for a germline C1183T polymorphism in the MnSOD gene by three methods—PCR-RFLP (restriction fragment length polymorphism), INVADER assay, and PCR-INVADER assay. Of the 20 samples, PCR-RFLP genotyped 16, the PCR-INVADER assay 18, and the INVADER assay two. This methodology was then used to analyse five additional genotypes and confirmed the general applicability of the method.
Conclusions: This study demonstrated the feasibility of (1) using several paraffin wax embedded breast tissues as a source of DNA for germline genetic analysis, with lymph nodes providing the highest yield, and (2) using the combination of a common extraction method with a high throughput SNP analysis method, the PCR–INVADER assay.
PMCID: PMC1770813  PMID: 16126877
Dna genotyping; paraffin wax embedded tissue blocks; single nucleotide polymorphisms
17.  Disease and Injury Among Participants in the Agricultural Health Study 
The Agricultural Health Study ( is a cohort of 89,658 pesticide applicators and their spouses from Iowa and North Carolina assembled between 1993 and 1997 to evaluate risk factors for disease in rural farm populations. This prospective study is just now reaching sufficient maturity for analysis of many disease endpoints. Nonetheless, several analyses have already provided interesting and important leads regarding disease patterns in agricultural populations and etiologic clues for the general population. Compared to the mortality experience of the general population in the two states (adjusted for race, gender, age and calendar time), the cohort experienced a very low mortality rate overall and for many specific causes and a low rate of overall cancer incidence. A few cancers, however, appear elevated, including multiple myeloma and cancers of the lip, gallbladder, ovary, prostate, and thyroid, but numbers are small for many cancers. A study of prostate cancer found associations with exposure to several pesticides, particularly among individuals with a family history of prostate cancer. Links to pesticides and other agricultural factors have been found for injuries, retinal degeneration, and respiratory wheeze. Methodological studies have determined that information collected by interview is unbiased and reliable. A third round of interviews scheduled to begin in 2005 will collect additional information on agricultural exposures and health outcomes. The study can provide data to address many health issues in the agricultural community. The study investigators welcome collaboration with interested scientists.
PMCID: PMC1237013  PMID: 15931940
Agriculture; Cancer; Farmers; Injuries; Mortality; Pesticides; Prospective study; Respiratory disease
18.  Mortality and cancer incidence among alachlor manufacturing workers 1968–99 
Background: Alachlor is the active ingredient in pre-emergent herbicide formulations that have been used widely on corn, soybeans, and other crops. It has been found to cause nasal, stomach, and thyroid tumours in rodent feeding studies at levels that are much higher than likely human exposures.
Aims: To evaluate mortality rates from 1968 to 1999 and cancer incidence rates from 1969 to 1999 for alachlor manufacturing workers at a plant in Muscatine, Iowa.
Methods: Worker mortality and cancer incidence rates were compared to corresponding rates for the Iowa state general population. Analyses addressed potential intensity and duration of exposure.
Results: For workers with any period of high alachlor exposure, mortality from all causes combined was lower than expected (42 observed deaths, SMR 64, 95% CI 46 to 86) and cancer mortality was slightly lower than expected (13 observed deaths, SMR 79, 95% CI 42 to 136). Cancer incidence for workers with potential high exposure was similar to that for Iowa residents, both overall (29 observed cases, SIR 123, 95% CI 82 to 177) and for workers exposed for five or more years and with at least 15 years since first exposure (eight observed cases, SIR 113, 95% CI 49 to 224). There were no cases of nasal, stomach, or thyroid cancer.
Conclusions: There were no cancers of the types found in toxicology studies and no discernible relation between cancer incidence for any site and years of alachlor exposure or time since first exposure. Despite the small size of this population, the findings are important because these workers had chronic exposure potential during extended manufacturing campaigns, while use in agriculture is typically limited to a few days or weeks each year.
PMCID: PMC1740830  PMID: 15258274
19.  ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer 
British Journal of Cancer  2003;89(8):1513-1516.
PMCID: PMC2394328  PMID: 14562025
ATM gene screening; 7271T>G mutation; IVS10-6T>G mutation; breast cancer; bilateral breast cancer
20.  Occupational exposure to formaldehyde and wood dust and nasopharyngeal carcinoma 
OBJECTIVES—To investigate whether occupational exposures to formaldehyde and wood dust increase the risk of nasopharyngeal cancer (NPC).
METHODS—A multicentred, population based case-control study was carried out at five cancer registries in the United States participating in the National Cancer Institute's SEER program. Cases (n=196) with a newly diagnosed NPC between 1987 and 1993, and controls (n=244) selected over the same period from the general population through random digit dialing participated in structured telephone interviews which inquired about suspected risk factors for the disease, including a lifetime history of occupational and chemical exposure. Histological type of cancer was abstracted from clinical records of the registries. Potential exposure to formaldehyde and wood dust was assessed on a job by job basis by experienced industrial hygienists who were blinded as to case or control status.
RESULTS—For formaldehyde, after adjusting for cigarette use, race, and other risk factors, a trend of increasing risk of squamous and unspecified epithelial carcinomas was found for increasing duration (p=0.014) and cumulative exposure (p=0.033) but not for maximum exposure concentration. The odds ratio (OR) for people cumulatively exposed to >1.10 ppm-years was 3.0 (95% confidence interval (95% CI) 1.3 to 6.6) compared with those considered unexposed. In analyses limited to jobs considered definitely exposed, these trends became stronger. The associations were most evident among cigarette smokers. By contrast, there was no association between potential exposure to formaldehyde and undifferentiated and non-keratinising carcinomas. There was little evidence that exposure to wood dust increased risk of NPC, as modest crude associations essentially disappeared after control for potential exposure to formaldehyde.
