Breast cancer in mothers prescribed diethylstilbestrol in pregnancy, 1993 further follow-up

Further assessment of the long-term risk of breast cancer associated with DES during pregnancy

image of woman-thinking
Contrary to prior indications, the modest but statistically significant increased risk of breast cancer does not appear to increase greatly over time. Image via Hernán Piñera.

1993 Study Abstract

OBJECTIVE:
Further assessment of the long-term risk of breast cancer associated with diethylstilbestrol (DES) during pregnancy.

DESIGN:
Follow-up continuation through June 1, 1989, of a historical cohort of DES-exposed and unexposed mothers ascertained by review of obstetric records.

PARTICIPANTS:
Totals of 3029 each of DES-exposed and unexposed mothers who had delivered live babies at four centers in the United States during 1940 through 1960. Questionnaires were returned for 92.6% of the DES-exposed and 88.8% of the unexposed women.

MAIN OUTCOME MEASURES:
Breast cancer incidence and mortality assessed from returned questionnaires and review of medical records and death certificates.

MAIN RESULTS:
The relative rate of breast cancer associated with DES exposure, after adjustment for demographic and reproductive variables, was 1.35 (95% confidence interval, 1.05 to 1.74). For 30 years or more following exposure, the relative rate was not appreciably higher (relative rate, 1.33; 95% confidence interval, 0.95 to 1.87) than that in earlier periods. Surveillance and increased detection seemed unlikely explanations for the increased risk, since DES-exposed women had excesses of both large and small breast cancers and the two cohorts reported similar breast cancer detection practices. A history of miscarriage before first term delivery was not associated with breast cancer occurrence.

CONCLUSION:
Exposure to DES during pregnancy is associated with a modest but statistically significant increased risk of breast cancer. Contrary to prior indications, the risk does not appear to increase greatly over time. The findings are sufficient to exclude the possibility of a doubling of risk for the period of 30 or more years following exposure.

Sources
  • Breast cancer in mothers prescribed diethylstilbestrol in pregnancy. Further follow-up., Colton T1, Greenberg ER, Noller K, Resseguie L, Van Bennekom C, Heeren T, Zhang Y. NCBI PMID: 8468763. 1993 Apr 28;269(16):2096-100.
  • Full text, JAMA, 1993;269(16):2096-2100. doi:10.1001/jama.1993.03500160066033, April 28, 1993.
More DES DiEthylStilbestrol Resources

World Health Assembly endorses a global action plan to tackle antibiotic resistance

Tackling antimicrobial drug resistance, WHO Media centre, May 2015

This post content is published by the World Health Organization, the United Nations’ health agency.

World Health Assembly addresses antimicrobial resistance, immunization gaps and malnutrition

The World Health Assembly today agreed resolutions to tackle antimicrobial resistance; improve access to affordable vaccines and address over- and under-nutrition.

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Sweden introduces the results of hard joint work on draft resolution on Antimicrobial resistance.

Tackling antimicrobial drug resistance

Delegates at the World Health Assembly endorsed a global action plan to tackle antimicrobial resistance – including antibiotic resistance, the most urgent drug resistance trend. Antimicrobial resistance is occurring everywhere in the world, compromising our ability to treat infectious diseases, as well as undermining many other advances in health and medicine.

The plan sets out 5 objectives:

  1. improve awareness and understanding of antimicrobial resistance;
  2. strengthen surveillance and research;
  3. reduce the incidence of infection;
  4. optimize the use of antimicrobial medicines;
  5. ensure sustainable investment in countering antimicrobial resistance.

The resolution urges Member States to put the plan into action, adapting it to their national priorities and specific contexts and mobilizing additional resources for its implementation. Through adoption of the global plan, governments all committed to have in place, by May 2017, a national action plan on antimicrobial resistance that is aligned with the global action plan. It needs to cover the use of antimicrobial medicines in animal health and agriculture, as well as for human health. WHO will work with countries to support the development and implementation of their national plans, and will report progress to the Health Assembly in 2017.

Immunization

The Assembly agreed a resolution to improve access to sustainable supplies of affordable vaccines – a key issue for low- and middle-income countries aiming to extend immunization to the entire population. In 2012, the Assembly endorsed the Global Vaccine Action Plan, a commitment to ensure that no one misses out on vital immunization by 2020. A report from WHO’s Strategic Advisory Group of Experts on immunization, warns, however, that progress towards the Action Plan’s targets is slow and patchy.

