Amy Shafrir

Using PM2.5 concentrations to estimate the health burden from solid fuel combustion, with application to Irish and Scottish homes

BackgroundThis study estimates the potential population health burden from exposure to combustion-derived particulate air pollution in domestic settings in Ireland and Scotland.MethodsThe study focused on solid fuel combustion used for heating and the use of gas for cooking. PM2.5 (particulate matter with an aerodynamic diameter < 2.5 μm) was used as the pollutant mixture indicator. Measured PM2.5 concentrations in homes using solid fuels were adjusted for other sources of PM2.5 by subtracting PM2.5 concentrations in homes using gas for cooking but not solid fuel heating. Health burden was estimated for exposure indoors 6 pm - midnight, or all day (24-hour), by combining estimated attributable annual PM2.5 exposures with (i) selected epidemiological functions linking PM2.5 with mortality and morbidity (involving some re-scaling from PM10 to PM2.5, and adjustments ‘translating’ from concentrations to exposures) and (ii) on the current population exposed and background rates of morbidity and mortality.ResultsPM2.5 concentrations in coal and wood burning homes were similar to homes using gas for cooking, used here as a baseline (mean 24-hr PM2.5 concentrations 8.6 μg/m3) and so health impacts were not calculated. Concentrations of PM2.5 in homes using peat were higher (24-hr mean 15.6 μg/m3); however, health impacts were calculated for the exposed population in Ireland only; the proportion exposed in Scotland was very small. The assessment for winter evening exposure (estimated annual average increase of 2.11 μg/m3 over baseline) estimated 21 additional annual cases of all-cause mortality, 55 of chronic bronchitis, and 30,100 and 38,000 annual lower respiratory symptom days (including cough) and restricted activity days respectively.ConclusionNew methods for estimating the potential health burden of combustion-generated pollution from solid fuels in Irish and Scottish homes are provided. The methodology involves several approximations and uncertainties but is consistent with a wider movement towards quantifying risks in PM2.5 irrespective of source. Results show an effect of indoor smoke from using peat (but not wood or coal) for heating and cooking; but they do not suggest that this is a major public health issue.

An updated investigation of cancer incidence and mortality at a Scottish semiconductor manufacturing facility with case-control and case-only studies of selected cancers

Objectives An earlier investigation raised concern that some cancer cases might be linked to work at a semiconductor manufacturing plant. The aim of this study was to describe an update of the cancer incidence and mortality of these workers and assess whether workplace exposures contributed to any increased risk of selected cancers. Methods Standardised mortality ratios and standardised incidence ratios were calculated for cancer site groups of a priori interest in a cohort previously flagged against the National Health Service Central Register, with follow-up extended to the 2007 for deaths and 2006 for cancer registrations. Cases of female breast cancer, lung and stomach cancer, and male brain cancer, and a random sample of control subjects individually age-matched to the breast cancer cases, were identified from within the cohort dataset and invited to participate via General Practitioners. Exposures were estimated using a job exposure matrix developed from a historical hygiene assessment and assigned to job histories obtained from personal interview of subjects (or proxies). Results Though the findings were uncertain, there were no excesses of mortality or cancer incidence, either overall or for specific cancer sites, suggestive of a workplace effect. Logistic regression analyses comparing 20 cases of breast cancer with 83 matched controls showed no consistent evidence of any relationship with occupational exposures. Assessment of commonalities of workplace exposures among case sets for other cancer types was limited by the small numbers. Conclusions These results do not support earlier concerns about occupational cancer risks among this cohort.

