The higher risk group of DES-exposed women need early detection of cervical and vaginal adenocarcinomas
2015 Study Abstract
BACKGROUND: Women in the 1940s-1960s were prescribed Diethylstilbestrol (DES), a nonsteroidal estrogen, to prevent miscarriages, but the practice was terminated after it was discovered that the daughters so exposed in utero were at increased risk for developing clear cell adenocarcinoma (CCA) of the vagina or cervix at early ages. Pap smear screening is one of the principal methods used to identify tumor development and is necessary in this group of women to maintain their health. Currently, little is known about the factors associated with nonutilization of this screening tool in this high-risk population of women.
METHODS: National cohort data from the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study during 1994, 1997, 2001, and 2006 were used to determine which factors were associated with Pap smear screening nonutilization in 2006 among DES-exposed and unexposed women. Self-reported questionnaire data from 2,861 DES-exposed and 1,027 unexposed women were analyzed using binary logistic regression models.
RESULTS: DES exposure, not having a previous gynecologic dysplasia diagnosis, lack of insurance, originating cohort, increasing age, and previous screening behavior were all factors associated with not reporting a Pap smear examination in the 2006 questionnaire, although college education reduced nonutilization.
CONCLUSIONS: Understanding which factors are associated with not acquiring a screening exam can help clinicians better identify which DES-exposed women are at risk for nonutilization and possibly tailor their standard of care to aid in the early detection of cervical and vaginal adenocarcinomas in this high-risk group.
Factors associated with a lack of pap smear utilization in women exposed in utero to diethylstilbestrol, NCBI PMID: 25768943, J Womens Health (Larchmt). 2015 Apr;24(4):308-15. doi: 10.1089/jwh.2014.4930. Epub 2015 Mar 13.
Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between DES and adult obesity, weight gain from age 20 to mid-life, central adiposity and height among 2871 prenatally exposed and 1352 unexposed women between 23 and 52 years of age (median 41.5) at baseline in 1994. DES exposure status was confirmed by prenatal medical record review. We used multivariable log-binomial models to calculate risk ratios (RRs) for obesity in 2006, and linear regression to calculate mean differences in body mass index, weight gain, waist circumference and height.
The adjusted RR for DES and obesity was 1.09 [95% confidence interval (CI): 0.97, 1.22],
and RRs were 1.23 (CI: 1.07, 1.42)
and 1.05 (CI: 0.91, 1.20) for low and high estimated total DES dose, respectively, compared with no exposure.
DES-exposed women gained slightly more weight than unexposed women [mean difference, 0.70 kg (CI: -0.27, 1.66)].
This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity.
Prenatal diethylstilbestrol exposure and risk of obesity in adult women, NCBI PMID: 25697972, J Dev Orig Health Dis. 2015 Jun;6(3):201-7. doi: 10.1017/S2040174415000033. Epub 2015 Feb 20.
DDT in Pregnancy May Raise Breast Cancer Rates in Daughters
Women who were exposed to higher levels of the pesticide DDT in utero were nearly four times more likely to be diagnosed with breast cancer as adults than women who were exposed to lower levels before birth, according to a 54-year case-control study.
2015 Study Abstract
Context: Currently no direct evidence links in utero dichlorodiphenyltrichloroethane (DDT) exposure to human breast cancer. However, in utero exposure to another xenoestrogen, diethylstilbestrol, predicts an increased breast cancer risk. If this finding extends to DDT, it could have far-reaching consequences. Many women were heavily exposed in utero during widespread DDT use in the 1960s. They are now reaching the age of heightened breast cancer risk. DDT exposure persists and use continues in Africa and Asia without clear knowledge of the consequences for the next generation.
Hypothesis: In utero exposure to DDT is associated with an increased risk of breast cancer.
Design: This was a case-control study nested in a prospective 54-year follow-up of 9300 daughters in the Child Health and Development Studies pregnancy cohort (n = 118 breast cancer cases, diagnosed by age 52 y and 354 controls matched on birth year).