The resolution calls on WHO to coordinate efforts to address gaps in progress. It urges Member States to increase transparency around vaccine pricing and explore pooling the procurement of vaccines. It requests the WHO Secretariat to report on barriers that may undermine robust competition that can enable price reductions for new vaccines, and to address any other factors that might adversely affect the availability of vaccines. The resolution also highlighted that immunization is a highly cost-effective public health interventions, playing a major role in reducing child deaths and improving health. It recommends scaling up advocacy efforts to improve understanding of the value of vaccines and to allay fears leading to vaccine hesitancy.

Last week, on the margins of the Health Assembly, the Secretariat brought together high-level representatives of 34 countries with low immunization coverage to discuss challenges and explore solutions to overcome them.

Rome Declaration on Nutrition and Framework for Action

Delegates approved a resolution endorsing the Rome Declaration on Nutrition and a Framework for Action which recommend a series of policies and programmes across the health, food and agriculture sectors to address malnutrition. Governments had previously agreed both documents at the Second International Conference on Nutrition (ICN2), organized by WHO and the Food and Agriculture Organization of the United Nations (FAO) in November 2014.

The Health Assembly called upon governments to implement commitments to make policy changes and investments aimed at ensuring all people have access to healthier and more sustainable diets. They requested that WHO report back on progress with implementation every 2 years. Delegates also referred to ongoing discussions in New York on a UN General Assembly resolution to welcome the Rome Declaration on Nutrition and a proposal to declare ‘ten years of sustained action in multiple sectors to improve nutrition’.

Indicators to measure nutrition among mothers, babies and young children

Member States agreed a set of indicators to monitor progress for global nutrition targets set in 2012 when the World Health Assembly endorsed a comprehensive implementation plan on maternal, infant and young child nutrition.

The plan listed 6 global targets to be achieved by 2025 on stunting (low height-for-age), wasting (low weight-for-height), overweight, low birth weight, anaemia, and breastfeeding. The decision called upon Member States to begin reporting on most indicators from 2016, and others from 2018. They recommended a review of the global nutrition monitoring framework in 2020.

More information:

The Cancer Assassin: how does a killer T Cell kill its target?

How specialised members of our white blood cells known as cytotoxic T cells destroy tumour cells and virally-infected cells

Cambridge University new film captures the behaviour of cytotoxic T cells – the body’s ‘serial killers’ – as they hunt down and eliminate cancer cells before moving on to their next target. Video published on 19 May 2015.

More info and videos
  • A collaboration of researchers from the UK and the USA, led by Professor Gillian Griffiths at the University of Cambridge, describe how specialised members of our white blood cells known as cytotoxic T cells destroy tumour cells and virally-infected cells. Using state-of-the-art imaging techniques, the research team, with funding from the Wellcome Trust, has captured the process on film.
  • Body’s ‘serial killers’ captured on film destroying cancer cells, cam.ac.uk, 19 May 2015.
  • Actin Depletion Initiates Events Leading to Granule Secretion at the Immunological Synapse, Immunity;DOI: http://dx.doi.org/10.1016/j.immuni.2015.04.013, 19 May 2015. PDF.
  • Watch more research videos on our YouTube channel.

DES Researcher Doctor Arthur Herbst and DES Activists

Doctor Arthur Herbst, Frances K. Howell,
Kari Dordal Christianson and Susan Helmrich

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Doctor Arthur Herbst, Frances K. Howell, Kari Dordal Christianson and Susan Helmrich.

Four decades ago the New England Journal of Medicine published Dr. Arthur Herbst’s article telling of an association between DES exposure and cancer. Today, Dr. Arthur Herbst key message is that DES research must continue!

More DES DiEthylStilbestrol Resources

Been handed a till receipt today? Do you know that many contain BPA?

Hormone disrupting chemical BPA can transfer from receipts into our bloodstream

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Thermal receipt paper – which you probably have sitting in your purse or wallet now – can contaminate your hands with hormone disrupting BPA, which can then be absorbed into your body. Image by Paul Downey.