Prioritising action on occupational carcinogens in Europe: a socioeconomic and health impact assessment

Background:Work-related cancer is an important public health issue with a large financial impact on society. The key European legislative instrument is the Carcinogens and Mutagens Directive (2004/37/EC). In preparation for updating the Directive, the European Commission commissioned a study to provide a socioeconomic, health and environmental impact assessment.Methods:The evaluation was undertaken for 25 preselected hazardous substances or mixtures. Estimates were made of the number of cases of cancer attributable to workplace exposure, both currently and in the future, with and without any regulatory interventions, and these data were used to estimate the financial health costs and benefits.Results:It was estimated that if no action is taken there will be >700 000 attributable cancer deaths over the next 60 years for the substances assessed. However, there are only seven substances where the data suggest a clear benefit in terms of avoided cancer cases from introducing a binding limit at the levels considered. Overall, the costs of the proposed interventions were very high (up to [euro ]34 000 million) and the associated monetised health benefits were mostly less than the compliance costs.Conclusions:The strongest cases for the introduction of a limit value are for: respirable crystalline silica, hexavalent chromium, and hardwood dust.

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

Purpose: A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. Experimental Design: We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. Results: This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Conclusions: Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. Clin Cancer Res; 24(6); 1389–401. ©2017 AACR.

Reproductive and hormonal factors in relation to survival and platinum resistance among ovarian cancer cases.

Background:Ovarian cancer survival is poor, particularly for platinum-resistant cases. The previous literature on pre-diagnostic reproductive factors and ovarian cancer survival has been mixed. Therefore, we evaluated pre-diagnostic reproductive and hormonal factors with overall survival and, additionally, platinum-chemotherapy resistance.Methods:We followed 1649 invasive epithelial ovarian cancer cases who were enrolled between 1992 and 2008 for overall mortality within the New England Case-Control Study and abstracted chemotherapy data on a subset (n=449). We assessed pre-diagnostic reproductive and hormonal factors during in-person interviews. We calculated hazard ratios (HRs) using Cox-proportional hazards models.Results:We observed 911 all-cause deaths among 1649 ovarian cancer cases. Self-reported endometriosis and longer duration of hormone therapy use were associated with improved survival (HR: 0.72; 95% confidence interval (CI): 0.54–0.94 and HR, ⩾5 years vs never: 0.70; 95% CI: 0.55–0.90, respectively). Older age at menopause and menarche were associated with worse survival (HR, ⩽50 vs >50 years: 1.23; 95% CI: 1.03–1.46 and HR, 13 vs <13 years: 1.24; 95% CI: 1.06–1.44, respectively). We observed no association between oral contraceptive use, parity and tubal ligation, and overall survival. No significant associations were observed for any of the reproductive and hormonal factors and platinum resistance.Conclusions:These results suggest that pre-diagnostic exposures such as endometriosis and HT use may influence overall survival among ovarian cancer patients.

Risk for and consequences of endometriosis: A critical epidemiologic review

Endometriosis affects approximately 10% of women of reproductive age. Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk. Relationships with other potential characteristics including physical activity, dietary factors, and lactation have been less consistent, partially because of the need for rigorous data collection and a longitudinal study design. Critical methodologic complexities include the need for a clear case definition; valid selection of comparison/control groups; and consideration of diagnostic bias and reverse causation when exploring demographic characteristics, medical history, and lifestyle factors. Reviewers and editors must demand a detailed description of rigorous methods to facilitate comparison and replication to advance our understanding of endometriosis.