Setting and Participants: Kaiser Foundation Health Plan members who received obstetric care in Alameda County, California, from 1959 to 1967, and their adult daughters participated in the study.
Main Outcome Measure: Daughters’ breast cancer diagnosed by age 52 years as of 2012 was measured.
Results: Maternal o,p′-DDT predicted daughters’ breast cancer (odds ratio fourth quartile vs first = 3.7, 95% confidence interval 1.5–9.0). Mothers’ lipids, weight, race, age, and breast cancer history did not explain the findings.
Conclusions: This prospective human study links measured DDT exposure in utero to risk of breast cancer. Experimental studies are essential to confirm results and discover causal mechanisms. Findings support classification of DDT as an endocrine disruptor, a predictor of breast cancer, and a marker of high risk.
Sources and more information
DDT Exposure in Utero and Breast Cancer, The Journal of Clinical Endocrinology & Metabolism, doi/10.1210/jc.2015-1841, June 16, 2015.
Prenatal DDT exposure tied to nearly 4-fold increase in breast cancer risk, THE ENDOCRINE SOCIETY, eurekalert, 16-JUN-2015.
Prenatal DDT exposure linked to increased risk of breast cancer, medicalnewstoday, 17 June 2015.
Startling link between pregnant mother’s exposure to DDT and daughter’s risk of breast cancer, washingtonpost, June 17 2015.
Dans leur nouvelle enquête, Marina Carrère d’Encausse, Michel Cymes et Benoît Thevenet s’intéressent aux accidents dus aux médicaments. Effets secondaires, surdosages, mauvaises indications, interactions, le remède se révèle parfois pire que le mal…
Après la diffusion du documentaire, les spécialistes invités sur le plateau – dont LeemFrance et Formindep – répondent aux questions des téléspectateurs, posées par sms, internet et via les réseaux sociaux.
Médicaments: ces ordonnances qui tuent, FRANCE 5, 9 JUIN 2015.
Enquête de santé : médicaments, ces ordonnances qui tuent, allodocteurs A REVOIR et se soigner 10/06/2015.
Do I really need this test or procedure? What are the risks? Are there simpler safer options? What happens if I do nothing?
This post content is published by The BMJ, aiming to lead the debate on health, and to engage doctors, researchers and health professionals to improve outcomes for patients.
The idea that some medical procedures are unnecessary and can do more harm than good is as old as medicine itself. In Mesopotamia 38 centuries ago, Hammurabi proclaimed a law threatening overzealous surgeons with the loss of a hand or an eye. In 1915, at the height of a surgical vogue for prophylactic appendicectomy, Ernest Codman offended his Boston colleagues with a cartoon mocking their indifference to outcomes and asking, “I wonder if clinical truth is incompatible with medical science? Could my clinical professors make a living without humbug?” Looking at the rates of tonsillectomy in London boroughs in the 1930s, John Alison Glover discovered that they were entirely governed by the policy of school doctors and bore no relation to need or outcomes. John (Jack) Wennberg established the science of outcomes research when in 1973 he described patterns of gross variation in the use of medical and surgical procedures in the United States, which lacked any clinical rationale but was closely related to supply.
Diagnosis drives treatment, and in recent years the term overdiagnosis has been used to describe various situations where diagnoses lead to unnecessary treatment, wasting resources while increasing patient anxiety. Overdiagnosis can be said to occur when “individuals are diagnosed with conditions that will never cause symptoms or death” often as a “consequence of the enthusiasm of early diagnosis.” Overtreatment includes treatment of these overdiagnosed conditions. It also encompasses treatment that has minimal evidence of benefit or is excessive (in complexity, duration, or cost) relative to alternative accepted standards. A recent report by the Academy of Medical Royal Colleges argued that doctors have an ethical responsibility to reduce this wasted use of clinical resource because, in a healthcare system with finite resources, one doctor’s waste is another patient’s delay.
