Ipri Biennial Report 2015 - 2016

12/2016 Creation iPRI Africa 07/2016 12th NCID

07/2015 11th NCID 06/2011 07/2011 7th NCID Epidemiology and Biostatistics 02/2012 World Published Breast Cancer Report Published 12/2009 MOU 07/2014 10th NCID U. Dundee 07/2010 First Summer School 10/2013 State of Oncology 2013 07/2010 6th NCID Published iPRI 04/2009 iPRI Founded 06/2012 Boyle 07/2013 9th NCID awarded LLD (honoris causa) 12/2010 Boyle Inducted Hungarian Science Academy 09/2012 Autier PhD Erasmus University 07/2010 06/2013 Creation of World Prevention Alliance Strathclyde Institute of 01/2013 Founded Global Public Health at iPRI Mullie professorship VUB 03/2013 Alcohol: Science, Policy and Public Health Published iPRI Biennial

Per indicium ad excellentia R e port 2015 - 2016 port

Perhaps we are - going too fast. Perhaps we are driving ahead, leaving too many people behind, quite literally in the dust. Perhaps we are not doing enough for the disen- franchised in low resource countries and for the poorest among us.

iPRI believes in progress. We believe in providing the best possible evidence for better global health. But we are doubly committed to ensuring that our knowledge be a conduit for better health, not just in privileged quarters, but in the most destitute ones as well.

All scientific and policy roads must lead to prevention and better health for all.

iPRI Biennial Report 2015 - 2016

Contents cannot be copied or otherwise reproduced without express consent of iPRI.

Printed in France Photographed in Ghana in 2011. iPRI - International Prevention Research Institute — Contents iPRI Biennial Report: 2015 – 2016 iPRI

Contents

The International Prevention Research Institute ...... 1 Education and Training ...... 95 iPRI: More than an Acronym, a Commitment ...... 3 Vaccination and Infectious Disease Modelling, and Modelling of Other Biomedical Phenomena . . . 97 Executive Summary ...... 4 Nutrition ...... 103 Strathclyde Institute of Global Public Health at iPRI 9 Liver Cancer (Hepatocellular Carcinoma): Curbing the Epidemics ...... 106 Guiding Principles ...... 10 Pancreatic cancer: in search of new targets for therapy 109 Ethics ...... 11 Guidelines for a Healthier and Longer Life ...... 110 Global Connections ...... 12 Use of Social Security Databases and Patient Registries ...... 111 New Global Relationships ...... 14 Cancer Leadership 2015 ...... 112 Vietnam National Cancer Hospital ...... 14 Cancer Leadership 2016 ...... 114 National Institute of Oncology of Hungary 15 National Cancer Institutes Directors Meetings ...... 117 Poland’s Fundacja Promocja Zdrowia ...... 15 WPA/iPRI Cancer Control Awards ...... 118 Ukraine’s RE Kavetsky Institute ...... 16 2015 WPA/iPRI Awards for Cancer Control ...... 118 International Alliance of Patients’ Organizations ...... 16 2016 WPA/iPRI Awards for Cancer Control ...... 120 The Road to Restrictions on Sunbeds 19 ABOUT US ...... 122 Exposure and Risk: A Thirty Year History ...... 19 People ...... 125 PRINCIPAL CONTRIBUTIONS 22 iPRI Senior Faculty ...... 125 Cancer ...... 25 iPRI Faculty 132 Breast Cancer Screening ...... 25 iPRI Staff ...... 136 Screening for Colorectal Cancer ...... 28 iPRI Senior Research Fellows 138 Screening for Cutaneous Melanoma 30 Activity Report ...... 161 Screening for Prostate Cancer ...... 33 Invited Lectures and Talks ...... 161 Breast Cancer and Physical Activity ...... 34 Publications - Peer Reviewed ...... 165 Active and Passive Smoking and Risk of Breast Cancer ...... 36 Publications - Books ...... 180 Risk of Cancer in the Rubber Manufacturing Industry 39 PhD Examinations, Jurys and Student Supervision 182 Chemotherapeutic Waste Disposal 43 Visitors ...... 183 Cancer Scenarios in Scotland ...... 44 Diabetes ...... 47 Diabetes and Pancreas Cancer ...... 47 Retinopathy and Eye Light ...... 49 White Paper on Diabetes Epidemiology ...... 51 “I may dispute, Diabetes Treatments and Cancer Risk ...... 53 in favour of my chosen road, Diabetes and Physical Activity 54 the road that someone else has taken. Diabetes, Diabetes Treatments and Lung Cancer Risk 59 I may criticize the workings of his logic... Africa ...... 62 State of Oncology in Africa 64 But I must respect the man, Cancer is... Attacking Africa - Television Documentary ...... 67 if he toils towards the same star.” Pathways of Care in Lung Cancer in Africa ...... 68 Antoine de Saint-Exupéry iPRI Education and Training Programmes: A New Initiative ...... 70 UV and Skin Cancer ...... 73 Health and Conflict ...... 83 Health in Conflict and Post-Conflict Environments 83 IMPORTANT CONTRIBUTIONS 90 Multiple Sclerosis 91 iPRI - International Prevention Research Institute — Overview iPRI

The International Prevention Research Institute

iPRI

P er tia indicium ad excellen

he International Prevention Research Institute (iPRI) was formally established in April 2009 in France Twith eight founding members. In March 2010, iPRI Services was created and moved into new premises in Ecully. It provides private and public sector organisations with independent authoritative evidence and guidance on critical health risk issues. iPRI is an academic, problem-solving institute that works closely with a number of senior figures from different corners of the world on a variety of projects. These have accepted appointments as iPRI Senior Research Fellows. The international flavour of iPRI activities is reflected in the international nature of the staff: three nationalities in iPRI Management, six in iPRI Services and thirty among the Senior Research Fellows.

The International Prevention Research Institute (iPRI) comprises Glasgow, Scotland. This established the Strathclyde Institute two legal entities: iPRI Management and iPRI Services. of Global Public Health at iPRI. The aims of this Institute are The former comprises the initial partners and the latter the many but there are several dominant goals. First of all, there salaried staff. Each is run as a not-for-profit with any funds left is the opening of possibilities for research programmes to over at the end of a year used to allow iPRI to grow or to fund be developed between iPRI and the University. Strathclyde studies or activities which could not find funding otherwise. University has many strengths including in the broad area of Engineering. Developments in Social Engineering have made The World Prevention Alliance was established as an Association an enormous contribution to the current state of public health in France under the Loi 1903. This is used to facilitate the funding in high-resource countries and the transfer of knowledge to of studies and other activities in lower-resource settings where lower-resource settings will almost certainly make a signifi- all funds collected for such activities can be spent directly. cant contribution to public health. In addition, a Master’s and For example, the Annual Meeting of National Cancer Institute Directors attracts upwards of 100 Cancer Experts from many doctoral programme have been created aimed at students countries with the majority of participants from low- or middle- from lower-resource countries, allowing the Institute to make income countries. Travel costs and all local expenses of these a contribution to capacity building in lower-resource countries. participants are covered by the World Prevention Alliance. In collaboration with colleagues in the University of Strathclyde and King’s College London, iPRI is a partner in a wide-ranging In June 2013, a formal Memorandum of Agreement was programme dealing with Health during Conflict and post- signed between iPRI and the University of Strathclyde in Conflict Public Health.

1 iPRI - International Prevention Research Institute — Overview iPRI

iPRI: More than an Acronym, a Commitment

iis for International An international vision is essential if one hopes to be relevant and effective in prevention. This said, we chose to put our first letter in lower case so as not to lose sight of the need for prevention and public health action at local and national levels.

Pis for Prevention Prevention of chronic or infectious disease is the most important aspect of Public Health at this time. Prevention is also the cornerstone of iPRI’s mission. Of course, while it is essential to prevent those diseases which can be prevented, it is also essential to treat those diseases which can be treated and to cure those diseases which can be cured while providing palliation whenever it is needed. Prevention encapsulates a wide spectrum of interventions ranging from primary prevention (avoiding the onset of disease) through secondary prevention (screening and early detection to avoid patients presenting to medical services with advanced disease) and tertiary prevention (appropriate treatment to avoid patients dying from their disease). The application is not only to chronic disease or infectious disease directly, but also to the prevention of risk factors in individuals and populations.

Ris for Research Research is another key iPRI activity since there are still aspects of chronic disease and lifestyle behaviours which are not understood and hinder prospects for prevention. Research is still needed in many areas. Risk factors exist for approximately one half of all forms of cancer defining the limit of what is theoretically preventable within our current knowledge. How to change the lifestyle behaviours of populations is still a challenge iPRI requiring major research activity.

Iis also for Institute Institutes aim to be selfless. iPRI chose the institutional route to emphasise its intent to make a difference. The partners aimed to undertake research projects that would directly impact prevention and public health, using state of the art epidemiological and biostatistical methodologies.

3 iPRI - International Prevention Research Institute — Overview iPRI

Executive Summary

ncreasingly international attention is turning towards a focus on prevention. Prevention ranges over work on a not-for-profit basis. In addition, iPRI has close on Epidemiology and Global Health between 2010 and 2012. IPrimary Prevention, to reduce the risk of particular diseases, through Secondary Prevention, identifying collaborations with a number of leading Institutes including the We developed a textbook on Epidemiology and Biostatistics chronic diseases early in their natural history when clinical disease may be avoided or the disease identified University of Strathclyde and King’s College London; these and designed for students attending such a short course and this text when it is curable, and Tertiary Prevention, preventing patients with disease from dying from their disease. other partnerships will be described throughout this Report. has been widely used at other courses, notably in China. In 2013, Successful prevention relies on having secure information about disease determinants, the subset of risk iPRI signed an agreement with the University of Strathclyde to factors whose alteration would lead directly to a reduction in risk, and then working with various sections Our academic credentials are laid out in our lists of publica- create the Strathclyde Institute of Global Public Health at iPRI. of society to bring about the necessary changes. It is clear that any unilateral approach to prevention could tions as books or in the peer-reviewed scientific literature. As well as having a research focus, it has a teaching focus. not be successful. We have signed Memorandum of Understanding (MOU)s with the International Alliance of Patients’ Organizations, National Successful and widespread implementation of effective preven- The road that leads from the discovery of a hazard to preven- This report presents the work of the International Cancer Institutes (and Ministries of Health) in Vietnam, Hungary tion strategies will not only lead to increases in life expectancy tion is usually long and full of obstacles. The path to successful Prevention Research Institute (iPRI) in the previous two and Ukraine and three more countries have agreed to sign in but also, and importantly, healthy life expectancy. Prevention prevention leads through research to build the scientific years of its existence (2015-2016) and outlines the contri- early 2017. These agreements cover Cancer Control with a focus recommendations, unfortunately, have been made in silos: database on which to build successful prevention programmes bution which iPRI has made in some thematic areas notably on Prevention and we have a partnership with the Prevention Cancer, Cardiovascular Disease, Diabetes, Infectious Disease, etc. in populations. There are many difficulties which still need to Cancer, Diabetes, Africa, Ultraviolet Light and Skin Cancer Foundation in Poland to help us. To integrate knowledge of prevention strategies over common be overcome even once the scientific evidence becomes over- and Health during Conflict and post-conflict Public Health. diseases, iPRI has produced evidence-based ‘Guidelines for a whelming. The classical example is of cigarette smoking where Studies in these themes cover activities conducted in a wide Statistics are Patients with the Tears wiped away. Healthier and Longer Life’. the risk of various chronic diseases has been increasingly estab- range of settings and all have had an impact on prevention. lished since the middle of the twentieth century but decades To help develop our focus on Cancer Control, we have an Developing a stronger focus on ‘prevention’ should passed before inroads were made to prevention. The temporal iPRI cannot undertake many of its prevention activities on agreement ready to sign with the International Association hopefully increase population and legislation awareness gap between the time when the evidence is available and its own and depends on close cooperation with many other of Patients Organisations. This philosophy comes across very about the need for prevention and lead to a more rapid certain and when the prevention strategy is implemented is still specialist groups. iPRI staff are augmented by an international clearly in the ‘State of Oncology in Africa’ Report and film which implementation of scientifically-based strategies. cause for concern. The example of the harmful effects of sunbed network of Senior Research Fellows who work actively with iPRI we will formally launch on World Cancer Day 2017. use and the history of the road to prevention of melanoma staff on a variety of projects. The establishment of iPRI-Italy, iPRI- Professor Peter Boyle caused by this exposure is outlined in this Report. Africa and iPRI-MENA allows deeper focus on regional issues iPRI also has Education as one of its central aims. In conjunc- President, iPRI of public health significance. Like iPRI itself, these subsidiaries tion with the University of Dundee, we held a Summer School

The road that leads from the discovery of a hazard to prevention, is usually long and full of obstacles.

5 iPRI - International Prevention Research Institute — Overview

01/2016 ESMO: Boyle, Faculty Coordinator for Cancer Prevention 12/2015 UKCTOCS, London 02/2016 Cancer Prevention, Monaco 11/2015 ESO, Barcelona 04/2016 IAPO, London 10/2015 Jubilée J-L Touraine 04/2016 Diabetes Emerging Stars, Barcelona 09/2015 ESMO, Vienna 06/2016 ASCO, Chicago 07/2015 11th Annual NCID Meeting 06/2016 ADA, New Orleans 06/2015 Eurasia Course, Moscow 07/2016 12th Annual NCID Meeting 06/2015 ADA, Boston 10/2016 National Cancer Congress, Vietnam 06/2015 UKCTOCS, London 11/2016 Masterclass, St. Luke’s Week, Dublin 05/2015 ASCO, Chicago 11/2016 Boyle: Honorary Fellowship, Royal College of Physicians, Ireland 05/2015 American Urology Mtg., New Orleans 11/2016 RIVM, Bilthoven 04/2015 Diabetes Global Public Health, Athens 12/2016 Creation of iPRI Africa 04/2015 Rhode Island Senate Mtg 12/2016 MOU, NOI, Budapest 02/2015 TIC Lecture, Strathclyde U. 01/2017 MOU, Ukraine 01/2015 Mermorial , Nigel Gray 02/2017 MOU, IAPO 06/2013 Creation of U. of Strathclyde Institute of Global Public Health at iPRI 06/2013 Lecture: ASCO, Chicago 06/2013 Autier, Boetta, Boniol, Boyle and Hainaut Professors at Strathclyde 05/2013 Publication: P53 in the Clinics (Springer 05/2013 Lecture: Israel National Nutrition Week, Tel Aviv 04/2013 Lecture: AACR, Washington DC 03/2013 Alcohol: Science, Policy and Public Health Published 03/2013 Lecture: IADR, Seattle 02/2013 Lecture: Komen Global Breast Summit, Washington DC 01/2013 Lecture: Diabetes Expert Summit, Paris 11/2012 Lecture: The Economist Health Meeting, London 11/2012 Lecture: ASEAN Region Health Ministers Meeting, Jakarta 03/2013 Publication: Alcohol: Science, Policy and Public Health (OUP) 02/2011 Controversies in Breast Cancer, Muscat 01/2011 Lecture: Diabetes Symposium, Frankfurt 01/2013 Mullie professorship, The Vrije Universiteit Brussel 02/2011 Lecture: U. of Indiana, Indianapolis 12/2010 Boyle Inducted Hungarian Science Academy 10/2012 Seminar: Yale University, New Haven 04/2011 Lecture: American Academy of Oral Medicine, Puerto Rico 11/2010 Lecture: Chile National Diabetes, Santiago 09/2012 Lecture: ESMO, Vienna 04/2011 Lecture: Anniversary Hacettepe University, Ankara 04/2009 iPRI Founded 09/2010 Expert: Saudi Arabia FDA, Riyadh 09/2012 Lecture: EASD, Berlin 05/2011 Lecture: Mexican National Diabetes, Cancun 05/2009 Lecture: ASCO, Orlando 09/2010 Lecture: ESSO, Bordeaux 09/2012 Autier PhD Erasmus University 06/2011 Epidemiology and Biostatistics Published 09/2009 Lecture: NCRI, Birmingham 09/2010 ASCO Intl Advisory Committee, DC 09/2012 Lecture: American Ass. Clinical Endocrinology, NY 06/2011 Lecture: ASCO, Chicago 11/2009 Lecture: Dasman Diabetes Inst., Kuwait 08/2010 Lecture: UICC World Congress, Shenzen 07/2012 8th Annual NCID Meeting 06/2011 Lecture: American Diabetes Association, San Diego 12/2009 MOU U. Dundee 07/2010 6th NCID 06/2012 Peter Boyle, LLD (honoris causi), University of Dundee 07/2011 7th NCID 04/2010 Lecture: APOCP, Istanbul 07/2010 First Summer School 06/2012 Expert: Food and Drug Administration of Venezuela 07/2011 Seminar: Dublin City University 04/2010 Lecture: Physicians of Britain & Ireland 06/2012 Lecture: American Diabetes Association, Philadelphia 09/2011 Lecture: EASD, Lisbon 05/2010 Lecture: Polish National Diabetes, Warsaw 06/2012 Lecture: ASCO, Chicago 10/2011 Lecture: Turkish Association of Endocrinology, Antalya 06/2010 Lecture: EuroCancer, Paris 06/2012 Boyle awarded LLD (honoris causa) 11/2011 Lecture: Health Ministers Meeting European Council, Poznan 07/2010 World Prevention Alliance Founded 05/2012 Lecture: Association of Breast Surgeons, Bournemouth 11/2011 Lecture: Bulgarian Cancer Congress, So a 05/2012 Lecture: German National Diabetes, Stuttgart 01/2012 Lecture: Centre for Excellence in Auto-Antibodies, Derby 04/2012 Lecture: French National Diabetes, Dijon IN MEMORIAM 02/2012 World Breast Cancer Report 04/2012 Lecture: French National Diabetes, Dijon 02/2012 World Breast Cancer Report Published 03/2012 Seminar: Yale U., New Haven Since the publication of iPRI’s previous Report, Cancer Control has lost four giants who had a close association with iPRI.

Nigel Gray was a pioneer in Tobacco Control whose special contribution was to 06/2013 NIDDK-NIH-FDA, Bethesda 06/2013 Lecture: ADA, Chicago 09/2014 ESMO: Boyle, Lifetime Achievement Award organise the integration of the disparate elements of the anti-tobacco movement 07/2013 9th NCID 07/2014 10th Annual NCID Meeting 05/2014 Lecture: Tongji Medical College, Wuhan 07/2013 9th Annual NCID Meeting 04/2014 Lecture: ASEAN Health Ministers, Kuala Lumpur into the most organic whole that it could be, short of being one big centralised body. 07/2013 Additional premises in Ecully 03/2014 Lecture: ESMO Lung Cancer, Geneva 09/2013 Lecture: EASD, Barcelona Umberto Veronesi was one of the great men of modern Medicine. He was a 03/2014 Seminar: U. of Strathclyde, Glasgow 09/2013 Lecture: ECCO, Amsterdam 03/2014 Lecture: European Breast Cancer Congress, Glasgow pioneering surgeon who made many of the great contributions to breast cancer 10/2013 Publication: State of Oncology 2013 03/2014 Lecture: Swiss National Diabetes Day, Zurich 10/2013 State of Oncology 2013 Published care and treatment, the survival and quality of life of millions of women with 03/2014 Lecture: BioBridges, Florence 10/2013 Lecture: European Health Forum, Bad Gastein 02/2014 Lecture: Intl Cancer Congress, Madrid breast cancer have benefited from Veronesi’s lifetime dedication and work. 10/2013 Lecture: U. of Pennsylvania, Philadelphia 02/2014 Lecture: ICACT, Paris 11/2013 John A Rock Visiting Professor, Louisiana State U., New Orleans 01/2014 Lecture: Royal College of Physicians of England, London Marvin Zelen pioneered the development of the Biostatistics of 11/2013 Elected Member of Academia Europaea 12/2013 Pasterk leaves, becomes Admin. Dir., BBMRI-ERIC U. of Graz 11/2013 Lecture: World Cancer Leaders, Cape Town Randomised Clinical Trials and built up the Department of Biostatistics of Harvard School of Public Health into a world leader.

Sandor Eckhardt made an outstanding contribution not only to Oncology in his native Hungary, but also globally through his work with the UICC which emerged under his leadership as a global powerhouse.

The work of this trio has had a major impact on reducing the numbers of cases of cancer and improving patients’ survival and quality of life. Their contribution was immense. May they Rest in Peace. i2009P R˜ 2016I 7 iPRI - International Prevention Research Institute — Overview iPRI

Strathclyde Institute of Global Public Health at iPRI

Useful Learning Research into Causes Worldwide

Evidence-Based

ounded in 2009 with the broad goal of contributing to the improvement of health in populations Fworldwide, the International Prevention Research Institute (iPRI) aims to increase prospects for prevention through training, education, prevention research and research into causes worldwide with a focus on low and lower-middle income countries. In order to help further these aims, in June 2013, the International Prevention Research Institute signed an agreement with the University of Strathclyde, established in Glasgow, Scotland, to create the Strathclyde Institute of Global Public Health at iPRI.

The University of Strathclyde was established in 1796 as ‘the should bring mutual added value to both the University of place of useful learning’ and this remains the mission today: Strathclyde and the International Prevention Research Institute Institute of to combine academic excellence with social and economic (iPRI). relevance. In 2012, the University of Strathclyde was awarded the title ‘University of the Year 2012’ by The Times Higher Peter Boyle was the inaugural Director of the Institute and Global Public Health Educational Supplement and in 2013 was awarded ‘Innovative became co-Director when Sir Harry Burns, former Chief Medical University of 2013’. As ‘the place of useful learning’ the University Officer for Scotland, joined the Institute. As well as Professor is committed to the advancement of society through the pursuit Boyle and Professor Burns, Philippe Autier, Mathieu Boniol and of excellence in research, education and knowledge exchange, Pierre Hainaut from iPRI were appointed as Professors within and through creative engagement with partner organisations at the University of Strathclyde. iPRI local, national and international levels and through teaching and research, the University aims to contribute to the development The joint efforts of the International Prevention Research and quality of life of Glasgow (where it is situated), Scotland and Institute and the University of Strathclyde should see the devel- the United Kingdom and the international community. opment and growth of an Institute which, through programmes of research, training and education, would make a difference to The Institute of Global Public Health aims to be unique the health of the world. In this regard, a Master’s programme in its evidence-based approach to practical global Public and a doctoral programme have been launched aimed at Health problems. The Institute would have the potential to students from lower-resource regions focusing on the theory act as (1) a focal point for activities of other Departments and practical aspects of Public Health in those regions of the and Faculties (e.g. Engineering, Law, Social Sciences world. Training and Pharmacology and Pharmacy) of the University of Strathclyde in establishing international programmes; The model for the future of Health and Public Health research and (2) a centre where other Universities, Research Institutes, will increasingly focus around public-private initiatives and Governments and NGOs could come together on specific funding. This will be a strategic axis for continual development. research and intervention projects. The project developed Prevention Research Focus on Lower and Middle Income Countries

iPRI 9 iPRI - International Prevention Research Institute — Overview iPRI

Guiding Principles Ethics

iPRI guiding principles are: BE PRINCIPLED ll studies iPRI is performing are based on scientific excellence and undergo strict ethical review. • Independence AThe ethical review is performed by an International Governance and Ethics Committee. • Transparency • Integrity iPRI follows all established international ethics recommenda- iPRI believes that all study subjects, no matter their background, • Impartiality, and tions including: have the right to the same level of protection. This is particularly • Timing. important given the international dimension of all iPRI projects, • International Ethical Guidelines for Biomedical Research often including countries with less developed ethics guidelines All scientific findings are sent for publication in peer-reviewed PEER REVIEWED Involving Human Subjects, CIOMS 2002 and practices. journals. • International Ethical Guidelines for Epidemiological Studies, Specific provisions are made for avoiding any role of public and ADOPT NEUTRALITY CIOMS 2009 iPRI has established an International Governance private sponsors in reporting of scientific findings. and Ethics Committee to have all research studies • Convention for the Protection of Human Rights and Dignity which involve human subjects or data reviewed. Our iPRI recognizes the following documents as additional of the Human Being with regard to the Application of Committee Members come from around the world: guidelines: Biology and Medicine: Convention on Human Rights and Biomedicine, Council of Europe 1997 • Mr David Byrne, Chairman (Ireland) • European Commission Recommendation of 11 March 2005 ADHERE TO CODE OF CONDUCT • Professor Clement Adebamowo (Nigeria) on the European Charter for Researchers and on a Code of • Directive 2001/20/EC of the European Parliament and of the • Dr Kazem Behbehani (Kuwait) Conduct for the Recruitment of Researchers Council of 4 April 2001 on the approximation of the laws, • Ambassador Mireille Guigaz (France) regulations and administrative provisions of the Member • Lord Mackay of Clashfern (United Kingdom) • Council of Science Editors’ White Paper on Promoting ESPOUSE INTEGRITY States relating to the implementation of good clinical • Dr Edith Olah (Hungary) Integrity in Scientific Journal Publications practice in the conduct • Professor Luis Pinillos Ashton (Peru) • Maître Jean Luc Soulier (France) • International Committee of Medical Journal Editors’ Uniform FOLLOW GUIDELINES • The Nuremberg Code, 1949 • Professor Jean-Louis Touraine (France) Requirements for Manuscripts Submitted to Biomedical • Dr Andrzej Wojtyła (Poland) Journals: Writing and Editing for Biomedical Publication, • UNESCO Universal Declaration on the Human Genome and • Professor Charles Gillis, Convenor (United Kingdom) February 2006 Human Rights, 1997 The role of this important committee is currently evolving. Its new remit will be reflected soon on the iPRI • The ENCePP Code of Conduct, for scientific independence BE TRANSPARENT • UNESCO International Declaration on Human Genetic Data, website. and transparency in the conduct of pharmacoepidemio- 2003 logical and pharmacovigilance studies, May 2010 • World Medical Association Declaration of Helsinki Ethical • Moose Guidelines, April 2000 COMPLY Principles for Medical Research Involving Human Subjects, 1964 in its last version from 2008 • Prisma Guidelines, July 2009 DEMAND EVIDENCE • UNESCO Universal Declaration on Bioethics and Human Rights, 2005

iPRI 11 iPRI - International Prevention Research Institute — Overview iPRI

Global Connections

It has never been iPRI’s intention to be everywhere. Ours is not a quest for size and reach. We are therefore grateful that, despite our reserve, collaboration has come our way from the four corners of the Earth. Our staff is international. We have experts that work on a full time basis continents away.Our Senior Research Fellows are in the United States but in Oman too. And, visitors from over 100 countries come to the annual National Cancer Institute Directors’ meeting and other iPRI events. iPRI Sta , Consultants, Partners

Thank you to all, for your support. We are humbled, indebted iPRI Senior Research Fellows and doubly motivated to pursue our work. iPRI Presentations, Visitors, Meeting Participants

iPRI 13 iPRI - International Prevention Research Institute — Overview iPRI

New Global Relationships

It is iPRI’s view that to better fulfil its mission, it is paramount to work with leaders in National Institute of Oncology of Hungary epidemiology, biostatistics, cancer, diabetes, global public health and other fields he International Prevention Research Institute the key reference for Hungary’s Ministry of Health Tand the National Institute of Oncology of when making decisions on cancer control policy and of interest for iPRI. 2015 and 2016 were busy years for new, formal iPRI relationships. Hungary have signed an important Memorandum of strategy. Understanding. The National Institute of Oncology is

Prof. Boyle signing MOU with Prof. Tran Van Thuan Prof. Miklós Kasler signing MOU with Prof. Boyle Prof. Withold Zatonski signing MOU with Prof. Boyle The International Prevention Research Institute and the National Institute of Oncology, situated in Budapest, share a long-standing commitment to increase capacity in Cancer Prevention. Together, they continue to strive to reduce the burden of cancer both in Hungary and in surrounding countries.

Hungary has a long tradition in medical research which stretches back many decades. Even in difficult times, the tradition of high quality cancer treatment and research has been a feature of Hungarian Medicine. Having collaborated successfully in the past, the parties share a common interest in further strengthening relations and broadening the scope of their collaboration and academic activities.

More specifically, The International Prevention Research Institute and the National Institute of Oncology of Hungary will work together to develop training opportunities and to implement multiple Cancer Prevention, and Cancer Control activities in Hungary. Both parties will work with other Cancer Institutes world-wide to examine the effectiveness of treatments in the general population Vietnam National Cancer Hospital of cancer patients.

n 2016, The International Prevention Research Ministry of Health when making decisions on cancer IInstitute (iPRI) signed an important Memorandum control policy and strategy. Hospital K is by far, the of Understanding (MOU) with Vietnam’s National country’s largest cancer hospital treating up to 5000 Poland’s Fundacja Promocja Zdrowia Cancer Hospital (Hospital K). The National Cancer patients daily on three different campuses. Hospital (Hospital K) is the key reference for Vietnam’s he International Prevention Research Institute Understanding to collaborate on a range of concrete T(iPRI) and the Fundacja Promocja Zdrowia actions. These two European-based organizations The participants in this Memorandum of Understanding share a long-standing commitment to increase capacity in Cancer (Health Promotion Foundation – HPF) of Poland, with a long-standing commitment to Prevention Prevention. Together, they continue to strive to reduce the burden of cancer both in Vietnam and abroad. represented by its President Professor Witold both in Europe and worldwide, have come together A. Zatonski have signed a Memorandum of to further enhance each other’s capacity. Having collaborated successfully in the past, the parties share a common interest in further strengthening relations and broadening the scope of their collaboration and academic activities. Activities outlined in the MOU include training opportunities for Polish professionals in Prevention Research and Policy, the open exchange of advanced information and knowledge in disease prevention, provision of teaching materials to Polish professionals, More specifically, the International Prevention Research Institute and the National Cancer Hospital (K Hospital) will work together to the organisation of joint scientific events and others including joint fundraising efforts to further the aspirations of the joint effort. develop training opportunities and to implement multiple Cancer Prevention, and Cancer Control, activities in Vietnam “After years of working alongside the world renowned anti-tobacco advocate Professor Zatonski, this MOU represents an opportunity to escalate our efforts in a more formal setting; I believe that our partnership will lead to quantifiable improvements in Prevention Research and Policy,” says Professor Boyle. He adds, “It is also an honour to be working with an organization whose Honorary President is his Eminence Kazimierz Cardinal Nycz.” Professor Zatonski concurs adding, “I believe that the Health Promotion Foundation of Poland, will benefit greatly from iPRI’s incomparable experience and impact in Global Public Health and Prevention in particular.”

15 iPRI - International Prevention Research Institute — Overview iPRI

Ukraine’s RE Kavetsky Institute

he International Prevention Research Institute, RE Kavetsky Institute of Experimental Pathology, Trepresented by its President, Professor Peter Oncology and Radiobiology of the National Academy Boyle, concluded discussions and signed an of Science of Ukraine, represented by Academician important Memorandum of Understanding with the Vasyl F. Chekhun, Director of the Institute.

iPRI, and RE Kavetsky Institute, situated in Kyiv, share a long-standing commitment to increase capacity in Cancer Prevention. iPRI and RE Kavetsky Institute will work together to develop training opportunities and to implement multiple Cancer Prevention, and Cancer Control, activities in Ukraine. “Believe that a further shore RE Kavetsky Institute was established under the Ministry of Health of the Ukrainian SSR in July 1960. The founder and first director of the Institute was Rostislav E. Kavetsky, Member of the Academy of Sciences of the Ukrainian SSR. Today, is reachable from here.” the Institute is a strong academic center with considerable material and human resources and more than 50 years of experience. Research fellows of the Institute have been awarded 18 State Prizes in Science and Technology, 19 laureates of personal prizes of eminent scientists of the NAS of Ukraine, eight titles of Honoured Workers of Ukraine, and one title of Honoured Doctor of Ukraine. The Institute’s research interests include the study of the Environment and Cancer Seamus Heaney looking at the effects of potentially carcinogenic environmental factors (chemical carcinogens, ionizing and non-ionizing radiation) on the molecular and cellular processes of carcinogenesis and development of the agents that can modify them. There are also substantial programmes in Translational Medicine looking at innovations in diagnosis and treatment and in Personalised Medicine.

International Alliance of Patients’ Organizations

PRI, represented by its President, Professor Peter International Alliance of Patients’ Organizations iBoyle, concluded discussions and signed an (IAPO), represented by the Chair of the Board, important Memorandum of Understanding with the Jolanta Bilińska.

The role of patients’ organisations is morphing rapidly from its initial lobbying focus to a much more involved and proactive role in matters such as clinical trial design and advocacy in the design of healthcare organisation and delivery. IAPO activity is focused on promoting patient-centric healthcare. IAPO achieves this by being the global voice for all who suffer from any disease, disability, illness, impairment or syndrome, and by being the focal point for patients’ organisations worldwide. IAPO’s unique global alliance is committed to improving the lives of patients beyond borders. IAPO nurtures relationships with members, partners and all those involved in healthcare, and builds dialogue with global decision-makers to promote patient-centric healthcare. There are currently 276 Member Organisations in IAPO, representing 71 countries and 51 disease areas.

iPRI will work with IAPO in strengthening its research portfolio and providing the evidence-based information necessary in the current environment. iPRI will also benefit from having access to the patient’s voice in planning and executing its own research in a wide variety of disease areas including cancer, diabetes and multiple sclerosis.

iPRI 17 iPRI - International Prevention Research Institute — Sunbeds iPRI

The Road to Restrictions on Sunbeds

Exposure and Risk: A Thirty Year History

n the closing years of the 1980s, realizing that of the UV spectrum was deemed to be an innocent Imelanoma incidence in Europe was increasing wavelength, while the UVB represented the carci- and that there had been no substantial progress in nogenic fraction of the solar spectrum reaching the treatments, some members of the EORTC Melanoma earth ground. Because the UV spectrum of sunbed Group met in the office of Ferdy Lejeune in Brussels devices consisted mainly of UVA, this exposure was to discuss possibilities of melanoma prevention. considered as not being involved in skin carcino- Two options were at stake at this moment: a cohort genic processes. However, two case-control studies study of individuals with dysplastic atypical naevi, to in England and Canada pointed out that a relation- determine whether this was a melanoma precursor ship between exposure to sunlamps and sunbeds or a marker of risk, and an epidemiological study might exist. In addition, a survey in Brussels showed addressing the risk of use of psoralens (a known that melanoma patients were greater users of artifi- mutagen and carcinogen) as tanning accelerators cial ultraviolet sources than the general population, in sunscreens and the risk eventually associated and that the incidence of melanoma in different with artificial ultraviolet tanning. Concern about geographical areas in Belgium increased propor- a possible role of sunbed exposure in the devel- tional to the percentage of people using tanning opment of cutaneous melanoma arose in the last devices (Autier et al, 1991). years of the 1980s. In those years, the UVA portion

In the following months, Peter Boyle convened a meeting at the International Agency for Research on Cancer to discuss the possibility of introducing a multi-national study of melanoma into the SEARCH Programme, which he directed. Invitees included EORTC Melanoma Group members (Stéphane Carrel, Jean-Pierre Césarini, Jean-François Doré, and Ferdy Lejeune,) together with melanoma epidemiologists (Bruce K Armstrong, Mark Elwood, Rick Gallagher, Ole Moller-Jensen and Calum Muir). It was agreed to abandon the idea of a cohort of dysplastic nevi since its pathological definition was not unanimous, and to concentrate on a case-control study of melanoma risk factors which had only been investigated in Scotland and Denmark and not elsewhere in Europe. Consequently in 1991, with the help of a grant from the Europe against Cancer programme, a multicentre case-control study was launched in Belgium, France and Germany.