Abstract DPOC-008: LIFESTYLE AND REPRODUCTIVE RISK FACTORS AND OVARIAN CANCER RISK BY p53 AND MAPK EXPRESSION

BACKGROUND: One recent model of ovarian cancer development divides ovarian cancer into two types. Type II tumors are fast growing, potentially arising from the fallopian tubes, and characterized by tubal precursor lesions with p53 mutations. Type I tumors are slow–growing, arising from the ovary, and characterized by KRAS, BRAF, and PTEN mutations. The purpose of this study was to evaluate the association between selected lifestyle and reproductive risk factors and risk of ovarian cancer defined by expression of p53 (as a marker of Type II disease) and mitogen–activated protein kinase (MAPK), which is upregulated by KRAS and BRAF (as a marker of Type I disease). METHODS: Epithelial ovarian cancer cases with available tumor blocks and cancer–free controls were identified from the Nurses9 Health Study (NHS) and NHS II prospective cohorts, and from the population–based New England Case–Control (NECC) study of ovarian cancer. We performed immunohistochemical assays for p53 and MAPK expression. Age– and multivariable–adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the association between each lifestyle or reproductive risk factor (e.g. parity, oral contraceptive use, tubal ligation, age at menarche, menopausal status, age at menopause, hormone therapy use, and family history of ovarian cancer) and ovarian cancer using polytomous logistic regression. RESULTS: 249 cases and 1051 controls from the NHS/NHS II and 77 cases and 857 controls from the NECC study were included in the analyses. Overall there were few significant differences in lifestyle or reproductive risk factors by p53 or MAPK tumor expression. Increasing parity was associated with a greater decreased risk of p53 negative tumors (OR=0.40; 95% CI=0.26–0.62) than p53 positive tumors (OR=0.85; 95% CI=0.46–1.57) (pheterogeneity=0.03). Family history of ovarian cancer was associated with risk of developing MAPK negative (OR=1.87; 95% CI=1.28–2.74) but not MAPK positive tumors (OR=0.76; 95% CI=0.46–1.23) (pheterogeneity CONCLUSIONS: These findings provide evidence that parity and family history may be associated with tumor subtypes defined by p53 and MAPK expression. However, in future studies other immunohistochemical markers that more clearly define these subtypes should be considered. Citation Format: Holly R. Harris, Megan S. Rice, Amy L. Shafrir, Elizabeth M. Poole, Jonathan L. Hecht, Kathryn L. Terry, Shelley S. Tworoger. LIFESTYLE AND REPRODUCTIVE RISK FACTORS AND OVARIAN CANCER RISK BY p53 AND MAPK EXPRESSION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-008.

Abstract B33: Reproductive and hormonal risk factors in relation to ovarian cancer survival and platinum resistance.

Introduction: Ovarian cancer survival is poor particularly for women with platinum-resistant disease. Therefore evaluating pre-diagnostic risk factors that are associated with ovarian cancer survival and platinum resistance in particular may help identify women who will not benefit from standard therapy. However, limited research has assessed pre-diagnostic reproductive and hormonal factors in relation to ovarian cancer survival and no studies have assessed these factors with platinum resistance. Objective: To evaluate the association of pre-diagnostic reproductive and hormonal factors with both ovarian cancer survival and platinum resistance among ovarian cancer patients. Methods: We included 1,648 cases of invasive epithelial ovarian cancer from a population-based case-control study with cases and controls recruited in Eastern Massachusetts and New Hampshire from 1992-2008. Reproductive and hormonal factors, including oral contraceptive use, parity, tubal ligation and endometriosis, were assessed during in-person interviews. Invasive ovarian cancer cases who received platinum chemotherapy and had medical record follow-up data (n=610) were included in the analyses on platinum resistance, which was defined as a recurrence within the first six months after the end of platinum-based chemotherapy. We used Cox proportional hazards models to calculate overall ovarian cancer survival and platinum resistance controlling for age, enrollment wave, reproductive factors, and tumor histology and stage. The same reproductive and hormonal factors were assessed for ovarian cancer survival and platinum resistance. As the cause of death was not known for all cases, we also restricted follow-up to the first five years when the vast majority of deaths should be from ovarian cancer in a secondary analysis. Results: We observed 906 deaths during 13,920 person-years of follow-up. Self-report of a physician diagnosis of endometriosis was associated with a 28% (95% CI: 0.55-0.95; p=0.02) decreased risk of death from ovarian cancer. We observed no association between oral contraceptive use, parity, age at first birth, and ovulatory years and ovarian cancer survival (p>0.17). Restricting analyses to the first five years did not substantially change the results. In preliminary analyses, 162 of the 610 women with platinum-based therapy had a disease recurrence within six months of ending treatment over 3,216 person-months of follow-up. Ever having a spontaneous or induced abortion was associated with a 44% (95% CI: 1.00-2.07; p=0.05) increased risk of platinum resistance but was not associated with overall ovarian cancer survival (p=0.18). Additionally, there was a suggestion that increasing age at menarche (Hazard ratio (HR): 1.13; 95% CI: 0.99-1.29 per year; p=0.07) and physician-diagnosed endometriosis (HR: 0.45; 95% CI: 0.19-1.05; p=0.06) were associated with platinum resistance. No association was observed for oral contraceptive use, parity, age at first birth, and ovulatory years (p>0.53), although the results were based on a small sample size. Conclusion: Increasing age at menarche and ever having a spontaneous or induced abortion were associated with an increased risk of platinum chemotherapy resistance. Additionally, physician-diagnosed endometriosis was associated with a reduced risk of ovarian cancer death and a suggestion of a reduced risk of platinum-resistance after adjusting for various factors including tumor histology. Although endometriosis increases the risk of endometrioid and clear cell tumors, which tend to have a more favorable prognosis, our data suggest endometriosis may improve survival through pathways other than tumor histology. Citation Format: Amy L. Shafrir, Ana Babic, Rulla M. Tamimi, Bernard A. Rosner, Shelley S. Tworoger, Kathryn L. Terry. Reproductive and hormonal risk factors in relation to ovarian cancer survival and platinum resistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B33.