Choosing Wisely in the NHS
Even before the inception of the NHS, the British tradition has generally been one of late adoption and cautious use of new medicines, procedures, and technologies. Nevertheless, the UK shows similar patterns of variation in use of medical and surgical interventions to those in the US, though less extreme in absolute terms. The National Institute for Health and Care Excellence (NICE) was set up in 1999 in part to address these unwarranted variations in clinical practice and has identified over 800 clinical interventions for potential disinvestment. However, engaging clinicians with stopping familiar or ingrained practices requires a different approach to that for introducing new treatments.
An initiative recently developed in the US and Canada called Choosing Wisely aims to change doctors’ practice to align with best practice by getting them to stop using various interventions that are not supported by evidence, free from harm, and truly necessary, including those that duplicate tests or procedures already received. Choosing Wisely asks medical organisations (such as medical royal colleges in the UK) to identify tests or procedures commonly used in their specialty, the necessity of which should be questioned and discussed. These are compiled into lists, and the “top five” interventions for each specialty should not be used routinely or at all. So far, more than 60 US specialist societies have joined in the Choosing Wisely initiative. It has also been adopted by other countries, including Australia, Germany, Italy, Japan, Netherlands, and Switzerland—a clear sign that wasteful medical practices are a problem for all health systems.
The Academy of Medical Royal Colleges, which represents all medical royal colleges in the UK, is launching a Choosing Wisely programme in collaboration with other clinical, patient, and healthcare organisations. Participating organisations will work together to develop top five lists of tests or interventions with questionable value. The academy, royal colleges, and partners, including The BMJ, will then promote dissemination of this information and Choosing Wisely conversations between clinicians and patients. These new conversations will rebalance discussions about the risks and benefits of tests and interventions, such that doctors and patients will be supported to acknowledge that a minor potential benefit may not outweigh potential harm, the minimal evidence base, and substantial financial expense and therefore that, sometimes, doing nothing might be the favourable option.
Tackling the underlying causes of overtreatment
A culture of “more is better,” where the onus is on doctors to “do something” at each consultation has bred unbalanced decision making. This has resulted in patients sometimes being offered treatments that have only minor benefit and minimal evidence despite the potential for substantial harm and expense. This culture threatens the sustainability of high quality healthcare and stems from defensive medicine, patient pressures, biased reporting in medical journals, commercial conflicts of interest, and a lack of understanding of health statistics and risk.
The system has no incentive to restrict doctors’ activity; the NHS in England has a system of payment by results, which in reality is often a payment by activity and encourages providers to do more both in primary and secondary care. General practice is increasingly pressured to focus less on open dialogue with patients about treatment options and more on fulfilling the demands of the Quality and Outcomes Framework (QOF, a pay for performance instrument) and adhering to local commissioning decisions.
The quality measures in both primary and secondary care are based on guidelines produced by NICE, but doctors should not consider these as tramlines because decisions need to be made with reference to individual patient circumstances, the wishes of the patient, clinical expertise, and available resources. Some people would choose to take a hypothetical pill with no side effects daily, even for a few weeks’ gain in life expectancy, whereas others would prefer not to, even if they were told it would add 10 years to their lifespan. It is instructive to note that a large and comprehensive longitudinal study recently concluded that higher reported achievement incentivised under QOF has not reduced premature death in the population.
We suggest that guideline committees should increasingly turn their efforts towards the production of tools that help clinicians to understand and share decisions on the basis of best evidence. Rather than prespecifying the outcome of such dialogue, and trying to get medicine “just right,” they should try to ensure that decisions are based on the best match between what is known about the benefits and harms of each intervention and the goals and preferences of each patient.
More informed decision making can also alleviate, perhaps disproportionate, fears for those patients who may not want treatment. A recent study revealed that when patients were told the lack of prognostic benefit for angioplasty, only 46% elected to go ahead with the procedure versus 69% who were not explicitly given this information. Responding to similar concerns about getting patients’ consent for elective coronary angioplasty in the UK, NHS England’s cardiology lead, Huon Gray, stated, “It is important that doctors are clear with their patients about this.”