This case-control-study was incredibly productive, demonstrating that exposure to sunlamps or sunbeds starting 10 years before diagnosis was associated with an increased risk of melanoma for at least 10 hours of accumulated exposure, the risk being higher for subjects who experienced skin-burn due to sunlamps or sunbeds, and for those who exposed their skin for tanning purposes (Autier et al, 1994; Autier et al, 1995). The study also showed that sunscreens prepared with psoralen were a direct melanoma risk factor – which subsequently resulted in their ban by the European Commission. Because of this finding, the company manufacturing the psoralen sunscreen sued Philippe Autier for dissemination of “unscientific information”, leading to a trial that the company eventually lost. Norway and Sweden were among the first countries to implement national regulations for indoor tanning devices, in 1982 and 1983, respectively. And in 1997, France was the first country to regulate access to commercial use of sunbeds, limiting UVB to 1.5% of the emitted UV, banning unstaffed machines and prohibiting use by minors <18 years.

A further EORTC case control study, investigating the association between sunbed use and cutaneous melanoma in adults and conducted between 1999 and 2001 in Belgium, France, The Netherlands, Sweden and the United Kingdom failed to demonstrate an association: overall adjusted odds ratio (OR) associated with ever sunbed use was 0.90 (95% CI: 0.71, 1.14) (Bataille et al, 2005). This

19 iPRI - International Prevention Research Institute — Sunbeds iPRI

publication is frequently cited by the proponents of sunbed use as a large European study showing the safety of sunbed exposure Shortly after IARC classification of sunbeds as a Group 1 carcinogen, Brazil issued a total ban on commercial tanning facilities. This … while deliberately ignoring the companion article (de Vries et al, 2005) demonstrating that, probably due to increased public ban was followed by bans in Australia and now, all Australian States have banned commercial tanning facilities. awareness, cases may have under-reported their sun exposure and, most likely, their sunbed exposure. In addition, high percent- ages of sunbed use among controls indicated possible recruitment bias: eligible controls who were sunbed users were probably Since the IARC classification of sunbeds, several major studies confirmed the carcinogenicity of sunbed exposure. Among these, more likely to accept the invitation to participate than non-users, possibly due to a feeling of ‘guilt’ or ‘worry’ about their habits. Such the analysis of an epidemic of melanoma in Iceland could relate the sharp increase in incidence of melanoma on the trunk among selective participation may have strongly influenced the risk estimates of sunbed use in this study. women younger than 50 years to the development of indoor tanning facilities in the Reykjavik area (Hery et al, 2010). Another analysis of a previously published case-control study, but excluding those who had reported burns from indoor tanning use, inves- The concern that there may be an association between exposure to artificial UV radiation and skin cancer was reactivated in 2003-4 tigated the interaction between sunbed use and sunburns from outdoor solar radiation and the risk of melanoma. Significantly when the 10th Report on Carcinogens published by the National Toxicology Program in the USA classified UVA radiation as a “Known increased risk was found for melanoma across all sunburn categories, the highest risk being found for those who reported zero Carcinogen to Humans”. The concern was fuelled by the evidence that the tanning industry used biased arguments for promoting lifetime sunburns (OR=3.87 (95% CI: 1.68, 8.91)) (Vogel et al, 2014). An accumulation of other epidemiological data has documented exposure to artificial UV sources (Autier, 2004), and expended much efforts for convincing public health authorities that profession- the likelihood that the UVA is involved in carcinogenic processes taking place in the skin (Autier et al, 2011a). ally supervised artificial UV tanning was safer than sun tanning (Autier et al, 2011b). More recently, following a request from the European Commission, the Scientific Committee on Health, Environmental and Emerging In spring 2004, irritated by a press release from the tanning industry falsely citing a WHO fact sheet on sunbeds and advocating Risks (SCHEER) reviewed recent evidence to update the 2006 SCCP Opinion on the Biological effects of ultraviolet radiation relevant artificial tanning as a preparation to summer sun exposure, the NGO Sécurité Solaire wrote to the French President Jacques Chirac to health, with particular reference to sunbeds for cosmetic purposes. The public consultation on the preliminary opinion raised to ask him to ban such advertisements. Subsequently, in October 2004, the French Ministry of Health contacted the Director of the nearly 1,000 comments, in majority from sunbed industry representatives and sunbed associations. In its final opinion, SCHEER International Agency for Research on Cancer (IARC), Dr Peter Boyle, raising a particular concern about the continuous increase in concluded that “that there is strong evidence that exposure to UVR, including that emitted by sunbeds, causes cutaneous melanoma incidence of melanoma in France and in the world, and requested IARC to investigate the possibility of re-evaluating the carcino- and squamous cell carcinoma at all ages and that the risk for cancer is higher when the first exposure takes place in younger ages. genic risk associated with UV radiation, particularly concerning artificial UV sources and the use of indoor tanning facilities. Since There is also moderate evidence that exposure to UVR, including that emitted by sunbeds, also increases the risk of basal cell the last IARC Monograph on UV radiation in 1992, a large number of epidemiological and experimental studies had been conducted carcinoma and ocular melanoma”, and added that “there is no safe limit for exposure to UV radiation from sunbeds” (SCHEER, 2016). on the risks associated with exposure to UV radiation. The carcinogenicity of sunbed exposure should no longer be a matter of debate. Sunbed exposure represents a major public health In response IARC Director Peter Boyle convened in June 2005 a small working group (Philippe Autier, Mathieu Boniol, Jean-François concern. Its contribution to skin cancer incidence is far from being negligible: it has been estimated that In Europe, 3,438 (5.4%) Doré, Sara Gandini, Adele Green, Julia Newton-Bishop, Martin A Weinstock, Johan Westerdahl, and Stephen D Walter) that conducted of 63,942 new cases of melanoma diagnosed each year are attributable to sunbed use, women representing most of this burden an extensive literature analysis and a meta-analysis. Based on 19 studies (18 case-control studies, of which 9 were population based, (Boniol et al, 2012), and the risk concentrates in the population that started sunbed use before the age of 30-35. In addition, sunbed and one prospective study) that included 7,355 melanoma cases and 11,275 controls from case-control studies and 106,378 cohort exposure is associated with early onset melanoma. members, the group concluded that ever-use of sunbeds was associated with an increase in melanoma risk (RR=1.15 (95% CI: 1.00, 1.31)), more especially when exposure started before 30 years of age (RR=1.75 (95%CI: 1.35, 2.26)) (IARC, 2006). The strong It required thirty years of research and analysis, including legal action against researchers, to lead to the current situation where the association between sunbed exposure starting at an early age and melanoma prompted public health warnings recommending carcinogenic effects of sunbeds are established and that steps are taken to legislate against their use and thereby leading to reduce to ban the access to sunbeds to subjects less than 18 years of age (Autier et al, 2008). It is worthy of note that, a few years later, a the risk of melanoma in the population. The road between identification of a hazard and its prevention can be long and can contain new meta-analysis conducted by the same group and based on 27 studies, fully confirmed these results (Boniol et al, 2012). These many obstacles which need to be overcome. works encouraged many European countries and states in Australia, the USA and in Canada to put an age restriction on the access to artificial suntan parlours. Autier P. Perspectives in melanoma prevention: the case of sunbeds. Eur J Cancer. de Vries E, Boniol M, Severi G, Eggermont AM, Autier P, Bataille V, et al. Public awareness about risk 2004;40(16):2367-76. factors could pose problems for case-control studies: the example of sunbed use and cutaneous In 2006, the Scientific Committee on Consumer Products (SCCP) from the European Commission issued an Opinion on “Biological Autier P, Boyle P. Artificial ultraviolet sources and skin cancers: rationale for restricting access to melanoma. Eur J Cancer. 2005;41(14):2150-4. effects of ultraviolet radiation relevant to health with particular reference to sunbeds for cosmetic purposes”, of which the conclusion sunbed use before 18 years of age. Nat Clin Pract Oncol. 2008;5(4):178-9. Hery C, Tryggvadottir L, Sigurdsson T, Olafsdottir E, Sigurgeirsson B, Jonasson JG, et al. A melanoma was “SCCP is of the opinion that the use of UVR tanning devices to achieve and maintain cosmetic tanning, whether by UVB and/or Autier P, Dore JF, Eggermont AM, Coebergh JW. Epidemiological evidence that UVA radiation is epidemic in Iceland: possible influence of sunbed use. Am J Epidemiol. 2010;172(7):762-7. involved in the genesis of cutaneous melanoma. Curr Opin Oncol. 2011a;23(2):189-96. IARC. Radiation. IARC Monogr Eval Carcinog Risks Hum. 2012;100(Pt D):7-303. UVA, is likely to increase the risk of malignant melanoma of the skin and possibly ocular melanoma”. In addition, SCCP proposed to Autier P, Joarlette M, Lejeune F, Lienard D, Andre J, Achten G. Cutaneous malignant melanoma IARC working group. Exposure to artificial UV radiation and skin cancer. Lyon, France: 2006. limit erythemally weighted irradiance of sunbeds to 0.3 W/m2, i.e. 11 standard erythema doses (SED) per hour, equivalent to tropical and exposure to sunlamps and sunbeds: a descriptive study in Belgium. Melanoma Res. SCCP. Request for a scientific opinion: Biological effects of ultraviolet radiation relevant to health sun, which the WHO terms “extreme exposure” (SCCP, 2006). 1991;1(1):69-74. with particular reference to sun beds for cosmetic purposes. Scientific committee on consumer Autier P, Dore JF, Breitbart E, Greinert R, Pasterk M, Boniol M. The indoor tanning industry’s double products (SCCP), 2006. game. Lancet. 2011b;377(9774):1299-301. SCHEER. Opinion on Biological effects of ultraviolet radiation relevant to health with particular In June 2009, IARC re-evaluated the carcinogenicity of solar and ultraviolet radiation. And based on the available data, and more Autier P, Dore JF, Schifflers E, Cesarini JP, Bollaerts A, Koelmel KF, et al. Melanoma and use of reference to sunbeds for cosmetic purposes. Brussels, Belgium: Scientific Committee on Health, especially on the IARC (2005) meta-analysis, the working group concluded that “there is sufficient evidence in humans for the sunscreens: an Eortc case-control study in Germany, Belgium and France. The EORTC Melanoma Environmental and Emerging Risks 2016. Cooperative Group. Int J Cancer. 1995;61(6):749-55. Vogel RI, Ahmed RL, Nelson HH, Berwick M, Weinstock MA, Lazovich D. Exposure to indoor tanning carcinogenicity of the use of UV-emitting tanning devices. UV-emitting tanning devices cause cutaneous malignant melanoma and Bataille V, Boniol M, De Vries E, Severi G, Brandberg Y, Sasieni P, et al. A multicentre epidemiological without burning and melanoma risk by sunburn history. J Natl Cancer Inst. 2014;106(7). ocular melanoma. Use of UV-emitting tanning devices is carcinogenic to humans (Group 1)” (IARC, 2012). study on sunbed use and cutaneous melanoma in Europe. Eur J Cancer. 2005;41(14):2141-9. Boniol M, Autier P, Boyle P, Gandini S. Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ. 2012;345:e4757.

iPRI 21 iPRI - International Prevention Research Institute — Principal Contributions iPRI

PRINCIPAL CONTRIBUTIONS

The International Prevention Research Institute was established to bring about change.

From day one, we have never been satisfied with doing the least. Our goal is to be exhaustive, continuously. To this end, we self-fund projects that we believe, can help steer global public health in a better direction.

What follows in the coming pages are a series of major contributions made by iPRI in tandem with our partners and sometimes on our own.

We believe that the road to better health is evidence; when it comes to people’s health, getting to the destination quickly, efficiently but also accurately, saves lives for many and improves quality-of-life for the living.

iPRI 23 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Cancer

Breast Cancer Screening

creening impacts cancer mortality through had presented a hazard to a women’s health in her Sdecreasing the number of advanced cancers lifetime (i.e., overdiagnosis). These gloomy conclu- with poor prognosis, while patient management sions on mammography screening were reached by impacts cancer mortality through decreasing the iPRI studies that have shown no or modest decline in fatality of cancers. The effectiveness of cancer the incidence of advanced cancers, including that of screening is the ability of a screening method to de novo metastatic (stage 4) cancers at diagnosis in reduce cancer mortality by reducing the incidence populations where mammography screening is of advanced cancers in populations. Breast cancer widespread for long periods (Autier et al, 2012a; mortality is declining in most high income countries Autier et al, 2011b; Autier et al, 2014). These findings since around 1990. Dramatic mortality declines of are in contradiction with the well-known fact that 30 to 45% over 20 to 25 years have been observed in effective cancer screening impacts cancer mortality more than twenty European and North American through decreasing the number of advanced countries (Autier et al, 2010), updated in abstract No cancers with poor prognosis. Additional iPRI studies P5-08-04 by Pizot et al presented at the San Antonio found that breast cancer mortality reductions are Breast Cancer Symposium (SABCS) 2016). The contin- similar in areas with early introduction and high uous improvements in the management of breast penetration of screening than in area with late intro- cancer patients are playing a major role in these duction and low penetration of screening (Autier et mortality reductions (Park et al, 2015). In contrast, al, 2011a; Autier et al, 2012b). The conclusions of the impact of mammography screening on mortality iPRI’s studies have been largely confirmed by similar reductions seems to be limited, while at the same studies done by other groups in Europe and in North time this screening has led to the detection of many America (Bleyer, 2011; Bleyer et al, 2012; de Glas et small cancers or of lesions (e.g., the “in situ cancers”) al, 2014; Harding et al, 2015). of unknown clinical significance, that would never

30%

28% 27% In randomised trials on cancer screening, the reduction 25% of the risk of cancer death reported in articles (the observed reduction) should be similar to the risk of 20% 21% cancer death predicted on the basis of the reduction of the numbers of advanced cancers.1 The absence of 15% similarity in the three breast screening trials diplayed 11% in the figure indicates a probability of biases in the 10% 10% trial conduct and analysis (after Autier et al (2016))

% reduction of risk breast cancer death 2%

0 HIP Two-county UK Age

Observed reduction in the risk of breast cancer death 1 *Three trials on breast screening reported data allowing the calculation of predicted risk reduction Predicted reduction in the risk of breast cancer death

25 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Mammography screening programmes have been implemented in most high income countries when six randomised trials, and As a consequence, the number of women needed to screen for preventing one breast cancer death increases with treatment especially the four trials conducted in Sweden, showed that periodic breast screening of women 40 to 74 years of age could reduce potency (see figure). Moreover, the imbalance between screening effectiveness and overdiagnosis augments with the potency the risk of breast cancer death by about 20 to 25% (Independent UK Panel on Breast Cancer Screening, 2012). The contradiction of treatments. Because there is a fairly great chance that in many countries, dying from breast cancer will become increasingly between results of the randomised trials and of population studies led iPRI scientists to re-appraise the Swedish mammography uncommon, the possible role of mammography screening in breast cancer mortality reductions will become increasingly marginal, trials. Our research conducted in 2013 to 2016 has demonstrated that the design and statistical analysis of the breast screening while the harms will remain the same. randomised trials were different than that of all trials on screening for cancers other than breast cancer (Autier et al, 2015). iPRI scientists found compelling indications that these trials overestimated reductions in breast cancer mortality associated with screening In conclusion, if the implementation of screening programmes has undoubtedly contributed to increase breast awareness and the (see figure), in part because of the statistical analyses themselves, in part because of improved management and underreporting of quality of health services to breast cancer patients, there remains an urgent need to direct research efforts on alternative technolo- breast cancer as the underlying cause of death in screening groups (Autier et al, 2016). gies for breast cancer screening, i.e., a test which is really able to early detect cancers before they progress to an advanced stage that is difficult to treat and with minimal harm in terms of over-diagnosis. Also, for preserving an acceptable harm-benefit balance, It was also found that if the Swedish trials had published some crucial results as other randomised trials on screening for non-breast screening should be targeted to women at high risk of breast cancer death. cancers, the imperfections of Swedish trials would have been more apparent. The Greater New-York Health Insurance Plan (HIP) trial was the first randomised study suggesting the efficacy of breast screening. However, the iPRI re-appraisal found that results of the HIP trial are biased because of the underreporting of breast cancer cases and deaths that occurred in women who did not Autier P. Breast cancer: Doubtful health benefit of screening from 40 years of age. Nat Rev Clin Autier P, Boniol M, Middleton R, Dore JF, Hery C, Zheng T, et al. Advanced breast cancer incidence Oncol. 2015;12(10):570-2. following population-based mammographic screening. Ann Oncol. 2011b;22(8):1726-35. participate to screening (Autier et al, 2016). Finally, the re-appraisal also examined the UK Age trial which was conducted among Autier P. Efficient Treatments Reduce the Cost-Efficiency of Breast Cancer Screening. Ann Intern Biller-Andorno N, Juni P. Abolishing mammography screening programs? A view from the Swiss women 39 to 41 years of age at randomisation. It was found that after 17 years of follow-up, the UK Age trial showed no benefit of Med. 2016a. Medical Board. N Engl J Med. 2014;370(21):1965-7. mammography screening starting at age 39-41, while overdiagnosis was considerable (Autier, 2015). Autier P. Efficient Treatments Reduce the Cost-Efficiency of Breast Cancer Screening. Ann Intern Birnbaum J, Gadi VK, Markowitz E, Etzioni R. The Effect of Treatment Advances on the Mortality Med. 2016b;164(4):297-8. Results of Breast Cancer Screening Trials: A Microsimulation Model. Ann Intern Med. 2016. Autier P, Boniol M. The incidence of advanced breast cancer in the West Midlands, United Kingdom. Bleyer A. US breast cancer mortality is consistent with European data. BMJ. 2011;343:d5630. Eur J Cancer Prev. 2012a;21(3):217-21. Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer The more treatments are efficient, the greater the number of women need to be screened for preventing one breast cancer death, and the more overdiagnosis Autier P, Pizot C, Boniol M. Stable incidence of advanced breast cancer argues against screening incidence. N Engl J Med. 2012;367(21):1998-2005. caused by screening, and the greater the number of women with overdiagnosed breast cancer for one breast cancer death prevented with screening. These effectiveness. BMJ. 2014;349(nov25 10):g6358. de Glas NA, de Craen AJ, Bastiaannet E, Op ‘t Land EG, Kiderlen M, van de Water W, et al. Effect Autier P, Boniol M, Gavin A, Vatten LJ. Breast cancer mortality in neighbouring European countries of implementation of the mass breast cancer screening programme in older women in the relationships deteriorate with decreasing effectiveness of screening (After Autier (2016b)) with different levels of screening but similar access to treatment: trend analysis of WHO mortality Netherlands: population based study. Bmj. 2014;349:g5410. database. BMJ. 2011a;343:d4411. Fletcher SW. Breast cancer screening: a 35-year perspective. Epidemiol Rev. 2011;33(1):165-75. Number of women to be screened to prevent Number of women with overdiagnosis to prevent Autier P, Koechlin A, Smans M, Vatten L, Boniol M. Mammography screening and breast cancer Harding C, Pompei F, Burmistrov D, Welch HG, Abebe R, Wilson R. Breast Cancer Screening, one breast cancer death one breast cancer death with screening mortality in Sweden. J Natl Cancer Inst. 2012b;104(14):1080-93. Incidence, and Mortality Across US Counties. JAMA Intern Med. 2015. 3000 25 Autier P, Boniol M, Smans M, Sullivan R, Boyle P. Statistical analyses in Swedish randomised trials Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer 2857 on mammography screening and in other randomised trials on cancer screening: a systematic screening: an independent review. Lancet. 2012;380(9855):1778-86. review. J R Soc Med. 2015;108(11):440-50. 2500 21 Jatoi I. The impact of advances in treatment on the efficacy of mammography screening. Prev Med. 20 Autier P, Boniol M, Smans M, Sullivan R, Boyle P. Observed and Predicted Risk of Breast Cancer 2011;53(3):103-4. Death in Randomized Trials on Breast Cancer Screening. PLoS One. 2016;11(4):e0154113. Park JH, Anderson WF, Gail MH. Improvements in US Breast Cancer Survival and Proportion 2000 Autier P, Boniol M, La Vecchia C, Vatten L, Gavin A, Hery C, et al. Disparities in breast cancer 1905 15 Explained by Tumor Size and Estrogen-Receptor Status. J Clin Oncol. 2015;33(26):2870-6. mortality trends between 30 European countries: retrospective trend analysis of WHO mortality USPSTF. Screening for testicular cancer: U.S. Preventive Services Task Force reaffirmation recom- 1500 database. BMJ. 2010;341:c3620. 1429 1429 mendation statement. Ann Intern Med. 2011;154(7):483-6. 10 10 1000 9 952

Number of women to screen 714 5 500 4 Number of women with overdiagnosis 1.3 0.6 0 0 0% 25% 50% 0% 25% 50%

% Mortality reduction due to breast cancer patient management % Overdiagnosis

20% Mortality reduction with screening mammography 20% Mortality reduction with screening mammography 10% Mortality reduction with screening mammography 10% Mortality reduction with screening mammography

A recurring question is whether the advent of effective therapies and the improvement in performances of all relevant medical, radiotherapy and surgical disciplines after 1990 has affected the effectiveness of screening mammography (Biller-Andorno et al, 2014; Fletcher, 2011; Jatoi, 2011). As a matter of fact, the high effectiveness of cis-platinum based therapies on testis cancer, even when already metastatic, has rendered obsolete the few attempts made to promote screening for this cancer (USPSTF, 2011). On the basis of studies that have estimated how the availability of efficient adjuvant and chemo treatments has changed reductions in risks of breast cancer death reported by randomized trials on breast screening (Birnbaum et al, 2016), we have documented that increasingly efficient patient management reduces the number of screen-prevented breast cancer deaths (Autier, 2016a).

iPRI 27 iPRI - International Prevention Research Institute — Principal Contributions iPRI

In collaboration with the University of Melbourne, we have studied changes in colorectal cancer mortality in European countries (Ait Ouakrim et Screening for Colorectal Cancer al, 2015). Since 1989, many European countries have undergone changes in the prevalence of risk factors for colorectal cancer such as obesity and alcohol intake, participation to screening programmes, and access to specialised care and effective treatments. As a result, colorectal cancer olorectal cancer is a major public health issue in Europe. In 2012, it was estimated that 241,600 mortality is falling in an increasing number of mainly Nordic, and Western European countries, presumably because of favourable changes in Cin most western countries. Colorectal cancer is European men were diagnosed with colorectal risk factors, access to screening, less late presentation when metastases have already spread in distant organs (e.g., in the liver), the develop- the second most commonly diagnosed cancer in cancer, and that 113,200 men died from the disease. ment of therapies with increased efficiency and more generally, better management of patients. For the sake of comparison, the mortality the world and has poor prognosis when metasta- For European women, 205,200 cases of colorectal change in the USA is displayed in the figure. In Central, Eastern and Southern European countries, colorectal cancer mortality is still on the rise, sised to lymph nodes or distant organs. After lung cancer and 101,500 related deaths were recorded sometimes markedly like in Romania, Croatia and Poland. These unfavourable trends are essentially due to poor dietary patterns, high alcohol cancer, it is the most common cause of cancer death that year. consumption, late stage at cancer diagnosis, reflecting low awareness and absence of screening, and limited availability of effective therapies.

The persistent greater colorectal cancer mortality in men than in women suggest that differences in risk factors play a major role, because Changes in CRC mortality* from 1989 to 2010 is highly variable across European countries (after Ait Ouakrim et al (2015)) women tend to be more health aware and to adopt healthier behaviours, while participation to screening tends to be similar in both sexes. Screening methods for early detection of the colorectal cancer are gradually improving. The old guaiac-based faecal occult blood test (gFOBT) is Women - % Change 1989 - 2010 progressively replaced by the immunology-based FOBT (iFOBT) which is more sensitive and can detect adenomatous polyps. The most efficient screening methods are those based on the endoscopic examination of the distal colon (sigmoidoscopy) and of the entire colon (colonoscopy). -50% -40% -30% -20% -10% 0 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% The iFOBT and endoscopic methods lead to the removal of polyps from which most colorectal cancer arise. This iterative polypectomy leads on Austria Germany Czech Republic its turn to a decrease in both the incidence and mortality of this cancer. UK Luxembourg (‘89-’09) Switzerland (‘89-’07) Ireland (‘89-’09) The role of screening can be illustrated by the comparison of mortality trends in countries having similar socio-economic status and access to France (‘89-’09) UK, Northern Ireland modern therapies (see figure below). In Austria and Germany, endoscopic screening has been widely promoted in the 2000s, while colorectal UK, England and Wales Belgium cancer screening is in pilot phases in the Netherlands and in Sweden. Surveys using a same methodology for inquiring about past exposure UK, Scotland EU27 (‘89-’09) to endoscopic examinations of the large bowel have shown examination rates two to three times higher in Austria and Germany than in the Men - % Change 1989 - 2010 Finland Italy (‘89-’09) Netherlands and Sweden (www.share-project.org). Reductions in colorectal cancer mortality are more pronounced in the former than in the Iceland (‘89-’09) -50% -40% -30% -20% -10% 0 10% Hungary (‘89-’09) latter countries (see figure below). Because of the many similarities between the four countries, such difference can hardly be explained by Austria Denmark (‘89-’09) Switzerland (’89-’07) Malta changes on the influence of factors other than screening. Germany Portugal Czech Republic Slovakia (‘92-’10) France (‘89-’09) The Netherlands Luxembourg (‘89-’09) Slovenia UK Estonia UK, England and Wales -50% -40% -30% -20% Sweden Ireland (‘89-’09) Norway Proportions of men and of women aged 50 or more who reported at least one endoscopic examination of the large bowel over the last 10 years and Belgium Spain Norway Belarus (‘89-’09) reductions in colorectal cancer mortality from 2009 to 2011 in selected European countries with similar access to high quality health care Finland Ukraine UK, Northern Ireland Bulgaria Latvia Italy (‘89-’09) Greece (‘89-’09) 60% Denmark (‘89-’07) Lithuania Men: 23% or more EU27 (‘89-’09) Poland Sweden Russian Federation (‘89-’09) Women: 23% or more UK, Scotland Croatia 50% The Netherlands Macedonia (‘91-’10) Iceland (‘89-’09) Romania Malta USA Hungary (‘89-’09) Slovenia -10% 0 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 40% Slovakia Men: 10% or less Latvia 20% Portugal Women: 10% or less Ukraine 30% 30% Russian Federation (‘89-’09) Belarus (‘89-’09) Bulgraia Spain 40% 50% 60% 70% 80% 90% 100% Greece (‘89-’09) 20% Estonia Lithuania

Poland % reduction in CRC mortality Croatia 10% Macedonia (‘91-’10) Romania USA -50% -40% -30% -20% -10% 0 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 0 Austria Germany The Netherlands Sweden

Ait Ouakrim D, Pizot C, Boniol M, Malvezzi M, Boniol M, Negri E, et al. Trends in colorectal cancer mortality in Europe: retrospective analysis of the WHO mortality database. BMJ. 2015;351:h4970.

iPRI 29 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Aitken JF, Elwood JM, Lowe JB, Firman DW, Balanda KP, Ring IT. A randomised trial of population screening for melanoma. J Med Screen. 2002;9(1):33-7. Screening for Cutaneous Melanoma Boniol M, Autier P, Gandini S. Melanoma mortality following skin cancer screening in Germany. BMJ Open. 2015;5(9):e008158. utaneous melanoma is the most deadly form of tested in an experimental design. The conduct Breitbart EW, Waldmann A, Nolte S, Capellaro M, Greinert R, Volkmer B, et al. Systematic skin Cskin cancer. It is known that subjects harbouring of a community-based randomised trial on skin cancer screening in Northern Germany. J Am Acad Dermatol. 2012;66(2):201-11. Force USPST. Screening for skin cancer: Us preventive services task force recommendation many melanocytic naevi (or moles) are at higher risk screening has been attempted in Queensland, statement. JAMA. 2016;316(4):429-35. of melanoma. It has thus been proposed that subjects Australia, that part of the world where the highest Katalinic A, Waldmann A, Weinstock MA, Geller AC, Eisemann N, Greinert R, et al. Does skin cancer with skin nevi should have their skin periodically risk of melanoma is observed among light-skinned screening save lives?: an observational study comparing trends in melanoma mortality in regions with and without screening. Cancer. 2012;118(21):5395-402. examined for the identification of pigmented spots subjects (Aitken et al, 2002). However the trial did Wolff T, Tai E, Miller T. Screening for skin cancer: an update of the evidence for the U.S. Preventive that could evolve into life-threatening melanoma. not succeed in recruiting sufficient numbers of Services Task Force. Ann Intern Med. 2009;150(3):194-8. The ability of regular skin screening to reduce one’s subjects to reach a conclusion on the public health chance to die from a melanoma has never been value of screening for melanoma.

In 2003, an intervention study on skin screening was conducted in Northern Germany (Breitbart et al, 2012; Katalinic et al, 2012). The intervention consisted of total body skin examinations of adults performed by general practitioners and by dermatologists. Despite a low participation rate of 20%, investigators reported a dramatic reduction in the mortality due to melanoma starting around screening initiation and lasting for a few years. These results prompted considerable interest and public health agencies were invited to consider new recommendations more favourable to skin screening. In particular, the US Preventive Services Task Force (USPSTF) was asked to reconsider its review of 2009 in which it was concluded that the evidence on the health benefits of skin cancer screening was insufficient for issuing a recommendation (Wolff et al, 2009).

In 2014, iPRI performed a detailed analysis of the mortality statistics related to melanoma in Germany. When the analysis was confined to areas where the screening intervention took place, it was found that in recent years, the melanoma mortality had returned to rates prevailing before screening (see figure) (Boniol et al, 2015a). Thus there was a fairly high chance that the apparent transient decline in melanoma mortality was spurious and due to the misreporting of causes of death by doctors who had also been involved in the skin screening intervention. The iPRI research served as a reference for the USPSTF to justify the absence of change of conclusions reached in the review of 2009 (Force, 2016).

First pilot project SCREEN project Trend in cutaneous melanoma mortality 4 in the screened area Schleswig–Holstein (SH) as compared with the whole 3.5 Men of Germany. Data from the Federal 3 Statistical Office (http://www.gbe-bund. de) as of 15 December 2014 and 2.5 from GEKID as of 10 December 2014. 2 Box=period of SCREEN project (Skin 1.5 Cancer Research to Provide Evidence for Effectiveness of Screening in Northern 1 Germany) (July 2003–June 2004). Women

Melanoma mortality/100,000 0.5

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Screened area (SH) Germany

iPRI 31 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Screening for Prostate Cancer

he use of the serum prostate specific antigen to the overtreatment of many prostate cancers that T(PSA) concentration for prostate cancer early would have remained asymptomatic during lifetime detection is not recommended, and most public (i.e., overdiagnosed cancers). The harms consist health agencies recommend against the use of mainly of incontinence and in erectile dysfunction. PSA testing for mass screening purposes. The main The harms due to overdiagnosis is a high price to pay reason for these recommendations is the consider- for an uncertain number of prostate cancer deaths able amount of harm associated with screening, due avoided.

The recommendations have generally been directed to occasional or PSA testing in men free of prostate symptom. The case of periodic PSA testing with monitoring of PSA levels was not really addressed by most recommendations. According to some studies, raising PSA levels over time could indicate the presence of a fast growing prostate cancer, in other words, of a cancer that would deserve radical therapy with minimal risk of overdiagnosis.

30% Distribution of the percentage variation of prostate- specific antigen level between the first and the second 25% measurement in the PLCO study. The blue curve is a kernel density estimation with bandwidth = 0.6. 20% PLCO, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; PSA, prostate-specific antigen. 15% Curve: Kernel (c=0.6) The iPRI carried out an analysis of the risk 10% of prostate cancer according to changes in serum PSA concentrations over time using 5% the data form the large randomised trials in the USA called the Prostate, Lung, Colorectal 0 0 and Ovarian Cancer Screening trial (Andriole -80% -60% -40% -20% 20% 40% 60% 80% -100% 100% 120% 140% 160% 180% 200% et al, 2009). The analysis found that time- Percentage variation of PSA level variations in PSA concentrations followed a quasi-normal distribution without evidence of extreme changes that would represent the signature of the presence of a fast growing prostate cancer (see figure) (Boniol et al, 2015). Statistical analyses further showed that if raising levels over time could predict the diagnosis of a prostate cancer, there was no relationship with the aggressiveness (i.e., the Gleason score) of the prostate cancer. Hence, rising PSA concentrations are not helpful for determining whether a men is developing a potentially life-threatening prostate cancer.

Andriole GL, Crawford ED, Grubb RL, 3rd, Buys SS, Chia D, Church TR, et al. Mortality results from a Boniol M, Autier P, Perrin P, Boyle P. Variation of Prostate-specific Antigen Value in Men and Risk randomized prostate-cancer screening trial. N Engl J Med. 2009;360(13):1310-9. of High-grade Prostate Cancer: Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study. Urology. 2015;85(5):1117-22.

iPRI 33 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Breast Cancer and Physical Activity Results from stratified meta-analyses of breast cancer risk and physical activity

bservational studies have shown that physical our study was to quantify the association between Oactivity could reduce the risk of breast cancer physical activity and breast cancer and to investi- and the use of hormone replacement therapy (HRT) gate the influence of HRT use and other risk factors increases the risk of breast cancer. The objective on this association.

A systematic literature search and quantitative analysis was conducted and reported following PRISMA guidelines regarding meta-analysis of observational studies. Eligible articles for this study had to: (i) report data on incident cases of breast cancer or on breast cancer deaths; (ii) report measurement of physical activity, being occupational and/or non-occupational, and using any metrics to quantify physical activity; (iii) have a prospective design. Articles with prevalent cases of breast cancer were excluded.

A meta-analysis was undertaken using a random effects model to investigate the association between physical activity and breast cancer risk. As physical activity assessment and reporting of results were very heterogeneous across studies, breast cancer risk associated with the highest level of physical activity was compared with the lowest level of physical activity. Heterogeneity between studies was evaluated by the I² statistics and publication bias was assessed with Begg test, Egger test and Macaskill test. Sensitivity analyses were carried out and stratified meta-analyses considering several confounding factors were performed. A dose-response analysis, using a non-parametric approach, was also conducted with studies reporting physical activity either in hours/week or in MET-h/week (Metabolic equivalent of task).

Thirty eight studies were included in our analysis representing 4,124,275 women of which 116,304 were diagnosed with a breast cancer during the study period. The summary relative risk (SRR) for breast cancer in the highest vs. the lowest category of physical activity was 0.88 (95% CI: 0.85, 0.90) with 29% of heterogeneity and no strong evidence of publication bias. The stratified analyses revealed that physical activity decreased the risk of breast cancer by about 12% irrespective of the place of residence, type of physical activity, adiposity, menopausal status, and the hormone receptor status of tumours (see figure). Nevertheless, the decreased risk was more pronounced in women with low BMI (SRR=0.84 (95% CI: 0.78-0.90)), women with ER-/PR- phenotype (SRR=0.80 (95% CI: 0.69, 0.92)) and women who never used HRT (SRR=0.78 (95% CI: 0.70, 0.87)). Studies conducted before 1989 reported greater decreases in breast cancer risk than studies conducted after 1989 (SRR=0.80 (95% CI: 0.72, 0.90)) and SRR=0.89 (95% CI: 0.86, 0.92), respectively) that could be partly explained by the less prevalent use of HRT before 1990.

Dose-response analyses were performed with the 18 studies that reported physical activity either in MET-h/week or in hours per week. Significant dose-response relationships were found (p < 0.0001) between amounts of physical activity and breast cancer risk irrespective of the metric used indicating steady reductions in risk with increasing physical activity, without evidence for a threshold. For example, a physi- cally inactive women engaging in at least 150 min per week of vigorous physical activity would reduce their lifetime risk of breast cancer by 9%, a reduction that might be two times greater in women who never used HRT.

This meta-analysis demonstrates three important findings. Firstly, increased levels of physical activity lead to reductions in the risk of breast Pizot C, Boniol M, Mullie P, Koechlin A, Boniol M, Boyle P, et al. Physical activity, hormone replacement therapy and breast cancer risk: A meta-analysis of prospective studies. Eur J Cancer. cancer irrespective of the type of physical activity, place of residence, adiposity, menopausal status, and the hormone receptor status of 2016;52:138-54. tumours. Secondly, breast cancer risk seems to decline with increasing physical activity, without a threshold effect. Thirdly, women who ever used HRT had no reduction of breast cancer risk associated with physical activity which raises the hypothesis that HRT use would cancel out the preventive effect of physical activity against breast cancer.

