Environmental Chemical Agents and the Risk of Myelodysplastic Syndrome: A Systematic Review of the Literature

e18571 Background: Indications of lenalidomide (Len) include treatment of multiple myeloma (MM) in combination with dexamethasone (Dex) and myelodyplastic syndrome (MDS). The reported incidence and risk of rash varies widely and has been inconsistently reported in trials. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing rash. Methods: Relevant studies were identified from PubMed (1998-2011), abstracts presented at ASCO conferences (2004-2011) and the Web of Science database (1998-2011). Eligible studies were limited to prospective Phase II-III clinical trials in which patients received daily Len doses of either 10mg or 25 mg with or without 40mg of Dex. Incidence, relative risk (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on heterogeneity of included studies. Results: Data from a total of 1,127 patients in 15 trials were available for analysis. The overall incidence of all-grade and high-grade (grade ≥3) rash was 29.9% (95% CI: 24.8- 35.5) and 3.8% (95% CI: 2.7-5.5), respectively. Len was associated with increased risk of all-grade rash (RR=1.7, 95% CI: 1.3-2.3; P<0.001) when compared to patients treated with a placebo and Dex. Risk of high-grade rash was increased (RR=3.7, 95% CI: 0.8-16.0) with a trend toward statistical significance (P=0.08). No significant difference in incidence of all-grade rash between patients receiving LEN doses of 10mg or 25mg (25.6%, 95% CI: 19.6-32.8% vs. 30.8%, 95% CI: 24.7-37.7%, respectively, p=0.28) was observed. Similarly, no difference was observed between patients receiving LEN monotherapy or in combination with Dex (31.0%, 95% CI: 26.6-43.3% and 23.8%, 95% CI: 14.9-35.8%, respectively, p=0.17). Conclusions: Patients with MM or MDS who are treated with Len are at significant risk for developing rash. The risk appears to be independent of LEN dosage or in combination with Dex. Further studies for prevention and treatment of this untoward toxicity are needed in order to maintain patient’s quality of life and minimize the need for dose modification, all of which may impact clinical outcome.

Risk of rash associated with lenalidomide in cancer patients: a systematic review of the literature and meta-analysis.

Introduction: It is generally believed that the environment plays some role in the development of prostate cancer, but the extent of that role is not understood. The objective of this study is to perform a systematic review of the literature to bring together the best available evidence on the suspected relationship between the environment and prostate cancer. Methods: PubMed, Web of Science, CINAHL, CancerLit, and the Cochrane Library were searched. We examined peer-reviewed English language studies examining the association between the environment and prostate cancer risk between 1990 and May 31, 2019. We further included studies if they met all of the following criteria: (1) considered at least one chemical or biological agents; (2) reported risk for incidence, mortality, serious adverse events, or hospital admissions. We extracted data from each study, including location, health outcome, and risk estimates. Results of the studies were combined using a qualitative synthesis due to the variation across and within outcomes in reported results. Results: We assessed 198 studies, of which we selected 51 for an in-depth review. Thirty-four articles fulfilled our predetermined inclusion criteria and were included in the qualitative synthesis. Of the 34 articles, 16 were prospective cohort studies, and 9 were case-control studies. These 34 articles explored a number of environmental agents including chemicals, ionizing radiation, electromagnetic fields, and infectious agents. Chemical exposures included second-hand exposure to industrial chemicals and to environmental carcinogens. Several of the studies (n=21) were based on ecological comparisons and did not provide a quantitative risk estimate. Exposure to ionizing radiation and electromagnetic fields showed no association with risk of prostate cancer. There is an inconsequential link between pesticides and an increased risk of prostate cancer through a potential endocrine-disrupting mechanism based on androgen imbalance. In most cases the overall evidence was inadequate in number, reported outcomes, quality of study to establish a relationship between a specific environmental agent and risk of prostate cancer; the evidence from chemical exposure studies was not sufficient to draw an inference. Conclusions: Overall, the reviewed epidemiologic evidence provides a weak level of evidence supporting the hypothesis that there is a causal relationship between environmental exposures and increased risk of prostate cancer. Because a large number of individuals are exposed to suspected environmental carcinogens, investigation of the association between prostate cancer and environmental chemical and biological agents deserves to be a high priority. Such investigations do not only have health implications but can also provide a fundamental understanding of the process of prostate carcinogenesis. Citation Format: Oluwabunmi Dada, Hadiza Galadima, John Cyrus, Georges Adunlin. Can exposure to environmental chemical and biologic agents increase the risk of prostate cancer and its outcomes? [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D090.