It is easy to misunderstand health statistics, and doctors can find themselves needing to manage unrealistic expectations of patients who may find it difficult to obtain reliable information. Communicating relative risks as opposed to absolute risk or numbers needed to treat can often unintentionally mislead. As Gerd Gigerenzer, director of Harding Centre for Risk Literacy in Berlin, summarised in 2009, “It is an ethical imperative that every doctor and patient understand the difference between absolute and relative risks, to protect patients against unnecessary anxiety and manipulation.”
Doctors’ health illiteracy is well documented. Misunderstanding of statistics often leads to a belief that screening is more beneficial than it actually is and, in some cases, to no acknowledgment of its potential harms. In a study of 150 gynaecologists, one third did not understand the meaning of a 25% risk reduction from mammography. Many believed that if all women were screened 25% of women (or 250 fewer out of every 1000) would die of breast cancer, when actually the best evidence based estimate is actually one less death per 2000 women (from Cochrane’s analysis of randomised studies including 500 000 women).
Both medical and surgical overtreatment can place patients at high risk of adverse events. Shared decision making can help to reduce this overtreatment and may be particularly beneficial to disadvantaged groups, significantly improving health outcomes and reducing health inequalities.
One of the major concerns about the development of top five lists in the US is the potential for individual societies to choose low hanging fruit. For example, the American Academy of Orthopaedic Surgeons included the use of an over the counter supplement but no major procedures, despite evidence of wide variation in elective knee replacement and arthroscopy rates among Medicare beneficiaries. Currently, there is also no evidence that lists reduce use of low value medical practices. One crucial and relevant marker of success would be universal awareness of the Choosing Wisely programme among doctors and patients. However, despite much publicity in the medical literature, a random telephone survey of 600 US doctors recently conducted by the American Board of Internal Medicine found that only 21% had heard of Choosing Wisely. The level of public awareness of the campaign, which is a fundamental component to its progress, has not been assessed.
Reducing wasteful and harmful healthcare will require commitment from both doctors and patients, in addition to objective evidence of effectiveness. The NHS already has good systems for evidence appraisal and health technology assessment, but better and simpler tools are needed to facilitate informed discussion in clinical settings. Without such robust and easily shared decision aids, systematically updated without bias, patients may be swayed by potential exaggerated claims in the media when new drugs or procedures are introduced. Lastly, shared decision making does not guarantee lower resource use; greater involvement of patients in deciding their care will require a new set of consultation skills as well as a better range of decision aids.
Call to action and next steps
To ensure the development of a Choosing Wisely culture in clinical practice, the academy suggests:
Doctors should provide patients with resources that increase their understanding about potential harms of interventions and help them accept that doing nothing can often be the best approach
Patients should be encouraged to ask questions such as, “Do I really need this test or procedure? What are the risks? Are there simpler safer options? What happens if I do nothing?”
Medical schools should ensure that students develop a good understanding of risk alongside critical evaluation of the literature and transparent communication. Students should be taught about overuse of tests and interventions. Organisations responsible for postgraduate and continuing medical education should ensure that practising doctors receive the same education
Commissioners should consider a different payment incentive for doctors and hospitals
Support from the media and medical publications will be vital because the public education campaign is crucial to the programme’s success. The academy will ensure that the programme is thoughtfully implemented and rigorously evaluated by demonstrating a reduction in wasteful practices within a fixed time scale. It will begin by asking specialty organisations to compile top five lists. All lists will be accompanied by an implementation plan and will be evaluated and monitored to assess their effect on reducing low value healthcare.
The academy has set up a steering group to provide policy advice and direction for the project. The group comprises individual experts, patient groups, college representatives and key stakeholders. It is time for action to translate the evidence into clinical practice and truly wind back the harms of too much medicine.
Sources and more information
Choosing Wisely in the UK: the Academy of Medical Royal Colleges’ initiative to reduce the harms of too much medicine, BMJ 2015;350:h2308, 12 May 2015.
Estimating the benefits to men of offering HPV vaccination to boys
This post content is published by The BMJ, aiming to lead the debate on health, and to engage doctors, researchers and health professionals to improve outcomes for patients.