This study indicates that avoidance of sedentary behaviours and promotion of physical activity may contribute to control the increase in breast cancer burden taking place in most populations over the world. The time is ripe for organising large population randomised trials that will better inform on the feasibility of policies encouraging physical activity to prevent breast cancer occurrence. On the other hand, other lifestyle risk factors such as alcohol drinking that are known to be associated with an increased risk of breast cancer should also be considered in strategies aiming at preventing breast cancer (Pizot et al, 2016).

iPRI 35 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Active and Passive Smoking and Risk of Breast Cancer Summary of meta-analyses results, stratified by studies design and types of exposures

2 bservational studies on active or passive up-to-date quantitative estimates of the association Meta-analysis Number of studies Studies design Total number of cases Summary relative risk Confidence interval Heterogeneity I Osmoking and breast cancer, as well as meta- between active and passive smoking, and the risk of Active smoking exposure and breast cancer risk analyses and reviews have reached a wide range of breast cancer, a systematic review and meta-analysis Ever active smoking 71 P & R 125,251 1.09 1.06, 1.12 46 % Ever active smoking 27 P 68,440 1.10 1.09, 1.12 0 % conclusions, from a lack of association to sugges- of case-control and cohort studies published until Ever active smoking 44 R 56,811 1.08 1.02, 1.14 59 % tion of a causal association. In order to provide March 2015 were conducted. Current active 49 P & R 103,893 1.11 1.06, 1.16 56 % smoking A total of 86 prospective and case-control studies were included in 4 main meta-analyses estimating the risk of incident invasive Current active 27 P 63,087 1.13 1.09, 1.17 35 % breast cancer in ever/current/former smokers compared to never smokers, and in never active but passive smokers compared to smoking women never exposed. Current active 22 R 40,806 1.08 0.97, 1.20 69 % smoking Former active 49 P & R 103,774 1.09 1.06, 1.12 37 % Active smoking: Results of meta-analyses were indicative of statistically significant moderate increased risks of breast cancer associ- smoking ated with ever, current and former active tobacco smoking (between 8% and 13% increased risk) (see table). Former active 27 P 62,968 1.09 1.06, 1.12 25 % smoking The results of the dose-response analysis indicated that with every additional year of smoking the relative risk of breast cancer Former active 22 R 40,806 1.09 1.02, 1.16 49 % smoking incidence is multiplied by 1.005 (see figure). As a consequence, the risk of breast cancer in women who smoke during 10, 20 or 30 Passive smoking exposure and breast cancer risk years is increased by 5, 10, and 16%, respectively. Ever passive smoking 31 P & R 34,715 1.20 1.07, 1.33 67 % Ever passive smoking 11 P 18,022 1.07 1.02, 1.13 1 % The likelihood of an association is further supported by the quasi absence of heterogeneity in results of prospective studies and by Ever passive smoking 20 R 16,693 1.30 1.10, 1.54 74 % the stability of results across different subgroups, notably in pre-menopausal and post-menopausal women, after adjustment for alcohol consumption, and when passive smokers were excluded from the referent group. P = prospective design and R = retrospective design

Passive smoking: Exposure to environmental tobacco smoke also seems associated with a moderately increased risk of breast cancer (between 7% and 30%). However, results for passive smoking are more delicate to interpret because of the difficulty to assess exposure to second-hand smoking exposures, and of the relatively small number of available studies.

Robustness of results: The heterogeneity of results between studies was more manifest for retrospective designs, with zero to low heterogeneity among results from prospective studies. The summary relative risk estimates have remained remarkably stable over time, and the accumulation of studies has steadily reduced the variance of estimated risks.

Results were robust across stratified analyses and leave-one-out sensitivity analysis did not identify any one study that strongly influenced the results. There was little to no evidence of publication bias.

As time passes, the evidence accumulates for considering that active tobacco smoking is associated with a modest, but real increase in the risk of breast cancer. The consistency of findings, the low heterogeneity of results of prospective studies, the dose-response found in prospective studies, the permanent higher risk since the first studies done on the topic, and the absence of influence of major confounders on associations are all indicating that the relationship would be causal.

For passive smoking also, the evidence for a modest but real association with breast cancer strengthens with the accumulation of data. In this respect, public health policies should inform women about the risk of breast cancer associated with both active and passive smoking. (Macacu et al, 2016).

iPRI 37 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Relative risk of breast cancer incidence in function of the duration of ever actively smoking (in years) among 12 studies Risk of Cancer in the Rubber Manufacturing Industry with prospective designs. The colour of the points indicates the original study, and the size of the points is inversely propor- tional to the variance of the RR estimate given in this study. The linear regression trend line is drawn in black, using the orking in the rubber manufacturing industry the 1960s and yet little data is available for more summary slope estimate b = 1.005, and the dotted lines represent the 95 % confidence interval of the slope estimate Wwas classified as carcinogenic to humans by recently employed workers. The mortality and the International Agency for Research on Cancer cancer incidence of rubber industry workers first (IARC 1982, 1987, 2012). This evaluation was mainly employed after 1975 was studied in five European

G G based on workers first employed in the first half of countries. In a second part, a meta-analysis on the the XXth century. Many technological and occupa- risk of cancers in the rubber manufacturing industry tional changes have occurred in this industry since was conducted.

1.4 G Study Subjects were recruited in five European countries (Germany, Italy, Poland, Sweden and the United Kingdom), if they had at least one year G G G AlDelaimy2004 of employment in the rubber manufacturing industry and were first employed on or after 01/01/1975. Workers were followed-up to 2012 G G Bjerkaas2013 for mortality (all countries) and cancer incidence (Sweden and the UK). Mortality and cancer incidence were compared with those observed G G Catsburg2014 G Catsburg2015 in the general population using age-, gender-, country- and period-specific standardised mortality/incidence ratios (SMRs/SIRs). SMRs were G G G G G Cox2011 1.2 G computed for all-cause mortality, cardiovascular mortality, respiratory mortality and major cancer sites. SIRs were computed for major cancer G G G G G Gram2005 RR G G G G sites only. Heterogeneity analyses were conducted type of industry (tyres; general rubber goods/GRG; mixed), and duration of employment. G G G G Land2014 G G G G G Luo2011 G G G G Manjer2004 In total, 38,457 subjects (77% men) contributing 949,370 person-years and 2,275 deaths were included in the mortality study (Boniol et al, G G Olson2005 G G G G Reynolds2004 2016). No statistically significant increased risk of any cause of mortality was observed (see table), including for bladder cancer. Significantly G G Xue2011 G reduced risks were found for lung cancer, all forms of cancers and all-cause mortality. Risks were lower in the tyre industry than in the general 1.0 G G G G rubber goods industry. For example the SMRs for all forms of cancers were 0.68 (95% CI: 0.60, 0.76); 0.74 (95% CI: 0.61, 0.88) and 1.03 (95% CI: G 0.91, 1.18) for workers employed in the tyre, mixed and GRG industries, respectively. Analysis of all-cause mortality by duration of employment

G G revealed decreasing SMRs with increasing duration of employment.

G The analysis of cancer incidence was restricted to Sweden and the United Kingdom, for which complete data were available (Boniol et al, 0 20 40 60 Duration smoking (years) 2017b). In total, 16,026 individuals (397,975 person-years) were included in the analysis, and 846 cancer cases (excluding non-melanoma skin) were recorded. No statistically significant risk of cancer of any site was observed (see table). Significantly reduced risks were identified for lung cancer, all forms of cancer (excluding skin), non-Hodgkin’s lymphoma and prostate cancer. Overall, results were similar to those observed for mortality. Al-Delaimy WK, Cho E, Chen WY, Colditz G, Willet WC. A prospective study of smoking and risk Luo J, Margolis KL, Wactawski-Wende J, Horn K, Messina C, Stefanick ML, et al. Association of of breast cancer in young adult women. Cancer Epidemiol Biomarkers Prev. 2004;13(3):398-404. active and passive smoking with risk of breast cancer among postmenopausal women: a prospec- The cohort study of rubber manufacturing industry workers was contextualised by conducting a global meta-analysis on the risk of cancer Bjerkaas E, Parajuli R, Weiderpass E, Engeland A, Maskarinec G, Selmer R, et al. Smoking duration tive cohort study. BMJ. 2011;342:d1016. before first childbirth: an emerging risk factor for breast cancer? Results from 302,865 Norwegian Macacu A, Autier P, Boniol M, Boyle P. Active and passive smoking and risk of breast cancer: a in the rubber manufacturing industry (Boniol et al, 2017a). Observational studies reporting a risk estimate of cancer in this population were women. Cancer Causes Control. 2013;24(7):1347-56. meta-analysis. Breast Cancer Res Treat. 2015;154(2):213-24. systematically searched. Summary relative risks (SRRs) were computed for each cancer site with at least four risk estimates. A sensitivity analysis Catsburg C, Kirsh VA, Soskolne CL, Kreiger N, Rohan TE. Active cigarette smoking and the risk of Manjer J, Johansson R, Lenner P. Smoking is associated with postmenopausal breast cancer in breast cancer: a cohort study. Cancer Epidemiol. 2014;38(4):376-81. women with high levels of estrogens. Int J Cancer. 2004;112(2):324-8. was conducted by restricting the study to workers first employed on or after 01/01/1960. Catsburg C, Miller AB, Rohan TE. Active cigarette smoking and risk of breast cancer. Int J Cancer. Olson JE, Vachon CM, Vierkant RA, Sweeney C, Limburg PJ, Cerhan JR, et al. Prepregnancy exposure 2015;136(9):2204-9. to cigarette smoking and subsequent risk of postmenopausal breast cancer. Mayo Clin Proc. The literature search identified 46 cohort and 59 case-control studies. Summary relative risks by cancer site are described in the figure. An Cox DG, Dostal L, Hunter DJ, Le Marchand L, Hoover R, Ziegler RG, et al. N-acetyltransferase 2 2005;80(11):1423-8. polymorphisms, tobacco smoking, and breast cancer risk in the breast and prostate cancer cohort Reynolds P, Hurley S, Goldberg DE, Anton-Culver H, Bernstein L, Deapen D, et al. Active Smoking, increased risk was found for bladder cancer (SRR=1.36 (95% CI: (1.18, 1.57))), leukaemia (1.29 (95% CI: 1.11, 1.52)), lymphatic/haematopoietic consortium. Am J Epidemiol. 2011;174(11):1316-22. Household Passive Smoking, and Breast Cancer: Evidence From the California Teachers Study. JNCI system (1.16 (95% CI: 1.02, 1.31)), and larynx cancer (1.46 (95% CI: 1.10, 1.94)). There was a borderline significant increased risk of lung cancer Gram IT, Braaten T, Terry PD, Sasco AJ, Adami HO, Lund E, et al. Breast cancer risk among women Journal of the National Cancer Institute. 2004;96(1):29-37. (1.08 (95% CI: 0.99, 1.17)). SRRs were not statistically significantly increased nor decreased for all other cancer sites. In stratified analyses, risks who start smoking as teenagers. Cancer Epidemiol Biomarkers Prev. 2005;14(1):61-6. Xue F, Willett WC, Rosner BA, Hankinson SE, Michels KB. Cigarette smoking and the incidence of Land SR, Liu Q, Wickerham DL, Costantino JP, Ganz PA. Cigarette smoking, physical activity, and breast cancer. Arch Intern Med. 2011;171(2):125-33. of cancer were no longer increased for workers employed after 1960, including for cancer sites that showed a statistically significant increased alcohol consumption as predictors of cancer incidence among women at high risk of breast cancer risk when all studies were considered. in the NSABP P-1 trial. Cancer Epidemiol Biomarkers Prev. 2014;23(5):823-32. Risk of bladder cancer, lung cancer, larynx cancer and leukaemia were increased among workers in the rubber manufacturing industry. However, elevated risks were no longer seen among workers first employed after 1960. The cohort study of workers employed in the European rubber manufacturing industry since 1975 found no increased risk of cancer incidence or cancer mortality. As these cohorts are relatively young, continued surveillance is required for confirming the absence of long-term risk. In addition, confirmation from other cohorts would be useful.

iPRI 39 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Results of meta-analyses on occupational exposure to rubber manufacturing industry and risk of cancer, results presented for each cancer site. Observed deaths and standardised mortality ratios (SMRs) among 38,457 workers first employed in the European rubber manufacturing industry since 1975, by gender. Statistically significant associations are in bold. All* 0.97 [ 0.92 , 1.02 ] Bladder* 1.36 [ 1.18 , 1.57 ] Men Women Combined Lung* 1.08 [ 0.99 , 1.17 ] Cause of deaths Observed SMR (95% CI:) Observed SMR (95% CI:) Observed SMR (95% CI:) Stomach 1.06 [ 0.95 , 1.17 ] Leukaemia* 1.29 [ 1.11 , 1.52 ] Primary outcomes Hodgkin's disease 1.30 [ 0.78 , 2.16 ] Bladder cancer 16 0.87 (0.49, 1.52) 1 0.36 (0.06, 2.29) 17 0.80 (0.46, 1.38) Non−Hodgkin's Lymphoma 0.98 [ 0.77 , 1.24 ] Lung cancer 157 0.80 (0.68, 0.94) 29 0.91 (0.61, 1.35) 186 0.81 (0.70, 0.94) Multiple Myeloma 1.05 [ 0.82 , 1.35 ] Secondary outcomes Lymphatic and haematopoeitic system NOS 1.16 [ 1.02 , 1.31 ] All cancers 582 0.81 (0.74, 0.88) 187 0.83 (0.72, 0.97) 769 0.81 (0.76, 0.87) Gallbladder* 1.91 [ 0.97 , 3.77 ] Liver 0.96 [ 0.79 , 1.17 ] Stomach cancer 47 1.15 (0.84, 1.56) 10 1.23 (0.61, 2.46) 57 1.16 (0.88, 1.53) Bone and connective tissue 1.41 [ 0.62 , 3.22 ] Leukaemia 18 0.97 (0.58, 1.63) 4 0.76 (0.14, 4.02) 22 0.84 (0.53, 1.35) Brain and central nervous system 1.05 [ 0.88 , 1.25 ] Non-Hodgkin’s 14 0.74 (0.40, 1.37) 4 0.85 (0.28, 2.57) 18 0.79 (0.47, 1.34) Head and Neck* 1.12 [ 0.89 , 1.42 ] lymphoma Oesophagus* 1.10 [ 0.83 , 1.44 ] Multiple myeloma 12 1.55 (0.81, 2.98) 4 1.68 (0.56, 5.11) 16 1.54 (0.89, 2.68) Colon 1.03 [ 0.93 , 1.14 ] Exploratory outcomes** Rectum 1.05 [ 0.93 , 1.18 ] Colorectum 1.01 [ 0.95 , 1.07 ] All causes of death 2,259 0.80 (0.71, 0.89)* 466 0.86 (0.78, 0.94) 2725 0.81 (0.73, 0.89)* Digestive system NOS 1.00 [ 0.93 , 1.06 ] Cardiovascular 655 0.80 (0.71, 0.90) 110 0.75 (0.61, 0.90) 765 0.79 (0.70, 0.89) Larynx* 1.46 [ 1.10 , 1.94 ] diseases Pleura/mesothelioma* 2.11 [ 0.42 , 10.47 ] Respiratory 68 0.93 (0.72, 1.19) 12 0.74 (0.38, 1.42) 80 0.90 (0.71, 1.13) Melanoma 0.76 [ 0.44 , 1.30 ] diseases excluding Non−Melanoma skin 0.85 [ 0.63 , 1.13 ] pneumonia Pancreas 0.96 [ 0.87 , 1.05 ] Brain and central 33 0.95 (0.66, 1.39) 9 0.99 (0.46, 2.14) 42 0.96 (0.69, 1.34) Kidney 0.98 [ 0.83 , 1.15 ] nervous system Thyroid 2.03 [ 0.80 , 5.15 ] cancer Prostate 0.94 [ 0.83 , 1.07 ] Colorectal cancer 39 0.61 (0.44, 0.86) 20 1.16 (0.71, 1.91) 59 0.72 (0.55, 0.94) Testis 0.59 [ 0.18 , 2.00 ] Kidney cancer 18 0.83 (0.49, 1.38) 3 - 21 0.82 (0.51, 1.32) Other Male Genital 0.92 [ 0.69 , 1.23 ] Breast 0.93 [ 0.74 , 1.18 ] Larynx cancer 17 1.18 (0.69, 2.04) 0 - 17 1.12 (0.65, 1.93) Body of uterus* 1.04 [ 0.20 , 5.36 ] Liver cancer 15 0.73 (0.40, 1.31) 2 - 17 0.69 (0.40, 1.20) Cervix 0.77 [ 0.40 , 1.45 ] Melanoma 11 0.88 (0.45, 1.71) 1 - 12 0.68 (0.36, 1.28) Ovary 0.89 [ 0.60 , 1.30 ] Oesophagus 23 0.90 (0.57, 1.41) 1 - 24 0.84 (0.54, 1.30) Oral cavity and 23 0.97 (0.62, 1.53) 1 - 24 0.92 (0.59, 1.43) pharynx 0.50 0.75 1.00 1.50 2.00 2.50 Pancreas cancer 33 0.93 (0.64, 1.36) 13 1.31 (0.70, 2.44) 46 0.98 (0.72, 1.35) SRR with 95% CI Prostate cancer 26 0.79 (0.52, 1.21) - - - - *: statistically significant heterogeneity between studies Breast cancer 1 - 36 0.86 (0.60, 1.23) - - Cervical cancer - - 17 1.25 (0.74, 2.10) - - Ovarian cancer - - 12 0.73 (0.38; 1.40) - -

* Significant heterogeneity between the five countries (p<0.05). ** Results of exploratory analysis with less than five deaths observed were not reported.

iPRI 41 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Observed cases and standardised incidence ratios (SIRs) among 16,026 workers first employed in the European Chemotherapeutic Waste Disposal rubber manufacturing industry since 1975, by country. Statistically significant associations are in bold. emarkable efforts continue to be made to and potentially the general public from exposure to Sweden (N=7,424; PY=174,767) United Kingdom (N=8,602; PY=223,208) Combined (N=16,026; PY=397,975) Ridentify human carcinogens which are causes cancer causing chemicals relates to the excretions Cancer sites Observed SIR (95% CI:) Observed SIR (95% CI:) Observed SIR (95% CI:) of cancer in men and women. Once such causes of patients who are receiving chemotherapy. Some Primary outcomes have been identified, steps can be taken to avoid of these excretions, whether in sweat, urine, vomit Bladder 23 1.15 (0.73, 1.72) 22 0.68 (0.42, 1.02) 45 0.88 (0.61, 1.28) the exposure of populations wherever possible. An or faeces contain identified carcinogens and little Lung 30 0.78 (0.63, 1.34) 52 0.72 (0.53, 0.94) 82 0.74 (0.59, 0.93) important topic in protecting cancer patients, carers attention has been given to such exposures. Secondary outcomes All cancers combined 409 0.90 (0.81, 0.99) 437 0.76 (0.69, 0.85) 846 0.83 (0.74, 0.92)* (except skin) Chemotherapy drugs have been proven to cause second primary neoplasms in patients receiving them and once this had been iden- Stomach 8 0.87 (0.37, 1.71) 16 0.97 (0.55, 1.57) 24 0.93 (0.61, 1.43) tified, steps were initially introduced to avoid exposure to medical personnel in the preparation and delivery of these compounds. Leukaemia 4 0.34 (0.09, 0.88) 15 0.96 (0.54, 1.58) 19 0.79 (0.48, 1.28) Many drugs are used to treat cancer and over 20 chemotherapy drugs, including widely used agents such as cyclophosphamide, Non-Hodgkin’s 10 0.64 (0.31, 1.18) 18 0.69 (0.41, 1.08) 28 0.67 (0.45, 1.00) doxorubicin, 5-FU and etoposide, cause patients receiving them to excrete identified human carcinogens in vomit, sweat, urine or lymphoma faeces. Multiple myeloma 1 0.19 (<0.01, 1.04) 8 1.04 (0.45, 2.05) 9 0.92 (0.44, 1.91) Exploratory outcomes** With the cancer burden increasing with the ageing of the population and the increasing tendency to give patients chemotherapy Brain and central 15 0.90 (0.50, 1.49) 10 0.65 (0.31, 1.20) 25 0.79 (0.52, 1.21) nervous system as out-patients, the potential for increasing numbers of individuals to be exposed to carcinogens in excreted material is increasing Colon, rectum and 48 1.06 (0.78, 1.41) 37 0.55 (0.39, 0.75) 85 0.77 (0.49, 1.22)* also. It is of considerable concern that systems for the collection of this carcinogenic waste outside the hospital environment are to anus the largest extent unavailable. Kidney 11 0.87 (0.43, 1.55) 16 0.85 (0.49, 1.39) 27 0.86 (0.57, 1.29) Larynx 3 - 7 0.91 (0.37, 1.87) 10 0.98 (0.49, 1.96) Guidelines have been prepared for hospitals, oncology doctors and nurses and cancer drug producers to avoid or minimise their Melanoma 39 1.30 (0.92, 1.78) 12 0.43 (0.22, 0.75) 51 0.79 (0.37, 1.70)* exposure to these carcinogenic risks. When patients are sent home following treatment, advice is given to restrict use to one Oesophagus 4 - 14 0.82 (0.45, 1.37) 18 0.84 (0.51, 1.39) specified toilet to the patient or, if not possible, to ‘flush’ twice. This will reduce the exposure to patients and their carers but will Oral cavity and 13 1.18 (0.63, 2.02) 19 0.93 (0.56, 1.44) 32 1.02 (0.71, 1.48) pharynx not eliminate the potential exposure. In addition, it could be foreseen that there are circumstances in which failure to deal with this Pancreas 8 0.88 (0.38, 1.74) 9 0.72 (0.33, 1.37) 17 0.80 (0.47, 1.34) source of carcinogens could lead to wider exposure in communities. Prostate 70 0.80 (0.63, 1.02) 53 0.72 (0.54, 0.94) 123 0.77 (0.64, 0.92) Testis 13 1.26 (0.67, 2.16) 11 0.61 (0.32, 1.04) 26 0.87 (0.53, 1.45) Every step needs to be taken to reduce exposure to all known cancer causing agents. It is essential to pay more attention to the Breast 51 0.82 (0.60, 1.08) 38 1.04 (0.67, 1.29) 89 0.91 (0.73, 1.13) protection of care givers and the environment. Many types of chemotherapy excrete identified human carcinogens in the hours Endometrial 6 0.69 (0.25, 1.50) 5 1.00 (0.32, 2.33) 11 0.82 (0.42, 1.58) and days following treatment (e.g. adriamycin), in sweat, faeces, urine or vomit exposing care-givers to these dangerous chemicals. Ovary 9 1.14 (0.52, 2.16) 7 1.23 (0.50, 2.54) 16 1.18 (0.69, 2.02) In hospital there are special procedures for dealing with such hazardous waste but these do not exist in the home environment. * Significant heterogeneity between the two countries (p<0.05). General advice such as ‘restrict use of one toilet to the cancer patient’ or ‘flush twice’ do not solve the problem. Apart from posing a ** Results of exploratory analyses with less than five cases observed were not reported. threat to care givers and family members, these hazardous chemicals enter into our sewage systems and general environment and have been doing so on a daily basis for several decades. Disclosure: The study was partially funded by an unrestricted research grant from the European Tyre and Rubber Manufacturers’ Association (ETRMA) and was conducted and reported in full independence from the sponsor. Preventing these chemicals from posing a threat to care givers and entering our waterways and water supply must be an issue of paramount importance. The medical profession, the insurance industry, the pharmaceutical companies and politicians must join forces to fight this cause of human suffering on all fronts. Boniol M, Koechlin A, Boyle P. Meta-analysis of occupational exposures in the rubber-manufac- IARC. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 28: The Rubber turing industry and risk of cancer. Int J Epidemiol. 2017a;(submitted). Industry. Lyon, France: International Agency for Research on Cancer; 1982. Boniol M, Koechlin A, Sorahan T, Jakobsson K, Boyle P. Cancer incidence in cohorts of workers in the IARC. The rubber industry. Overall Evaluations of Carcinogenicity: an Updating of IARC Monographs, rubber manufacturing industry first employed since 1975 in the UK and Sweden. Occup Environ Volumes 1 to 42, Suppl 7. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans. Med. 2017b;(in press). Lyon, France: International Agency for Research on Cancer; 1987. p. 332-4. Boniol M, Koechlin A, Swiatkowska B, Sorahan T, Wellmann J, Taeger D, et al. Cancer mortality in IARC. Occupational exposures in the rubber-manufacturing industry. Chemical Agents and Related cohorts of workers in the European rubber manufacturing industry first employed since 1975. Ann Occupations. IARC Monographs on Evaluation of Carcinogenic Risks to Humans. 100F. Lyon, France: Oncol. 2016;27(5):933-41. International Agency for Research on Cancer; 2012. p. 541-62.

iPRI 43 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Cancer Scenarios in Scotland Ratio of predicted over observed incidence and mortality age standardised rates, for 17 cancer sites in men, for 4 time periods. Cancer sites are listed in increasing order of number of observed new cases for the period 2010-2014. n 2001, NHS Scotland published a report on mortality rates for 19 cancers would change in the I“Cancer Scenarios”, designed as an “aid to planning following years. Fifteen years after the publication cancer services in Scotland in the next decade” of that report, observed incidence and mortality (Scottish Executive Health Department, 2001). data have become available, and an assessment of The authors made predictions of how incidence and the predictions made previously was timely.

Observed incidence and mortality data for each of the cancers concerned were down- loaded from ISD Scotland (Information Services Division) website. Observed absolute numbers of new cancer cases and deaths, as well as age-standardised incidence and mortality rates were compared to predicted ones.

Incidence rates in men were mostly underestimated, with colorectal and kidney cancers being accurately predicted. Similar results were observed for mortality rates in men: most cancers were underestimated, with head and neck cancers, oesophageal and stomach cancers being accurately predicted (see top figure).

Incidence rates in women were mostly underestimated, with colorectal, breast and ovarian cancers being accurately predicted. The accuracy of mortality rates’ predictions in women was cancer site-dependent; for some cancers mortality rates were underestimated, while for others Ratio of predicted over observed incidence and mortality age standardised rates, for 19 cancer sites in women, for 4 time overestimated, with oesophageal and stomach cancer mortality being accu- periods. Cancer sites are listed in increasing order of number of observed new cases for the period 2010-2014. rately predicted (see bottom figure).

A large relative deviation from one of the ratio predicted/observed, could mean a small variation in terms of absolute numbers, for cancers with a low number of cases and deaths. Reversely, a small deviation from 1 of the ratio predicted/observed could mean a large variation in terms of absolute numbers, for cases with high numbers of cases and deaths.

For three cancer sites – non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and leukaemia in adults – assessment of the accuracy of the predictions was not feasible, due to important discrepancies between the predicted and observed databases for the observed period of 1990- 1994, which was used as control. Bladder cancer assessment was also hindered, by coding changes implemented after the projections were made. These coding changes led to a reclassification of invasive bladder cancers, and an artificial reduction of the incidence of bladder cancer.

The accuracy of the projected incidence and mortality rates was variable across cancers and genders, and it was generally poorer for predictions further in time (as is to be expected with future projections models). However, an important point to keep in mind is that projections can indicate possible future outcomes for current trends and how these may potentially be influenced by policies and interventions. By having sufficient notice and knowledge, these outcomes can be influenced through actions meant for improvement, so that even if originally projected outcomes are not realised, the projections’ Scottish Executive Health Department. Cancer Scenarios: An aid to planning cancer services in purpose can be considered fulfilled if they have led to changing an undesirable outcome. The Cancer Scenarios project in Scotland Scotland in the next decade. Executive. ETS; 2001. has helped better orient Scotland’s cancer plan and has led to continued projections, evaluations and updates.

iPRI 45 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Diabetes

Diabetes and Pancreas Cancer

ancreas cancer is the 12th most common type and the older age of patients which represents Pof cancer in the world with men being more an obstacle to surgery. Moreover, there is a lack affected than women. Disparities in pancreas cancer of primary prevention that would act on modifi- Diabetes is sneaking up on the world, incidence prevail around the world with developed able risk factors and no early detection through a countries more affected than developing countries. screening of people at risk for this cancer. Thereby, one step at a time. While policy- Pancreas cancer is a poor prognosis cancer with there is an important need to know the aetiology of a 5-year survival rate below 10% that is mostly pancreas cancer to improve the current situation. makers have been paying attention explained by the advanced stage at diagnosis Recent meta-analyses suggested that primary prevention should focus on modifiable risk factors such as smoking, alcohol consump- to communicable diseases and, tion and adiposity. Moreover, other meta-analyses suggested higher surveillance of people with a family history of pancreas cancer or with a history of gallbladder diseases as well as the eradication of HBV and HCV infections in Asian and African countries in order at best, cancer, diabetes has been to control the burden of pancreas cancer. steadily invading populations both in The association between diabetes, pancreatitis and pancreatic cancer has been long studied and several studies suggested that diabetes and pancreatitis would be the strongest risk factors of pancreas cancer. If these relations are true, early diagnosis of developed and developing countries. pancreas cancer could be made through the screening of diabetic people and people with a history of pancreatitis. In order to clarify the association between diabetes and its medication, pancreatitis and the risk of pancreas cancer, a series of systematic reviews and Indeed, Diabetes is poised to become meta-analyses were undertaken. the world’s leading chronic disease. Regarding diabetes and the risk of pancreas cancer, 64 cohort studies were included in our meta-analysis and the summary relative risk (SRR) of pancreas cancer in patients with diabetes was 1.94 (95% CI: 1.77, 2.12) with a large degree of heterogeneity between In light of this, iPRI has increased studies (I2=97%, p<0.01) and some evidence of publication bias. When the effect modification by duration of diabetes was investigated, a higher increased risk was observed in studies with the shortest history of diabetes and lower risk was observed in studies with a longer duration of diabetes but the association remained statistically significant with a SRR of 1.36 (95% CI: 1.19, 1.55) for its commitment to providing the more than ten years of diabetes duration (Batabyal et al, 2014). This result suggests that diabetes could be the initial presentation of pancreas cancer. evidence and guidance required to Regarding pancreatitis and the risk of pancreas cancer, 29 cohort studies were included in our meta-analysis on all forms of pancrea- spur effective actions and policies. titis and the SRR of pancreas cancer in patients with a history of pancreatitis was 9.72 (95% CI: 6.01, 15.73) with a large degree of heterogeneity between studies (I²=93%, p<0.0001) and no evidence of publication bias. The restriction of the analysis to acute or unspecified pancreatitis gave a lower effect with a SRR of 5.15 (95% CI: 4.13, 6.41) while the restriction to chronic pancreatitis gave a stronger association with a SRR of 11.68 (95% CI: 5.19, 26.26) with still large degree of heterogeneity in both sub-analyses. Moreover, several studies reported a higher risk within the first year of diagnosis of acute pancreatitis and suggested that acute pancreatitis could be an initial presentation of pancreas cancer.

As diabetes and pancreatitis are both strong risk factors for pancreas cancer, a meta-analysis of the risk of pancreatitis among diabetic patients was performed. Eight independent observational studies were selected for the analysis and a statistically significant 2-fold increased risk of pancreatitis was found in patient with diabetes (SRR=1.94 (95% CI: 1.61, 2.35), with a large amount of heterogeneity between studies (I²=93%, p<0.01) and no evidence of publication bias.

47 iPRI - International Prevention Research Institute — Principal Contributions iPRI

As diabetes is associated with a 2-fold increased risk of pancreatitis and pancreas cancer, one would say that these increased risk are driven by anti-diabetic treatments (ADT), therefore this hypothesis was investigated in several meta-analyses. Retinopathy and Eye Light

Based on published meta-analyses, Sulphonylureas and insulin treatments appeared to significantly increase the risk of pancreas iabetic Retinopathy (DR) is a complication of with Diabetes will develop DR. The International cancer. Sulphonylureas were significantly associated with a 70% (SRR=1.70 (95% CI: 1.27, 2.28)) (Singh et al, 2013) increased risk of DDiabetes Mellitus, which affects the eye. As one Diabetes Federation (IDF) states that the number of pancreas cancer in observational studies but this result was no longer significant in randomized controlled trials (RCTs). The effect of the major causes of visual impairment in the world people living with diabetes is expected to rise from of insulin seems to be stronger as meta-analyses reported a significant 2.5 fold increased risk of pancreatic cancer (SRR=2.66 (95% it is a major Public Health challenge. Any patient with 415 million (2015) to 642 million by 2040 (+ 54%) CI: 2.07, 3.43)) (Bosetti et al, 2014). However, when the analysis was stratified by duration of use, the association was stronger for a diabetes is at risk, regardless of the type of Diabetes if no urgent action is taken (International Diabetes shorter insulin use (<5y) but declined with increasing duration of use and became not significant after 10y of use. (I or II). On average, more than 25% of patients Federation, 2015).

Inversely, Metformin seems to reduce the risk of pancreas cancer but most of the results remained statistically non-significant. Diabetic Retinopathy results from damage to the small blood vessels of the retina (i.e. the fundus of the eye) through changes in the blood flow. Generally, Retinopathy has no symptoms until it is advanced because damage to the blood vessels is the direct cause of Regarding Thiazolidinediones, no association with pancreas cancer was found neither in observational studies nor in RCTs. blindness but its consequence around the macula, the seeing part of the eye.

Concerns have been raised on the potential association between incretin-related therapies and the risk of developing pancreatitis, which could result in an increased risk of pancreas cancer. Hence, meta-analyses were undertaken in order to assess the risk of Lesions of Diabetic Retinopathy and anatomy of the eye in a colour fundus image pancreatitis and pancreatic cancer associated with the use of incretins compared to the use of other anti-diabetics treatment. Based Hard Exudates on 19 observational studies, a borderline significant increased risk of pancreatitis (SRR=1.31 (95% CI: 1.01, 1.70)) was observed in The only way to prevent people with diabetes from becoming blind is users of incretins compared to non-users with a large amount of heterogeneity (I2 =89%, p-value<0.05) and some evidence of publi- with regular screening of their eye fundus, consisting of an examination Optic Disk cation bias. However, this association was no longer significant when the analysis was conducted by type of incretins (e.g. GLP-1RAs of their eye fundus and a visual assessment test. Direct ophthalmoscope and DPP-4 inhibitors). Pancreas cancer risk was investigated in nine prospective studies and the SRR in incretin users was 1.23 (95% or digital colour photographs of the retina are the methods used for first Microaneurysm CI: 0.88, 1.73) with significant heterogeneity between studies (I2 =81%, p-value<0.0001) and no indication of publication bias. line screening (see figure). Then, a severity grade is given by trained staff. Macula In case of a severe stage, the patient must be referred to an ophthal- As mentioned earlier, new-onset of diabetes may be a manifestation of early pancreas cancer, and this can potentially confound mologist for further examination and treatment. Good glucose, blood an association between anti-diabetic treatments and pancreas cancer. Thereby, these results must be interpreted with caution and pressure and cholesterol control can also reduce the risk of developing long term RCTs with large sample size especially design to detect long term outcomes should be needed for establishing causality. sight-threatening complications. Haemorrhage + Cotton wool spot

In this study, we demonstrated that early diagnosis of pancreas cancer through screening of diabetic people or people with a Remote screening programmes fo patients with Diabetes have been in history of pancreatitis may be an important advancement in the control of pancreas cancer. However, further studies are need to existence for some years in countries such as in Wales where every diabetic patients over the age of 12 is registered in the Diabetic Eye clarify if diabetes and pancreatitis are consequences or causes of pancreas cancer. Screening Service for Wales (DESW) programme. For every patient four images of the retina (two per eye) are taken and sent to the screening service where graders give them a severity mark and decide if the patient must be referred to an ophthalmologist.