2014 Study Abstract

Bisphenol A (BPA) is an endocrine disrupting environmental contaminant used in a wide variety of products, and BPA metabolites are found in almost everyone’s urine, suggesting widespread exposure from multiple sources. Regulatory agencies estimate that virtually all BPA exposure is from food and beverage packaging. However, free BPA is applied to the outer layer of thermal receipt paper present in very high (~20 mg BPA/g paper) quantities as a print developer. Not taken into account when considering thermal paper as a source of BPA exposure is that some commonly used hand sanitizers, as well as other skin care products, contain mixtures of dermal penetration enhancing chemicals that can increase by up to 100 fold the dermal absorption of lipophilic compounds such as BPA. We found that when men and women held thermal receipt paper immediately after using a hand sanitizer with penetration enhancing chemicals, significant free BPA was transferred to their hands and then to French fries that were eaten, and the combination of dermal and oral BPA absorption led to a rapid and dramatic average maximum increase (Cmax) in unconjugated (bioactive) BPA of ~7 ng/mL in serum and ~20 µg total BPA/g creatinine in urine within 90 min. The default method used by regulatory agencies to test for hazards posed by chemicals is intra-gastric gavage. For BPA this approach results in less than 1% of the administered dose being bioavailable in blood. It also ignores dermal absorption as well as sublingual absorption in the mouth that both bypass first-pass liver metabolism. The elevated levels of BPA that we observed due to holding thermal paper after using a product containing dermal penetration enhancing chemicals have been related to an increased risk for a wide range of developmental abnormalities as well as diseases in adults.

Sources and more information
  • Holding Thermal Receipt Paper and Eating Food after Using Hand Sanitizer Results in High Serum Bioactive and Urine Total Levels of Bisphenol A (BPA), PLOS one, O2014, DOI: 10.1371/journal.pone.0110509, ctober 22.
  • Hormone disrupting chemical Bisphenol A can transfer from receipts into our bloodstream, chemtrust, OCTOBER 22, 2014.

Neonatal exposure to DES alters expression of DNA methyltransferases and methylation of genomic DNA

DES alters the expression levels of Dnmts and DNA methylation

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DES alters the expression levels of Dnmts and DNA methylation. Image by Steph Hillier.

 

2009 Study Abstract

Perinatal exposure to diethylstilbestrol (DES) can have numerous adverse effects on the reproductive organs later in life, such as vaginal clear-cell adenocarcinoma. Epigenetic processes including DNA methylation may be involved in the mechanisms.

We subcutaneously injected DES to neonatal C57BL/6 mice. At days 5, 14, and 30, expressions of DNA methyltransferases (Dnmts) Dnmt1, Dnmt3a, and Dnmt3b, and transcription factors Sp1 and Sp3 were examined. We also performed restriction landmark genomic scanning (RLGS) to detect aberrant DNA methylation. Real-time RT-PCR revealed that expressions of Dnmt1, Dnmt3b, and Sp3 were decreased at day 5 in DES-treated mice, and that those of Dnmt1, Dnmt3a, and Sp1 were also decreased at day 14. RLGS analysis revealed that 5 genomic loci were demethylated, and 5 other loci were methylated by DES treatment. Two loci were cloned, and differential DNA methylation was quantified.

Our results indicated that DES altered the expression levels of Dnmts and DNA methylation.

Sources
  • Neonatal exposure to diethylstilbestrol alters expression of DNA methyltransferases and methylation of genomic DNA in the mouse uterus, Sato K1, Fukata H, Kogo Y, Ohgane J, Shiota K, Mori C. Endocr J. 2009;56(1):131-9. Epub 2008 Nov 8. NCBI PMID: 18997445.
  • Full text, The Japan Endocrine Society, PDF.
More DES DiEthylStilbestrol Resources

Angela Merkel Statement on Resistance to Antibiotics

68th session of the WHO World Health Assembly in Geneva on 18 May 2015

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Angela Merkel, Chancellor of Germany, called on all countries to take steps to curb the spread of antibiotic resistance.

The third issue that Germany would like to address during its G7 Presidency is resistance to antibiotics. We have obtained the advice of the National Academies of Sciences on this issue – and indeed on the subject of neglected tropical diseases. I think this is an issue of crucial importance for the entire human race – for people in developed and less developed countries alike. We must ensure that existing antibiotics remain effective, and that they are used only when medically necessary – not only when treating humans, but animals as well. To this end we want to agree on the strictest standards possible at the G7 meeting, in particular for industrialised countries.