Introduction: High noise exposure during critical periods in gestation is a potential stressor that may result in increased risk of implantation failure, dysregulation of placentation or decrease of uterine blood flow. This paper systematically reviews published evidence on associations between reproductive outcomes and occupational and environmental noise exposure. Methods: The Web of Science, PubMed and Embase electronic databases were searched for papers published between 1970 to June 2014 and via colleagues. We included 14 epidemiological studies related to occupational noise exposure and nine epidemiological studies related to environmental noise exposure. There was some evidence for associations between occupational noise exposure and low birthweight, preterm birth and small for gestational age, either independently or together with other occupational risk factors. Five of six epidemiologic studies, including the two largest studies, found significant associations between lower birthweight and higher noise exposure. There were few studies on other outcomes and study design issues may have led to bias in assessments in some studies. Conclusions: There is evidence for associations between noise exposure and adverse reproductive outcomes from animal studies. Few studies in have been conducted in humans but there is some suggestive evidence of adverse associations with environmental noise from both occupational and epidemiological studies, especially for low birthweight.

Background. Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders of hematopoietic stem cells that are characterized by ineffective hematopoiesis, multilineage dysplasia, peripheral cytopenias, and susceptibility to leukemic transformation. Even without progression to leukemia, there is substantial morbidity and mortality. Therefore, a better understanding of the etiology of this disease can lead to a significant reduction in the incidence and the mortality as a consequence, but it remains largely unknown. Smoking and alcohol are important modifiable risk factors for human cancers. However, only a few epidemiological studies have investigated their association with the risk of MDS. Here, we evaluated the association of smoking and alcohol consumption and the risk of MDS in a large-scale population-based cohort study in Japan. Methods. We included 95,950 Japanese subjects (45,451 men and 50,059 women; age 40-69 years at baseline) of the Japan Public Health Center-based Prospective Study who completed a questionnaire about their smoking and alcohol habits. During 18.3 years of follow-up, we identified 70 MDS cases (50 men and 20 women). We calculated hazard ratios (HRs) and their 95% confidence intervals (95% CI) using the Cox proportional hazards model to describe the relative risk of MDS associated with the smoking categories at baseline (never smokers, former smokers, current smokers, ever smokers of <30 and ≥30 pack-years) and the drinking categories at baseline (non-drinkers, occasional drinkers, and regular drinkers of 1-299 or ≥300 g/week of ethanol) after adjustment for potential confounders. Results. Smoking was marginally associated with an increased risk of MDS among men, with a HR for current smokers relative to never smokers of 2.11 (95% CI: 0.91-4.89). This risk increase was also observed in ever smokers with more than 30 pack-years compared to never smokers (HR=2.22, 0.95-5.19). A linear increase in HR with increasing pack-years was also seen, albeit without statistical significance (p-trend=0.083). In contrast, alcohol consumption was associated with a dose-dependent decrease in the risk of MDS among men (nondrinkers: reference, occasional drinkers: HR=0.48, 0.16-1.43; 0-299 g/week: HR=0.37, 0.19-0.74; ≥300 g/week: HR=0.45, 0.20-0.99, p for trend=0.008). All types of alcohol beverages (sake, distilled spirit and beer) consistently showed a protective effect. We also explored a possible interaction between smoking and alcohol consumption, but no obvious interaction was observed. Conclusions. This study showed that alcohol has a significant protective effect on the risk of MDS among Japanese men. In addition, this study also provides evidence that smoking increases the risk of MDS among Asian population, as it does among Western populations. Previous findings on the association between alcohol and the risk of MDS have been inconsistent, and further investigation across multiple populations is needed. Citation Format: Tomotaka Ugai, Keitaro Matsuo, Norie Sawada, Motoki Iwasaki, Taiki Yamaji, Taichi Shimazu, Shizuka Sasazuki, Manami Inoue, Yoshinobu Kanda, Shoichiro Tsugane. Smoking and alcohol and the risk of myelodysplastic syndrome: The JPHC study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2282. doi:10.1158/1538-7445.AM2017-2282