Batabyal P, Vander Hoorn S, Christophi C, Nikfarjam M. Association of diabetes mellitus and pancre- Singh S, Singh PP, Singh AG, Murad MH, McWilliams RR, Chari ST. Anti-diabetic medications and As the grading is based on eye fundus images, their quality is essential. However, a significant number of images can have strong contrast atic adenocarcinoma: a meta-analysis of 88 studies. Ann Surg Oncol. 2014;21(7):2453-62. risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis. variation (due to the geometry of the eye or the acquisitions conditions). This can be a limiting factor for the diagnosis of the disease. Bosetti C, Rosato V, Li D, Silverman D, Petersen GM, Bracci PM, et al. Diabetes, antidiabetic medica- Am J Gastroenterol. 2013;108(4):510-9; quiz 20. tions, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Currently to address this problem, graders have to manually adjust their contrast. Consortium. Ann Oncol. 2014;25(10):2065-72. We have initiated a research project to improve diagnosis of Diabetic Retinopathy. First of all, it is necessary to standardize contrast across the entire image. A fully automatic method, based on image processing, evens the contrast of dark and bright elements across the entire image. This method is much more powerful than the state of the art methods used now for grey scale images.

Our method has been tested on more than 2000 images acquired from different screening services and taken under different conditions both in high- and low-income countries. Some images were bright, while others were dark. For all images, the contrast has been enhanced for lesions such as micro-aneurysms and the vascular structures (see figure below). The lesions are now easier to detect by graders.

The results obtained are very promising. Our method will vastly improve the diagnosis of Diabetic Retinopathy and other lesions in colour eye fundus images. Indeed, the lesions become far more evident in comparison of the original image. Importantly, our method is fully automated and can easily be integrated in the screening system.

iPRI 49 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Comparison between original and enhanced images acquired both in good and in harsh conditions White Paper on Diabetes Epidemiology

Original image – acquired in optimal conditions Enhanced image e have put together an updated review of the related to diabetes mellitus, awaiting publication as Wresearch done on the most relevant topics the ‘White Paper on the Epidemiology of Diabetes’.

Diabetes is a collection of disorders characterised by hyperglycaemia and glucose intolerance, due to either lack of insulin in the body, or to the body’s inefficient way of using it. Morbidity and mortality from diabetes arise from a large list of complications associated with diabetes and they represent a large burden to the public health sector.

Burden of Diabetes

Type 1 diabetics represent about 5% of the diabetic population, while type 2 diabetes mellitus (T2DM) represents the grand majority with 90% to 95% of diabetics. The incidence and prevalence estimates were found to be highly heterogeneous. The global prevalence of both forms of diabetes mellitus (DM) combined varied approximately between 5% and 11% on average, between regions. A higher prevalence of DM among older populations and in urbanized areas was observed. A large proportion of people living with diabetes mellitus remains undiagnosed, especially in low and middle income countries. Evidence points to an increasing trend of Original image – acquired in harsh conditions Enhanced image T2DM among children and adolescents. In 2012, an estimated 1.5 million deaths were directly caused by diabetes (T1DM and T2DM combined), more than 80% of which occurred in low- and middle-income countries. Aetiology of diabetes: Type 1 diabetes has a strong genetic component, although other risk factors have been identified such as Enterovirus infection and Non-Hispanic White ethnicity. No difference in T1DM risk was observed by gender and the evidence regarding the association between physical activity and nutrition and T1DM has been inconsistent so far. Well established risk factors that are known to increase the risk of T2DM are family history of diabetes, increasing age, obesity, ethnicity and low socio-economic status. Healthy dietary patterns and all types of physical activity were found to be protective factors for T2DM, while unhealthy dietary patterns, sedentary time and smoking significantly increased the risk of T2DM. Among potential risk factors, depression, vitamin D status, and sleep disorders all increased significantly the risk of T2DM.

Epidemiology of Complications from Diabetes

The main complications under review were acute complications – hypoglycaemia and ketoacidosis – and microvascular, long-term complications - neuropathy (nerve damage), retinopathy (eye damage) and nephropathy (kidney damage). Risk factors identified for hypoglycaemia were duration of diabetes (for T1DM) and older age and duration of insulin treatment (for T2DM). Diabetic Eye Light - Eye fundus colour images enhancement service for Diabetic Retinopathy diagnosis (www.i-pri.org/eye-light) has ketoacidosis (DKA) is mostly seen in T1DM patients. In children, at T1DM diagnosis, the prevalence of DKA varies between 12.8% in received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No Sweden and 80% in the United Arab Emirates. DKA at diagnosis of T2DM varies between 5% and 25%. Main causes of DKA recur- 717108. Guillaume Noyel, iPRI, has been coordinator of the project. An abstract and a poster were presented at the World Diabetes rences are (usually preventable) insulin treatment interruptions. The risk of developing diabetic neuropathy and retinopathy (DR) Conference 2015 of the International Diabetes Federation: (Noyel et al, 2015b). Other conference papers in image processing have increases with longer duration of diabetes. Diabetic peripheral neuropathy was generally more prevalent in T2DM than in T1DM been presented: (Noyel et al, 2015a, 2016). patients. The prevalence of DR was estimated to be higher in T1DM than in T2DM patients (77.3% vs 25.2%). Diabetic nephropathy (DN) affects ~20-40% of diabetic patients. Microvascular long-term complications can be prevented and delayed through early detection and good glycaemic, blood tension and lipids control. International Diabetes Federation. IDF Diabetes Atlas. International Diabetes Federation,, 2015. Noyel G, Jourlin M, editors. Spatio-colour Asplünd ‘s metric and Logarithmic Image Processing Noyel G, Jourlin M. Asplünd’s metric defined in the logarithmic image processing (LIP) framework for Colour Images (LIPC). CIARP2016 - XXI IberoAmerican Congress on Pattern Recognition; 2016 for colour and multivariate images. IEEE International Conference on Image Processing; Quebec 2016-11-08; Lima, Peru. City: IEEE; 2015a. p. 3921-25. Noyel G, Jourlin M, Thomas R, Bhakta G, Crowder A, Owens D, et al. Contrast enhancement of eye Diabetes and Risk of Cancer fundus images. IDF 2015; Vancouver2015b. The relative risks of diabetic patients compared to non-diabetics were two fold or higher for cancers of the endometrium, liver and pancreas. Prostate cancer appeared to be less present in diabetic men. Lung and thyroid cancer did not seem to be associated with

iPRI 51 iPRI - International Prevention Research Institute — Principal Contributions iPRI

diabetes. Bladder cancer, breast cancer, colorectal, gallbladder and biliary tract cancer, gastric cancer, and renal cancer were more present in diabetics than in non-diabetics, but the evidence was inconclusive. Overall studies showed a substantial risk of bias and Diabetes Treatments and Cancer Risk high heterogeneity among results, representing a major limitation in the interpretation of the results. hile T1DM patients need lifelong insulin severity, which is then followed by an increase in the Wtherapy, patients with T2DM advance in a use of hypoglycemic therapy. The selection of an Diabetes and Risk of Cardiovascular Disease progressive way, which usually starts from a pre- appropriate decision on the type of therapy is under diabetic state characterised by hyperinsulinaemia continuous discussion between patients and their Diabetes is an established risk factor for cardiovascular disease. For all outcomes considered (cardiovascular mortality, coronary to diabetes itself which is characterised by constant doctors, based on risks and benefits specific to each heart disease and stroke), the risk associated with diabetes was approximately doubled in type 2 diabetic patients, and multiplied insulin resistance and a progressive reduction in patient. by eight in type 1 diabetic patients. The risk of cardiovascular diseases was more marked among women than among men, and also insulin secretion. This results in an increase in disease in younger subjects and in non-smokers. Diabetes and other disorders: Evidence indicated that patients with diabetes had a higher risk of an episode of acute pancreatitis, of tuberculosis, of dementia and of depression. When diet and physical activity are no longer enough to control the hyperglycemia, patients need to start taking anti-diabetic medications (ADM), which are various and act at different levels of the glycemic pathway.

Gestational Diabetes Mellitus In order to quantify and have an overview of the available data on the possible associations between the use of treatments for diabetes and a potential excess risk of cancer in diabetic patients, an online literature search was carried out in PubMed (January Gestational diabetes mellitus is a condition in which women without previously diagnosed diabetes develop glucose intolerance 1966-July 2015) for all meta-analyses and pooled analyses evaluating the association between diabetic treatments (metformin, and insulin resistance during pregnancy. It usually occurs in the third trimester of pregnancy, and disappears after the baby is sulfonylureas (SU), thiazolidinedione (TZD), incretins or insulin) and the risk of cancer. Complementary manual searches were done delivered. Prevalence of GDM varied globally between ~2% and ~10% using older diagnostic criteria, and between ~10% and ~30% on the references of relevant publications. using recent diagnostic criteria. There are a series of non-modifiable risk factors which are associated with GDM: increasing gestational age, history of previous GDM, family history of DM, hypertension, history of macrosomic pregnancies, history of poor obstetric Metformin is often the therapy of choice for the first line treatment. Its primary mode of action is by re¬ducing hepatic glucose outcomes, increasing body height, as well as modifiable risk factors such as: overweight and obesity, weight gain during pregnancy output, therefore reducing the blood levels of circulating glucose and insulin. Although the underlying mechanisms are not known, and higher intake of fat. Gestational diabetes is associated with perinatal and neonatal complications such as macrosomia and pre- results from a growing number of observational studies suggest that metformin would reduce the risk of developing cancer. eclampsia. Women who had GDM have an increased risk of developing T2DM after delivery. However, results should be interpreted From Gandini et al (2014) with care given the highly heterogeneous nature of the diagnostic criteria, both for gestational diabetes and for the complications. • 25 cohort studies, 16 case-control studies, 6 randomized trials In addition, the variation in research protocols and in the gestational care among countries, and in time, limit even more the compa- • 65,504 cases of cancer, 1,177,857 subjects rability and interpretation of studies of GDM. • SRR for cancer incidence: 0.69 (95% CI: 0.52, 0.90) • SRR for cancer mortality: 0.66 (95% CI: 0.54, 0.81) This White Paper on the state of the knowledge on the epidemiology of diabetes mellitus has provided up-to-date estimates of the • SRR for cancer incidence from randomized clinical trials: 0.95 (95% CI: 0.69, 1.30) current global burden of diabetes and its complications, has reviewed the evidence on the potential associations between diabetes Metformin appears to reduce the risk of cancer, but this needs to be verified by randomized clinical trials and other diseases and identified areas where further research is still needed. Sulfonylureas are another type of therapy for diabetes; they act by stimulating beta cells of the pancreas to produce insulin. From Wu et al (2015) Bota M, Pizot C, Koechlin A, Dragomir M, Macacu A, Franchi M, Valentini F, Coppens K, Noyel • SRR all studies: 1.20 (95% CI: 1.13, 1.27) G, d’Onofrio A and Boyle P. White paper. Epidemiology of diabetes. iPRI Technical Report 2015, International Prevention Research Institute, Lyon, France (2015) • SRR RCT: 0.91 (95% CI: 0.81, 1.02) • Among studies, results were very heterogeneous, and not conclusive

Thiazolidinediones are an insulin-sensitising class of drugs; to date, two drugs from this class are available: pioglitazone and rosiglitazone. Some suspicion of an associated increased risk of bladder cancer has been raised by a number of population based studies. There is strong evidence for an association between Thiazolidinedione (TZD) use and risk of bladder cancer and more precisely for Pioglitazone use: From Bosetti et al (2013) • 6,068 cases and 2,151,031 participants • SRR for TZD: 1.13 (95% CI: 1.05, 1.23) • SRR for Pioglitazone: 1.20 (95% CI: 1.07, 1.34) • SRR for Rosiglitazone: 1.08 (95% CI: 0.95, 1.23) Regarding other cancer sites or all cancer combined, no association was found between TZD use and cancer risk.

iPRI 53 iPRI - International Prevention Research Institute — Principal Contributions iPRI

The incretin based therapies act by improving glucose-dependent insulin secretion. Two types of drugs are available on the market: reporting a change in FBG or HbA1c were considered eligible. Both studies not reporting a physical activity contrast between glucagon-like peptide 1 receptor agonists (GLP1 RA) and dipeptidyl-peptidase-4 inhibitors (DPP-4). The recent arrival on the market groups and those including differential co-interventions (e.g. diet, medication, etc.) between study groups were excluded. of these drugs makes it impossible to report their potential association with cancer. Consequently, data on this subject is scarce, conflicting and of poor quality. Further studies are need in order to establish causality between incretin based therapies and risk of Mixed-effects random models were used to compute the change of FBG (mg/dL) and HbA1c (%) associated with an increase of 100 cancer. minutes of physical activity per week, allowing the inclusion of more than two exposure groups per study and therefore, accounting for inter- and intra- study variability. When possible, i.e. when convergence of the model was met, a random effect was employed Insulin is required by all T1DM patients and many of the late stages T2DM patients. It is available in a wide variety of formulations: on both intercept and slope of each study (random model); in the contrary case, a random effect on slope and a fixed-effect of long acting, medium acting, and short acting. Concerns for an increased risk of cancer among diabetic patients using insulin have intercept was computed (fixed intercept model). Heterogeneity across studies was assessed with the ratio of the standard error of been raised in the recent past. However, none of the concerns have been validated by epidemiological studies free of bias and fixed intercept and random models, reflecting the amount of heterogeneity explained by inter-study variability. Publication bias confounding. was evaluated by means of visual inspection of funnel plots and with the Macaskill test. Insulin therapy may increase the risk of several cancer compared with other antidiabetic medication: • SRR for colorectal cancer: 1.69 (95% CI: 1.25, 227) (Bu et al, 2014) Stratified analyses were carried out according to several population or intervention characteristics. Conjointly, meta-regressions • SRR for pancreatic cancer: 2.66 (95% CI: 2.07, 3.43) (Bosetti et al, 2014) were computed to test if these characteristics interacted significantly with changes in FBG and HbA1c associated with physical • SRR for hepatocellular cancer: 2.61 (95% CI: 1.46, 4.65) (Singh et al, 2013) activity. Sensitivity analysis were performed according to publication year, study size, outcome data completeness and existence of • SRR for lung cancer: 1.23 (95% CI: 1.10, 1.35) (Wu et al, 2014) a co-intervention, etc. • SRR for all cancer: 1.21 (95% CI: 1.08, 1.36) (Wu et al, 2015) • An increased risk was also suggested for stomach, kidney and respiratory cancers A total of 125 independent studies were included in the meta-analysis. For FBG, based on 105 studies, an increase of 100 minutes SRR for cancer incidence failed significance when the analyses were restricted to cohort studies or RCT hence there is a need of new of physical activity per week was associated with an average change of -2.75mg/dl of FBG (95%CI -3.96, -1.55) (see figure), with studies (RCT and/or cohorts) to clarify the situation. high heterogeneity (83.5%). When the analysis was restricted to type 2 diabetes and prediabetes subjects (56 studies), the average change in FBG was significantly higher, respectively -4.71 mg/dl (95% CI: -7.42, -2.01).

Based on 76 studies reporting data on HbA1c, each additional 100 minutes of physical activity per week were associated with an Bosetti C, Rosato V, Buniato D, Zambon A, La Vecchia C, Corrao G. Cancer risk for patients using Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepa- average change of -0.14% of HbA1c (95% CI: -0.18, -0.09) (see figure). High heterogeneity (73%) between studies was observed and thiazolidinediones for type 2 diabetes: a meta-analysis. Oncologist. 2013;18(2):148-56. tocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol. 2013;108(6):881- the inspection of funnel plot and the Macaskill test suggested publication bias (p<0.001): smaller studies seemed to be published Bosetti C, Rosato V, Li D, Silverman D, Petersen GM, Bracci PM, et al. Diabetes, antidiabetic medica- 91; quiz 92. tions, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Wu L, Zhu J, Prokop LJ, Murad MH. Pharmacologic Therapy of Diabetes and Overall Cancer Risk and more often when reporting positive results. Similarly to FBG, when restricting the analysis on type 2 diabetes and prediabetes Consortium. Ann Oncol. 2014;25(10):2065-72. Mortality: A Meta-Analysis of 265 Studies. Sci Rep. 2015;5:10147. subjects (60 studies), the decrease in HbA1c was significantly higher, respectively-0.16% (95% CI: -0.21, -0.11). Bu WJ, Song L, Zhao DY, Guo B, Liu J. Insulin therapy and the risk of colorectal cancer in patients with Wu Y, Liu HB, Shi XF, Song Y. Conventional hypoglycaemic agents and the risk of lung cancer in type 2 diabetes: a meta-analysis of observational studies. Br J Clin Pharmacol. 2014;78(2):301-9. patients with diabetes: a meta-analysis. PLoS One. 2014;9(6):e99577. Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, et al. Metformin and For both FBG and HbA1c, pooled estimates did not vary when the analysis was stratified by gender, study duration, age or BMI, and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and heterogeneity remained high in all sub-group analyses. Also, most sensitivity analyses did not alter the results; however, differences Confounders. Cancer Prev Res (Phila). 2014;7(9):867-85. in pooled estimates were observed when stratifying by study size. Slightly higher decreases were observed in larger studies (>40 subjects) for FBG, and in smaller studies for HbA1c, but meta-regressions showed no statistically significant difference (see table).

The associations between physical activity and decreases of FBG and HbA1c were independent of the type, duration or intensity of physical activity. Nevertheless, slightly larger reductions for both FBG and HbA1c were observed in interventions with supervised Diabetes and Physical Activity physical activity when compared to unsupervised interventions. This difference was however not statistically significant for FBG (p=0.20 test for interaction), while it was for HbA1c (p=0.01 test for interaction). ohort studies suggest a positive impact of al, 2007; Sigal et al, 2014). However, the roles of Cphysical activity in decreasing the risk of the type and intensity of physical activity remain The observation of a constant impact of physical activity on FBG and HbA1c irrespective of the type and intensity of the intervention diabetes (Ekelund et al, 2012; Grontved et al, 2014; unclear. The aim of this study was to quantitatively increases prospects for prevention. For diabetics encountering several barriers to the practice of physical activity, these results are Laaksonen et al, 2005; Weinstein et al, 2004). Also, evaluate the role of physical activity on changes in encouraging, suggesting that as long as the duration of physical activity is maintained, tailored interventions taking into account some intervention studies report decreases in fasting blood glucose (FBG) and glycated haemo- age, health condition and potential discomfort would still be proven effective. Increased physical activity should be, therefore, main diabetes markers (fasting blood glucose and globin (HbA1c) in different populations, including recommended strongly as an adjunct to any anti-diabetes therapy. glycated haemoglobin) with increasing physical people with type 2 diabetes and pre-diabetes. activity level (Balducci et al, 2010; Nishijima et

A systematic literature search and quantitative meta-analysis was conducted and reported following PRISMA guidelines for meta- analyses of interventional studies. Randomized trials of physical activity interventions with more than 1 week of follow-up and

iPRI 55 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Forest plot of the association between physical activity and change in fasting blood glucose Forest plot of the association between physical activity and change in fasting blood glucose

Change Change Study with 95% CI Study with 95% CI Almenning2015 0.4 [ 0.1 , 0.7 ] Kerling2015 0.0 [ −0.5 , 0.5 ] Kim2015 −0.1 [ −0.4 , 0.2 ] Mendham2015 −0.2 [ −0.3 , 0.0 ] Mendham2015 −0.2 [ −0.7 , 0.3 ] Natesan2015 −0.2 [ −0.3 , 0.0 ] Motahari−Tabari2015 −0.5 [ −1.3 , 0.2 ] Park2015 −0.2 [ −0.4 , 0.0 ] Vasconcellos2015 −0.3 [ −0.7 , 0.0 ] Vinetti2015 −0.3 [ −0.9 , 0.4 ] Tomas−Carus2015 −0.3 [ −0.4 , −0.1 ] Zou2015 −0.4 [ −0.8 , −0.1 ] Vinetti2015 −0.2 [ −0.3 , 0.0 ] Arciero2014 −0.5 [ −0.7 , −0.2 ] Zou2015 −0.1 [ −0.2 , 0.1 ] Geliebter2014 −0.3 [ −0.7 , 0.1 ] Herzig2014 −0.2 [ −0.7 , 0.2 ] Kanaya2014 −0.1 [ −0.2 , 0.1 ] Kanaya2014 −0.5 [ −1.3 , 0.2 ] Mitranun2014 −0.1 [ −0.4 , 0.1 ] Mitranun2014 −0.3 [ −1.3 , 0.6 ] Sigal2014 0.0 [ −0.1 , 0.1 ] Sigal2014 0.0 [ −0.1 , 0.2 ] Sousa2014 −0.5 [ −1.2 , 0.2 ] Sousa2014 −0.2 [ −0.4 , 0.0 ] Fritz2013 0.0 [ −0.1 , 0.2 ] Fritz2013 0.0 [ −0.1 , 0.0 ] Grieco2013 0.0 [ −0.3 , 0.3 ] Venojarvi2013 −0.1 [ −0.2 , 0.1 ] Trussardi Fayh2013 0.1 [ −0.3 , 0.5 ] McCormack2013 −0.1 [ −0.3 , 0.2 ] Choi2012 −0.1 [ −0.2 , 0.1 ] Ortega2013 −0.1 [ −0.3 , 0.1 ] Dobrosielski2012 −0.2 [ −0.3 , 0.0 ] Racil2013 0.0 [ −0.4 , 0.3 ] Venojarvi2013 0.1 [ −0.3 , 0.5 ] Gibbs2012 −0.2 [ −0.4 , 0.0 ] Choi2012 −0.2 [ −0.6 , 0.2 ] Nordby2012 −0.1 [ −0.2 , 0.0 ] Dobrosielski2012 0.0 [ −0.5 , 0.4 ] Oliveira2012 −0.1 [ −0.3 , 0.1 ] Kim2012 −0.5 [ −0.9 , −0.2 ] Lee2012a −0.5 [ −0.9 , 0.0 ] Snel2012 −0.2 [ −0.4 , 0.0 ] Lee2012b 0.0 [ −0.1 , 0.2 ] Sung2012 −0.2 [ −0.4 , 0.0 ] Nordby2012 0.0 [ −0.2 , 0.2 ] Tunar2012 −0.1 [ −0.3 , 0.1 ] Oliveira2012 −0.4 [ −1.1 , 0.3 ] Snel2012 −1.2 [ −1.9 , −0.5 ] Andrews2011 0.0 [ −0.1 , 0.1 ] Straznicky2012 −0.2 [ −0.6 , 0.2 ] Belli2011 −0.2 [ −0.4 , 0.0 ] Sung2012 −0.5 [ −1.2 , 0.2 ] D'hooge2011 −0.1 [ −0.4 , 0.1 ] Andrews2011 0.2 [ −0.1 , 0.5 ] Belli2011 −0.3 [ −1.1 , 0.4 ] Ferrer−Garcia2011 −0.1 [ −0.3 , 0.0 ] Dhooge2011 −0.3 [ −1.2 , 0.7 ] Kurban2011 −0.2 [ −0.4 , 0.0 ] Drapeau2011 0.2 [ −0.1 , 0.5 ] Church2010 −0.1 [ −0.3 , 0.0 ] Ferrer−Garcia2011 −0.6 [ −1.2 , 0.1 ] Friedenreich2011 0.0 [ −0.2 , 0.2 ] Kadoglou2010a −0.2 [ −0.3 , −0.1 ] Kurban2011 −0.4 [ −1.1 , 0.3 ] Kadoglou2010b −0.3 [ −0.4 , −0.1 ] Mason2011 0.0 [ −0.2 , 0.1 ] Koo2010 0.0 [ −0.1 , 0.0 ] Wu2011 0.2 [ −0.1 , 0.5 ] Arikawa2010 −0.3 [ −1.1 , 0.6 ] Ku2010 −0.1 [ −0.3 , 0.0 ] Desch2010 0.0 [ −0.2 , 0.3 ] Morton2010 −0.1 [ −0.3 , 0.1 ] Ibanez2010 −0.1 [ −0.7 , 0.5 ] Negri2010 −0.1 [ −0.3 , 0.0 ] Kadoglou2010a −0.7 [ −1.2 , −0.1 ] Kadoglou2010b −0.9 [ −1.3 , −0.5 ] Okada2010 −0.2 [ −0.3 , 0.0 ] Koo2010 0.1 [ −0.1 , 0.3 ] Plotnikoff2010 −0.1 [ −0.3 , 0.1 ] Ku2010 0.0 [ −0.5 , 0.4 ] Morton2010 −0.3 [ −1.1 , 0.5 ] Salem2010 −0.3 [ −0.5 , −0.2 ] Negri2010 −0.5 [ −1.3 , 0.2 ] Wycherley2010 −0.1 [ −0.3 , 0.1 ] Okada2010 0.2 [ −0.3 , 0.7 ] Yavari2010 −0.3 [ −0.4 , −0.1 ] Plotnikoff2010 0.0 [ −0.6 , 0.7 ] Sartor2010 −0.2 [ −0.9 , 0.5 ] Arora2009 −0.2 [ −0.5 , 0.0 ] Wycherley2010 −0.7 [ −1.4 , 0.0 ] Hordern2009 −0.1 [ −0.2 , 0.1 ] Yavari2010 −1.0 [ −1.5 , −0.5 ] Leehey2009 −0.1 [ −0.3 , 0.1 ] Burtscher2009 0.1 [ −0.3 , 0.5 ] Davis2009 −0.1 [ −0.5 , 0.2 ] Loimaala2009 −0.2 [ −0.4 , 0.0 ] Hordern2009 0.0 [ −0.4 , 0.4 ] Shenoy2009 −0.2 [ −0.4 , 0.0 ] Shah2009 −0.1 [ −0.3 , 0.1 ] Brun2008 −0.1 [ −0.4 , 0.1 ] Shenoy2009 −2.1 [ −2.7 , −1.4 ] Brun2008 −0.2 [ −1.2 , 0.7 ] Cheung2008 0.0 [ −0.2 , 0.2 ] Davison2008 0.2 [ −0.2 , 0.5 ] KrouselWood2008 −0.1 [ −0.4 , 0.1 ] Gordon2008 −2.0 [ −2.6 , −1.3 ] Lambers2008 −0.1 [ −0.4 , 0.1 ] Lambers2008 −0.8 [ −1.7 , 0.1 ] Sixt2008 0.0 [ −0.4 , 0.3 ] Sixt2008 0.0 [ −0.1 , 0.1 ] Winnick2008 0.1 [ −0.3 , 0.4 ] Tsang2008 −0.1 [ −0.3 , 0.0 ] Wycherley2008 −0.8 [ −1.5 , −0.1 ] Wycherley2008 −0.2 [ −0.4 , 0.0 ] Zhang2008 −0.7 [ −1.3 , 0.0 ] Middlebrooke2006 −0.1 [ −1.0 , 0.7 ] Nishijima2007 0.0 [ −0.1 , 0.0 ] Orr2006 0.1 [ −0.8 , 0.9 ] Sigal2007 −0.3 [ −0.4 , −0.2 ] Shaibi2006 0.1 [ −0.4 , 0.5 ] Wagner2006 −0.2 [ −1.0 , 0.6 ] Middlebrooke2006 −0.1 [ −0.3 , 0.1 ] Weiss2006 0.0 [ −0.2 , 0.2 ] Wagner2006 −0.1 [ −0.3 , 0.1 ] Bjorgaas2005 −0.5 [ −1.1 , 0.0 ] Bjorgaas2005 −0.2 [ −0.4 , 0.0 ] Dunstan2005 −0.1 [ −0.8 , 0.7 ] Frank2005 0.0 [ −0.8 , 0.7 ] Dunstan2005 −0.1 [ −0.3 , 0.1 ] Giannopoulou2005 −1.0 [ −1.4 , −0.6 ] Giannopoulou2005 −0.2 [ −0.4 , 0.0 ] ODonovan2005 −0.2 [ −0.7 , 0.2 ] Thomas2005 0.0 [ −0.1 , 0.1 ] Stewart2005 0.0 [ −0.2 , 0.1 ] Thomas2005 −0.2 [ −0.5 , 0.1 ] VanRooijen2004 −0.1 [ −0.3 , 0.1 ] Ross2004 0.0 [ −0.2 , 0.2 ] Baldi2003 −0.1 [ −0.4 , 0.1 ] Baldi2003 −0.3 [ −1.2 , 0.5 ] Cuff2003 −0.1 [ −0.2 , 0.1 ] Castaneda2002 −0.4 [ −1.2 , 0.3 ] Janssen2002 0.0 [ −0.4 , 0.3 ] Castaneda2002 −0.2 [ −0.4 , 0.0 ] Kang2002 0.0 [ −0.3 , 0.2 ] Boudou2000 −0.2 [ −0.4 , 0.0 ] Boudou2000 0.0 [ −0.8 , 0.8 ] Dunstan1998 −0.1 [ −0.3 , 0.1 ] Dunstan1998 −0.2 [ −1.0 , 0.6 ] Dunstan1997 −1.5 [ −1.8 , −1.1 ] Raz1994 −0.2 [ −0.4 , 0.1 ] Torjesen1997 −0.1 [ −0.2 , 0.0 ] Vanninen1992 −0.2 [ −0.4 , 0.0 ] Raz1994 −0.5 [ −1.2 , 0.2 ] Huttunen1989 −0.1 [ −0.3 , 0.1 ] Vanninen1992 −0.3 [ −0.9 , 0.3 ] Huttunen1989 −0.2 [ −1.2 , 0.7 ] Verity1989 −0.1 [ −0.3 , 0.1 ] Verity1989 −0.2 [ −1.0 , 0.6 ] Ronnemaa1986 −0.2 [ −0.4 , 0.0 ] Ronnemaa1986 −0.4 [ −1.2 , 0.4 ] Wallberg1986 −0.3 [ −1.1 , 0.6 ] Wallberg1986 −0.1 [ −0.3 , 0.1 ] Landt1985 0.1 [ −0.1 , 0.4 ] Landt1985 −0.1 [ −0.4 , 0.1 ] Campaigne1984 −0.3 [ −1.3 , 0.6 ] Campaigne1984 −0.2 [ −0.4 , 0.1 ] Besnier2015 −0.1 [ −0.5 , 0.3 ] Kacerovsky−Bielesz2012 0.0 [ −0.8 , 0.7 ] Besnier2015 0.0 [ −0.2 , 0.1 ] Lucotti2011 −0.7 [ −1.3 , −0.1 ] Kacerovsky−Bielesz2012 −0.1 [ −0.3 , 0.1 ] Praet2008 −0.2 [ −0.8 , 0.5 ] Lucotti2011 −0.2 [ −0.4 , 0.1 ] Ahmadizad2007 0.0 [ −0.7 , 0.6 ] Lindgarde2007 −0.6 [ −1.1 , 0.0 ] Praet2008 −0.1 [ −0.3 , 0.1 ] DiPietro2006 0.0 [ −0.4 , 0.4 ] Cauza2005a −0.1 [ −0.4 , 0.1 ] Cauza2005a −0.8 [ −1.6 , 0.0 ] Mean FBG change −0.28 [ −0.40 , −0.15 ] Mean HbA1c change −0.14 [ −0.18 , −0.09 ]

−0.6 −0.4 −0.2 0.0 0.2 −3.0 −2.0 −1.0 0.0 1.0 Change in FBG(mg/dl) per 10 minutes per week of physical activity Change in HbA1c(%) per 100 minutes per week of physical activity

iPRI 57 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Changes in fasting blood glucose (FBG) and glycated haemoglobin (HbA1c) per 100 minutes of physical activity per week Diabetes, Diabetes Treatments and Lung Cancer Risk

Change in FBG (mg/dl) Change in HbA1c (%) ung cancer is such a common disease that even a (higher) risk of developing lung cancer requires Analysis Nb. of studies (arms) Physical activity Nb. of studies (arms) Physical activity a small, real increase in risk associated with to be clarified. A series of meta-analyses were (per 100mn/week) (95% CI:) (per 100mn/week) (95% CI:) L diabetes would represent a significant problem for conducted to investigate associations with diabetes Main analysis 105 (257) -2.75 (-3.96, -1.55) 76 (184) -0.14 (-0.18, -0.09) Stratified analysis by : Public Health. The association between diabetes and and diabetes treatments and lung cancer risk. Gender: Men* 12 (30) -0.39 (-1.24, 0.46) 10 (24) -0.19 (-0.34, -0.04) A total of 37 risk estimates of lung cancer risk among diabetic patients are available from 35 studies. The Summary Relative Risk Women* 25 (62) -2.47 (-4.76, -0.19) 12 (29) -0.05 (-0.08; -0.01) (SRR) from the meta-analysis of all studies was SRR=1.04 (95% CI: 0.96, 1.12). This indicates that there is no significant increase in risk Both genders 69 (165) -3.55 (-5.40, -1.70) 55 (131) -0.15 (-0.20, -0.10) of lung cancer among patients with diabetes compared to a comparable group without diabetes (see figure below). However, there Study duration: was a great deal of heterogeneity indicating the potential impact of small studies on the overall result. <20 weeks 69 (169) -2.93 (-4.56, -1.31) 50 (119) -0.12 (-0.17, -0.07) >20 weeks* 36 (88) -2.08 (-4.94, 0.78) 26 (65) -0.14 (-0.22, -0.06) Age: Risk of lung cancer in patients with diabetes Children* 12 (29) 0.36 (-0.79, 1.51) 7 (17) -0.23 (-0.53, 0.07) Adults 93 (228) 3.05 (-4.44, -1.65) 69 (167) -0.13 (-0.17, -0.09) BMI: Normal weight* 8 (17) -3.16 (-8.40, 2.08) 5 (11) -0.00 (-0.05; 0.05) Overweight 36 (89) -2.69 (-5.08; -0.30) 23 (54) -0.07 (-0.12; -0.03) Obese 56 (137) -1.65 (-2.76, -0.54) 43 (105) -0.15 (-0.21, -0.09) Patients type: All Diabetic and prediabetic 61 (143) -4.68 (-7.29, -2.32) 67 (159) -0.17 (-0.22, -0.12) T2DM and prediabetic 56 (133) -4.71 (-7.42, -2.01) 60 (144) -0.16 (-0.21, -0.11) T1DM* 5 (10) 1.36 (-0.66, 3.37) 7 (15) -0.19 (-0.61, 0.24) Other*† 44 (114) -0.29 (-1.28, 0.70) 9 (25) -0.04 (-0.09; -0.01) Physical activity type: Aerobic (AE)** 51 (122) -2.63 (-4.28, -0.97) 28 (63) -0.22 (-0.31; -0.13) Resistance(RT)* 20 (42) -1.24 (-4.05, 1.58) 14 (30) -0.01 (-0.28; 0.08) Combined AE and RT*** 14 (30) -2.55 (-4.56, -0.53) 19 (39) -0.23 (-0.32, -0.15) Walking** 16 (34) -5.92 (-11.48; -0.36) 14 (34) -0.18 (-0.30, -0.07) Other**‡ 9 (18) -7.88 (-13.88, -1.88) 8 (16) -0.04 (-0.14, 0.07)

*Main model did not converge for both outcomes; results are presented for the same model, where the intercept was fixed ** Main model did not converge for HbA1c; results are presented for the same model, where the intercept was fixed *** Main model did not converge for FBG; results are presented for the same model, where the intercept was fixed † Other: patients not reported as diabetic, e.g. healthy ‡Other types of physical activity e.g. Tai chi, yoga, football, etc.