Antibiotics have to be used restrictively, because once pathogens have become resistant to them, it is much, much harder to develop new treatments – in contrast to the situation for example with neglected tropical diseases. The pharmaceutical industry is an important partner in the fight against disease, but it can only provide new products through research and development. I have been told how difficult it is to develop new varieties of antibiotics to replace the old ones. We must therefore tread carefully if we are to make progress. We must pursue a “one health” approach for both humans and animals.

I am delighted that the World Health Assembly has undertaken to draw up the first global action plan to address the problem of antimicrobial resistance. Every country should have a plan of this sort. Only a few days ago the German Cabinet adopted its own antimicrobial resistance strategy. It will require close cooperation in the fields of human and veterinary medicine. ”

Sources and more information

  • Statement by Federal Chancellor Angela Merkel at the 68th session of the WHO World Health Assembly in Geneva on 18 May 2015, WHO Media centre, 18 May 2015.
  • WHO: WHA 68 – Speech by Angela Merkel, Chancellor of Germany, World Health Organization (WHO), 20 May 2015.

It is okay to ask about clinical research

OK to Ask: the NIHR campaign to empower patients and encourage engagement in clinical research

This post content is published by The National Institute for Health Research, dedicated to improving the health and wealth of the nation through research.

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OK to Ask: the NIHR campaign to empower patients and encourage engagement in clinical research .

The research community is reaching out to patients and the public across England this week and encouraging them to ‘ask’ about research opportunities that could be available to them by celebrating International Clinical Trials Day on 20 May 2015.

More than 100 events and activities are taking place across the country to celebrate the day and encourage more people to ‘ask’ about clinical research through the NIHR ‘OK to ask’ campaign.

Simon Denegri, NIHR National Director for Patients and the Public and sponsor of the OK to ask’ campaign said:

The ‘OK to ask’ campaign is now in its third year and the number of events and activities grows each year but we’ve really hit a milestone this year which is wonderful. The campaign gives a voice to the research community to make research more visible to people locally and patients and the public get an opportunity to ‘ask’ about research and what it could mean for them. It’s a win-win for all concerned.”

A recent survey conducted by the NIHR Clinical Research Network showed that 95 per cent of people surveyed said it was important to them that the NHS carries out clinical research but less than 21 per cent said they would feel very confident about asking their doctor about research opportunities.

Simon Denegri added:

With more than 600,000 people taking part in clinical research studies in the NHS last year, it’s vitally important that research is visible to people so that they can access information about research opportunities. This will encourage more people to ask about how they can get involved and eventually help to improve treatments and care across the NHS.”

In the run up to International Clinical Trials Day, a series of weekly research focused Twitter chats have taken place using the #oktoaskhour. Expert panellists from some of the largest research specialty areas have joined the conversation each week to answer questions about research from healthcare professionals and members of the public.

You can catch up on the chat summaries by clicking the links below:

Don’t forget to post your event pictures to Twitter and Facebook using the #NIHRoktoask or email them to upload on your behalf.

DES video presentation for the University of Michigan ENVIRON 310

By Rafaela Marocci Lima Pimenta, 2014

Presentation by Rafaela Marocci Lima Pimenta published on 14 April 2014 for ENVIRON 310, Winter semester, 2014, University of Michigan.

More DES videos
  • Watch more DES videos on @DES_Journal  YouTube channel.
More DES DiEthylStilbestrol Resources

International Clinical Trials Day

Clinical Trials are a vital element of the work supported and funded by the NIHR

This post content is published by The National Institute for Health Research, dedicated to improving the health and wealth of the nation through research.

NIHR-Research banner image
On International Clincial Trials Day, the NIHR promotes its “OK to ask” campaign to encourage patients and the public to ask medical professional about clinical research.

International Clinical Trials Day is celebrated around the world on or near the 20 May each year, to commemorate the day that James Lind started his famous trial on the deadly disease scurvy. It provides a focal point to raise awareness of the importance of research to health care, and highlights how partnerships between patients and healthcare practitioners are vital to high-quality, relevant research.

Professor Dame Sally Davies, Chief Medical Officer and Chief Scientific Adviser at the Department of Health said:
Clinical Trials are a vital element of the work supported and funded by the National Institute for Health Research (NIHR). Our role is to develop the research evidence to support decision making by professionals, policy makers and patients, make this evidence available, and make it available through publication to encourage its uptake and use.”

The NIHR funds a wide range of programmes and infrastructure initiatives to support this aim.