PurposeEndometriosis is a chronic debilitating inflammatory pathology which interests females in their reproductive age. Its pathogenesis has not yet been clearly defined. Recent evidence linked chemical agents as endocrine-disrupting chemicals to endometriosis. Phthalates are a widely used class of such compounds. This study aimed to summarize the current literature evaluating the link between exposure to phthalates and occurrence of endometriosis.MethodsA systematic review of literature and meta-analysis has been carried out following PRISMA guidelines to assess such link. Fourteen studies have been included in the review. Risk of bias has been assessed through the Newcastle Ottawa Scale.ResultsWe observed association between endometriosis and increased urinary levels of MBP/MnBP, MEOHP, and MEHHP, but not for others. Blood-derived analysis showed statistically significant link between endometriosis and BBP, DEHP, DnBP, and MEHP.ConclusionGiven the wide heterogeneity of included studies, results should be taken with caution. Further studies with more rigorous methodology are encouraged to unravel the true link between this class of toxic compounds and manifestation of endometriosis.

Environmental biological and chemical agents can modulate innate and acquired immunity in the lung via the stimulation of Toll-like receptors (TLRs). To investigate the effect of environmental chemical agents on the activation of NF-κB and activator protein (AP)-1 subunits and the role of TLR4 signaling in the lung, C3H/HeN and C3H/HeJ (TLR4-defective) mice were exposed to 0 or 50 ppm of toluene for 6 hr/day, 5 days/week for 6 weeks. Some groups of mice were also stimulated with OVA or LPS as a biological agent. The DNA-binding activities of the NF-κB subunits (p50, p52, p65 and RelB) and AP-1 family members (FosB, c-Fos, +c-Jun, JunD) were compared using TransAM ELISA kits. Exposure to toluene alone produced no significant changes in both mice. Although stimulation with OVA or LPS alone significantly increased the DNA binding activities of p50 and p52 in C3H/HeN mice, there were no interactions between biological factors and toluene. In the C3H/HeJ mice, stimulation with OVA or LPS increased p65 and p52 binding activity and the combination of exposure to toluene and OVA significantly increased the DNA binding activities of the p65 and p52 in the lung. During AP-1 activation, co-exposure to toluene and OVA increased JunD binding activity in C3H/HeJ mice, while co-exposure to toluene and LPS influenced c-Fos binding activity in C3H/HeN mice. These results indicate that TLR4 may play an important role in activation of NF-κB or AP-1 family following exposure to environmental biological and chemical agents.

Although coffee and green tea are suggested to reduce the risk of some types of cancers, only a few epidemiological studies have investigated their effect on the risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here, we investigated the association of coffee and green tea consumption and the risk of AML and MDS in a large-scale population-based cohort study in Japan. A total of 95,807 Japanese subjects (45,937 men and 49,870 women; age 40-69 years at baseline) were followed to the end of 2012, for an average of 18 years. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between coffee and green tea consumption at baseline and the risk of AML and MDS were assessed using a Cox proportional hazards model with adjustment for potential confounders. During 1,751.956 person-years, we identified 85 AML cases and 70 MDS cases. Our findings showed no significant association between coffee consumption and the risk of AML, or between green tea consumption and the risk of AML or MDS. In contrast, we observed a decreasing dose-response relationship between coffee consumption and the risk of MDS among men (almost none: reference, 1-4 times/week: HR = 0.83, 95% CI: 0.43-1.62; ≥1cups/day: HR = 0.47, 0.22-0.99, p for trend = 0.049). Stratified analysis by smoking status suggested that the observed relative risk for AML and MDS of coffee drinkers relative to non-coffee drinkers might be due to residual confounding by smoking. These findings deserve further investigation in future studies.