Balducci S, Zanuso S, Nicolucci A, De Feo P, Cavallo S, Cardelli P, et al. Effect of an intensive exercise Nishijima H, Satake K, Igarashi K, Morita N, Kanazawa N, Okita K. Effects of exercise in overweight intervention strategy on modifiable cardiovascular risk factors in subjects with type 2 diabetes Japanese with multiple cardiovascular risk factors. Med Sci Sports Exerc. 2007;39(6):926-33. mellitus: a randomized controlled trial: the Italian Diabetes and Exercise Study (IDES). Arch Intern Sigal RJ, Alberga AS, Goldfield GS, Prud’homme D, Hadjiyannakis S, Gougeon R, et al. Effects of Med. 2010;170(20):1794-803. aerobic training, resistance training, or both on percentage body fat and cardiometabolic risk Ekelund U, Palla L, Brage S, Franks PW, Peters T, Balkau B, et al. Physical activity reduces the risk markers in obese adolescents: the healthy eating aerobic and resistance training in youth rand- of incident type 2 diabetes in general and in abdominally lean and obese men and women: the omized clinical trial. JAMA Pediatr. 2014;168(11):1006-14. EPIC-InterAct Study. Diabetologia. 2012;55(7):1944-52. Weinstein AR, Sesso HD, Lee IM, Cook NR, Manson JE, Buring JE, et al. Relationship of physical Grontved A, Pan A, Mekary RA, Stampfer M, Willett WC, Manson JE, et al. Muscle-strengthening activity vs body mass index with type 2 diabetes in women. JAMA. 2004;292(10):1188-94. Heterogeneity analyses revealed no significant difference between studies that adjusted for smoking status of participants (SRR = and conditioning activities and risk of type 2 diabetes: a prospective study in two cohorts of US women. PLoS Med. 2014;11(1):e1001587. 0.98 (95% CI: 0.90, 1.06) based on 15 risk estimates) and studies that did not adjust for smoking (1.08 (95% CI: 0.95, 1.24)) based on Laaksonen DE, Lindstrom J, Lakka TA, Eriksson JG, Niskanen L, Wikstrom K, et al. Physical 17 risk estimates). Similarly, geographical region where the studies were conducted had little impact on the summary relative risk. activity in the prevention of type 2 diabetes: the Finnish diabetes prevention study. Diabetes. The SRR and 95% CI: were 1.02 (95% CI: 0.89, 1.18), 1.01 (95% CI: 0.88, 1.17) and 1.10 (95% CI: 0.93, 1.31) in North America, Europe 2005;54(1):158-65. and Asia, respectively (see table).

iPRI 59 iPRI - International Prevention Research Institute — Principal Contributions iPRI

Stratified analyses according to smoking status and geographical region Risk of lung cancer in diabetic patients treated with non-glargine insulin (blue), insulin glargine (red) and all insulins combined (black)

Number of estimates SRR 95% CI: I2 All Studies 37 1.04 (0.97, 1.12) 96% Studies adjusting for Smoking 15 0.98 (0.90, 1.06) 70% Studies not adjusting for 22 1.08 (0.97, 1.20) 98% smoking Studies conducted in North 9 1.02 (0.89, 1.18) 59% America Studies conducted in Europe 17 1.01 (0.89, 1.14) 95% Studies conducted in Asia 9 1.10 (0.96, 1.27) 66%

In total 15 risk estimates were found on the risk of lung cancer in insulin users; six for thiazolidinediones (TZDs) and nine for metformin (see table below). There was a borderline increased risk of lung cancer in insulin-treated diabetic patients as compared to other treated diabetic patients (SRR=1.16 (95% CI: 1.00, 1.36)). This increased risk was limited to non-glargine users: based on five risk estimates, the SRR was 1.37 (95% CI: 0.96, 1.94) with strong heterogeneity (I² = 81%). The risk of lung cancer in insulin glargine users was close to unity: SRR=1.04 (95% CI: 0.91, 1.19) based on ten studies (see figure).

There was a statistically significant decreased risk of lung cancer in patients treated with TZD: SRR=0.67 (95% CI: 0.51, 0.87). However, as only six studies were found, more detailed analyses were not possible. From nine studies, there was no increased or decreased risk of lung cancer among metformin users. The summary relative risk was 0.91 (95% CI: 0.77, 1.06) with large heterogeneity (I² = 72%).

Stratified analyses of lung cancer risk in diabetes patients according to treatment therapy

Number of estimates SRR 95% CI: I2 All Insulins: all studies 15 1.16 (1.00, 1.36) 64% All Insulins: observational 13 1.16 (0.98, 1.37) 69% Koechlin A, Boyle P. Diabetes, Diabetes Treatments, and Lung Cancer Risk. American Diabetes Koechlin A, Boyle P. Lung cancer risk, diabetes and diabetes treatments. American Society of Non-glargine insulins 5 1.37 (0.96, 1.94) 81% Association; New Orleans, United States of America 2016a. Clinical ONcology; Chicago, United States of America 2016b. Glargine: all studies 10 1.04 (0.91, 1.19) 0% Glargine: observational 8 1.02 (0.88, 1.18) 0% Thiazolidinediones 6 0.67 (0.51, 0.87) 55% Metformin 9 0.91 (0.77, 1.06) 72%

In conclusion, the risk of lung cancer is not increased among patients with diabetes compared to non-diabetic subjects. Among diabetic patients, those prescribed with glargine did not have an increased risk of lung cancer although users of other insulins had a non-significant increased risk. Users of TZD had a decreased risk of lung cancer while there was no significant protection conferred by using metformin.

This work was selected for a poster presentation at the American Diabetes Association’s (ADA) 76th Scientific sessions in June, 2016 (Koechlin et al, 2016a) and at the American Society of Clinical Oncology (ASCO) annual meeting (Koechlin et al, 2016b).

iPRI 61 iPRI - International Prevention Research Institute — Principal Contributions iPRI AfricaAfrica

Africa fatigue: the belief that Africa must help itself and that Africa is no longer a continent in need. The first is true, the second is false. Yes, Africa can, and is, helping itself, but Africa is still in need of international support and collaboration. Let us not take another wrong turn; let us continue to accompany Africa, especially in matters of public health. We do.

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State of Oncology in Africa CALL TO ACTION

he State of Oncology in Africa 2015 is a unique from all disciplines, oncology nurses and the other Treport about cancer in Africa, written by health necessary health professionals and technicians to This is a Call to Action to African governments, foreign governments, ODA funders professionals working in Africa or international support their work. There is a lack of treatments and colleagues working closely with Africa. Overall, it treatment centres. Most countries do not have any of health such as the World Bank and international NGOs to rise to the challenge of paints a depressing and deplorable picture of the radiotherapy equipment or access to opioid drugs current situation. It demonstrates how too many for palliative care and pain control. The situation is patients do not seek, or cannot access, professional bound to get worse as the population grows and Cancer in Africa with specific, coordinated actions. The cancer situation in Africa is medical advice. Those who do, do so when the cancer ages and cancer risk factors imported from high- is at an advanced stage when cure is no longer resource countries add to the local risk factors with critical. Global Society cannot, once again, react too slowly to an African health crisis. possible. Africa suffers from a lack of oncologists infections still top of the list.

Over the next decades, cancer will cause Africans to suffer and die in much greater numbers than today. Yet there is hope. Those profes- 1… The International Covenant on Economic Social and Cultural Rights (ICESCR) should be invoked as the basis for action. sionals who do care for Africa’s cancer patients are doing a magnificent job, frequently in desperate circumstances: they deserve our full This multilateral treaty provides that State Parties to the Covenant recognize the right of everyone to the enjoyment of respect and admiration. There is hope from the success of high-quality, sustainable collaborations but, unfortunately, it is not enough. the highest attainable standard of physical and mental health. Article 12.2 contains important determinants of the right to health such as prevention and treatment of diseases essential for the enjoyment of the right. Significantly, such extraordinary examples rely on international charitable donations rather than governmental funding or structural funds from official development assistance (ODA). 2… There is a need to train more oncologists and health professionals in cancer care and provide the necessary infrastructure which is urgently needed to identify and treat patients. More general and specialist surgical capacity is critical as are There is a wide variety of statistics available regarding cancer in Africa although most are estimates. However, statistics are patients with concomitant enhancements in imaging and pathology. the tears wiped away. It is bad to have cancer and worse to have cancer if you are poor and disconnected from the public health system. Radical solutions to improve the situation in Africa and other poor countries are urgently needed: the status quo is not an appropriate. 3… The drugs and equipment necessary to treat patients with cancer must be made available. We need to deliver, install and New models are needed to cope with and improve this situation. maintain adequate numbers of resource appropriate Radiotherapy machines. It should be the right of cancer patients, no matter where they are to have access to the appropriate treatment of their disease. It is impossible to avoid the conclusion that there is an urgent need for major increases in domestic public funding of cancer care, the recognition that cancer care should be part of ODA and better Private-Public Partnerships, involving a number of sources from different areas, 4… Opioids must be available for controlling the pain of patients with terminal cancers (and other diseases). International to make the necessary progress with the briefest delay. These partnerships need the commitment of the wide span of industries involved Agencies should make this a priority activity and come to agreements with Governments of countries where these are in the technology for diagnosis and treatment. It needs the commitment and engagement of Governments and Non-Governmental not available. Organisations to be effective. Effective will be measured against the Right of every patient with cancer to have the most appropriate treatment and care for their disease. 5… Since half of cancer in Africa is currently caused by chronic infection, relevant infection control and vaccination programmes must be funded and implemented continent-wide. The International Covenant on Economic Social and Cultural Rights (ICESCR) was voted by the United Nations General Assembly in 1966 Information and education campaigns to wipe out stigma and misinformation must be conceived and disseminated. and came into force in 1976. This multilateral treaty provides that State Parties to the Covenant recognize the right of everyone to the 6… enjoyment of the highest attainable standard of physical and mental health. Article 12.2 contains important determinants of the right to 7… Making Universal Health Coverage globally available and strengthening health systems is critical for improving cancer health such as prevention and treatment of diseases essential for the enjoyment of the right. There are 164 parties to the treaty. Why has care. This is also a critical area for the corporate and social responsibility agendas for the private industries including all it not been effective in dealing with the cancer problem in Africa? Why has it not been invoked? trans-African corporations.

It is essential to move from a passive position to an active voice. We can turn our heads and walk away from this situation (as we often 8… High quality cancer institutions, all over the world, should establish collaboration ventures with cancer centres and insti- do,) and betray all those dedicated clinicians, nurses and other personnel grasping with the overwhelming problem of cancer on the tutes in every African country, as well as with public health services. Continent. Or, we can do something. As with cancers everywhere, African cancers deserve to be prevented, to be treated, to be cured and to be palliated. If we do not do it now, starting immediately, it will be too late and Africa’s cancer crisis will continue to spiral out of control. 9… Finally, international philanthropy is vital to help fund these efforts.

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“I don’t want Cancer is... Attacking Africa - Television Documentary hy would an internationally recognized more sense? Wouldn’t it be reasonable to produce, Wepidemiology and biostatistics institute say, a series of interviews of specialists simply to leave you.” decide to produce a film? If it did choose to produce commenting on data analysis? Why would it step a film, wouldn’t a film on its core competence make into the realm of advocacy? Jovia In late 2014 and throughout 2015, Peter Boyle, Cemil Alyanak and several experts and co-authors, were working on the State of Oncology in Africa Report. The data was irrefutable, Cancer in Africa was a clear and present danger that was being ignored by both international public health organizations, governments and aid agencies, and most African governments. But if the data was so clear, why wasn’t more being done?

The report, they felt, would speak to the urgency of the problem. It would make the case for developing appropriate prevention, treatment, care and palliation policies. How could one argue with these numbers: over half of African countries have no radiotherapy units and/or outlaw the use of opiodes to treat pain? But would the Report succeed in elevating the crisis to an emotionally committed level? Would they manage to incite policymakers to act swiftly? Plainly, would policymakers be sufficiently swayed by the data alone, to invest now in a disease that will peak in ten or twenty years?

Thus came about the idea of a film that would, first and foremost, bring the suffering to the forefront. It would fearlessly shine a light on all that was missing from the fight against cancer in Africa. It would use interviews, images and data. It would not give anyone a pass, ensuring that the message was clear: Cancer is... Attacking Africa!

But the film would not stop there. It would not allow itself to be cornered into darkness. It would also shine a bright light on the amazing efforts of medical professionals working tirelessly in clinics, hospitals and even in people’s homes throughout Africa. It would show the efforts of an organization in Uganda dedicated to home-based care for the terminally ill. It would give us the tour of a Hospital in Kenya that dares to aspire to the standards of a developed country. It would take us to Senegal where despite ‘inhumane’ conditions in some of the care facilities, the staff press on providing chemotherapy in tiny over-crowded rooms and radiotherapy with a single Cobalt unit which is more often broken than working.

The result has been the film: ‘Cancer is... Attacking Africa.’ It was entirely produced by iPRI faculty, senior research fellows, staff and consultants. The film was funded both by iPRI and by an unrestricted grant from Pfizer, Inc. who entirely respected their commitment to have zero influence on the film whatsoever. The film has been edited into two versions, a 22-minute synopsis and the full length 59-minute version. Starting in 2017 they will be shown widely on African television stations, on the internet and in congresses and on campuses worldwide.

iPRI plans to produce future films to further leverage the data that overwhelming demonstrates that Global Public Health, though substantially funded, often lacks the aggressive and selfless policy-making that is our Human Right.

The film was produced by Professor Peter Boyle and Dr. Cemil Alyanak, entirely filmed and edited by Alyanak and guided by the on-the-ground expertise of African cancer authority Professor Twalib Ngoma.

Finally, without hesitation, the hero of the film is a young woman, Jovia, born and raised in Kampala, who alone, without parents, without a husband who had left her years back, burdened by the care of a daughter and a younger brother, had to face both the See Cancer is... Attacking Africa, and other iPRI videos, at: scourge of HIV/AIDS and cancer of the cervix. She was interviewed three weeks before she passed, weak and destitute, yet still full http://www.i-pri.org/publications/video/ of the life and hope of a 29-year old. RIP Jovia.

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Pathways of Care in Lung Cancer in Africa Investigate the Relationship Between Tuberculosis and Lung Cancer in High Risk Groups

Lung cancer is the commonest cancer worldwide, and while most new lung cancer cases were reported in less developed regions Tuberculosis and lung cancer share many symptoms and clinical signs (Fontenelle et al, 1970), and it is very likely that cases of lung (58%), low incidence rates were estimated for Africa (7.7 and 2.6 per 100,000 in men, and women, respectively) (Ferlay et al, 2015). cancer are misdiagnosed as tuberculosis (TB), at least initially. Through the use of a recently developed blood test for lung cancer These numbers are best guess estimates of the lung cancer situation in Africa, because very little accurate data is available from (Jett et al, 2014; Lam et al, 2011), EarlyCDT-Lung, high risk patients or patients with suspected lung cancer, will benefit from earlier African countries. Most countries lack nationwide cancer registries, and have no reliable source of mortality data (Ferlay et al, 2015; diagnosis. In addition, there is an important research question in evaluating the use of this test in the differential diagnosis of Joubert et al, 2012). In most African settings, due to the low awareness of cancer, and the lack of, or inadequate screening services, tuberculosis and lung cancer. patients are diagnosed with cancers at advanced stages of the disease, when therapeutic solutions, where available, are likely less effective (Nanguzgambo et al, 2011). In many cases they are not diagnosed at all. African regions have high prevalence of Partnerships will be developed in order to engage relevant stakeholders and have their support and collaboration. Collaboration tuberculosis (WHO, 2016) and high prevalence of HIV (UNAIDS, 2016), both of which have been shown to increase the risk of lung will be sought with research institutions, ministries, government-international partners, private sector, NGOs, and civil society. cancer (Sigel et al, 2012; Yu et al, 2011). All of these elements lead to the hypothesis that lung cancer in Africa is an under-estimated problem, poised to escalate in the near future. The scope of the programme is two-fold. On one hand, answer crucial questions about misdiagnosis of lung cancer due to TB, the pathways of care of lung cancer, and potential differential diagnosis of lung cancer and tuberculosis. On the other hand, move a step In order to start developing a programme tackling the issues of lung cancer in Africa, a consultative two day meeting was held in further towards progressing lung cancer in sub-Saharan Africa, by increasing awareness of cancer in general, and of lung cancer in Johannesburg, at the beginning of November 2016, to discuss components of a multi-country protocol, in Swaziland, Lesotho, particular, educating health-care workers on signs and diagnosis of lung cancer, and achieving earlier diagnosis, which will in turn Tanzania, Kenya and South Africa. Representatives presented the state of lung cancer in each country, and the common themes that lead to improved survival. emerged were: general lack of awareness (even among health-care workers), lack of oncology personnel and equipment, lack of data, delays in diagnosis as well as late stage diagnosis implying very poor survival outcomes for patients. The meeting identified key areas where a programme to progress lung cancer in Africa should focus: education, training and increasing awareness, data collec- Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and Lam S, Boyle P, Healey GF, Maddison P, Peek L, Murray A, et al. EarlyCDT-Lung: an immunobio- mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. marker test as an aid to early detection of lung cancer. Cancer Prev Res (Phila). 2011;4(7):1126-34. tion systems, earlier diagnosis. The program is in its infancy, with a grant application expected beginning 2017. The programme’s 2015;136(5):E359-86. Nanguzgambo AB, Aubeelack K, von Groote-Bidlingmaier F, Hattingh SM, Louw M, Koegelenberg main objective is to help advance the case of lung cancer in Africa, through several concerted steps. Fontenelle LJ, Campbell D. Coexisting bronchogenic carcinoma and pulmonary tuberculosis. Ann CF, et al. Radiologic features, staging, and operability of primary lung cancer in the Western cape, Thorac Surg. 1970;9(5):431-5. South Africa: a 1-year retrospective study. J Thorac Oncol. 2011;6(2):343-50. Jett JR, Peek LJ, Fredericks L, Jewell W, Pingleton WW, Robertson JF. Audit of the autoantibody test, Sigel K, Wisnivesky J, Gordon K, Dubrow R, Justice A, Brown ST, et al. HIV as an independent risk EarlyCDT(R)-lung, in 1600 patients: an evaluation of its performance in routine clinical practice. factor for incident lung cancer. AIDS. 2012;26(8):1017-25. Clearly Identify Pathways of Lung Cancer Care Lung Cancer. 2014;83(1):51-5. UNAIDS. Fact sheet. Global HIV statistics. 2016. Joubert J, Rao C, Bradshaw D, Dorrington RE, Vos T, Lopez AD. Characteristics, availability and uses WHO. Global tuberculosis report. 2016. of vital registration and other mortality data sources in post-democracy South Africa. Glob Health Understanding Pathways of Care is a basic requirement which, once understood, can impact on determining where issues of Access Action. 2012;5:1-19. Yu YH, Liao CC, Hsu WH, Chen HJ, Liao WC, Muo CH, et al. Increased lung cancer risk among patients with pulmonary tuberculosis: a population cohort study. J Thorac Oncol. 2011;6(1):32-7. could be optimally introduced to the process of care with optimal effect. This information is unknown at present and may well vary between countries, regions and cultural groups. It is essential information to have in order to build a programme.

Strengthen Hospital-Based Registries

Hospital-based registries have direct access to key clinical information such as disease stage, pathology, treatment and follow-up information to calculate survival. Some regions/countries already have started implementing cancer registries, while others would welcome the opportunity to do so. An important part of the programme will focus on strengthening those registries already in place and on starting up new registries where there are none.

Achieve Earlier Diagnosis

Having earlier diagnosis, and gradually down-staging lung cancer cases (e.g. no longer diagnosing a cancer at stage IV, but at stage III) would be an important step towards improving lung cancer outcomes for African patients. In order to achieve earlier diagnosis, there is a need for education, training, and raising awareness. Part of the project will focus on education and training of healthcare workers and community workers on signs and symptoms of lung cancer, as well as lung cancer care and support. Awareness of cancer in general, and of lung cancer in particular, at the community level would be increased through the use of tailored messages, which would be previously adapted and validated in the communities for which they are intended.

iPRI 69 iPRI - International Prevention Research Institute — Principal Contributions iPRI iPRI Education and Training Programmes: A New Initiative

Development of learning resources for partnership with a consortium of Universities

Since its inception iPRI has been committed to developing appropriate education and training programmes for low and middle income countries (LMIC). An early initiative established a summer school (2009-11) for Public Health and Epidemiology in collaboration with the University of Dundee (Course directors Prof. Peter Boyle, Prof Irene Leigh – VP Dundee and Prof Margaret Smith Dean of Nursing). This was very successful: many students were sponsored to attend and over 100 applicants wished to attend the third course. Subsequently a Dundee University on-line learning Master’s programme in Global Health was launched in 2012, which enrolled some alumni from summer schools and has grown in strength since that time (through the School of Nursing, which also graduates nurses around the world via an on-line and blended learning undergraduate degree). Additionally the Strathclyde institute of Global Public Health has been launched (co Director Sir Harry Burns, previous CMO Scotland), with the intention of initiating Master’s programmes including appropriate technology for bioengineering and to perform research in epidemiology and public health policy.

Masters programmes in the UK welcome students from LMIC but extremely high international fees make this route available to the few candidates from LMIC who can obtain international sponsorship. There is a need to develop in-country educational resources and programmes, which can be made available to a consortium of Universities, who both accredit the programme and provide in-country learning facilities. With the development of iPRI. Africa and other international partnerships, the academic infrastructure of iPRI makes possible an integrated framework for such programmatic approaches. Therefore, existing educational material for modules on biostatistics and epidemiology will be converted into an on-line learning resource. This is enabled by a fellowship from the British Association of Dermatologists to iPRI for Prof Irene Leigh to coordinate this project. Other modules, which follow, could include modules on Public Health, Infectious Diseases and Non-Communicable Diseases. This project has been greeted enthusiasti- cally by both iPRI staff and potential educational collaborators. iPRI is committed to developing As Prof. Irene Leigh is a dermatologist, some of the Fellowship will be concerned with Skin cancer in Africa (see chapter on Skin cancer in iPRI publication “The State of Oncology in Africa”). Skin cancers are a huge and increasing health burden globally equal education and training to the total of all other cancers combined, and they are associated with substantial morbidity, mortality and costs to healthcare programmes. providers. Although predominantly in Western populations, this appears to be a problem also in Sub-Saharan Africa particularly in genetically predisposed patients such as those suffering from albinism, xeroderma pigmentosum or those with HIV. There is little information concerning the size of this problem. Irene will spend some of her Fellowship time at the Regional Dermatology Training School on Moshi, North Tanzania, where a centre for the care for local albinos has been in place for many years. She will also develop on line learning resources for “Dermatology in Africa” and investigate the possibilities of new research activity in Moshi. She will also be seeking support for a World Skin Cancer Report.

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UV and Skin Cancer

revention of Ultraviolet (UV) exposure and tertiary prevention of skin cancer. Those regarding Pskin cancer is an important activity of iPRI. secondary prevention of skin cancer are reported Between 2015/2016, several research activi- in a broader chapter on cancer screening (See the ties were conducted on primary, secondary and Cancer Chapter).

The activities on primary prevention focused on the application of knowledge and competence acquired at iPRI on the assessment of population UV exposure through the success of the European project Eurosun conducted between 2010 and 2012. From this project, methods were developed for estimating, from satellite images, ground exposure to UV radiation and individual chronic exposure to UV (see figure below).

Map of the daily average UV irradiation (in J/ cm2) in Europe for the month of June, averaged over the period 1988-1992

From this expertise, new projects were conducted on UV exposure and risk of non-skin diseases. For instance, another project, UVPro, focused on occupational UV exposure in France.

Past studies conducted by iPRI senior researchers have suggested there was sufficient evidence to consider sunbed use to increase the risk of cutaneous melanoma (Boniol et al, 2012). The exposure to this risk factor fits particularly well with the role of intense UV exposure in childhood for the initiation of melanoma in adulthood. Between 2015/2016, original studies were conducted to better understand the aetiology of cutaneous melanoma, and more particularly the risk factors associated with melanoma mortality.

Lastly, research activities were conducted on new candidate factors to be considered as melanoma prognostic factors such as UV exposure, vitamin D level and nevi count.

UV exposure and risk of non-skin disease Safe tanning is simply a myth. Ocular Disease From a collaboration between Cecile Delcourt (University of Bordeaux, France) and Mathieu Boniol (iPRI, Lyon), a study on the association between residential ultraviolet exposure and risk of cataract and age-related macular degeneration (AMD) was conducted within the Alienor Study (Delcourt

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et al., 2014). The Alienor Study was a population-based study of 963 residents of Bordeaux (France), aged 73 years or older, who These studies suggested that higher residential UV exposure may be positively associated with a higher incidence of PBC-ALL in underwent an eye examination, including intraocular pressure (IOP), central corneal thickness (CCT), and biomechanical properties early childhood independently of known and suspected risk factors. The critical time window of exposure could also be prenatal of the cornea measurements using the Ocular Response Analyser. Early and late AMD was classified from retinal colour photo- and further investigations are required. graphs. Cataract extraction was defined as absence of the natural lens at slit-lamp. Individual residential UV exposure was estimated from Eurosun satellite data. ELFE Cohort

This study showed that highly exposed subjects (higher quartile of ambient UV) were at increased risk for cataract extraction A childhood cohort of 18,000 children recruited in a representative sample and followed from birth to adulthood (current age: 5 (odds ratio [OR]=1.53 (95% confidence interval [CI]: 1.04, 2.26); P = 0.03) and of early AMD (OR=1.59 (95% CI: 1.04, 2.44); P = 0.03), years) is currently ongoing in France. The study involved research projects since its inception; and iPRI is participating in the assess- compared to subjects in the intermediate quartiles. Mean corneal hysteresis (CH), corneal resistance factor (CRF), and CCT were 9.4 ± ment of individual UV exposure of children at different time during the follow-up. Methodology was developed to link individual 1.9, 9.8 ± 1.9 mm Hg, and 551.6 ± 36.8 μm, respectively (Schweitzer et al, 2016). In the multivariate analysis, CH and CRF values were place of residence and main holidays locations to Eurosun database; in addition, different metrics of sun exposure were constructed significantly lower in subjects having higher ambient UV exposure (-0.50 (95% CI: -0.88, -0.12)); P < 0.01; and -0.46 (95% CI: -0.78, from past iPRI experience in conducting observational studies on UV exposure. The study is currently ongoing and data analysis will -0.13); P < 0.05, respectively). Central corneal thickness was not significantly associated with ambient UV exposure. be possible in the coming years. Several markers could be investigated: early UV exposure and impact on children development, on allergies, on infectious disease, or on early biomarkers of cancer such as nevi development. This study further confirmed the increased risk for cataract extraction in subjects exposed to high ambient UVR and also suggested a risk of early AMD; encouraging the use of UV exposure information when assessing progression of ocular diseases.

It also showed that biomechanical properties of the cornea were modified by metabolic and lifetime environmental factors, espe- Occupational UV Exposure cially UV exposure. However, the process through which these factors may influence onset and progression of ocular diseases or IOP measurements needs further investigation. Outdoor workers are potentially at risk of high UV exposures during their occupations both as the cumulative amount of UV received and by the intensity of exposures. Some countries, such as Germany, have recently considered occupational outdoor jobs as eligible Haematological Malignancies for compensation in case of UV related diseases caused by such activities. A European directive was prepared to promote the legal framework for increasing protections of outdoor workers from UV exposures. However, only scarce data exists on UV exposure A consortium of three institutes coordinated by Jean-Francois Doré (Inserm, Lyon), Jacqueline Clavel (Inserm, Paris) and Mathieu assessments and these come from measurements conducted in highly selected group of workers such as shipmen. Very few studies Boniol (iPRI, Lyon) joined their expertise in an ANSES funded project named HelmeUV investigating the role of UV radiation exposure actually exist on broader, population-based, estimation of occupational exposure to UV, and aside of expert opinions, no study ever and risk of childhood haematological malignancies (CHM) in France (Coste et al, 2015). evaluated who can be considered as exposed outdoor.

This project conducted two complementary investigations, one ecological linking Eurosun UV data to the French National Registry of Childhood Haematological Malignancies, and the other observational by including individual UV exposure to ESCALE and ESTELLE studies, two nationwide case-control studies conducted in 2003-2004 and 2010-2011, respectively. Residential UV exposures at diagnosis were estimated using the Eurosun database by linkage to one of the 36,326 Communes with mainland France. The annual daily average UV exposure of the children ranged from 85.5 to 137.8 J/cm2.

The French national registry identified 9,082 cases of acute leukaemia and 3,563 cases of lymphoma diagnosed before the age of 15 years from 1990 to 2009. The incidence of CHM was calculated by Commune, year, age and gender and expressed as the standardized incidence ratio (SIR). UV data from 1988 to 2007 were extracted from the Eurosun database. For each additional 25 J/ cm2 of UV exposure, there was a significant increase in precursor B-cell acute lymphoblastic leukaemia (PBC-ALL) in children of less than 5 years old (SIR 1.18 (95% CI: 1.10, 1.27)). Further analysis of PBC-ALL in young children suggested a better fit of models with a threshold, with the risk increasing above 100 J/cm2, for which the SIR was 1.24 (95% CI: 1.14, 1.36) for a 25 J/cm2 increase. The results remained stable when analyses were stratified by deprivation index or degree of urbanization of the Communes.

When analysing the association between CHM and UV exposure in the two case-control studies, and adjusting for confounding factors (breastfeeding, birth order, early infections, day-care, parental use of home pesticides during pregnancy, pre-conception paternal smoking, exposure to road traffic, to garage and petrol stations), residential exposure to UV was associated with PBC-ALL (OR=1.30 (1.16, 1.45)) for the 3 highest deciles of exposure (UV>105.5 J/cm²) compared to the others (UV≤105.5 J/cm²), which was similar to the ecological association.

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The UVPro project was an ANSES funded project coordinated by four institutions represented by David Vernez (IST Lausanne), The yearly median exposure of the outdoor worker population ranged from 77 kJ/m2 to 116 kJ/m2, and road workers, building Jean-Francois Doré (Inserm, Lyon), Jean-Luc Bulliard (University Hospital, Lausanne) and Mathieu Boniol (iPRI, Lyon). The aim of this workers, and gardeners were the most exposed. project was to investigate the level of UV exposure of outdoor workers in France and estimate their level of exposure accounting for postures adopted in different occupations. This whole project developed the necessary tools and demonstrated the possibility to evaluate the level of occupational UV exposure as well as their distribution by anatomical body part in a broader population. Occupational UV Exposure in French Outdoor Workers

The first part of UVPro consisted in evaluating the jobs that could be considered as exposed to occupational UV in France. A random Melanoma aetiology survey was conducted in 2012 in individuals aged 25 to 69 years for which the median daily standard erythemal UV dose (SED) was estimated from exposure time and place and matched to Eurosun satellite UV data. Sunbed Use as an Additive Risk of Melanoma

A total of 889 individuals were exposed to solar UV with highest doses observed among gardeners (1.19 SED), construction workers Sunbed use is a risk factor for cutaneous melanoma (Boniol et al, 2012), and their use were classified as carcinogenic to humans by (1.13 SED), agricultural workers (0.95 SED), and culture/art/social science workers (0.92 SED). Information and communication tech- the International Agency for Research on Cancer. iPRI researchers were involved between 2015 and 2016 in several scientific publi- nology, industry, and transport workers were highly exposed (>0.70 SED). Significant factors associated with high occupational UV cations that were used to confirm the opinion of major health agencies. The task of getting a clear opinion is more and more exposure were sex (P < 0.0001), phototype (P = 0.0003), and taking lunch outdoors (P < 0.0001). This study established a ranking of impaired by intrusive and delusive activities of the indoor tanning industry (Autier et al, 2011). occupations, including unexpected occupations, according to various classifications (ISCO, ISIC and grouping of jobs under broader categories) that could be used to estimate the burden of occupational exposure in France and be reproduced in other countries (Boniol et al, 2015b).

General Model to Predict Individual Exposure to Solar UV

Measured daily ambient doses over the year 2012

In parallel of the estimation of occupational UV exposure at a population level, specific modelling was developed with a 3D numeric model (SimUVEx) to compute UV exposure ratios (ER) for various body sites and postures (Vernez et al, 2015a) (see figure). From the 3D numeric model, a regression Among gaps in knowledge, some authors argued that the risk of melanoma associated with sunbed use was restricted to skin was developed to define ER sensitive population and that sunbeds could be safely used by the majority of the population. This statement is in theory not predictors and showed good plausible from previously published observational studies which already adjusted for skin sensitivity. Nevertheless, the publication agreement with simulated data of a reanalysis of a large case-control study in USA closed this debate (Vogel et al, 2014). This study provided another demonstration (r2=0.988). In addition, relative that the risk associated with sunbed use was not limited to skin-sensitive populations; it also showed increased risk even in those errors were relatively small from not having experienced sunburns in their lifetimes. +20% to -10% in daily doses predictions, and on average only 2.4% (-0.03% to 5.4%) in yearly dose predictions. These ER will be very helpful for future research to estimate anatomical exposure of outdoor workers based only on ambient UV data and postural In addition, we further re-analysed the reported risk estimates and further proposed that the risk of melanoma associated with cadastre. sunbed use could act in an additive relationship rather than the classical multiplicative model (Boniol et al, 2015a). As a consequence, the overall population impact of sunbed use could be even greater than anticipated. Anatomical UV Exposure in French Outdoor Workers

By combining both approaches – estimation of UV exposure at population level, and modelling of anatomical estimation of UV exposure based on ambient UV – anatomical exposure was assessed (Vernez et al, 2015b).

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Changing Mortality as a Marker of Change in Melanoma Aetiology A simple question is whether UV exposure is a potential prognostic factor. Most guidelines recommend to dermatologists to encourage decrease exposure to UV of melanoma patients. This recommendation is pragmatically justified by the increased risk of To better understand the aetiology of cutaneous melanoma, a study was conducted on long time-trends of cutaneous melanoma secondary melanoma following the diagnosis of a primary tumour. But this practice has never received a systematic scientific evalu- mortality by major countries throughout the globe (Autier et al, 2015). ation. With raising concerns on vitamin deficiencies, some melanoma patients receive a vitamin D supplementation to compensate for their supposed decreased sun exposure, should they follow dermatologist’s recommendations. Using the World Health Organisation (WHO) mortality database, age-period-cohort models were fitted for seven regions with light- skinned populations. The analysis showed that cohort effects better explained changes in melanoma mortality over time than period effects with an increased risk in successive generations from 1875 until a peak year. Peak years were for subjects born in First 25(OH)D3 measurements performed within 180 days after diagnosis on melanoma patients participating to MelanCohort A) before and B) after standardiza- 1936-1940 in Oceania, 1937-1943 in North America, 1941-1942 in Northern Europe, 1945-1953 in the United Kingdom (UK) and tion on age, sex, body mass index, and month of blood sampling. The line corresponds to the Loess curve (locally weighted scatterplot smoothing) fitted to Ireland, 1948 in Western Europe and 1957 in Central Europe (see figure). After peak years, lifetime risk of melanoma death gradually 25(OH)D3 measurements and date of blood sampling, and the corresponding 95% confidence limits. This Loess curve was estimated for display purpose only. decreased in successive generations and risks of subjects born in 1990-1995 were back to risk levels observed for subjects born before 1900-1905. In Southern Europe, birth years with highest lifetime risk of melanoma death have not yet been attained. As time UV exposure passes, melanoma deaths will steadily rarefy in younger age groups and concentrate in older age groups, and ptentially fade away after 2040-2050. Eurosun’s UV data were linked by Cristina Fortes (Istituto Dermopatico dell’Immacolata, IDI, Rome, Italy) and Mathieu Boniol (iPRI, Lyon) to the hospital registry of cutaneous melanoma of IDI Rome. With data from 972 Cumulative lifetime risk of melanoma death in regions according to year of birth relative to the risk in men and women born around 1935 primary cutaneous melanoma cases, prognostic factor of UV exposure was assessed (Fortes et al, 2016). First, no protective effect was found for UVB or individual sun exposure variables on melanoma mortality. However, an increased risk of mortality was found among patients with cutaneous melanoma located on the lower limbs and in the highest decile of UVB exposure (≥3.298 J/cm) after controlling for sex, age and Breslow thickness (relative risk: 4.78 (95% confidence interval: 1.30, 17.5)). The increased risk of mortality for the highest decile of UVB was also confirmed in the subsample after controlling for sex, age, education, use of sun lamps, pigmentary characteristics and diet. These results suggested no protective effect of sun exposure for melanoma mortality but suggested increased risks for melanomas located on the Independently from screening or treatment, over next decades, death from melanoma is likely to become an increasingly rare lower limbs. Studies on UV exposure before event. The temporary epidemic of fatal melanoma was most probably due to excessive UV-exposure of children that prevailed in and after diagnosis do not yet allow to derive 1900-1960, and mortality decreases would be due to progressive reductions in UV-exposure of children over the last decades. a firm conclusion on the positive or negative role of sun exposure on melanoma prognosis. Further studies, in particular randomised trials, Prognostic factors of melanoma would be required to conclude on the need to maintain or reduce sun exposure after the The search for new prognostic factors of melanoma remains an important research topic with increasing questions on the potential diagnosis of cutaneous melanoma. role of Vitamin D supplementation of melanoma patients. Without clear evidence of any beneficial impact of vitamin D supplement use in melanoma patient, this appears as a more and more frequent practice and even becomes a standard in some countries (NICE, 2015). Our research evaluated association between sun exposure, vitamin D level and other phenotypic markers as prognostic factors of cutaneous melanoma.