NIHR Infrastructure provides the support and facilities the NHS need for first-class research that results in high-quality care for patients and the public. Our entire infrastructure supports collaborations with industry. Key facilities include the Clinical Research Network, part of the NIHR which helps to provide the infrastructure that allows high-quality clinical research to take place in the NHS. The network helps researchers to:

  • set up clinical studies quickly and effectively,
  • support the life-sciences industry to deliver their research programmes,
  • provide health professionals with research training; and
  • work with patients to ensure their needs are at the very centre of all research activity.

In addition, the Clinical Research Network helps patients, carers and the public get involved in all stages of the research process, either as participants voluntarily taking part in clinical or other research studies or by getting actively involved in the different stages of research and related activities. The network has a range of support information on its Patient and Public Information pages.

NIHR Clinical Trials Unit Support Funding was introduced to strengthen capacity for designing and conducting clinical trials and other evaluation studies. It does this by providing funding to offer additional stability and flexibility, and giving units increased capacity to support applications and projects to NIHR research programmes.

The NIHR Trainees Coordinating Centre (TCC) makes training awards to researchers whose work focuses on people and patient-based applied health research. These include NIHR Clinical Trials Fellowships designed to support existing NIHR Trainees. The trainees have an interest in, and experience of, working with clinical trials as part of their current training and would benefit from further CTU based training.

Research is commissioned and funded through a range of NIHR programmes. Our main priority is to make sure that funding for research is focused where it is needed. In addition, it is to provide quality outputs and value for money through a transparent and accountable system. Most of these programmes are coordinated and managed by two centres: the NIHR Central Commissioning Facility (CCF) and the NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC).

The NIHR Health Technology Assessment (HTA) programme produces independent research information about the effectiveness, costs and broader impact of healthcare treatments and tests for those who plan, provide or receive care in the NHS.

The Efficacy and Mechanism Evaluation (EME) programme is broadly aimed at supporting ‘science driven’ studies with an expectation of substantial health gain, and aims to support excellent clinical science with an ultimate view to improving health or patient care. Its remit includes clinical trials and evaluative studies, in patients. It evaluates clinical efficacy of interventions (where proof of concept in humans has already been achieved) which may add significantly to our understanding of biological or behavioural mechanisms, and processes. The EME programme is funded by the MRC and NIHR, with contributions from the CSO in Scotland and NISCHR in Wales and the HSC R&D, Public Health Agency in Northern Ireland.

The NIHR Research for Patient Benefit (RfPB) programme is a national, response-mode programme established to generate high quality research for the benefit of users of the NHS in England. It funds regionally-derived applied research projects in health services and social care. Its main purpose is to realise, through evidence, the huge potential for improving, expanding and strengthening the way that healthcare is delivered for patients, the public and the NHS.

NIHR Programme Grants for Applied Research (PGfAR) are prestigious awards of up to £2m over a period of three to five years. It is directed towards leading researchers who can demonstrate an impressive track-record of achievement in applied health research. Each programme funds a series of related projects, which form a coherent theme in an area of priority or need for the NHS.

The NIHR, as the lead organisation for funding clinical trials, has now taken over responsibility for the Clinical Trials Toolkit.  This is a web-based resource providing practical advice and help to researchers in designing and conducting clinical trials. The Toolkit was originally developed for clinical trialists and research and development managers; however, much of the advice is relevant to the wider clinical trials and research environment.

The UK Cochrane Centre (UKCC) is part of the NIHR, providing training and support to Cochrane entities and contributors to The Cochrane Collaboration in the UK, Ireland, and some other countries. It also acts as a knowledge broker for Cochrane reviews and runs a programme of methodology research and audit, establishing a key link between the Collaboration, Cochrane reviews, and the National Health Service.

A series of podcasts has been compiled by The Cochrane Collaboration. This collection of evidence pods includes information on how the mega-trials of the last two decades. It has shown that the recruitment of 20,000 or more patients to a high priority study, such as the NIHR-funded CRASH-2 trial, can have a major impact on the care of millions of other people. It has been prepared in collaboration with the MRC’s Network of Hubs for Trials Methodology Research, highlighting the role of this network in conducting and disseminating research into the conduct of trials.

On International Clincial Trials Day, the NIHR promotes its “OK to ask” campaign to encourage patients and the public to ask medical professional about clinical research.