Vaccination of girls against the human papillomavirus (HPV) has been implemented in most developed countries, driven by prevention of cervical cancer as a public health priority. Bivalent (Cervarix, GSK) and quadrivalent (Gardasil, Merck) vaccines protect against subsequent infection with oncogenic HPV16/18, and quadrivalent vaccine protects against HPV6/11, which cause anogenital warts. Although HPV vaccination effectively protects against external genital lesions and anal intraepithelial neoplasia in males, only a few jurisdictions have so far recommended universal vaccination of boys. These include Australia, Austria, two Canadian provinces, and the United States. In other countries, a cautious approach has been due, in part, to uncertainties around the population level impact and cost effectiveness of vaccination of boys.
In a linked article, Bogaards and colleagues estimated the benefits to men of offering HPV vaccination to boys. They used a dynamic simulation and a bayesian synthesis to integrate the evidence on HPV related cancers in men. The analysis takes account of indirect protection from female vaccination: heterosexual men will benefit from reduced HPV circulation in females, so if coverage in girls is high the incremental benefit of vaccinating boys is driven by prevention of the residual burden of anal cancer in men who have sex with men.
The findings reinforce those of prior analyses that found that adding boys to established vaccination programmes in girls becomes less cost effective as female coverage increases. The cost effectiveness of vaccination of boys also depends on other local issues, especially vaccine type and vaccine and administration costs. A threshold total cost per vaccinated boy for cost effectiveness can be identified at any level of coverage in girls: such analyses can provide policy makers with the maximum rational vaccine price appropriate to the local environment. If vaccine coverage in girls is lower, however, the most effective use of resources is likely to involve increasing coverage in girls, if feasible.
In some countries, vaccination of boys might not be cost effective, even at lower vaccine prices, due to higher administration costs. Recent developments towards reduced dose schedules could help. In 2013 the European Medical Agency recommended a two dose schedule for the bivalent vaccine in girls, in 2014 the United Kingdom switched to a two dose schedule, and the World Health Organization now recommends two doses for girls <15. Two dose schedules are the most cost effective option for girls provided protection lasts for ≥20 years and reduced dose schedules in boys are also likely to increase cost effectiveness if adequate efficacy is maintained.
Bogaards and colleagues highlight the importance of vaccination for prevention of anal cancer in men who have sex with men. In part due to uncertainties in natural history, the effectiveness of anal cancer screening is not established. Primary prevention with targeted vaccination of men who have sex with men is an attractive option and is potentially more cost effective than universal vaccination of boys. The US Advisory Committee on Immunization Practices already recommends vaccination of men who have sex with men up to the age of 26 years. Older men who have sex with men could also potentially benefit. The UK’s Joint Committee on Vaccination and Immunisation, as an interim position, recently stated that a programme to vaccinate men aged 16-40 who have sex with men with a quadrivalent vaccine should be considered, if cost effective. Lower coverage rates expected with targeted versus universal male vaccination are an important consideration, and the two approaches are not mutually exclusive.
Several other new developments should be factored in to future policy decisions. A recent study showed that the bivalent vaccine is effective in women aged ≥25 without a history of HPV disease. With a transition to primary HPV screening occurring in several countries, an interesting possibility to be evaluated involves “screen and vaccinate” strategies in older women—that is, offering HPV screening, followed by vaccination for HPV negative women with extended (or perhaps no) recall for this group. Secondly, a nonavalent vaccine (Gardasil9, Merck), which protects against an extra five HPV types, has recently been recommended for use in the US. In women, this will increase protection against cervical cancer in those who are fully vaccinated (from about 70% to about 90%) but as most HPV cancers in men are attributed to types included in current vaccines, tiered pricing structures for new generation vaccines based on differential incremental benefits (and thus differential cost effectiveness thresholds) in girls versus boys could be considered.