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Vitamin D Autier P, Koechlin A, Boniol M. The forthcoming inexorable decline of cutaneous melanoma Newton-Bishop JA, Beswick S, Randerson-Moor J, Chang YM, Affleck P, Elliott F, et al. Serum mortality in light-skinned populations. Eur J Cancer. 2015;51(7):869-78. 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival From initially published studies and research hypothesis, it was suggested that a low level of circulating vitamin D at diagnosis could Autier P, Doré JF, Breitbart E, Greinert R, Pasterk M, Boniol M. The indoor tanning industry’s double from melanoma. J Clin Oncol. 2009;27(32):5439-44. be associated with a low prognosis of melanoma. game. The Lancet. 2011;377(9774):1299-301. NICE. Melanoma: assessment and management. 2015. Boniol M, Autier P, Boyle P, Gandini S. Cutaneous melanoma attributable to sunbed use: systematic Saiag P, Aegerter P, Vitoux D, Lebbe C, Wolkenstein P, Dupin N, et al. Prognostic Value of 25-hydroxy- review and meta-analysis. BMJ. 2012;345:e4757. vitamin D3 Levels at Diagnosis and During Follow-up in Melanoma Patients. J Natl Cancer Inst. To better understand the potential role of vitamin D level of melanoma patients, a collaboration was developed between Philippe Boniol M, Dore JF, Greinert R, Gandini S, Cesarini JP, Securite S, et al. Re: Exposure to 2015;107(12):djv264. Saiag (Université de Versailles St-Quentin, Boulogne-Billancourt, France) and Mathieu Boniol (iPRI, Lyon) and resulted in a research indoor tanning without burning and melanoma risk by sunburn history. J Natl Cancer Inst. Schweitzer C, Korobelnik JF, Boniol M, Cougnard-Gregoire A, Le Goff M, Malet F, et al. Associations project funded by the French National Agency on Cancer (INCA). Prognostic value of 25-hydroxyvitamin D3 levels at diagnosis was 2015a;107(5):djv102-djv02. of Biomechanical Properties of the Cornea With Environmental and Metabolic Factors in an Elderly Boniol M, Koechlin A, Boniol M, Valentini F, Chignol MC, Dore JF, et al. Occupational UV exposure in Population: The ALIENOR Study. Invest Ophthalmol Vis Sci. 2016;57(4):2003-11. assessed in 1,171 melanoma patients locate in Paris area and followed prospectively (Saiag et al, 2015) (see figure). French outdoor workers. J Occup Environ Med. 2015b;57(3):315-20. Vernez D, Milon A, Vuilleumier L, Bulliard JL, Koechlin A, Boniol M, et al. A general model to predict Coste A, Goujon S, Boniol M, Marquant F, Faure L, Dore JF, et al. Residential exposure to solar ultra- individual exposure to solar UV by using ambient irradiance data. J Expo Sci Environ Epidemiol. While 25(OH)D3 levels at diagnosis were inversely correlated with prognostic factors such as AJCC stage (P < .001 Kruskal-Wallis), violet radiation and incidence of childhood hematological malignancies in France. Cancer Causes 2015a;25(1):113-8. Control. 2015;26(9):1339-49. Vernez D, Koechlin A, Milon A, Boniol M, Valentini F, Chignol MC, et al. Anatomical UV Exposure in Breslow’s thickness (P < .001 Spearman correlation), and ulceration (P < .001 Kruskal-Wallis), these were not associated with the risk Delcourt C, Cougnard-Gregoire A, Boniol M, Carriere I, Dore JF, Delyfer MN, et al. Lifetime exposure French Outdoor Workers. J Occup Environ Med. 2015b;57(11):1192-6. of relapse. to ambient ultraviolet radiation and the risk for cataract extraction and age-related macular Vogel RI, Ahmed RL, Nelson HH, Berwick M, Weinstock MA, Lazovich D. Exposure to indoor tanning degeneration: the Alienor Study. Invest Ophthalmol Vis Sci. 2014;55(11):7619-27. without burning and melanoma risk by sunburn history. J Natl Cancer Inst. 2014;106(7). Fortes C, Mastroeni S, Bonamigo R, Mannooranparampil T, Marino C, Michelozzi P, et al. Can However, changes in 25(OH)D3 levels during follow-up were associated with worse prognosis: With a third quartile Q3 of average ultraviolet radiation act as a survival enhancer for cutaneous melanoma? Eur J Cancer Prev. change per year (-0.30 to 4.60 nmol/L/Y) used as reference, hazard ratios for the first, second, and fourth quarters were 1.94 (95% 2016;25(1):34-40. confidence interval [CI]: 1.36, 2.76), 1.23 (95% CI: 0.85, 1.78), and 1.61 (95% CI: 1.14, 2.28), respectively.

Figure 5: Hazard ratio (HR) of risk of relapse by yearly trend in 25(OH)D3 during follow-up of melanoma patients participating to MelanCohort adjusting on age, sex, body mass index, American Joint Committee on Cancer stage, and baseline 25(OH)D3 level. The reference category is -0.5 to 0.5 nmol/L/year. Gray vertical lines correspond to quartile of the distribution of the yearly trend in 25(OH)D3. CI = confidence interval.

This study showed that, contrary to published data from Newton-Bishop (Newton-Bishop et al, 2009), 25(OH)D3 level as diagnosis was not an independent prognostic factor of melanoma as long as the statistical analysis of data properly accounted for major prognostic factors, in particular Breslow’s thickness (see figure). In addition, this study showed that variation of 25(OH)D3 during follow-up was an independent melanoma prognostic marker. Further studies should investigate how much other modulators of 25(OH)D3 levels, such as inflammation, could explain such association.

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Health and Conflict

Health in Conflict and Post-Conflict Environments

The preservation of Health during conflict and preparing and implementing post-conflict Public Health is a major and neglected challenge for global public health. Particularly in the case of the latter (the transition from violence to security, stability and, eventually, legitimate functioning government), is not simply a matter of economic and fiscal policy, and donor support. It requires radically different, contextually sensitive understanding of the political economy of health in conflict, the bio-political aspects of health and deep knowledge of how any particular conflict effects the socio-cultural dynamics of populations from refugees, to internally displaced people and those remaining in the conflict environment, as well as host and neighbouring countries.

The International Prevention Research Institute, The Strathclyde Institute of Global Public Health@i-PRI and the World Prevention Alliance, have developed a programme of activities in this area with their partners from the Conflict and Health Research Group, King’s Centre for Global Health, King’s College London and the Department of Bioengineering at the University of Strathclyde in Glasgow, Scotland. Led by Richard Sullivan (King’s College London) this collaboration brings high-level expertise in a number of key domains to focus on this under-researched are of global health.

The following sections outline recent work to give a clearer idea of what such collaborations are capable of doing.

Battlefield Medicine

The link between military and civilian medicine has deep historical roots (Chatfield-Ball et al, 2015). In high-income countries each successive conflict that the military engages in affords the opportunity to contribute improvements in trauma care, many of which are translated into civilian healthcare systems. The wars of the last decade in Iraq and Afghanistan have changed the nature of injuries seen on the battlefield leading to further trauma management innovation. Lessons learned in these hostile environments have guided many developments in trauma care in high-income countries resulting in improved casualty outcomes and a lower mortality rate; an objective shared by the civilian and military trauma doctrine.

On the other hand, trauma management is a neglected epidemic in low- and middle-income countries, both in civilian and conflict settings. Trauma is responsible for more global deaths annually than HIV, malaria and tuberculosis combined, but receives a fraction of the attention and funding. Death from accidental or non-accidental injury has fast become the leading cause of death in young people in low–middle-income countries.

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One of the greatest challenges to implementing any sort of trauma intervention in a resource-poor setting is the inadequacies in Long after a conflict has ended, landmine and explosive remnants the health system in which it is set. Weak health systems and poor public funding test both the feasibility and the sustainability of of war (ERW) contaminated land continues to pose a threat to the trauma care development. With trauma constituting such a significant portion of mortality and economic impact, and with many health and human rights of the local population. Landmines and simple cost-effective solutions being pioneered in the military setting in high-income countries, this area should be one of the most ERW kill and maim, causing long term psychological and physical active research areas for cost-effective health investment and knowledge transfer. damage to health, and are a social and economic burden on individuals, families, communities and health systems. The battlefield has been a key area for innova- It has been estimated that, in 2013, there were a total of 3,308 casual- tions in trauma care and ties worldwide due to landmines and explosive remnants of war. As throughout the great many casualties go unreported it is likely that this figure is signifi- wars of the last two cantly higher. Although annual casualty numbers have been falling centuries, military and since 1999 the threat of injury and death remains for populations in civilian trauma care have the fifty-six landmine and ERW contaminated countries also denying evolved synergistically. arable land for agriculture and contributing in many countries to food insecurity. Landmines and ERW are designed to maim rather According to the Global than kill which means that the majority of victims survive but are Burden of Disease, trauma left with debilitating injuries that affect not only their own physical is now responsible for five and mental health but impacts upon their families and the local million deaths each year. community. High-income countries have made great strides The World Health Organisation (WHO) estimates that 650 million in reducing trauma people worldwide are disabled. This equates to approximately related mortality figures 10% of the world’s population. Of those people, 80% currently live but low–middle-income in low income countries (LICs) that are often at various stages of countries have been left economic development depending on active conflict or post conflict behind with high trauma- state. The World Health Survey carried out in 2004 found, across 59 related fatality rates, primarily in the younger population. Much of the progress high-income countries have made in managing countries, the prevalence rate of disability in the adult population trauma rests on advances developed in their armed forces. This analysis looks at the recent advances in high-income military trauma to be 15.6%, from 11.8% in High Income Countries to 18% in LICs. systems and the potential transferability of those developments to the civilian health systems particularly in low–middle-income LIC’s account for 84% of the world’s population and 90% of the total countries. It also evaluates some potential lifesaving trauma management techniques, proven effective in the military, and the disease burden. However, fewer than 3% of persons with disabili- barriers preventing these from being implemented in civilian settings. (Chatfield-Ball et al, 2015). ties in LIC’s have access to required rehabilitation services. Without access to the rehabilitation they require, those with disability may become entrenched in a cycle of poverty. Explosive Remnants of War The WHO estimates that amongst the disabled people living in During the Great War of 1914-1918, an estimated one tonne of explosives was fired for every square metre of territory on the Western LIC’s the need for prostheses will have risen to 30 million by 2011. front and clearance continued for decades after the conflict ended (Connolly, 1998). In the Ypres Salient, an estimated 300 million The need for orthotic intervention is thought to be even higher, projectiles that the British and the Germans forces fired at each other during World War I were duds (i.e. failed to explode): most of but remains underreported as requirements are not as visible as are them have not been recovered and in 2013, 160 tonnes of munitions, from bullets to 15 inch naval gun shells, were unearthed from those of prosthetics. The estimated 30 million low-income amputees the areas around Ypres (Hall, 2013). worldwide have limited access to qualitative prosthetic care. This is the reason why researchers from the University of Strathclyde The French Département du Déminage (Department of Mine Clearance) recovers about 900 tons of unexploded munitions every (Department of Bioengineering) , and members of Dutch-based year. Since 1945, over 600 French clearers have died handling unexploded munitions. Over 20 members of Belgian Explosive social enterprise organisation ProPortion initiated the concept of Ordnance Disposal (DOVO) have died disposing of First World War munitions since the unit was formed in 1919. Civilian deaths are the ‘leg bank’. The aim of LegBank is to increase the access to afford- also common. In the area around Ypres alone, 260 people have been killed and 535 have been injured by unexploded munitions able, high quality prosthetic service provision for people in low- and since the end of the First World War. Shells containing poisonous gas remain viable and will corrode and release their gas content. up-coming economies.

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Initially in post conflict countries and with the intention to Syria and the isolation of wild poliovirus type 1, traced to Pakistan, from sewage samples in Israel scaling up other countries. LegBank has developed an innova- towards the end of 2013. The successful eradication of wild poliovirus therefore rests on Pakistan’s tive device with a service model to reach low-incomes amputees immunisation programme and strategy. and increase access to high quality prosthetics. The device, developed by researchers from Strathclyde University and Since the launch of the Global Polio Eradication Initiative (GPEI) in 1988 the global incidence of design engineers from Reggs, known as Majicast, is a hands- poliomyelitis has fallen by nearly 99 %. From a situation where wild type poliovirus was endemic in free casting device used for manufacturing lower limb pros- 125 countries across five continents, transmission is now limited to regions of just three countries thetic sockets. The socket is the component which connects - Pakistan, Afghanistan and Nigeria. A sharp increase in Pakistan’s poliomyelitis cases in 2014 prostheses securely to patients’ residual limbs. It is unique for prompted the International Health Regulations Emergency Committee to declare the situation a every human being and therefore crucial for pain free walking. ‘public health emergency of international concern’. Global polio eradication hinges on Pakistan’s Sockets produced with this device, can increase user comfort, ability to address the religious, political and socioeconomic barriers to immunisation; including stability and fit. This will subsequently result in enhanced discrepancies in vaccine coverage, a poor health infrastructure, and conflict in polio-endemic quality of life. In addition, the total time and costs for socket regions of the country. This analysis provides an overview of the GPEI, focusing on the historical production decreases by an estimated 75%. and contemporary challenges facing Pakistan’s polio eradication programme and the impact of conflict and insecurity, and sheds light on strategies to combat vaccine hesitancy, engage local communities and build on recent progress towards polio eradication in Pakistan (Hussain et al, Eradicating Polio in Pakistan 2016). (Hussain et al, 2016) Pakistan’s polio eradication campaign is facing a range of challenges due to a poor health infra- Our continuing ability to control and eradicate infectious structure, managerial and operational deficits and serious inequities in immunisation coverage diseases is predicated on health security. With the world expe- across the country. Conflict and insecurity have been particularly damaging to polio eradication riecing ever more asymetric conflicts partiuclar involving non efforts in recent years, especially in FATA and KP, the main reservoirs of wild poliovirus in the state armed groups the impact on public health campagins is country. Operation Zarb-e-Azb, a military offensive launched in 2014 against militants in FATA, becoming more acute. Before the launch of the Global Polio has re-established access to vaccination teams and enabled more intensive SIAs, translating to a Eradication Initiative (GPEI) in 1988, poliomyelitis paralysed significant reduction in reported cases of poliomyelitis in 2015. Pakistan’s polio eradication effort and killed hundreds of thousands of people every year. Polio can capitalize on these gains by addressing the gross inequities in its strategy and infrastructure, is highly infectious and horizontal transmission usually occurs help shift perceptions against vaccination through more concerted community engagement and via the faeco-oral and oral-oral routes, with faeco-oral trans- education initiatives, and address vaccine hesitancy using tools such as mass-media campaigns. mission contributing to the majority of cases especially in Strengthening collaborations with influential religious leaders and organisations can also help regions with poor hygiene and sanitation. The development mitigate the religious and political dimensions of vaccine hesitancy in Pakistan. Addressing these of the inactivated poliovirus vaccine (IPV) in 1955, led to a social and systemic deficits is critical to eradicating polio from Pakistan and achieving the GPEI’s sharp reduction in viral transmission and cases in the USA from objectives. approximately 20,000 cases per year in the 1950s to less than 1000 cases by the 1960s. However, the live-attenuated oral Pakistan’s polio eradication campaign provides important lessons for the delivery of future global poliovirus vaccine (OPV) developed in 1963 remains the major health initiatives in regions in conflict; the role of traditional social and religious norms and their vaccine in the developing world due to its cost-effectiveness, wider diplomatic, security, economic and social repercussions in an era of increasing globalisa- easy oral administration and comparatively better induction of tion should not be underestimated in achieving global health outcomes and fostering broader intestinal immunity compared to the IPV. socioeconomic development.

In 2015, four of the six WHO regions were certified as polio- free, leaving Pakistan and Afghanistan as the remaining An Assessment of the Barriers to Accessing the Basic Package endemic reservoirs of wild poliovirus. Illiteracy, religious of Health Services (BPHS) in Afghanistan (Frost et al, 2016) misconceptions, conflict and insecurity in these regions have seriously hampered vaccination efforts and have been directly Afghanistan’s history is blighted by conflict, a repetitive cycle of externally and internally driven associated with a rise in wild poliovirus transmission with the warfare with only brief periods of peace. The decades of conflict decimated much of the social potential to unravel the progress made by the GPEI. These fears infrastructure including the country’s health system. By 2002, Afghanistan had some of the poorest were realised following an outbreak of 36 cases of polio in health indicators of any country in the world particularly in the areas of infant, child and maternal

iPRI 87 iPRI - International Prevention Research Institute — Principal Contributions iPRI mortality. In response to these immense health system challenges the Basic Package of Health Services (BPHS) was launched in 2003 Surging mobile populations, followed by the Essential Package of Hospital Services (EPHS) in 2005 by the Ministry of Public Health (MOPH) of the new Afghan interim government with support from international donors and non-governmental organisations (NGOs). cheap air travel and increasing With no history of a functioning healthcare system, the creation of the Basic Package of Health Services (BPHS) in 2003 was a international interconnections go hand in response to Afghanistan’s dire health needs following decades of war. Its objective was to provide a bare minimum of essential health services, which could be scaled up rapidly through contracting mechanisms with Non-Governmental Organisations (NGOs). Despite the good intentions of the BPHS, not enough has been done to overcome the barriers to accessing its services. This analysis, hand with the spread of infectious disease. enabled through a review of the existing literature, identifies and categorises these barriers into the three access dimensions of: acceptability, affordability and availability. As each of these is explored individually, analysis has shown the extent to which these barriers to access are a critical issue, consider the underlying reasons for their existence and evaluate the efforts to overcome these barriers. Understanding these barriers and the policies that have been implemented to address them is critical to the future of health system strengthening in Afghanistan.

The Role of Open Source, Signals and Image Intelligence Tools in Infectious Disease Outbreak

Infectious disease outbreaks – SARS, MERS, Ebola – have proved to be potent threats to national and international security. Interconnected trade, cheap air travel and increasingly mobile populations, including those as a result of conflicts such as Syria, will continue to make infectious disease outbreaks a significant threat to the global community. This discourse has its roots in the widening of the concept of security that occurred in the 1990’s. Moving away from a primarily inter-state approach, this new conceptualization considered other intra-state and transnational threats as important, including that of disease outbreak. Most previous discussion has focused primarily on whether national intelligence agencies should consider infectious disease as a security risk within their remit of operation, rather than an analysis of their practical techniques for doing so. However, there has been little discussion about how national intelligence agencies would go about this, beyond the occasional unspecific mention of their ability to use ‘clandestine’ methods to help detect and verify outbreaks.

Current conventional surveillance systems for the early detection of epidemics and other diseases fall short of being completely successful. We have explored the ways certain tools and concepts relating to Open Source Intelligence, Signals Intelligence and Image Intelligence from the world of intelligence could and are being applied to infectious disease detection and control as part of global health security. We explored how Open Source Intelligence can be useful due to the ubiquity of internet usage across the world, and analyse some of its previous deployment history in this role at the World Health Organisation. Image Intelligence is evaluated through the potential use of UAV drones, and we look at how they could aid in contact tracing and disease surveillance in areas with a widespread populace and a poor communications infrastructure. Through Signals Intelligence, we explore how the mass collection and analysis of communications data could potentially add to disease surveillance, and balance this against questions of ethicality and cost of use. Our research is not all encompassing by any means and is intended to provide an introductory discussion; it is hoped that this provides a base for future study and possible integration into an effective global surveillance system.

Chatfield-Ball C, Boyle P, Autier P, van Wees SH, Sullivan R. Lessons learned from the casual- Hall A. Mustard gas blisters and a daily risk of death: Bravery of soldiers still clearing the ‘iron ties of war: battlefield medicine and its implication for global trauma care. J R Soc Med. harvest’ of World War I shells from beneath Flanders’ fields.: Associated Newspapers Ltd; 2013. 2015;108(3):93-100. Available from: http://www.dailymail.co.uk/news/article-2497732/The-iron-harvest-Meet- Connolly K. Legacies of the Great War United Kingdom: BBC News; 1998. Available from: http:// soldiers-tasked-clearing-hundreds-tonnes-deadly-World-War-I-shells-mines-beneath-fields- news.bbc.co.uk/2/hi/special_report/1998/10/98/world_war_i/197406.stm. Flanders.html. Frost A, Wilkinson M, Boyle P, Patel P, Sullivan R. An assessment of the barriers to accessing the Hussain SF, Boyle P, Patel P, Sullivan R. Eradicating polio in Pakistan: an analysis of the challenges Basic Package of Health Services (BPHS) in Afghanistan: was the BPHS a success? Global Health. and solutions to this security and health issue. Global Health. 2016;12(1):63. 2016;12(1):71.

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IMPORTANT CONTRIBUTIONS

Multiple Sclerosis

ultiple Sclerosis (MS) is a chronic disease which has a substantial negative impact on quality of life Mis the most common non-traumatic cause of and activities of daily living. Thus, MS is one of major neurologic disability in young adults. MS-related challenges in Global Public Health. disability, as it progresses, can be life altering and

Aethiology of Multiple Sclerosis

The aetiology of MS remains unclear. It is accepted that auto-reactive lymphocytes, which attack the myelinated axons in the Central Nervous System (CNS) and destroy the myelin and the axons to varying degrees, play an essential role in MS, but the cause of this In addition to our key projects, auto-reactivity and its relapsing-remitting course are unknown (Kalman, 2008). Microbial infections can act as triggers inducing or promoting autoimmunity, resulting in clinical disease manifestations in geneti- iPRI is committed to more broadly cally predisposed individuals. Replication or activation of some infectious agents like Epstein Barr Virus, HSV1 and HSV2, HSV6, and Lyme disease has been observed during MS exacerbations. investigating and formulating According to “hygiene hypothesis”, an increased exposure to infections during childhood confers protection against MS because a recommendations regarding multiple heavy burden of microbial or parasitic infections creates a persistent effect on the immune system by shifting from a pro-inflammatory helper Th1 cell profile to an anti-inflammatory Th2 cell profile. The improvements in socioeconomic and lifestyle conditions in health issues. The following pages many countries during the past century might have eliminated the earlier exposure to infections at young ages and so the protection against autoimmune disorder (Bach, 2002). contain some, but not all, of this work. Other factors have been implicated in the pathogenesis of MS, among which diet, environmental toxins and sunlight, but none of this has been definitively confirmed. Great insights have been acquired recently in factors which vary with latitude like ultraviolet radiation (UVR) and vitamin D.

Clinical course of Multiple Sclerosis

The clinical course of MS is highly variable and unpredictable. In most patients the disease is characterized initially by episodes of reversible neurological deficits, which are often followed by progressive neurological deterioration over time.

The diagnosis is based on the 2010 version of the McDonald criteria which consist of a combination of clinical, imaging and para- clinical tests (ie, CSF, evoked potentials) (McDonald et al, 2001) demonstrating dissemination of central nervous system lesions in both space and time.

There is wide consensus among neurologists that patients may be grouped into four major categories based on the course of disease: relapsing remitting (RRMS), primary progressive (PPMS), progressive relapsing (PRMS), secondary progressive (SPMS).

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The dynamic evolution of the disease makes possible the conversion from one category to another, for instance from RRMS to SMPS. Because of its unpredictable course a strict and regular clinical follow up of patients is essential. The Teriflunomide PASS Study

On the 30th August 2013 the European Medicines Agency (EMA) approved the marketing authorisation for Teriflunomide (HMR1726), Multiple Sclerosis’ Epidemiology and Geo-epidemiology the active metabolite of Leflunomide used in the treatment of rheumatoid arthritis. Teriflunomide is an immune-modulator agent with both anti proliferative and anti inflammatory activity that has shown to be effective in remitting-relapsing forms of Multiple The prevalence of MS is approximately 1/1000 (83/100,000 in Europe) and the estimated number of people with Multiple Sclerosis Sclerosis (MS). The results of two studies of phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) and TOWER (Teriflunomide Oral is 2.3 millions in 2013. The typical onset is between the ages of 20 and 40 years, and women are affected more frequently than men in people With relapsing remitting multiple sclerosis) showed a significant reduction of annual relapses rate and handicap progres- (approximately 3:1). sion at two years in comparison with placebo.

An increase of the global median prevalence of MS from 30 per 100,000 in 2008 to 33 per 100,000 in 2013 has been observed, mostly Since 2014 the International Prevention Research Institute has been organising a five-year Post Approval Safety Study (PASS) for owing to increased life expectancy, more diagnostic accuracy, amelioration of socioeconomic structure, and better treatments. Teriflunomide that has been requested by the EMA in order to further evaluate the long-term risks of Teriflunomide (TF).

The global prevalence of Multiple Sclerosis shows a north–south gradient in the northern hemisphere: the prevalence is lower near This study called “Prospective Cohort Study of Long-Term Safety of Teriflunomide in Multiple Sclerosis Patients in Europe” proposed the equator (<5/100,000) and higher in northern countries (>100/100,000 in North America, Canada and northern Europe); the to investigate the incidence of selected safety events and overall safety in patients treated with TF in Europe in real life. The protocol reverse is observed in the southern hemisphere (Alonso et al, 2008). High prevalence rates are between 45 degrees and 65 degrees for the study has been developed in collaboration between iPRI and the CHMP of the EMA. north and the observed increased incidence of disease might be due to the reduction of sunlight exposure hours in the Northern countries. The study population comprises MS patients from study centres of four countries: Belgium, Denmark, Italy (namely, the region Lumbardy), Norway. All patients are treated with Teriflunomide or with other DMTs. It is not clear whether this geographical association is causal. The uneven distribution is influenced by population genetics, interplay between genes and physical environment and socioeconomic structure, including availability of medical facilities (Kurtzke, 1965). The primary objectives of this PASS study are : i) to characterize the long term safety profile of Teriflunomide by determining the incidence of adverse events of special interest (AESIs) in a real life setting in patients prescribed with Teriflunomide by considering Moreover, there is a complex interaction between space and time. Indeed, over the previous 25 years an inversion has been observed several comparison groups; ii) to evaluate whether the treatment is associated with an increased risk of any of the AESIs compared of this latitude gradient in Italian regions, Scandinavia and North Atlantic and an attenuation of latitude gradient in Europe and in to other approved DMTs. North America, whereas the latitudinal gradient on the Southern hemisphere remains unchanged. The AESIs from TF include acute liver injuries, infections, interstitial lung disease and pancreatic effects, notably pancreatitis and There is evidence that the risk of acquiring MS might be determined at the time of puberty or before with a lengthy latency before other potential risks, serious opportunistic infections including Progressive Multifocal Leukoencephalopathy (PML), malignan- symptom onset. Indeed, migrants from high to lower risk areas retain the MS risk of their birth place only if they are more than 15 cies, peripheral neuropathy, and cardiovascular events. The AESIs are associated with the International Statistical Classification of year old at migration time. Conversely, if they are less than 15 year old they appear to acquire the MS risk of new area. Diseases and Related Health Problems (ICD) codes (version 10) as a support to ensure consistency in the recording of the AESIs. Only adverse events leading to hospital admission will be analysed in this study.

Treatment Over the two past years different meetings with Principal Investigators (PIs) have been organized, with the purpose of drafting the preliminary aspects and the major elements of the protocol which has been written according to EMA requirements and approved Several drugs are available to potentially ameliorate the unpredictable course of this disease, the so-called disease modifying by EMA. therapy (DMTs) comprehensive of: i) the “basic therapy”, such as Interferon β-1a, β-1b, glatiramer acetate, dimethyl fumarate, teriflunomide; ii) “escalation therapy”, such as fingolimod, natalizumab, alemtuzumab, mitoxantrone. In particular, the key actions enacted in this PASS Study are the following: • Some national MS registries have been identified through literature search from the results of the MS Barometer 2011 and by The indication for therapy depends mainly on the clinical course, disease stage and disease activity. Therapy should be initiated as enquiring at 33 national MS societies (Flachenecker et al, 2014). early as possible with basic therapeutics and monitored clinically with periodic MRI. • All patients have been identified in a pooled analysis of existing National MS registries in Europe. All identified patients are followed by neurologic centres (managing the above registries) at time of MS diagnosis. The centres are used as “primary source” An ongoing clinical and/or radiological disease activity and/ or relevant side effects, justify the transition from basic to escalation since they collect routinely on baseline information in the MS Registries: age, gender, disease severity, MS diagnosis, approved therapy. therapies for MS, disease status, clinical course, relapses, country, month and year of initiation of the MS therapy. Moreover, the MS Registries also monitor the long-term therapy. So far, there are not validated efficacy monitoring protocols or criteria for changing the DMTs for MS, because of: i) the difficulty into • We organized site visits with local PIs to consult for a deeper knowledge of their study centres and their National MS registries distinguishing whether lack of apparent disease activity represents a therapeutic response or the natural history of the disease; ii) where patients are enrolled. the lack of biologic markers that allow one to distinguish treatment responders, partial-responders, and non-responders. • We made a study to compare the criteria for the diagnosis of MS in each country and to examine the impact of these criteria on the composition of each register.

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• Before the launch of the study a Pilot Study has been conducted to assess the completeness of patient data in the National MS registries. This has been done by comparing the rosters of each national MS Registry with the corresponding National Prescription Education and Training Database. This resulted in a population-based databases which will be employed to produce a registry of MS patients for use in the study and to identify exposure to the various therapies, if the National MS Registry is not complete. ducation and training in prevention is an It has been used as a reference material since 2010 • We also searched patient-related information in other national registries (Death Registers, Cancer Registers, Hospital Discharge Eessential objective of iPRI. As an illustration in the summer school organised by iPRI in collabo- Registers). In the northern regions these registers are available and they are linked to National MS registries, covering the entire of the importance of education and training, in ration with the University of Dundee to train future population in a region included in the Prescription Database. They interconnect as “secondary source” the information from particular in low and middle countries, the first book actors in epidemiology from low and middle income the several population based registries and link them together by a unique personal and anonymous identity number(passive published by iPRI in its “iPRI scientific publication” countries. follow-up). For Belgium and Italy, we have checked the efficiency and reliability of a recorded linkage of different databases. was the textbook on Epidemiology and Biostatistics. • We elaborated a common data collection protocol for use in each selected registry, after circulating among the local Principal Investigators a questionnaire on practical aspects of their registries. The aim is making the pooling of data from all registries feasible both for the retrospective phase (baseline information) and the prospective phase (informations about occurrence of Textbook on Epidemiology & Biostatistics AESIs). • We provided study centres also with the organization of data extraction, according to which the baseline informations must This first book in the “iPRI scientific publication” series is a textbook on Epidemiology and Biostatistics. be extracted by National MS registries, meanwhile data about AESIs must be extracted passively through linkage of the other This book provides an introductory to intermediate level of principles and methods in Epidemiology and registries to National MS registries. Biostatistics. The book is aimed at providing students and junior health workers from all over the world, • We provided the elaboration of a statistical analysis plan containing the variables necessary for iPRI to analyse the data of the MS but especially those from lower-resource settings with clear and concise examples in the subject areas. registries database and describing how they are going to be analysed. Al the database necessary for the PASS are created locally in each participating centre and they are not be transferred elsewhere. • We checked on reliability of different operating systems (IMED) and of different source codes (INAMI codes) to extract the Epidemiology and Biostatistics. Zheng T, Boffetta P and Boyle P. iPRI Scientific Publication 1, Lyon, iPRI, 2011, ISBN 978-2-9539268-0-4. requested data from the Belgian and Italian registries.

The high quality of the data recorded by the different National MS registries is allowing the conduct of the study in accordance with the EMA requirements. iPRI, in cooperation with the participating study centres, will provide the final study report to the EMA. iPRI - University of Dundee Summer School on Epidemiology and Global Health

The results from this study could be a great challenge for the new category of MS oral agents, since this category of drugs represents Between 2010 and 2012, iPRI organised jointly with the University of Dundee three consecutive years of a summer school on an effective improvement of therapy acceptance for many patients refusing injectable treatments. Epidemiology and Global Health. This summer school targeted health professionals from low- and middle-income countries for which fellowships were provided to encourage participation to these courses. Each year, the programme was organised Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Kalman B. Multiple Sclerosis. In: Kalman B, Brannagan TH, editors. Neuroimmunology in Clinical over three weeks, taught on-campus in Dundee, and Neurology. 2008;71(2):129-35. Practice. Malden: Blackwell Publishing Ltd; 2008. p. 27-82. provided an introductory course in Epidemiology, Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Kurtzke JF. Medical facilities and the prevalence of multiple sclerosis. Acta Neurol Scand. Med. 2002;347(12):911-20. 1965;41(5):561-79. Biostatistics and Global Health, with the aim of building a Flachenecker P, Buckow K, Pugliatti M, Kes VB, Battaglia MA, Boyko A, et al. Multiple sclerosis McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diag- developed understanding in these areas and stimulating registries in Europe - results of a systematic survey. Mult Scler. 2014;20(11):1523-32. nostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50(1):121-7. quality disease prevention research activities in resource- limited countries. The programme included several modules such as disease registration; design and analysis of observational studies; causal inference; principles of screening; introduction to biostatistics; analysis of age, period and cohort effect; multivariate analysis; statistical power; contextualising global health; environment and health; improving health outcomes; and reconstruction and capacity building. Over these three years, about a hundred health professionals originated from low and middle income countries were trained.

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Master Programme in Global Public Health Training in Systematic Reviews

The Strathclyde Institute for Global Public Health is an innovative collaboration in research and education between the University of In 2016, iPRI developed a detailed curriculum on training in systematic reviews for researchers and public health officers involved in Strathclyde and the International Prevention Research Institute (iPRI) in Lyon, France. The partnership risk assessment. This was originally planned as a proposal support to fulfil the needs of the European Food safety Authority, and will established in 2014-2015 a curriculum for a two-year full-time Master’s programme in Global Public be further integrated within the new project on online courses (see below). This course consists in a two-week course with 4 major Health. modules: 1. Systematic review and protocol development; 2. Extraction data from studies included in a systematic review, exploring heterogeneity and interpreting the results of a meta-analysis; 3. Appraising reliability of individual studies; 4. Information retrieval This Master’s Programme is a unique, high-level programme that merges the strengths of both institu- techniques. The originality of this curriculum is the use of several case studies built from the experience of iPRI’s senior researchers tions. The course was designed in response to the international need to improve global Public Health and and partners involved in this curriculum such as Dan Krewsky (university of Ottawa). to contribute to capacity building necessary for its successful implementation.