Study question Are paternal occupational exposures associated with a higher risk of fetal loss in the unexposed female partner? Summary answer Significant positive associations between paternal occupational exposures and fetal loss were retrieved, for chemical and physical agents and for several occupations. What is known already Adverse pregnancy outcomes are frequent and, in its recently updated guidelines, the ESHRE reinforced the interest of exploring the father’s exposures. Nevertheless, causes of fetal loss are still most often investigated only in mothers. Paternal risk factors for fetal loss have been scarcely explored, particularly occupational exposures. Though, males appear to be more exposed to occupational reprotoxic agents than females and are not always aware or sufficiently informed of these exposures. Reprotoxic mechanisms of father’s occupational exposures may include sperm nucleus alteration, seminal fluid contamination and/or indirect exposure of the mother to paternal occupational environment (via linen, dust…). Study design, size, duration A systematic review of the literature using PRISMA 2020 methodology was performed for full text English and French language articles in the Pubmed MEDLINE, Google Scholar, Web of Science and Embase databases. Participants/materials, setting, methods We included only original studies published until December 2022, performed in humans, including a control group and performing a multivariate analysis. The fetal losses analysed were early and/or late and we did not exclude studies analysing stillbirths. We excluded studies in which the female partner was also occupationally exposed. The dose-response relationship and mechanisms of action were noted where described. Main results and the role of chance The 33 studies included analysed a total of 540,246 pregnancies from 8,183 couples or 114,093 exposed male workers, and were classified into 3 groups according to the occupational hazards studied. Regarding chemical agents, the risk of miscarriage was significantly increased in cases of paternal occupational exposure to Thiocarbamate(OR = 1.9, 95% CI 1.1-3.3), Carbaryl (OR = 1.9, 95% CI 1.9-3.1), Dichloro-Diphenyl-Trichloroethane (OR = 1.57, 95% CI 1.13-2.18), printing solvents (OR = 5.5, 95% CI 1.8-17.2), ethylene oxide (OR = 4.7, 95% CI 1.2-18.4), petroleum refinery solvents (OR = 2.2, 95% CI 1.3-3.8) and stainless steel welding fumes (RR = 3.5, 95% CI 1.3-9.1). Regarding physical agents, the risk of stillbirth or perinatal mortality was significantly increased with exposure to ionising (OR = 1.86, 95% CI 1.21-2.76) and nonionising radiation (RR = 2.23, 95% CI 1.08-4.62). Regarding the type of occupation, the risk of miscarriage or stillbirth was significantly increased among crushers, grinders and calenders (OR = 2.20, 95% CI 1.13-4.30), to seamstresses (OR = 2.54, 95% CI 1.29-5), sheet metal workers and commercial aircrew (OR = 2.85, 95% CI 1.30-6.23). The dose-response relationships showed divergent results. The mechanisms of action hypothesized were mainly germ cell mutations. Limitations, reasons for caution The publications selected were mostly published before 2010 and showed high variation in the population sizes, types of male occupational exposure, and in the nature and number of confounding factors used for the multivariate statistical analysis. Due to the various nature of exposures analysed, no meta-analysis could be performed. Wider implications of the findings Men should be made more aware of male-mediated occupational reproductive risks. Occupational health professionals should participate in the investigation of the causes of foetal loss and act on male occupational exposures that may impact pregnancy outcomes. Further high-powered prospective studies are needed, which should include paternal current occupational exposures. Trial registration number not applicable