An updated investigation of cancer incidence and mortality at a Scottish semiconductor manufacturing facility

Objectives To describe an update of the cancer incidence and mortality of workers at a Scottish semiconductor manufacturing facility to assess potential workplace cancer risks. Methods Company records had been used to identify a cohort of 4388 workers employed at the facility between 1970 and 1999. Subjects were flagged against National Health Service records for notification of cancer registrations and deaths. Standardised mortality (to end 2007) and cancer registration (to end 2006) ratios (SMRs and SRRs) were calculated for cancer site groups of a priori interest, comparing with Scottish rates adjusted for local deprivation status. Results There was a substantial deficit of mortality overall, particularly among men, compatible, at least in part, with a healthy work effect: SMR% (males) 45, 95% CI 34 to 57; SMR% (females) 73, 95% CI 58 to 90. Total cancer registrations were consistent with expectation for men (SRR% 90, 95% CI 69 to 116) and women (SRR% 102, 95% CI 85 to 122). SRRs for four cancer sites highlighted in an earlier analysis (lung, stomach and breast cancer in women; and brain cancer in men) were not statistically significantly elevated overall; neither were those for any other cancer site group. Analyses of cohort subgroups (including a group more likely to have worked in areas using carcinogens) by time since first employment, and analyses by duration of employment did not reveal any associations suggestive of a workplace effect on cancer rates. Conclusions This analysis does not support earlier concerns about a possible link between working at the facility and increased risks of cancer.

Case-control and case-only studies of selected cancers at a Scottish semiconductor manufacturing facility

Objectives HSEs 2001 report on cancer in a Scottish cohort of semiconductor manufacturing workers showed some statistically significant results, suggestive of increased risks. Recently, the follow-up in the cohort was extended. We report on a case-based study to investigate these suggestions. Methods From the extended follow-up, cases of breast, stomach and lung cancer in women, and of brain cancer in men were identified. It was planned that the lung and breast cancer cases would be interviewed and compared with matched controls, and that the rarer stomach and brain cancers would be examined case-only. A questionnaire was designed to collect detailed employment histories within the factory and elsewhere, information relevant to possible asbestos exposure, and lifestyle and environmental factors. A historical hygiene assessment was carried out at the factory, to inform construction of a job-exposure matrix. Results Attempts to recruit cases (or proxy respondents) were only partially successful; as a result, the lung cancers element was converted to a case-only study. Comparison with controls was possible for only 20 breast cancer cases (including 7 proxy respondents). From an extensive programme of conditional logistic analyses, statistical significance was achieved for exposure to arsenic compounds, antimony trioxide and sulphuric acid mist and to gases in general, but only in a few of the analyses. Examination of proxy responses for stomach, lung and brain cancers did not suggest any common workplace factors for any of these outcomes. Conclusions We interpreted this evidence as not supportive of an occupational risk for any of the cancers.