During the first year, the programme emphasizes the basics in Epidemiology, Biostatistics and Public Health with teaching provided Development of Online Courses by iPRI’s professors and internationally renowned leaders in their fields. During the second year the students apply the skills acquired in the first year to global public health issues via a variety of modules such as Provision of Drinking Water, Sanitation, Public Health Since 2016, iPRI is working on a new project of online course in epidemiology and Law, Civil Engineering, Nutrition and Physical Activity. global health. Building on past education and training developments, and to enable broader access throughout the world in particular in low and middle income countries, iPRI is setting up online course using open source learning platform transferring all the Math For Public Health (M4PH) teaching material and experience gathered over past decades by iPRI’s senior faculty in remotely available resources. These resources will be constantly updated to incorpo- In 2015/2016, iPRI structured a consortium Math For Public Health (M4PH) setting together practical actors of public health, rate new elements in the field of epidemiology such as training in systematic reviews. academia and SMEs. The aim is to create a European Training Network on higher education on new mathematical and statistical models applied to public health (http://m4ph.org/). The objective is to prepare future research leaders, able to conceive multidisciplinary methodological and computational techniques, and to cope them with real public-health data to shape Public Health Policies. Equally important, the early stage scientists will be trained to develop solid communication skills, and they will be exposed to multiple Vaccination and Infectious Disease Modelling, and career avenues, at the interface between academic scientific institutes, public health centres and industries. Modelling of Other Biomedical Phenomena

he prevention of the spread of infectious birth of Epidemiology. In particular, the introduction ASSET Summer School Tdiseases is one of the major challenges for global of Vaccination is probably the medical development public health, and historically was at the root of the that had the largest impact on public health. Within the activities of the EU-funded project ASSET (http://www.asset-sciencein- society.eu/) of which iPRI is partner, iPRI was a key participant, from 21st to 24th An interesting feature of infectious diseases is that their spread can be analysed by means of statistical tools as well as investigated September 2015, in the first “Summer School on Science in Society related issues using mathematical models adapted from Statistical Physics models. Indeed, during the past century, synergies between Public in Pandemics”, Rome, Italy. The ASSET Summer School aimed at establishing an Health Sciences, Statistics and Mathematics have resulted in substantial progress in the prevention and control of epidemics and interactive learning space for researchers and practitioners in the field of Science pandemics. Eradication of smallpox late last century was arguably the most important Global Public Health success. in Society (SiS) related issues in Pandemics; sharing and exchanging issues related to conducting and communicating research in SiS according to a transdisciplinary In recent decades public health has faced an unexpected enemy: a growing opposition to vaccination for reasons ranging from perspective, ranging from public health to social science and communication; the spread of uninformed rumours, to philosophical objections to vaccination. Medium and hig income countries are particularly addressing and critically discussing current discourses on research methodologies vulnerable to this opposition. PROVA - Pseudo-Rational Objection to Vaccination - is one such rationale. It can be summarized as and findings as well as on practice-based cases. follows: “X disease is now very rare in my country: why should I vaccinate my children or myself ? In fact, as per the Internet, vaccines have multiple side effects”. Evidence demonstrates that this objection is myopic in that the reason a vaccine-preventable disease is close to eradication is directly due to extensive vaccination programs.

PROVA helps us to elucidate two underlying challenges facing Global Public Health’s fight against Infectious Disease. First, we live in what sociology calls the ‘Post-Trust-Age’ (Löfstedt, 2005) in which citizens increasingly distrust all suggestion by public and moral

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authorities. Second, the Internet and other media have become formidable rumour mills deprived of scientific foundation. This easy We observed substantial heterogeneities across Europe as regards vaccine accessibility, the target population, vaccination strategy, access to rumour vectors has been exploited by increasingly formidable anti-scientific groups who admittedly communicate better non-pharmaceutical infection control measures and respective responsibility of organisms involved in the management of different than the scientific community. aspects of the pandemic during the H1N1 crisis. The analysis of risk communication (RC) showed the lack of transparency and coherence of the process and the messages transmitted by authorities. In the field of methodologies a prominent role is assigned iPRI understands that both operational and methodological Public Health Science and Practice have to radically change to win to Behavioural Epidemiology. the battle against vaccine-preventable and other infectious diseases; new scientific avenues must be explored if we are to achieve societal change. We are exploring said avenues in collaboration with a network of institutions, in particular within the framework of In accordance with our analysis, the expert group recognized that rumours and suspicions regarding adverse effects of vaccines the SWFS-focused EU project ASSET and the M4PH Training Network. have shaken people’s trust in vaccination, contributing to what is known as a post-trust society. The most frequently cited research areas considered as vital for future pandemic preparedness stated by the expert group were: effectiveness of antiviral drugs, technology transfer, mechanism of the emergence of the viruses at the basic level, an epidemiological tool to monitor early detection of The EU Project ASSET outbreaks and trends, standardisation and flexibility of pandemic plans, sociological aspects of vaccination including risk perception, how to improve data sharing, efficiency of social distancing and its impact on the economics, tools for real time evolution of It is increasingly clear that to be effective, Global Public Health in a Post-Trust era, must go beyond the traditional one-way approach, pandemics, and how to optimize the use of mathematical models. wherein information and decision-making are uni-directional from the top down. Overall, re-building trust in the current post-trust society requires effective RC campaigns that consider the social and cultural The EU plans to overcome misinformation using the paradigm of Science With and for Society as manifested by their research direc- heterogeneity of the target population. It is also crucial to exploit and anticipate the role of Social Networks and Internet and tives in the Horizon 2020 and in the previous FP7 programmes. The key concept of Science With and for Society is that Public Health integrate their use in communication strategies. RC and PH-related decisions can no more be unidirectional but, to some extent, it (and other scientific fields) must not attempt to solve societal challenges single-handedly opting instead for partnerships with, for ought to be bidirectional. instance, Civil Society. This task has been done in collaboration with Lyonbiopole. The ASSET EU project (Action plan in Science in Society in Epidemics and Total Pandemics) is the Mobilisation and Mutual Learning Action Plan (MMLAP), which aims: Roadmap Responsible and Open, Citizen-Driven Research 1. To address scientific and societal challenges raised by major epidemics, pandemics and associated crisis management using the Science With and for Society paradigm The aim of this Task of ASSET has been the will design a roadmap towards responsible and open, citizens-driven, research and 2. To explore and map Science With and for Society related issues in global pandemics innovation on PH Sciences in the domains of epidemics and pandemics. Open innovation in pandemic related research requires 3. To define and test a participatory and inclusive strategy for success; ASSET combines global Public Health, epidemiological and initial investments because it demands a shift in the traditional, scientist-centered, approach. We reviewed existing experiences of vaccine research, social and political sciences, gender studies, science communication. user-driven innovation in the health and pharmaceutical sector. We had to answer to the question to what extent, and according to which conditions, user innovation is possible in the field of GPH research concerning prevention and control of major epidemics iPRI has provided substantial guidance to better define the aims and the practices of the Project, both from the operational and the and pandemics. Existing initiatives, projects related to the involvement of “users” in epidemic infectious diseases prevention and methodological points of view. response as well as other life sciences SWFS-centered applications were identified. From these listed existing initiatives, a roadmap of recommendations was elaborated (see figure). The central paradigm we adopted is the emerging concept of Public and Patient The project is headed by one of oldest and most important Public Health institutions in Europe, the Istituto Superiore di Sanita’ Involvement in medical and PH scientific research. (the NIH of Italy), whose consortium members include both academic institutions such as Haifa University and a series of SMEs and Institutions working at the juncture between Science and its Practical Applications to Societal Problems. This task has been done in collaboration with Lyonbiopole.

The iPRI researchers involved in this project are Dr. Alberto d’Onofrio (principal investigator), Ms. Miruna Dragomir, and Dr. Alina Macacu.

In the framework of ASSET the International Prevention Research Institute is actively involved in some key tasks.

Unsolved Scientific Questions in Pandemics and Epidemics

The aim of this ASSET task was to outline – within the guidelines of Science in Society - the main unsolved scientific questions regarding epidemics and pandemics, focusing on the H1N1 2009 pandemic. We complemented our analysis with a questionnaire sent to experts in the field of pandemics and epidemics, and by organizing a focused workshop with a number of EU experts in various scientific fields of Public Health and Sociology.

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An intrinsic limitation of traditional epidemic models is that they are based on a statistical mechanics approach: the contagion is Graphical Representation of the key points of the proposed Roadmap. abstracted as a chemical reaction that can or cannot occur upon the random encounter of two “particles”: the infectious and the susceptible subjects.

However useful it may be to describe many epidemic scenarios, this approach misses a critical factor: the above-mentioned behav- Key Players Implementation ioural component. Thus, event this theoretical approach fail in correctly describing the recent response to vaccination strategies Groups of patients & their in case of non-mandatory vaccination. This led in last ten years to the birth of a new branch of epidemiology: the behavioural Bidirectionality in networks EU & national associations epidemiology of infectious diseases, aimed at investigating the changes of behaviour of individuals of a population where an infec- public health decisions of consumers Neutralise tious disease is spreading, and their impact on the spread itself of the disease. As clearly shown by contributes of the first book ever Building the PPI published on this topic (Manfredi et al, 2013), the behavioural epidemiology is intrinsically multi-disciplinary, requiring the interven- negative side e ects Rethinking of the research tion not only of applied mathematics and statistical epidemiology but also of economy, sociology and anthropology. Moreover, this Minimize the risks related to a massive process and pipeline new field has large potentialities to interact with SWFS/SiS, as we recently stressed (Manfredi et al, 2013). Communication of PPI in health research & Education to PPI A major determinant, negatively influencing the propensity to vaccinate, is the vaccine-related side effects. The propensity to Rethinking of the research process and vaccinate is determined by the opposition of two forces: the fear of acquiring the disease, which is related to the perception of its pipeline spread, and the fear of suffering vaccine-related adverse events. This tension was modelled by coupling a classical epidemic model with an imitation game dynamic representing the temporal evolution of the average population-level propensity to vaccinate (d’Onofrio et al, 2011). However, vaccine awareness campaigns aimed at increasing vaccine propensity can be easily embedded in the model. The resulting model suggests that if the campaign is appropriately intense then it can favour the eradication of the Best Practice Platform and Stakeholder Portal target disease (d’Onofrio et al, 2012).

The Best Practice Platform (BPP) is a web-based, collection of best, good and promising practices on SIS related issues in GPH Recently we applied a classical tool of mathematical economics, Optimal Control, and a somewhat opposite heuristic tool of opti- concerning prevention of infectious diseases, and control of their spread. This platform will be sided by a Stakeholder Portal, which mization, Simulated Annealing, to optimally plan these awareness campaigns, by taking into the account the material impossibility will provide a gateway for interested stakeholders to register their interest in becoming involved. The Platform and the Portal of continuously updating the awareness campaign. Our simulations show that the theoretical optimal campaign is far less abstract will synergize in the seeking out and promotion (among researchers, PH institutions, industry etc…) of solutions that are already than believed since it is largely robust (Buonomo et al, 2017a) to large deviations. Moreover, in another work (Buonomo et al, 2017b) de-facto or potentially best practices but haven’t yet been widely adopted. we showed that alternating low/large numbers of contacts at risk of infection linked to alternating holidays/school terms can indi- rectly help awareness campaigns. Namely, we showed that the negative impact of the large number of contacts during the school The work on BPP will result in the development of Guideline for developing the above-outlined Best Practices, which will be part of terms is luckily over-compensated by the decrease of contacts at risk during the holidays. the platform. These guidelines will be validated through a consensus-building process among stakeholders such as: Organisations, PH institutions, Universities, etc. One of most striking phenomena observable in natural, economic and social domains is the so-called abrupt phase transition: the small change of single system parameter can cause a large “catastrophic” (or “hugely beneficial”) effect. The study of this class This in-progress task, leaded by iPRI is being done in collaboration with the National Health Institute of Italy and with ZADIG. of phenomena is one of most important aspects of statistical mechanics, and it is at the basis of catastrophe theory. Recently, we proposed a mathematical model (d’Onofrio et al, 2017) suggesting that the inclusion of behaviour-dependent vaccine propensity for vaccine-preventable infectious diseases can induce such catastrophic transitions in case of realistic imperfect vaccines (giving Behavioural Epidemiology non-permanent immunity and partial protection). Notably, it might induce transition from low to very large prevalence in the case where the parameter tuning the fear of vaccine -related side-effects exceeds a threshold, or the parameter tuning the perceived Both vaccine propensity and also the risk of infection depend on behavioural factors often dominated, as above mentioned, by risk of getting the infection decreases below a threshold. We are currently applying phase transition theory to other aspects of the irrational factors. influence of human behaviour on the spread infectious disease.

Disease-related risk perception and the consequent changes in the human behaviours impact onto the transmission of the disease, These examples demonstrate that the spread of infectious disease is an ideal object of investigation for methodologies coming which implies that it can modulate its population dynamics. from Theoretical Physics. We have illustrated these methods (“exotic” for epidemiology as their applications to epidemiology are for physics…) in the book “Statistical Physics of Vaccination” (Wang et al, 2016), of which iPRI contributed the chapters on classical The increasing qualitative consciousness of this phenomenon and the subsequent start of inflow of related epidemiologic data led (non-behavioural) and on behavioural modeling. in last ten year to a deep rethinking of the mathematical modelling of infectious diseases. These models are not only of intrinsic scientific interest, but they also are useful tools actively employed by national and international public health agencies to decipher epidemic dynamics, and to assess the impact of prevention measures.

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Modelling of Other Biomedical Phenomena Nutrition

We illustrate here our activity in the modelling of some intra-cellular phenomena that are important to he iPRI nutritional research plan focussed deciphering the pharmacodynamics of key classes of drugs. Ton two main research topics, i.e., the relation between nutrition and cancer, and the relation Classical models of protein dynamics are deterministic. Although useful, deterministic models have short- between sugar and health. The aims of both comings. Two are very we known: i) the presence of a random disturbance is most often of extra-cellular programs are the prevention of chronic diseases: origin; ii) in last two decades a number of experimental studies have revealed that some proteins are cancer and with obesity associated health present in very low concentration, which implies a stochastic dynamic due to their low number. However problems. a third major source of randomness is often neglected: genes induce the protein synthesis in a random fashion since they stochastically oscillate between an active and an inactive state. These oscillations, if slow, can induce large stochasticity even in the case where the produced protein is present in very large Diet, Nutrition and Cancer Project numbers. In a recent paper (de Franciscis et al, 2016) we fully investigate the effects of interplay between gene stochasticity and noise of extracellular origin, by taking into account that – as often is in biology The project aims to produce a report initially focussing on (d’Onofrio, 2013) - both these kind of randomness are bounded, i.e. they cannot be approximated by “diet, dietary practices, nutrition and cancer” and based on Gaussian variables. Our model suggests that the velocity of gene switching is the determinant of the findings from meta-analyses and pooled analyses to the cellular response to the external noises. largest extent possible. In addition to a series of reports, each section within the report would also be published in a peer- We used the paradigm of random gene fluctuations (Puszynski et al, 2014) to explain the experimental reviewed journal. The initial work will concentrate on nutri- dose-response curves of Nutlin, a drug that aims to restore the physiological level of the anti-tumour tional risk associated with specific cancers. There are eleven protein p53 (one of main guardians of the genome, controlling both cell proliferation and differentia- sites of cancer where there are sufficient studies published tion) by inhibiting its key inhibitor Mdm2. The mechanism we found is somewhat universal and does not to arrive at some solid conclusions: colorectal cancer, breast strictly depend on the complexity of the p53-Mdm2 network. Indeed, we obtained qualitatively similar cancer, prostate cancer, oesophageal cancer, lung cancer, results (Puszynski et al, 2016) for models of drugs acting on very simple linear and non-linear molecular oral cancer, kidney cancer, bladder cancer, liver cancer and networks. pancreas cancer. Following completion of the analyses outlined above, the project will continue and develop similar analyses in the fields of cardiovascular disease and diabetes. Buonomo B, d’Onofrio A, Manfredi P. Public Health Intervention to shape de Franciscis S, Caravagna G, Mauri G, d’Onofrio A. Gene switching rate deter- A first cancer was reported, i.e., colorectal cancer. Colorectal voluntary vaccination: continuous and piecewiese optimal control. mines response to extrinsic perturbations in the self-activation transcriptional (submitted). 2017a. network motif. Scientific Reports. 2016;6:26980. cancer is the third most common cancer in men and the Buonomo B, Carbone G, d’Onofrio A. Effect of seasonality on the dynamics of Löfstedt RE. Risk Management in Post-Trust Societies. United Kingdom: second in women. Significant international variations in the an imitation-based vaccination model with public intervention. Mathematical Palgrave Macmillan UK; 2005. distribution of colorectal cancer have been observed for Biosciences and Engineering (in press). 2017b. Manfredi P, d’Onofrio A. Modeling the interplay between human behavior and d’Onofrio A. Bounded Noises in Physics, Biology, and Engineering: Birkhäuser the spread of infectious diseases: Springer; 2013. many years, indicating that nutrition likely play a role in the Basel; 2013. Puszynski K, Gandolfi A, d’Onofrio A. The pharmacodynamics of the etiology. We performed a systematic review of meta- and d’Onofrio A, Manfredi P. Bistable endemic states in a Susceptible-Infectious- p53-Mdm2 targeting drug Nutlin: the role of gene-switching noise. PLoS pooled analyses of prospective cohort studies summarizing Susceptible model with behaviour-dependent Vaccination. (submitted). 2017. Comput Biol. 2014;10(12):e1003991. d’Onofrio A, Manfredi P, Poletti P. The impact of vaccine side effects on the Puszynski K, Gandolfi A, d’Onofrio A. The role of stochastic gene switching the evidence between foods and nutrients to colorectal natural history of immunization programmes: an imitation-game approach. in determining the pharmacodynamics of certain drugs: basic mechanisms. cancer. We found 41 meta-analyses and 6 pooled analyses. J Theor Biol. 2011;273(1):63-71. Journal of Pharmacokinetics and Pharmacodynamics. 2016;43(4):395-410. In total 48 summary risk estimates (SRE) related high to low d’Onofrio A, Manfredi P, Poletti P. The interplay of public intervention and Wang Z, Bauch CT, Bhattacharyya S, d’Onofrio A, Manfredi P, Perc M, et al. private choices in determining the outcome of vaccination programmes. PLoS Statistical physics of vaccination. Physics Reports. 2016;664:1-113. food consumption to incidence of colorectal cancer. Eight One. 2012;7(10):e45653. (17%) estimates were associated with a statistical lower risk of colorectal cancer, eleven (23%) with an increased risk, and 29 (60%) were not significant. Of the 46 SRE relating high to low nutrient intake to incidence of colorectal cancer, two (4%) had an increased risk, nine (20%) a decreased risk, and 35 (76%) were not significant. A progressive shift of 10% of consumption would avoid in total 6.8% of total colorectal cancer, with 3.6% coming from the shift in alcohol

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consumption, 1.8% for red meat and 1.6% for processed meat (see Figures). With the exception of consumption of alcohol, meat and Summary risk estimates and 95% confidence intervals from meta- and pooled analyses relating high versus low nutrient intake to colorectal cancer dairy, there was no consistent association reported with foodstuffs and nutrients and colorectal cancer risk.

Sugar and Health

Our research showed that in prospective studies on sugar-sweetened beverage consumption and body weight, the use of sugar exposure at baseline or of changes in sugar exposure during follow-up, as well as different statistical analysis modalities may end up in different results and conclusions. Basically, as main result, it is the change in total energy intake that was mainly associated with increase in weight. In addition, while on average body weight tended to increase over time, there was a concomitant decrease in sugar-sweetened beverage intake. These two results do not support the hypothesis that obesity would be essentially due to an increase in sugar-sweetened consumption. Rather, adiposity would mainly be the consequence of an imbalance between energy intake and expenditure. Indeed the consumption of sugar-sweetened beverage (and intake of other sugary foods or beverage) plays a role in adiposity due their energy content, but this role is similar to that played by other foods and caloric beverages.

The clustering of unhealthy dietary habits and lifestyles with sugar consumption in general suggests the existence of an obesogenic behaviour that is the simultaneous presence of risk factors for obesity and other metabolic disorders in the same individuals. Because of the clustering of sugar consumption with a more unhealthy diet and behaviours, observational studies can hardly disen- tangle the specific influence that each dietary item or lifestyle may have on outcomes.

This obesogenic behaviour implies that acting on a specific factor for preventing or treating weight gain is likely to fail if other factors are left unchanged. For instance, if all efforts are concentrated on the reduction of sugar intake, subjects are likely to adopt compensatory behaviors that will cancel out the benefits expected from reduced sugar intake. In this logic, a reductive single food approach would be poorly effective for preventing adiposity.

Summary risk estimates and 95% confidence intervals from meta- and pooled analyses relating high versus low food consumption to colorectal cancer

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potentially treatable stages of the disease is to identify biomarkers for early detection using simple and robust laboratory methods. Liver Cancer (Hepatocellular Carcinoma): The current diagnostic biomarker of reference, alpha-fetoprotein, is of limited interest for screening as low levels of AFP are poorly specific for HCC. This has led us to develop an international collaborative effort aimed at discovering and assessing new serum Curbing the Epidemics biomarkers tailored for optimal applicability in detecting early HB-related HCC (see figure).

iver cancer (hepatocellular carcinoma, HCC) is remarkably equipped in detoxifying systems that Lboth common and highly lethal in low-resource protect it against cytotoxic drugs. It is therefore Pipeline and strategy for plasma biomarker discovery in hepatocellular carcinoma. First, mini-case/control and case/case comparisons were developed and emerging countries, in which about 80% of extremely difficult to treat unless detected at an using plasma specimens from healthy HB carriers, patients with cirrhosis and patients with HCC from two distinct regions of high incidence (assembly). the 800,000 estimated annual case are expected early stage and completely removed by surgery. Plasma from these subjects were extensively analysed using a deep proteomics pipeline identifying over 2000 low-abundance peptides in each samples to occur. HCC often develops as the final stage of a However, in regions of high incidence, the pres- (discovery). Peptides distinguishing between HCC and cirrhotic patients in both Gambian and Thai series were selected (mining), and the two strongest complex history of chronic liver disease caused by entation is generally late and advanced, with no “hits” were validated using simple ELISA-based dosage in over 1100 plasma specimens of cases and controls form different countries (validation) infectious, metabolic, lifestyle and environmental manageable treatment option. In sharp contrast factors. The geographic distribution of HCC shows with this bleak clinical picture, the main risk factors a striking ecological correlation with areas of alter- that cause HCC are, in principle, largely preventable nating hot-humid seasons, high endemicity for at population level and patients who develop HCC chronic Hepatitis B Virus (HBV) and high dietary may be accessible for early detection since most contamination by aflatoxins, a group of carcino- of them develop precursor chronic liver disease. genic mycotoxins that contaminates many tradi- However, the patterns of chronic liver diseases in tional crops in these regions. As an organ, liver is a low-resource populations are still largely unexplored powerful ecosystem supporting cancer develop- and biomarkers and infrastructure is lacking for ment: it is rich in nutrient stores, very well supplied effective surveillance of these patients, in particular in oxygen, has specific immune privileges and is in sub-Saharan Africa.

Documenting Chronic Liver Disease Trajectories in Africa

There is only limited information on the prevalence of liver fibrosis and liver cirrhosis in the population and in at-risk groups of HB or HC chronic carriers in Sub-Saharan Africa. The 2010 Global Burden of Disease study provides estimates mostly from verbal autopsy given the lack of available vital registration data in most regions. According to this study, cirrhosis mortality varied between 12.9 (Southern Africa) and) and 24.2 (Middle Africa) per 100,000 person years. Due to lack of awareness and of systematic screening, most chronic HB or HC carriers are unaware of their status and are not being followed-up for liver functions and symptoms. To address this Using deep-plasma proteomics, two markers have been identified as performing better than AFP in discriminating cancer against question, we have conducted a study in Bamako, Mali, in collaboration with researchers of Centre d’Infectiologie Charles Mérieux, chronic liver disease and cirrhosis, with sensitivities and specificities >90% for HCC associated with HBV (da Costa et al, 2015). These Bamako, Service de Gastroentérologie of Hospital Gabriel Touré, Bamako, and Université Catholique de Lyon, France. A total of 276 two markers are Osteopontin (OPN) and Latent-TGFbeta Binding Protein 2 (LTBP2), two components of the extracellular matrix of HB carriers were identified in a cohort of 1466 adult volunteers without diagnosed liver dysfunction. Among these carriers, 32.9% the liver. A recent evaluation of circulating OPN levels in a prospective European cohort revealed that an increase in serum levels had plasma HBV loads > 104copies/mL, indicative of active viral replication. Furthermore, 35.6% had Fibrotest scores ≥ 2, indicative of OPN was predictive of HCC up to 2 years ahead of diagnosis. After adjusting for all variables such as AFP and liver enzymes, each of moderate to severe liver fibrosis (Traore et al, 2015). These results suggest that about one-third of adult HB carriers in this group 10% increment in OPN levels was associated with a significant increase of developing HCC after 2 years (OR multivariable=1.30 show signs of active hepatitis and might benefit from anti-HB treatment. Thus, the burden of chronic liver disease (chronic hepatitis, (95%CI: 1.14, 1.48)) (Duarte-Salles et al, 2016). Testing of OPN and LTBP2 can be performed using robust, low cost immunoassays. fibrosis, cirrhosis) is under-estimated in sub-Saharan Africa. Further studies are currently in progress to investigate the prevalence of Therefore, combining these two markers offer attractive characteristics for the screening of HCC in at-risk population groups but HB carriers and chronic liver diseases in other parts of Mali (Timbuktu Region, North Mali, with support of Region Auvergne Rhônes their efficacy remains to be evaluated in an African cohort. In another approach, we have used a mass spectrometry methodology Alpes). initially developed in the field of earth sciences to investigate imbalances in iron and copper isotopes in the plasma and tissues of patients with HCC or cirrhosis from a case-control study in Thailand. These two essential metals are tightly regulated in liver cells, which play a major role in their homeostasis. Our study, published in the Proceedings of the National Academy of Sciences USA New Biomarkers for Early Detection (Balter et al, 2015), shows that patients with HCC exhibit a specific isotopic copper signature in the plasma, which may occur as the consequence of perturbed metabolism of these redox-active ions in liver cancer cells. In high resource countries, screening is standard of care for patients at risk (e.g. patients with severe chronic liver disease) in high- resource countries, with ultrasonography at 3–6 monthly intervals as the current method of choice. There is no demonstration of the feasibility and efficacy of ultrasonography screening in a low-resource African context. The best option for anticipating diagnosis to

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The Way Forward: 36 steps Against Liver Cancer in Africa Pancreatic cancer: in search of new targets for therapy

In 2008, we proposed a set of 36 measures for reducing the mortality by liver cancer in Africa by the year 2050 (Hainaut et al, 2008). ancreatic ductal adenocarcinoma (PDAC) is a in growth factor and nutrient sensing, raising the These steps fall into 4 main areas: preventing HB carriage, mitigating aflatoxin exposure, treating HB and HC chronic infections Plethal form of cancer with very few therapeutic hypothesis that these cancers may be “addicted” and chronic liver disease, and improving liver cancer detection, diagnosis and therapy. None of these measures on its own will be options. To date, the causes of pancreatic cancer are to the activation of this specific pathway. If proven sufficient to significantly curb the number of death by liver cancer in the next decades. To have a realistic chance of limiting the not clearly identifies, although a number of risk correct, this hypothesis raises hope of a molecular natural increase in liver cancer cases due to population expansion and ageing, several of these measures need to be combined into factors have been identified, such as smoking, target, which may, in due course, be amenable an organized and structured action plan for Africa. In 2016, we have reviewed the current status of implementation of each of these obesity, genetics, diabetes, diet, and inactivity. Most to drug-based therapy. Indeed, whereas there is measures, highlighting that much remains to be done to fully implement them (Hainaut, 2016). cancers are detected at a late, metastatic stage. At currently no effective inhibitor of KRAS2 in the the gene level, pancreatic cancer often harbour clinics, the use of designer strategies may eventually To date, only infant HB vaccination has been rolled out as a structured program, thanks to the efforts of WHO, Unicef and the Gavi activating mutations in KRAS2, a critical regulator lead to the development of such drugs in the close Alliance. Since 2014, the vaccine is available in all African countries but population coverage remains insufficient to sustain the of intracellular growth signalling cascades involved future. hopes of decreasing liver cancer mortality in the next 30 years. Active mitigation of aflatoxin exposure requires a multi-level action plan but passive reduction seems to spontaneously occur through diversification of the diet as African countries move up from Despite often harbouring KRAS2 mutations, and despite having invariably poor prognosis, pancreatic cancers show an unpredict- low- income towards middle-income status. However, this diversification is likely to take place at different paces in more affluent able heterogeneity in their growth patterns and initial responses to cytotoxic therapies. In recent years, studies on patterns of genetic areas as compared to poorer (mostly rural) areas, which will continue to rely on local production of traditional foodstuff for their alterations using whole genome/exome approaches have identified a large intra- and inter-tumoral heterogeneity in the number subsistence. Since the very few cancer registries operating in West or Middle Africa are mostly based in urban areas, it is possible and extent of somatic alterations throughout the genome. Thus, a subset of PDAC appears to have highly rearranged genomes and that we may record in the coming year an apparent decrease in liver cancer incidence rates that might not reflect the burden of the is it possible that these forms may carry a particularly poor prognosis. Research carried out at The Institute of Advanced Studies at disease in the poorest part of the population. the Institute of Advanced Studies in Grenoble in the laboratory of P Hainaut (lead scientist: N Reynoird) have identified an important role of a relatively understudied family of enzymes, the methyltransferases, in regulating the KRAS-dependent signalling cascades Economic growth and dietary diversification are expected to cause many changes potentially impacting on the incidence rates in pancreatic cancer cells and in mouse models of pancreatic cancer. Methyltransferases have been the focus intense research, due of liver cancer. On the one hand, better awareness and access to care may improve the prevention and management of chronic to their roles in regulating DNA methylation and epigenetic control of gene expression. More recently, the attention has focused on liver diseases. On the other hand, a switch towards westernized hypercaloric diet may result in a rapid rise in obesity, metabolic the role of specific sub-families of methyltransferases in regulating the methylation of lysine in proteins, a critical regulatory change syndromes and diabetes, thus contributing to increase the prevalence of risk factors for liver cancer in both HB carriers and non- affecting histone and chromatin dynamics. Reynoird et al (2016) have shown protein methyltransferases may also control he activity carriers, including individuals in whom carriage has been prevented by neonatal vaccination. Monitoring these trends will be of proteins involved in growth signalling cascades. Specifically, they found that that levels of the lysine methyltransferase SMYD2 essential to sort out positive from negative impacts of these changes. were often elevated in PDAC and that genetic and pharmacological inhibition of SMYD2 restricted PDAC cell growth in vitro an in a mouse model of PDAC. This effect appeared to be due to the regulation by SMYD2 of the activity of the stress-response kinase Access to diagnosis, treatment and palliation is dramatically constrained by economic resources. Yet, the trajectory of liver cancer MAPKAPK3 (MK3), a downstream effector of KRAS2. Inhibition of MAPKAPK3 impeded PDAC growth, identifying a new and poten- in Africa suggests that a good window of opportunity exists for screening, early detection and early intervention. Achieving this tially druggable kinase target in PDAC. Furthermore, inhibition of SMYD2 cooperated with standard chemotherapeutic treatments requires developing biomarkers and drugs specifically designed to target the liver cancers in Africa. Indeed, these cancers appear to to reduce the development of experimental PDAC tumors. Overall, these findings underscore a pivotal role for SMYD2 in promoting correspond to specific subgroup of severe liver cancers, different from the most common molecular subtypes occurring in industri- pancreatic cancer and provide new insights on possible targets for future innovative therapies. alized countries. Another concern is that these biomarkers and drugs should be pitched for usage in low resource contexts and that their efficacy should be demonstrated in clinical trials involving African patients. Reynoird N, Mazur PK, Stellfeld T, Flores NM, Lofgren SM, Carlson SM, et al. Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer. Genes Dev. 2016;30(7):772-85. Balter V, Nogueira da Costa A, Bondanese VP, Jaouen K, Lamboux A, Sangrajrang S, et al. Natural Hainaut P. Africa: Liver Cancer. In: Boyle P, Ngomo T, Sullivan R, Ndlovu N, Autier P, Stefan S, Fleming variations of copper and sulfur stable isotopes in blood of hepatocellular carcinoma patients. Proc K, and Brawley OW. The State of Oncology in Africa 2015. iPRI Scientific Publication 4, iPRI, Lyon, Natl Acad Sci U S A. 2015;112(4):982-5. France (2016). da Costa AN, Plymoth A, Santos-Silva D, Ortiz-Cuaran S, Camey S, Guilloreau P, et al. Osteopontin Hainaut P, Boyle P. Curbing the liver cancer epidemic in Africa. Lancet. 2008;371(9610):367-8. and latent-TGF beta binding-protein 2 as potential diagnostic markers for HBV-related hepatocel- Traore F, Gormally E, Villar S, Friesen MD, Groopman JD, Vernet G, et al. Molecular characteristics lular carcinoma. Int J Cancer. 2015;136(1):172-81. of Hepatitis B and chronic liver disease in a cohort of HB carriers from Bamako, Mali. BMC Infect Duarte-Salles T, Misra S, Stepien M, Plymoth A, Muller D, Overvad K, et al. Circulating Osteopontin Dis. 2015;15:180. and Prediction of Hepatocellular Carcinoma Development in a Large European Population. Cancer Prev Res (Phila). 2016;9(9):758-65.