A healthy working life is fundamental for individuals and society. To date, increasingly research connects the earlier, pre-working life to later working life experiences and beyond, recognizing that a worker’s health and exposure starts before the working life begins. The research, however, often lacks a fundamental understanding of (i) the underlying mechanisms and pathways accounting for differences in different life stages and (ii) the role of the social environment in shaping working life experiences. By integrating a life course perspective in our research and crossing disciplinary borders in rigorous, collaborative research, we may get a better understanding of the complex and dynamic interplay between work, environment and health. A life course perspective for work environment and health research A life course perspective in work environment and health research emphasizes the importance of prior life experiences, including the environments in which individuals were raised and exposed, their familial and educational backgrounds, and their physical and mental health status before entering the workforce (1, 2). Life course research in different disciplines has been instrumental in developing more robust causal models (3, 4), particularly for understanding developmental health trajectories and socioeconomic health inequalities (eg, 5–7). Adopting an interdisciplinary life course perspective in work environment and health research helps researchers answering questions as to whether and how the timing, duration, intensity, and context of past and present exposures (ie, pre-working, working, and non-working exposures) are associated with later life work and health outcomes. For instance, the ‘exposome paradigm’ is a concept used to describe the sum of occupational and environmental exposures an individual encounters throughout life, and how these exposures impact biology and health (8). In exposome research, a broad range of genetic, biological, chemical, physical, social and lifestyle factors is examined throughout the life course to provide a comprehensive picture of potential risk factors impacting working life health (9). In exposome research and beyond, it is important to examine how the exposure-outcome relationships are shaped by specific social, cultural and historical contexts (2). The conceptual framework of the ‘Social Exposome’ may help to integrate the social environment in conjunction with the physical environment into the exposome concept (10). Moreover, focusing on both historical and contemporary contexts is essential not only for advancing research but also for informing policy and practice, for example by identifying entry points for interventions. Exposures during the life course During the individual’s life course, several vulnerable time windows for the impact of a multitude of exposures that potentially harm, protect or promote health, eg, occupational, environmental and social, can be distinguished. The (combinations of) exposures may operate in different life stages and contexts and – directly or indirectly via intergenerational transmission – contribute to health (figure 1). The individual may be particulary sensitive to harmful exposures or adverse experiences during developmental life stages, ie, pre/perinatal, childhood, adolescence, pregnancy and menopause/andropause. Other life stages may reflect vulnerable time windows due to a clustering of exposures, eg, work and family demands during parenthood, or an accumulation of exposures during the (working) life course at retirement and post-retirement age. As illustrated in figure 1, occupational exposure(s) can be divided in exposure through the parents’ exposure (early in life) and an individuals’ own exposure (later in life). Already in the pre/perinatal life stage, occupational exposure starts through the intergenerational transmission of the parents’ occupational exposures. Current and bioaccumulated occupational exposure of chemicals and particles in the father at the time of conception can affect sperm quality. Together with the mother’s exposure to occupational exposures of chemicals and particles prior to conception – or chemicals, particles, physical factors, ergonomic load, organizational and (psycho-)social conditions at work during pregnancy – this may affect fetal development and later disease development during the child’s life course (11–15). During childhood, the growing child is exposed to parental occupational exposure(s), directly through chemicals and particles in the work clothes and skin or indirectly through organizational and psychosocial factors in the work environment that may increase the risk for mental and physical health problems in parents, which in turn may affect their parental rearing quality (16, 17). During adolescence and early adulthood, individuals usually encounter their first direct occupational exposures through their first (student) job or jobs. Already from this life stage, occupational exposures may accumulate during the (working) life course and may affect not only the active working life but also the post working life. Also important to note is that brain plasticity is not limited to childhood, adolescence or young adulthood as it persists throughout life. Some studies indicate that high physical and chemical exposure during this life stage, can increase the risk of disease later in life (18). A poor psychosocial school or work environment in younger years may also increase the risk of adverse labour market outcomes and mental health problems later in life (19, 20). In adulthood, men and women often start with (the planning of) family formation. Some occupational exposures affect fecundability, others can increase the risk of pregnancy-related disease, such as preeclampsia, hypertension or diabetes, or affect the offspring (21, 22). Chemicals, heat and stress-related exposures affect the ability to conceive. During pregnancy, the bodily and mental systems are vulnerable with changes in the endocrine and inflammation response that can dysregulate the HPA-axis, resulting in a prolonged stress response. The placenta can filter out many hazards, but not all toxicants, such as methylmercury and arsenic (23, 24). Physical exposure, such as noise and vibration, but also shift and night work can affect the womb and cause fetal growth restriction, preterm birth, and hearing impairment (eg, 12, 13, 25–27). During parenthood, occupational exposures may affect the parents’ (mental) health and work-family balance (28, 29). Many chemical and physical exposures have now manifested in disease, eg, allergy, asthma and musculoskeletal diseases (28). During menopause in women, with a drastic decrease in oestrogen, and the slow testosterone decline in men (sometimes referred to as andropause), dysregulations of the hormone system may disrupt and affect the individual’s susceptibility for occupational exposures in a way similar to environmental exposures (30). Towards retirement, the total cumulative occupational exposure burden over the working life course and the current exposure will affect the ability to stay at work and in the labor market. Post retirement, most direct occupational exposures have ceased, but others may have (bio-) accumulated over time and may cause health problems that manifest after retirement (31, 32). Along with occupational exposures, a multitude of other exposures are present during the entire life course that may operate across different contexts to contribute to health (see figure 1). For instance, chemical, physical and social stressors during the life course leave traces (‘memories’) on the molecular and tissue levels that may affect later life health (33). Epigenetic marks act as heritable memories in the cell as they respond to different endogenous and exogenous signals and can be propagated from one generation of cells to the next generation of cells (33). Next to the epigenetic marks, the social environment and social determinants of health during the life course, eg, socio-economic and lifestyle factors, social relationships, social cohesion and support, are known to impact health and add to the multitude of exposures to be examined, among others in conjunction with the environmental exposome (eg, 34). In residential, family and school contexts, exposures such as air pollution, drinking water pollution, noise, artificial light at night, limited access to green space and crowding may play a role, as can adverse childhood experiences (eg, 35, 36). Moreover, on the overarching societal context, legislations, labor market conditions, norms, values and cultural aspects may affect worker health (2, 37). Main knowledge gaps and challenges Both conceptual and empirical challenges have to be tackled when conducting work environment and health research with an interdisciplinary life course perspective. On the conceptual level, different paradigms and nomenclature still exist in the various disciplines examining the impact of (occupational) exposures on later life health outcomes, which contributes to fragmented research and publication thereof in specialized journals. On the empirical level, questions arise such as: Is it feasible to examine mechanisms and pathways across different exposure levels considering a life course perspective? Is the follow-up duration of existing birth and other cohorts sufficient to address the dynamic interplay between the work environment and health? Are the multifaceted, constantly changing contexts captured? Effect sizes are often small on an individual level and statistical power decreases when several rare assumptions have to be fulfilled to examine clusters or combinations of exposures and contexts in relation to health outcomes. Big data, interdisciplinary research protocols and innovative, advanced statistical models to capture the life course perspective are needed to proceed beyond the exposome studies that are currently being finalized within the EU Horizon 2020 exposome call (https://www.humanexposome.eu). Moreover, a better understanding is needed of how occupational, environmental and social exposures affect individuals (i) in vulnerable time windows, eg, do exposures contribute to health advantages and/or disadvantages, and (ii) while transitioning between and within different life stages (38). Studies in different disciplines have focused on the childhood and retirement life stages, see eg, the research on the school-to-work transition or the work-to-retirement transition (39–41), but little is known about the menopause or andropause life stage. Last, rigorous examinations of different lifecourse models (eg, sensitive periods) and exposure models (eg, current, first, last, peak, single, chronic or accumulated), and their impact on health are needed within and across the different vulnerable time windows and life stages as exposure-outcome relationships may differ and thus call for targeted (preventive) policies and practices (42–44). Interdisciplinary research opportunities The challenges towards a better understanding of the complex and dynamic interplay between the work environment and health provide ample opportunities for rigorous, collaborative quantitative and in-depth qualitative life course research across different research strands. Researchers from different disciplines, such as occupational and environmental medicine, epidemiology, toxicology, health science, sociology, psychology, demography, public (mental) health, and genetics to name a few, should not shy away from the complexity, but embrace the opportunity to use their knowledge and skills to collectively address relevant research questions. Interdisciplinary research opportunities are already present today and will emerge even more in the years to come as more cohorts designed as birth cohorts or multi-generational cohorts mature (eg, LifelinesNext, 45). Researchers have or get access to (national) registers, databases with individual-level internal and external exposure information and neighbourhood-level exposure information or linkages of all these exposure and health data, allowing them to examine the impact of exposures in advanced causal models on later life health. To illustrate the value of and research opportunities with existing data, Ubalde-Lopez and colleagues (46) recently argued that parental work-related data collected in birth cohorts is a valuable yet underutilized resource that could be exploited more fruitfully in the collaboration between birth cohort research, occupational epidemiology and sociology. Having said that, the authors also refer to the possible constraints of eg, cross-national comparative research in terms of technical (ie, harmonization) and ethical challenges (46). In conclusion, to move research on the work environment and health forward, we call for a more integrated, interdisciplinary approach that considers the timing and accumulation of occupational, environmental and social exposures over the life course.