All these policy decisions must consider burden of disease, safety, effectiveness, acceptability, equity, and cost effectiveness. Although the focus in developed countries has now, appropriately, shifted to considering these issues for boys, men who have sex with men, and older women, broader efforts to prevent cervical cancer should remain the priority in low and middle income countries. Of the 610 000 cancers annually attributable to HPV worldwide, 87% are cancers of the cervix, and three quarters of these occur in countries with a low or medium human development index. Even if a substantial majority of young girls in such counties were vaccinated, hundreds of millions of older women would remain at risk—vaccination alone will not prevent an expected increase in cervical cancers in the next few decades, driven by population ageing. Here, the priority focus should be the development of integrated programmes for vaccinating young girls and screening older women. Based on experience in developed countries, this will also provide benefits for men through indirect vaccine protection.
Sources and more information: Who should be vaccinated against HPV? BMJ 2015;350:h2244, 12 May 2015.
Conference EDCs: criteria for identification and related impacts.
Brussels, 01 June 2015 Conference
The European Commission Directorate General for Health and Food Safety organises a one-day conference in Brussels on 1 June 2015 on the impact assessment on criteria to identify endocrine disruptors in the context of the Plant Protection Products Regulation (EC) 1107/2009 and the Biocidal Products Regulation (EU) 528/2012.
The aim of the conference is to inform Member States, Members of the European Parliament (MEPs), third countries representatives and stakeholders about the on-going impact assessment on criteria to identify endocrine disruptors and to provide a platform for further exchanges of views.
Registration is free of charge. Please register online by 19 May 2015 at the latest.
Places are limited and therefore only the registration of one representative per country/organisation can be accepted. The submission of the registration form does not constitute a confirmation.
Epigenetics can have a significant impact on human health and disease susceptibility
Over the past few years significant progress has occurred in this rapidly advancing field and much key research has been published.
The editor of Epigenetics: Current Research and Emerging Trends book has gathered together pioneers in the field of epigenetics to produce a volume of thought-provoking discussions on classic aspects of epigenetics and on the newer, emerging areas. The 17 chapters include topics on the impact of metabolism on the epigenome, how our actions may impact the health of our offspring several generations removed, and how exposure to environmental toxicants can have long-lasting effects on our epigenome with devastating consequences.
This up-to-date volume is a major resource essential for those working in the field and is recommended reading for anyone new to this fascinating and fast-moving area of research. Sources: horizonpress and PDF.
Table of contents
The Multifaceted Roles of YY1 in the Establishment of the Cellular Epigenetic Landscape
SETting up the Epigenome Through the Histone Methyltransferase SETDB1
Sirtuin Deacetylases in Fungi: Connecting Metabolism to Lifecycle Progression, Stress Response, and Genome Stability
Development-linked Differences in Cytosine 5-Hydroxymethylation in Mammalian DNA: Relationship to 5-Methylcytosine and Function
The Identification of Mammalian Proteins Involved in Epigenetics
Chromatin-mediated Response to Stimuli
The Epigenetics of Centromere Function
Dosage Compensation in Frogs and Toads
Ingenious Genes: The Diverse Roles of Long Noncoding RNA in Regulatory Processes
Epigenetic Mechanisms in Rett Syndrome
The Long and Short of Facioscapulohumeral Muscular Dystrophy
The Epigenetics of Nuclear Reprogramming to Pluripotency
Emerging Role of the Guanine-Quadruplex DNA Secondary Structure in Epigenetics
Clinical Epigenetics in Cancer: Applications in Diagnosis, Prognosis and Therapy
Environment and the Epigenetic Transgenerational Inheritance of Disease
L’émission “Le Monde en Face” du 10.02.2015 avec M. Carrère d’Encausse, C. Rambaud, I. Frachon, B. Toussaint et P. Errard. Publié le 11 février 2015 par la Journée de l’Épilepsie.
Après la diffusion du documentaire “Médicaments sous influence”, Marina Carrère d’Encausse ouvre le débat avec ses invités, Claude Rambaud, vice-présidente du CISS, un collectif regroupant 40 associations de patients, Bruno Toussaint, rédacteur en chef de la revue mensuelle “Prescrire”, Patrick Errard, président du LEEM, les entreprises du médicament et directeur général d’un laboratoire pharmaceutique, et le docteur Irène Frachon, pneumologue au CHU de Brest, qui a notamment joué un rôle important dans l’affaire du “Mediator”..