CONCLUSIONS—These results support the hypothesis that occupational exposure to formaldehyde, but not wood dust, increases risk of NPC. This association seems to be specific to squamous cell carcinomas. Established cohorts of workers exposed to formaldehyde and wood dust should continue to be monitored for NPC and other respiratory cancers. Future studies of NPC should take into account histological type in assessing risk from environmental and host factors.

Keywords: occupational exposure; formaldehyde; wood dust
PMCID: PMC1739963  PMID: 10810126
21.  Knowledge of the Tuskegee study and its impact on the willingness to participate in medical research studies. 
The under-representation of racial/ethnic minorities among medical research participants has recently resulted in mandates for their inclusion by the National Institutes of Health (NIH). Therefore, there is a need to determine how history, attitudes, cultural beliefs, social issues, and investigator behavior affect minority enrollment in medical research studies. From January 1998 to March 1999, 179 African-American and white residents of the Detroit Primary Metropolitan Statistical Area (PMSA) participated in a mail and telephone survey designed to examine impediments to African-American participation in medical research studies. Chi-square tests were performed to assess differences between the study groups using the Survey Data Analysis Program (SUDAAN). Eighty-one percent of African Americans and 28% of whites had knowledge of the Tuskegee Study (p = <0.001). Knowledge of the Tuskegee Study resulted in less trust of researchers for 51% of African-Americans and 17% of whites (p = 0.02). Forty-six percent of African-Americans and 34% of whites indicated that their knowledge of the study would affect future research participation decisions (p = 0.25). Of these, 49% of African-Americans and 17% of whites would not be willing to participate in future medical research studies (p = 0.05). This study confirms the need for medical researchers to confront the issue of the Tuskegee Study and its continuing impact on African-Americans' trust of medical research studies.
PMCID: PMC2568333  PMID: 11202759
22.  Use of methergine for the prevention of postoperative endometritis in non-elective cesarean section patients. 
OBJECTIVE: Methergine increases constriction of uterine musculature which may facilitate sloughing of endometrial debris, close uterine vessels, and prevent post-cesarean endometritis. The objective of this study was to evaluate the efficacy of methergine in preventing endometritis in patients undergoing non-elective cesarean section delivery. METHODS: Eighty patients undergoing non-elective cesarean section were enrolled in a prospective randomized clinical trial of methergine (41) versus no methergine (39) administration during the postpartum period. The hospital records were abstracted after discharge to compare the postpartum course. RESULTS: There were no significant demographic differences between the two groups. The women receiving methergine had a significant reduction in the rate of postoperative endometritis (10% vs. 36%, P < 0.005). In addition, the mean postoperative hemoglobin was significantly higher in the methergine treated group (P < 0.001). CONCLUSIONS: The use of methergine postpartum in women undergoing non-elective cesarean sections significantly reduces the incidence of postoperative endometritis and blood loss.
PMCID: PMC1784682  PMID: 10968597
23.  Medical libraries, bioinformatics, and networked information: a coming convergence? 
Libraries will be changed by technological and social developments that are fueled by information technology, bioinformatics, and networked information. Libraries in highly focused settings such as the health sciences are at a pivotal point in their development as the synthesis of historically diverse and independent information sources transforms health care institutions. Boundaries are breaking down between published literature and research data, between research databases and clinical patient data, and between consumer health information and professional literature. This paper focuses on the dynamics that are occurring with networked information sources and the roles that libraries will need to play in the world of medical informatics in the early twenty-first century.
PMCID: PMC226616  PMID: 10550026
24.  Exposure to atmospheric radon. 
Environmental Health Perspectives  1999;107(2):123-127.
We measured radon (222Rn) concentrations in Iowa and Minnesota and found that unusually high annual average radon concentrations occur outdoors in portions of central North America. In some areas, outdoor concentrations exceed the national average indoor radon concentration. The general spatial patterns of outdoor radon and indoor radon are similar to the spatial distribution of radon progeny in the soil. Outdoor radon exposure in this region can be a substantial fraction of an individual's total radon exposure and is highly variable across the population. Estimated lifetime effective dose equivalents for the women participants in a radon-related lung cancer study varied by a factor of two at the median dose, 8 mSv, and ranged up to 60 mSv (6 rem). Failure to include these doses can reduce the statistical power of epidemiologic studies that examine the lung cancer risk associated with residential radon exposure.
PMCID: PMC1566320  PMID: 9924007
25.  Lymphogranuloma venereum presenting as a rectovaginal fistula. 
Lymphogranuloma venereum (LGV) is a rare form of the sexually transmitted disease caused by Chlamydia trachomatis. In the United States, there are fewer than 350 cases per year. In a review of the world's literature, there has not been a case reported in the last thirty years of a case of LGV presenting as a rectovaginal fistula. We present a case of an otherwise healthy American woman who presented with a rectovaginal fistula. Although uncommon, LGV does occur in developed countries and may have devastating tissue destruction if not recognized and treated before the tertiary stage.
PMCID: PMC1784745  PMID: 10449269

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