3641 Background: Clinical trials have reported improved outcomes with PARPi (poly [adenosine diphosphate–ribose]-ADP polymerase inhibitor) therapy in ovarian, breast, pancreatic and lung cancers. There is concern that PARPi therapy may cause myelodysplastic syndrome (MDS). In this meta-analysis we seek to quantify the risk of MDS among patients treated with PARPi for solid tumor malignancies. Methods: We searched Medline, Embase, and Cochrane databases (up to January 6, 2020) to abstract randomized controlled trials that include a PARPi in the experimental arm in solid tumors. Combinations included PARPi versus (vs.) placebo, PARPi vs. cytotoxic treatment, and PARPi with cytotoxic treatment vs. cytotoxic treatment. We used to time-to-event curves to estimate person-time and calculated the incidence of MDS among all studies. We used random-effects Poisson regression models to estimate pooled incidence risk ratio (RR) for developing MDS. Results: We identified 14 studies, 10 in ovarian, 3 in breast, and 1 in pancreatic cancer patients. Of 5,646 patients, 62.3% received a PARPi alone or in combination with chemotherapy or bevacizumab, and 37.8% received treatment consisting of placebo alone or with chemotherapy or bevacizumab. PARPi were investigated as an upfront treatment in 2,827 patients, and as treatment for recurrence in 2,819 patients. The incidence of MDS was 6.73 cases vs. 3.85 per 1000 person-years in patients receiving PARPi as compared to control corresponding to a 3-year cumulative incidence of 2.0% and 1.1%. Accounting for intra-study clustering, PARPi use was associated with a 60% increase in risk (incidence RR 1.60, 95% Confidence Interval [CI] 0.89-2.87) of MDS compared to control. In the upfront setting, patients randomized to PARPi were twice as likely to develop MDS (RR 2.08, 95%, CI 1.39-3.64). Among patients treated for recurrence, the risk of MDS appeared to be similar among patient randomized to PARPi or control treatment (RR 1.13, 95% CI 0.35-3.64). In studies that compared PARPi in combination with other cytotoxic treatment vs. cytotoxic treatment alone, PARPi was associated with a large risk of MDS (RR 5.08, 95% CI 1.36-19.03). Conclusions: In pooled estimates from randomized controlled trials in solid tumors PARPi treatment appears to be associated with an increased incidence of MDS particularly in the upfront setting and when combined with cytotoxic treatment. Despite pooling 14 randomized trials our estimates remain imprecise due to the rarity of MDS.

Since 2007, a new class of biologic products for human use called “advanced therapy medicinal products (ATMP)” have been legally integrated in the European Medical Agency. They consist of recombinant nucleic acid, engineered cells, cells, or tissues. In the United States, ATMP fall under the regulatory framework of biological products and the term “cell and gene therapy product” is used in the legislative and regulatory documents. Potential clinical applications are broad, particularly, in the field of cancer, inherited genetic disease, and regenerative medicine. Indeed, the benefit conferred by CD19 chimeric antigen receptor T cells led to the first engineered cell therapy products to be approved by the Food and Drug Administration (FDA) in 2017. Gene therapy products to treat orphan diseases are also extensively developed with many clinical trials ongoing in the world. Nevertheless, the use of these therapeutic products is complex and requires careful considerations in the terms of regulatory and hospital setting requirements, such as storage, handling, administration, and disposal which justify the implementation of a secured medication circuit. Through this systematic review of the literature, the authors wanted to compile data on the assessment of environmental exposure related to the use of ATMP in healthcare setting to secure their medication circuit. A literature search was conducted on PubMed and Web of Science, and 32 publications dealing with environmental exposure assessment and ATMP were selected. In addition, marketed ATMPs were identified and data regarding the environmental concerns were extracted from product information sections from European Public Assessment Reports (EPAR). The environmental contamination assessments were mainly addressed in the reviews rather than in original articles related to the use of ATMP. Most of the product information sections from EPAR suggested precautions rather than requirements when dealing with environmental consideration following ATMP handling. Nevertheless, these precautions usually remain elusive especially concerning waste disposal and the detection of biological material on the work surfaces, and mainly relate to the genetically modified organisms (GMO) over non-GMO cellular products. Pharmaceutical oversight and adherence to the good preparation practices and good clinical practices are essential to ensure the safe use in term of environmental concern of these new therapeutic products in healthcare setting.

Background and objectiveAdherence to treatment in patients with psoriasis is often poor. An investigation of patient preferences and satisfaction with treatment may be important, based on the expected correlation with therapy compliance. This paper aims to examine and describe the current literature on patient preferences, satisfaction and adherence to treatment for psoriasis in the European Union (EU).MethodsElectronic searches were conducted using PubMed, ISI Web of Knowledge, Scopus, Spanish databases and Google Scholar. European studies published in English or Spanish between January 1, 2009 and December 31, 2014 regarding patient-reported outcomes in psoriatic patients were included. Studies conducted in non-EU countries, letters to the editor, editorials, experts’ opinions, case studies, congress proceedings, publications that did not differentiate between patients with psoriasis and psoriatic arthritis or studies related to specific treatment were excluded.ResultsA total of 1,769 titles were identified, of which 1,636 were excluded as they were duplicates or did not provide any relevant information. After a full-text reading and application of the inclusion/exclusion criteria, 46 publications were included. This paper will describe publications on adherence (n=4), preferences (n=5) and satisfaction with treatment (n=7). Results related to health-related quality of life articles (n=30) have been published elsewhere. Adherence rates are generally low in psoriasis patients regardless of the type of treatment, severity of disease or methods used to measure adherence. Biologic therapy is associated with greater clinical improvement. There is a direct association between physician recommendations, patient preferences and several domains of treatment satisfaction.ConclusionThe results of this review support the conclusion that adherence rates in patients with psoriasis are suboptimal and highlight the need to improve patient compliance and satisfaction with treatment. Patients’ preferences should be taken into account in the treatment decision-making process in order to improve patients’ clinical outcomes by ensuring satisfaction and adherence.

Radiation Treatment for Localized Prostate Cancer and the Risk of Developing Myelodysplastic Syndromes (MDS)

To determine the risk factors involved in myelodysplastic syndromes (MDS). A 1:2 case-control study was conducted in 20 Shanghai' hospitals over a 3-year period, covering 266 "de novo" MDS cases corresponded to FAB criteria, and 532 age- and gender-matched controls from same hospitals with MDS cases. Subjects were all surveyed using the same standard questionnaire including histories of medications (Chloramphenicol, Sulfonamides, Meprobamate, Phenytoin, Colchicine, Cyclophosphamide, Propylthiouracil, Anti-TB medication, Tolbutamide, Primaquine and Chinese traditional herbs such as Bezoar, Angelica, Arsenic, Thunder cloud vine) at least 5 years prior to the onset of the disease, tumors, exposure to benzene, heavy metal, organic phosphates, pesticides, petrol/diesel, organic solvents, dye and hair dye products, radiation, house decorating, alcohol and smoking. Occupational exposure to benzene increased significantly the risk of MDS (OR: 8.52, 95% CI: 2.30 - 31.10). Living near high voltage power lines (100 m) increased significantly the risk of MDS (OR: 1.60, 95% CI: 1.10 - 2.32). House decorating (one year prior to the onset of the disease) increased significantly the risk of MDS (OR: 2.40, 95% CI: 1.38 - 4.14). Other investigated occupational poisons did not increase significantly the risk of MDS. Hair dye products, alcohol and smoking did not increase significantly the risk of MDS. Occupational exposure to benzene, living near high voltage power lines and house decorating are the risk factors of MDS.