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Guidelines for a Healthier and Longer Life Use of Social Security Databases and Patient Registries

ociety is now taking conscious steps in looking many of which can lead to a healthier lifestyle. There ocial security databases register consider- registries, cancer registries, cause of death registers Sfor ways to prevent serious disease and to are also interventions that can be taken to prevent Sable amounts of information on medications and so on. Patient registries are complementary encourage individuals to develop a healthier infectious diseases by vaccination and to reduce and health services received by individuals. These to social security databases because they are used lifestyle. A Healthy Lifestyle has not been defined the impact of several chronic diseases by screening, databases can be linked to patient registries, hospital for the clinical follow-up of patients with chronic and it may never be possible to do so in a generic early detection and delivering appropriate therapy discharge registries, outpatient registries, pharmacy disease. manner: lifestyle choices are very individual centric. when chances for cure are much higher. There are lifestyle choices for the individual to take, These databases represent immense sources of “real world data” reflecting the complexity of modern medicine including patient journey in health care systems and consumption of resources. They have the potential to contribute to numerous types of projects, An evidence-based Report has been completed and a series of recommendations are made for a healthier lifestyle together with like epidemiological research, effectiveness studies, surveillance of adverse events, sociological approaches, health economics, the appropriate scientific support. In this first version, not every possible intervention could be covered but this document will health service research and so on. be continually reviewed, enlarged and brought up to date. However, the major issues have been covered. References have been chosen deliberately to demonstrate that knowledge which could be used in formulating prevention strategies has been available Demands for access to these sources of data is increasing because many governments and public health administrations are for decades and, on many occasions, this has been supplemented with the most up-to-date quantitative summaries. conscious that sensible use of the available information could lead to better use of resources, avoidance of wastes, identification of poorly efficient health services, improved quality of the health care systems, and ultimately better patient outcome. In addition Tobacco use, chiefly cigarette smoking, causes a wide variety of diseases many of which are highly fatal: chronic obstructive governments require steadily more real world evidence on the effectiveness and harms associated with health therapies and tech- pulmonary disease, lung cancer and a wide variety of other forms of cancer, cardiovascular disease and diseases of the gastroin- nologies (i.e., for health technology assessment (HTA)). testinal tract, neurological system, eyes and skin. Alcohol use causes a variety of diseases and premature death both resulting from excessive drinking and moderate drinking. In addition to a series of cancers, alcohol consumption is associated with a wide variety However, the “big data” approaches in the health domain face numerous legal and administrative hurdles and nourish a multitude of accidents and injuries, frequently during leisure activities. A healthy diet offers protection against cardiovascular disease and, of passionate and complex debates at all levels of the European society, from the citizen to the European institutions. perhaps, cancer (although evidence of this is still lacking). Avoiding underweight, over-weight and obesity is essential for avoiding increased risks of a variety of diseases and conditions. Care is essential in the sun and use of sunbeds should be avoided. Vaccination In order to address the concerns of authorities responsible for the social security databases and of health professionals running is important to reduce, even eliminate, many infectious diseases. patient registries, the iPRI proposes innovative working procedures that keep the data in owner’s computers during the entire study duration. To this end, the iPRI has established data handling and analyses procedures that are entirely conducted in the data owner Continual monitoring of key risk factors for cardiovascular disease and diabetes are also an essential component of a plan for a computer system so that no data is transferred to iPRI or any other recipient (figure). The procedures are based on the creation of a healthy life. There are active actions that can be taken against serious chronic disease. Screening for Breast Cancer, Cervix Cancer “working database” hosted in the data owner computer system in which all data relevant to a specific study are stored. Resolution and Colorectal Cancer is strongly recommended. For other forms of cancer, such as ovary, lung, melanoma, prostate and stomach of anomalous data, variable recodifications, computations, and if needed, linkages with external databases are all performed within there is no convincing evidence of efficacy at this time. Consideration should be given under medical advice, to prophylactic use of this working database. When all data handling procedures are terminated, the variables necessary for statistical analyses are trans- statins and aspirin against cancer and cardiovascular disease. ferred into an “analysis database” also located in the data owner computer system onto which statistical analysis scripts written by iPRI statisticians are applied. The scripts produce the study results as aggregated statistics in tabular format. These aggregated Making the correct lifestyle choices and following the appropriate recommendations outlined in this document, will lead to results are transferred to iPRI where further analyses can be carried out using meta-analytic techniques. increases in Healthy Life Expectancy as well as overall Life Expectancy. Not only should subjects live longer but they will do so with a better quality of life. There is more to Health than just the absence of disease. The recommendations here will improve health but will also have a substantial impact on many other aspects of quality of life.

iPRI 111 Cancer Leadership 2015 La grandeur d’un métier est peut être avant tout d’unir les hommes... Antoine de St. Exupéry

Attendees of the 2015 NCID Meeting held in Lyon, France Cancer Leadership 2016 La grandeur d’un métier est peut être avant tout d’unir les hommes... Antoine de St. Exupéry

Attendees of the 2016 NCID Meeting held in Lyon, France iPRI - International Prevention Research Institute — Cancer Leadership iPRI

National Cancer Institutes Directors Meetings

he tenth and eleventh meetings of National over 150 thought leaders, national cancer institute TCancer Institute Directors (NCID) took place in directors and Ministers of Health from 50 countries Lyon in July 2015 and 2016. These meetings attract at varying levels of income and resource.

As requested by participants, the focus on cancer in low resource countries continues to be a focus of these meetings.

During our 2015 and 2016 meetings, the iPRI/WPA Awards for Contribution to Cancer Control were awarded (see following pages for recipients and details).

The 2015 NCID meeting marked the fortieth anniversary of the discovery of the cure of testicular cancer. NCID participants were honored by the presence of and inspiring keynote address by Dr. Larry Einhorn (photograph). Dr Einhorn has been a major figure in Oncology and his discovery of the role of cis-platin in the treatment of disseminated testicular cancer remains one of the key contributions to cancer treatment.

NCID plenary sessions cover topics of specific interest to participants. It is a meeting at the highest level designed to facilitate the exchange of ideas between key global cancer control leaders.

The first NCID meeting was organized by Professor Peter Boyle in Milan in 2003.

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WPA/iPRI Cancer Control Awards

Dr. Anne Merriman was born in Liverpool and graduated in medicine from University College Dublin in Ireland. Anne subsequently spent 33 years working in Africa (including 10 in Nigeria as a missionary doctor and 20 in Uganda), seven in Southeast Asia, eight in the United Kingdom, and five in Ireland. She introduced palliative care into Singapore in 1985, which became an accepted form Thank you of care with the founding of the Hospice Care Association in 1989: this service is still fully functional in Southeast Asia. In 1990, Merriman returned to Africa, initially to Nairobi Hospice, before founding Hospice Africa. She introduced palliative care to Uganda 2015 WPA/iPRI Awards for Cancer Control in 1993, by forming an adaptable and affordable model, Hospice Africa Uganda (HAU). In Africa, the largest problem facing palliative care workers involves overcoming the stereotypes and negative connotations associated with morphine. Professor Merriman n the occasion of the 10th Annual National World Prevention Alliance / International Prevention stresses that if a patient’s pain cannot be controlled then holistic care cannot be brought in either. Through here work she has OCancer Institute Directors Meeting in Lyon Research Institute award in recognition of their pioneered Palliative Care in Africa. (NCID 2015), three outstanding individuals, working contribution to Cancer Control. in different health areas, were presented with the Professor Tadao Kakizoe had a distinguished career as a Urologist focussing on his work in experimental and clinical research on bladder cancer. He made seminal contributions to the development of bladder cancer and to the surgical management of the disease. In 1992, Professor Kakizoe became Director of the National Cancer Center Hospital in Tokyo, Japan and became Director Professor Peter Boyle, presenting the 2015 WPA/iPRI Awards for Cancer Control to General of the National Cancer Center in 2002. When his mandate had been completed, he became President of the Japanese Prof. Einhorn (left), Dr. Merriman (center) and Prof. Kakizoe (right) Cancer Society in 2007.

Professor Lawrence Einhorn is a Distinguished Professor of Medicine at Indiana University School of Medicine and an oncologist of international renown. Dr. Einhorn pioneered the development of the life-saving medical treatment in 1974 for testicular cancer, increasing the cure rate from 10% to 95%. Dr. Einhorn received a B.S. from Indiana University in 1965 and his M.D. from the University of Iowa in 1968. He served his internship and residency at IU Medical Center, followed by a fellowship in Haematology/ Oncology at the M.D. Anderson Hospital Tumor Institute in Houston, Texas. He returned to IU Medical Center in 1973 and was named Distinguished Professor of Medicine in 1987. He became the first Lance Armstrong Foundation Professor of Oncology in 2006. Shortly after his arrival at Indiana University, he tested Cisplatin, a drug which had already failed in a Phase I clinical trial with patients who had various end-stage cancers, including testis cancer. Cisplatin was found to be too toxic, causing severe vomiting, neuropathy, hearing loss and kidney damage in these patients, and it failed to stop the growth and spread of most of the cancers. Dr Einhorn developed a three-drug regimen which had superb results, curing testicular cancer and giving this group of men a near normal life expectancy. Subsequent clinical research directed by Dr. Einhorn established a model for a curable tumor, which has served as the basis of treatment of testicular cancer until the present day.

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2016 WPA/iPRI Awards for Cancer Control If only the road to fight cancer were as straight and simple... n the occasion of the 11th Annual National Cancer were presented with the World Prevention Alliance/ OInstitute Directors Meeting (NCID2016), three International Prevention Research Institute award in outstanding individuals working in different areas recognition of their contribution to Cancer Control.

Left to right, Professor Peter Boyle, presenting the 2016 WPA/iPRI Awards for Cancer Control to Mr. Byrne, Professor Loehrer and Professor Zaridze

Mr. David Byrne, the former Barrister and Attorney General for Ireland, was appointed European Commissioner for Health and Consumer Protection in 1999 and served until 2004. During his term as Commissioner, the European Centre for Disease Control (ECDC) and the European Food Safety Authority (EFSA) were created. Notably, he steered into European law Directive 2001/37/ EC of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States concerning the manufacture, presentation and sale of tobacco products: this pioneering law against Tobacco paved the way for individual national laws. This was followed-up by his sponsorship of the European Tobacco Advertising Directive (2003/33/EU) which banned all cross border advertising and sponsorship of tobacco products in Europe.

Professor Patrick Loehrer is director of the Indiana University Melvin and Bren Simon Cancer Center and the H.H. Gregg Professor of Oncology and associate dean for cancer research at the Indiana University School of Medicine. He is widely recognised as an outstanding clinician and clinical researcher and is a specialist in a variety of forms of cancer. His long-term activity and leadership in developing quality cancer treatment in Eldoret (Kenya) through long term support of AMPATH, which comprises Moi University, Moi Teaching and Referral Hospital and a consortium of North America academic centres led by Indiana University working in partnership with the Government of Kenya. This is an initiative of long standing and has provided high-level education in many aspects of Oncology and quality care where none existed before.

Professor David Zaridze was initially a pathologist but re-focussed on Epidemiology during a year spent working with Sir Richard Doll in Oxford, United Kingdom. After a spell at the International Agency for Research on Cancer (1979-1985) he returned to Moscow and in 1987 became Director of the Institute of Carcinogenesis at the N. N. Blokhin Cancer Research Centre. He is currently Deputy Director of the Russian Cancer Research Centre. Professor Zaridze has made a significant contribution to epidemiological research of non-communicable diseases and premature death. He has led a major effort in canсer epidemiology in Russia with his efforts in tobacco and alcohol of particular importance. He has clearly shown the impact of smoking and excessive alcohol drinking on life expectancy and several key diseases including cancer.

iPRI 121 iPRI - International Prevention Research Institute — About Us iPRI

ABOUT US

People Passion

People matter. So too, does their knowledge

and rigour. But most of all, it is their passion

that drives their work. iPRI is known for

this passion. We are proud of this, and are

committed to growing our organisation not

just in numbers, but primarily in the quality of

our Senior Faculty, Senior Research Fellows,

Faculty and Staff.

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People

iPRI Senior Faculty

Peter Boyle PhD DSc FRSE FFPH FRCPSG FRCPE FRCPI FMedSci President

eter Boyle’s appointment as President of the he held posts as Senior Scientist at IARC, Assistant PInternational Prevention Research Institute, Professor in Epidemiology and Biostatistics at Lyon, France follows immediately on his tenure as Harvard School of Public Health and the Dana- Director of the International Agency for Research on Farber Cancer Institute (Boston, United States), the Cancer (IARC/WHO). From 1991-2004 he was Director West of Scotland Cancer Surveillance Unit (Glasgow, of the Division of Epidemiology and Biostatistics at United Kingdom) and the Department of Medicine the Institute of Oncology in Milan, Italy. Prior to that at Glasgow University.

Professor Boyle is the inaugural Director of the University of Strathclyde Institute of Global Public Health at iPRI, which is situated in Lyon and Glasgow. He is Professor of Global Public Health at the University of Strathclyde and currently holds Honorary or Visiting Professorships at Glasgow University and Yale University. He is founder and President of the World Prevention Alliance, a non- governmental organisation committed to prevention research and actions in lower income countries.

Peter Boyle’s research interests lie in disease prevention and translational research in its broadest sense, from translating cutting- edge scientific discovery into new approaches to treatment to translating information about risk factors into changes in population behaviour. He led the EUROCAN+PLUS project which developed priorities for coordination of cancer research in Europe and was Editor of the World Cancer Report 2008 and the State of Oncology 2013 which highlighted the growing global cancer crisis. The recent publication of State of Oncology in Africa 2015 and the accompanying film Cancer is … Attacking Africa, highlight the need for action against chronic disease in low-resource countries.

Peter Boyle has previously been a Member of the European Cancer Advisory Board and worked as the scientific advisor to the European Commission on the European Tobacco Contents Directive which was voted into law in 2002. He was also responsible for the revisions of the European Code Against Cancer.

Peter Boyle has been awarded the Knight’s Cross of Order of Merit of the Republic of Poland; Fellowship of the Royal Society of Edinburgh; Honorary Membership in the European Society for Therapeutic Radiology and Oncology (ESTRO), the Hungarian Oncological Association and the Argentine Medical Association; Fellowship of the Royal College of Physicians and Surgeons (Glasgow); Fellowship of the Royal College of Physicians (Edinburgh); Honorary Fellowship of the Royal College of Physicians of Ireland; Fellowship of the Academy of Medical Sciences (United Kingdom); Membership of the European Cancer Academy; Membership of Academia Europea; and Honorary Membership of the Hungarian Academy of Science. He has been awarded honorary doctorates by the Universities of Aberdeen (DSc) and Dundee (LlD).

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epidemiological methods and meta-analytic methods. Between 2003 and 2009, he held the position of Senior Philippe Autier In particular, he has been involved in many analyses of Biostatistician at the International Agency for Research on Vice-President, Population Research temporal trends and of geographical patterns for exposures Cancer in Lyon. He was the coordinator of the EU-funded and outcomes. project EUROSUN. He is a member of the International Task Philippe Autier was born in Brussels, Belgium, and received a expertise in public health to low and middle income countries. Force on Skin Cancer Screening and Prevention that evaluates Doctor of Medicine degree from the Université Libre de Bruxelles In 1990 he received a Fulbright fellowship with a grant from Particular areas of expertise are the analysis of cancer registry the national skin cancer screening in Germany. From 2009 to and a diploma in tropical medicine from the Prince Leopold the Frank Boas Foundation to study at Harvard School of Public data on trends in incidence and mortality of diseases, the 2015, he was a member of the board of directors of Euroskin Institute of Tropical Medicine, Antwerp in 1983. He started his Health, Boston, Massachusetts, where he was awarded an analysis of exposure distribution and their impact on disease (the European Society of Skin Cancer Prevention) and President professional life by joining the humanitarian non-governmental MPH. In 2011, he received a PhD from the Erasmus University burden, statistical methods in pharmaco-epidemiology, evalu- of Euroskin between 2011 and 2013. in Rotterdam for his works on the ation of cancer screening and the analysis of disease registry cutaneous melanoma. Philippe Autier data (e.g. linkage between biobanks and medical records) for In 2013, he was appointed as Professor at Strathclyde University, has been head of the Prevention and the evaluation of health programmes or of medical activities. Glasgow. Mathieu Boniol is Vice-President, Biostatistics at the Screening Department of the Jules Mathieu Boniol has also contributed to various international International Prevention Research Institute, where he super- Bordet Institute in Brussels (1992-95 collaborative projects involving computation of attributable vises a team of statisticians, data managers and other functions. and 2002-2005), Deputy Director at fraction and to various meta-analyses (melanoma risk, artificial He has published more than 150 scientific articles and has an the European Institute of Oncology in light and skin cancer, vitamin D and cancer). h-index of 33 (as of January 2017). Milano (1995-2000), and Group Head at the International Agency for research on Cancer in Lyon (2000-2010). Michel Smans Chief Technology Officer Philippe Autier is a leading figure in several fields including research on Michel Smans was born in Brussels, cutaneous melanoma and breast Belgium, and received a Masters Degree cancer, especially in domains related to of Mathematics from the University organization Médecins Sans Frontières (MSF), where he helped the causation, prevention and early detection of these cancers. of Namur. After two years working in Honduras (1985 and 1986), and later in Chad (1987-88) as He is also very involved in the clinical testing of new methods as Research Assistant to Professor E. the medical coordinator of projects conducted by a team of for cancer detection and in health technology assessment. Schifflers, he joined the International approximately 50 expatriates and 200 Chadian health workers. Agency for Research on Cancer in Lyon In 2013 he was appointed Professor at Strathclyde University. and started to transpose advanced In 1988-89, Philippe Autier was the first head of the medical Philippe Autier is Vice President, Population Research, at the mathematical techniques to descrip- department of MSF-Belgium. He is one of the founders and International Prevention Research Institute tive epidemiology. He developed the a board member of the organisation AEDES that provides Cancer Mapping Project before moving to the unit of Biostatistics, and later created the IT Support team, expanding Mathieu Boniol its range of activities over the years. Vice-President, Biostatistics Michel has held board positions in IT user societies at the French and European level while keeping a strong interest in his original Mathieu Boniol was born in studies in descriptive epidemiology, particularly cancer mapping and Incidence and Mortality Databases. Nimes, France, and graduated in Biomathematics and Public Health Michel Smans joined the International Prevention Research Institute as Chief Technology Officer in March 2011 with the dual at the University Lyon 1, France and responsibility of ensuring the highest standards of information technology and mathematical excellence for the Institute. subsequently obtained a PhD in epidemiology from the Université de Bourgogne, Dijon.

His scientific activities mainly deal with etiologic research based on

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countries, namely on tumours of the upper-aerodigestive tract standards for biobanks. Pierre Hainaut is frequently lecturing Irene Leigh (squamous cell carcinoma of the oesophagus in Iran, Kenya, Latin and giving courses in Post-Graduate programs in different Research Director America; lung cancers) and on HepatoCellular Carcinoma (West countries and in international summer schools. In 2013 he was Africa, Colombia, Egypt, Thailand, China). From 2002 to 2008, he appointed as Professor at Strathclyde University. He has written Irene Leigh was born and educated in Liverpool. She obtained In 2006 Irene Leigh was honoured with an OBE for services to has led the Gambia Hepatitis Intervention Study (GHIS), a large about 375 articles and book chapters and is the editor of several her undergraduate medical training and intercalated BSc (Hons) medicine and also became Vice Principal and Head of College intervention trial aimed at testing the long-term efficacy of books on molecular epidemiology and on p53. Pierre Hainaut in Anatomy at the London Hospital Medical College and special- of Medicine, Dentistry and Nursing at the University of Dundee newborn HB vaccine against liver cancer in adults in West Africa. is a Research Director at the International Prevention Research ised in dermatology at postgraduate level. and additionally Vice Principal for Research in 2009. She stepped Since 2005 he has contributed to developing evidence-based Institute. down from these roles at the end of 2011 but retains a research professorship at the University of Dundee. Alberto d’Onofrio She was elected as Fellow of the Royal Society of Edinburgh Research Director in 2009. She has served on multiple scientific advisory boards in UK and Europe, is currently President of the Rene Touraine d’Onofrio’s main activities are on mathematical epidemiology of Foundation and has held officer positions in UK and European infectious diseases, epidemiology of cancer and cancer systems research societies. As past president of the ESDR she organised biomedicine. Broadly speaking, he is interested in the effects of IID 2013 in Edinburgh, the major investigative dermatology nonlinearity and randomness in biological phenomena, from meeting. She has directed the Cancer Research UK Skin Tumour microscopic to population level. He has also contributed to Laboratory since 1983, focusing on research in keratinocyte various projects involving computational biology, geographic biology, epithelial differentiation and skin carcinogenesis. This epidemiology of cancer, and the role of human behavior on the She spent two years as a lecturer in medicine at the University of continues as a joint London-Dundee activity identifying genetic spread of communicable diseases. He has been at the European Dar es Salaam, Tanzania, before returning to registrar and senior changes and molecular mechanisms in squamous cell carcino- Institute of Oncology in Milan from 2000 to 2013 starting registrar positions in London. In 1983, she was appointed as genesis in both immunosuppressed and immunocompetent as Professor Boyle’s postdoc fellow and ending as Principal Consultant Dermatologist to the London Hospital and became patients. She has also established the genetic basis of multiple Alberto d’Onofrio was born in Naples, Italy, graduated in Investigator in Systems Biomedicine. Alberto d’Onofrio is a Professor of Dermatology in 1992, having completed an MD genodermatoses, some with sensorineural deafness and cardio- Electrical and Control Engineering at the University of Pisa, Research Director at the International Prevention Research degree and Professor of Cellular and Molecular Medicine in 1999, myopathy, which is now leading to research in therapeutic Italy and subsequently obtained a PhD in Medical Computer Institute when she received a DSc (Med) and was elected as a Fellow of developments through the Dermatology and Genetic Medicine Sciences from the University of Rome-‘La Sapienza’, Italy. Alberto the Academy of Medical Science. She acted as Research Dean (DGEM) initiative in Dundee. She holds an ERC advanced inves- (1997-2002) and subsequently Joint Research Director of Barts tigator award to develop preclinical models for testing novel and the London School of Medicine and Dentistry/NHS Trust. therapies. Patrick Mullie Research Director

Pierre Hainaut Patrick Mullie was born in Mouscron, Belgium, and graduated in Epidemiology from the Catholic University of Leuven. Patrick Research Director Nutrition and Dietetics at the University College of Leuven and Mullie’s main research activities focus on nutritional epidemi- in Epidemiology and Applied Statistics at the University of ology, vitamin D and health, dietary pattern analysis, and Pierre Hainaut was born and educated in Belgium. He obtained molecular pathogenesis of cancers in low- and middle-resource Maastricht. He subsequently obtained a PhD in Nutritional e-learning methods for epidemiology. He is involved in many an Msc in Science in 1980 and a PhD in Biological Sciences in projects in the prevention of adiposity at population level. 1987 from the University of Liège. From 1987 to 1994, he has Those prevention projects are based on the nudging principle, been held postdoctoral positions in France (INSERM) and in the i.e., changing the food environment to making the healthy UK (University of Cambridge, University of York). Most of his choice the easiest. For the Belgian Army, he developed survival laboratory research was focused on molecular genetics, particu- food packs for extreme conditions, using his past experience as larly on the tumour suppressor protein p53. an international guide for arctic exploration in Greenland, Alaska and Siberia. He joined IARC as staff scientist in 1995 where he became head of Molecular Carcinogenesis in 1999. He is an internationally recog- In the past, he was President of the Belgian Association of nized scientist in the p53 mutation field and hasled the develop- Dietitians, introducing evidence-based nutrition to the field ment of the IARC TP53 database. His research has a focus on the of dietetics and organizing educational sessions of nutritional

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epidemiology, with focus on reading and understanding Patrick Mullie is a Research Director at the International negotiated a new collective labour agreement which is still International Fund for Agriculture and Development (IFAD) and systematic reviews and meta-analyses. Prevention Research Institute. He is also member of the Belgian used as a reference within the global public-private hospital participated in the global negotiations, which continue today, Superior Health Council and of the American Society for community. From 2005-2007, Mireille Guigaz served as the He is affiliated as Professor Systematic Review at the Faculty Nutrition. He is author of more than ten books about nutrition General Delegate of the Lyon-Auvergne-Rhône-Alpes research of Physical Education and Physical Therapy, Free University and more than 40 peer-reviewed publications. cancer hub, working on behalf of the National Cancer Institute of Brussels and as Research Director at the Queen Elisabeth (INCA). She was also serving as Chairperson of the Ethics Barracks, Belgian Army, Brussels. He is also a lecturer in Nutrition Committee of the International Agency for Research on Cancer and Epidemiology at the Erasmus University College, Brussels. (IARC). As Senior Operation Officer for the World Bank from 1984-1986, she started to develop an in-depth knowledge of international development. Guillaume Noyel Research Director In 2000 she was nominated as Director of International Development and Technical Cooperation for the Ministry of Guillaume Noyel was born in Saint-Chamond, France. He Guillaume Noyel has led several scientific joint efforts between Foreign Affairs and in 2004 became the first French Ambassador obtained a Diplôme d’Ingénieur in Electrical Engineering industry and public research centres. He joined iPRI in 2014 to take charge of the fight against HIV/AIDS, TB and Malaria, to establish a new international commitment to global food from CPE-Lyon in 2005, and a MSc in Image Processing, from as a Research Director where he developed a programme of working closely with many African countries at both govern- security. In December 2011, Mireille Guigaz has been awarded Université Jean Monnet, St Etienne in 2005. research in mathematics and image analysis for public health. mental, NGO and community-based levels. From 2007-2010 the French National Order of Merit (Commander’s class) and Mireille Guigaz was posted to Rome as Ambassador of in January 2012, she has been appointed again by the French In 2004, he spent three months engaged in research a the France, Permanent Representative to Food and Agriculture Conseil des Ministres as the French Ambassador for HIV-AIDS, University of Utah, Department of Radiology. In 2005, he spent Organization (FAO), World Food Programme (WFP) and the Tuberculosis and Malaria. five months at the Ecole Polytechnique Fédérale de Lausanne, working on colour reproduction. Guillaume received his PhD in Mathematical Morphology from Mines ParisTech in 2008 after Maria Paula Curado having developed morphological methods for multivariate and Senior Researcher hyperspectral images, with medical applications for tumour detection. During his PhD he participated in many international Maria Paula Curado regularly trained cancer registrars from conferences and in 2007 was awarded the prize of ‘young stere- Portuguese countries in Africa and Brazil. She was one of the ologist’ of the International Society of Stereology. He worked Editors of Cancer Incidence in Five Continents volume IX. She as a researcher in image processing at the Michelin Research was also elected from 2002 to 2006 as Regional Representative Centre for six years where he conceived scientific frameworks He is leading international collaborations with a special focus for Latin America at the International Association of Cancer in texture analysis, image segmentation and 3D image recon- on Diabetes and retinopathy. He has been published in several Registries (IACR). She joined IARC in 2007 to work within the struction with translation for large-scale industrial applications journals and has obtained several patents in these fields. Cancer Information Group, her main duties being to organize in quality control and 3D imaging. workshops and advisory missions to evaluate and support population-based cancer registries in low- and medium- resources countries as in Africa, Latin America, Caribbean and Mireille Guigaz Asia (Vietnam, India and China). She also has experience in Research Director Maria Paula Curado received a Doctor of Medicine degree and a collaborative multicentre studies, including Head and Neck PhD degree from the University of Goias. From 1990 to 2006 she Cancer in Brazil INHANCE and the Concord study with London Mireille Guigaz is a French Ambassador whose main expertise is Mireille Guigaz has acquired extensive, high-level public health held the position of Director of the Goiania Population-Based Hygiene School on survival. She is currently a Senior Researcher in Public Health and International Development. She graduated management experience through various assignments in the Cancer Registry in Brazil. This registry was able to produce data at the International Prevention Research Institute with the in Law and Political Sciences and completed a PhD in Medical field. Whilst leading the second public health care region of in order to be included by the International Agency for Research aim of promoting prevention research in low- and medium- Law and Health Care Economics at the University of Lyon. France, as Regional Director of Health Care and Social Affairs on Cancer’s (IARC) volume VI-IX of Cancer Incidence in Five resources countries. She also specialised in Hospital Management at the National (1991-1995), she held negotiations with over 200 public and Continents. School of Public Health and attended the National School of private hospitals, setting the path for a five-year strategic Administration. In 2002 she attained an international Masters regional development scheme. As General Delegate of the Degree in Mediation from the Kurt Bösch Institute, Switzerland. National Federation of the twenty comprehensive cancer centres in France (Centres de Lutte Contre le Cancer), she

iPRI 131 iPRI - International Prevention Research Institute — About Us iPRI iPRI Faculty Maria Bota

n organisation is as sustainable as its next dedicated junior faculty. They are here for tomorrow Maria Bota was born in Romania. In 2009 she graduated from of several Ageneration is capable. Indeed, a successful but also for today. Their current qualifications and INSA (National Institute of Applied Sciences) in Lyon, obtaining diabetes drugs organization is one that ensures its younger demonstrated achievements place them, we are an engineering diploma (Master in Science and Technology) in and meta- members are constantly challenged and nurtured confident, on par with any other academic institu- Bioinformatics and Modelling. During her studies she undertook analyses which with new knowledge. iPRI is fortunate to have a tion in our field. several academic and industry-based research internships in have been international and interdisciplinary environments: IARC (Lyon), published in The proof of iPRI Faculty effectiveness is in the many articles, awards and conference presentations that they regularly produce and Bioinformatics Lab at the University of Leeds, R&D Department peer-reviewed receive. All, regularly present papers and posters in prestigious meetings worldwide such as ASCO, ESMO and others. of Sanofi Pasteur (Marcy L’Etoile), and the Department of Ecology journals and presented during international conferences. In and Evolution of University of Lausanne. In 2010 she joined the addition, she has coordinated the preparation of a White Paper iPRI team as a Research Officer, specialising in epidemiology on the epidemiology of diabetes. In January 2014 she started a Alina Macacu and biostatistics applied to a series of public health projects. PhD in Mathematics and Statistics, focusing on Statistical Issues She took a particular interest in diabetes related projects: post- in the analysis of database studies. Alina Macacu was born in Bucharest, Romania. She graduated and assessment authorization safety studies for monitoring the long-term safety in 2010 from the National Institute of Applied Sciences (INSA) of effects of risk in Lyon, France, with an engineer’s degree and an MSc in factors, and Bioinformatics and Modelling. In 2014, she obtained a PhD early detection Cécile Pizot in Models, Methods and Algorithms in Biology, Health and measures, Environment from the Joseph Fourier University, Grenoble, on cancer Cécile Pizot was born in Lyon, France. She graduated from INSA Officer, special- France, for her work on mathematical modelling of the spread of incidence and Lyon (National Institute of Applied Science) in 2011, obtaining ised in biosta- avian influenza. In 2015, she joined the International Prevention mortality. Alina Macacu’s research activities focus on epidemi- an engineering diploma (Master in Science and Technology) tistics applied Research Institute as a Research Officer, specialising in ology of infectious diseases, epidemiology of cancer and math- in Bioinformatics and Modelling. During her studies, she to epidemi- Epidemiology and Biostatistics. She has contributed to various ematical modelling applied to public health, with an interest in undertook several academic and industry-based research ology and projects on topics such as meta-analytic approaches, science projects designed for health improvement in lower-resource internships in multidisciplinary environments including the public health. with and for society, assessment of models-based predictions, settings. Bioinformatics and Biostatistics team of IPSOGEN (Marseille) Her main and the Laboratory of Bioinformatics and Integrative Genomic research topics focus on cancer mortality trends especially for (LBGI) at IGBMC (Strasbourg). In January 2012, Cécile joined breast cancer, physical activity and breast cancer, vitamin D and Alice Koechlin the International Prevention Research Institute as a Research diabetes, epidemiology and aetiology of pancreas cancer.

Alice Koechlin grew up in Saint-Étienne, France, and graduated of Strathclyde in Bioinformatics and Modelling at the National Institute (Scotland) Miruna Dragomir of Applied Sciences (INSA) of Lyon in 2010, obtaining an on statistical engineering diploma (Master in Science and Technology). methods for Miruna Dragomir was born in Brasov, Romania. After her high iPRI projects on She undertook her end of curriculum internships in international meta-analyses school diploma in Romania, she graduated from INSA (National various topics and multidisciplinary environments at the International Agency in epidemio- Institute of Applied Sciences) in Lyon, obtaining an engineering including for Research on Cancer and at the Department of Ecology and logical studies. degree (Master in Science and Technology) in Bioinformatics physical Evolution of University of Lausanne (Switzerland). Alice Koechlin She was also involved in research projects focusing on occu- and Modelling (2014). During her studies, she undertook several activity, vitamin is a Research Officer at the International Prevention Research pational exposures to UV light and to rubber manufacturing research internships in interdisciplinary and international envi- D, diabetes and Institute. She concurrently conducts a PhD with the University industry. ronments such as BioMerieux and Laboratoire de Biométrie et science with Biologie évolutive (Lyon). She also worked for two years for a and for civil society, through approaches such as review and Junior Enterprise (ETIC INSA Technologies), as a Communications meta-analysis of existent published evidence, or analysis and Officer and General Secretary, enabling her to hone her assessment of cancer risk factors. communications and organizational skills. She completed her master’s degree internship at iPRI. She joined iPRI as an Assistant Statistician in 2015. Since then, she has contributed to

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Francesca Ciaraffa

Francesca Ciaraffa was born near Naples. She received a Doctor fellow in Neuro- of Medicine from the Catholic University of Rome in 2002, and Epidemiology a diploma in Neurology in 2007. In 2012 she obtained a PhD at IPRI now in Cognitive Neurosciences from the University Pierre et Marie working on a Curie Paris VI and from the Catholic University of Rome. 2009 to Prospective 2013 she worked at National Neurological Institute Carlo Besta in Cohort-Study Milan, as part of the experimental research project team Coma. of Long Term In 2013, joined the National Neurological Institute Mondino in Safety of Teriflunomide treatment in Multiple Sclerosis patients Pavia, department of Neurological Emergencies. Her clinical in Europe, in collaboration with Multiple Sclerosis Registries of and research focus is vascular events and other neurological Denmark, Belgium, Swedish, Norway, Italy. emergencies, on multiple sclerosis, on disorders of consciousness, and on neuropsychology. She is post-doctoral research

Magali Boniol

Magali Boniol was born in Lyon, France, and graduated with cancer registry a Master of Biological System Analysis and Models, from the data, and University Lyon 1 in 2003. Following her studies, she worked other statistical as Assistant Biostatistician within an association (Audipog) analysis of for five years, and then as Assistant of Clinical Research at the clinical data. Hospices Civils de Lyon. She joined iPRI as Assistant Statistician She has been in March 2012. Her activities cover several aspects of biomedical involved in research, including literature search for systematic reviews and projects on fetal growth restriction, diabetes, breast cancer, and meta-analysis, data extraction for meta-analysis, analysis of occupational UV exposure.

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Kim Coppens Frédérique Delbart Alina Blaj iPRI Staff

Kim Coppens

Kim Coppens was born in St. Agatha-Berchem, Belgium. She de Contabilidade e Administraçao do Porto, Portugal and graduated from the University College of Ghent, Belgium in undertook an internship at iPRI, afterwhich she joined the iPRI 2011 as an Office Manager specialised in translation. During team as Project Assistant. Since January 2017 she is the iPRI her last year, she studied translation at the Instituto Superior Communications Officer.

Florence Motais de Narbonne Aida Ben Brahim Nordine Mamoune Frédérique Delbart

Frédérique Delbart was born in Lyon. She graduated with a BTS industry at Merck Serono Laboratories in Lyon as Executive of Executive Assistant at Institut Pitiot, Lyon in 1990. Further to Assistant. She joined iPRI as Personal Assistant to the President her studies, she worked during 21 years in the pharmaceutical in September 2013.

Alina Blaj

Alina Blaj was born in Romania and studied bank finance at one year, volunteered for V.I.E (Volontariat International en Babes Bolyai University at Cluj Napoca in Romania. In 2010 Entreprise) for the French Economic Mission in Bucarest. She is she received a Masters Degree in Management from Lyon 2 currently studying to become a Chartered Certified Accountant. University. After working as a financial manager in Lyon for She joined the iPRI team in March 2012 as Accountant.

Florence Motais de Narbonne

Florence Motais de Narbonne was born in Paris. After her surgeon and then as Human Resources Manager Assistant to studies she managed teams for several event planning agencies the Chamber of Commerce and Industry of Rhône-Alpes. She in Lyon and Paris. She worked as Assistant to an orthopaedic joined iPRI in June 2014 as Administrative Assistant.

Aïda Ben Brahim

Aïda Ben Brahim grew up in Lyon, France. She has a general in Lyon to become a travel agent. Following these studies, she university studies diploma in Foreign Languages and worked in as a travel agent, administrative assistant and switch- Civilization. She continued her studies at the Peyrefitte School board operator. She joined iPRI as Receptionist in 2016.

Nordine Mamoune

Nordine Mamoune was born in St. Denis, La Réunion. After (Creys-Malville). In 1978 he founded Operator Taxis, a taxi his studies and military service he worked as a welder for the business targeting business and corporate accounts. He joined nuclear station of Petroplus Raffinage Reichstett, the Centre de iPRI in July 2012 as Driver/Clerical Assistant. Recherche Nucleaire Europeen (Pierrelate) and Superphénix

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MD, is responsible for promoting is a member of the Health Services and iPRI Senior Research Fellows the goals of cancer prevention, early Paul Burton Public Health Board at MRC, and the detection, and quality treatment through Study Design Expert Group at WT. PRI is particularly proud to have attracted such a and industry professionals who are able to deliver cancer research and education. He Paul Burton qualified in Medicine from idistinguished panel of Senior Research Fellows. both accurate evidence-based studies and excep- currently serves as professor of hema- the University of Leicester in 1983, taking Indeed, to a great degree, our international reach tionally well informed analyses and, when required, tology, medical oncology, medicine and an intercalated BSc in Genetics in 1981. Naftali Busakhala and recognized excellence would not be possible recommendations. epidemiology at Emory University. He is As an MRC Training Fellow (1986-1989), were it not for scientists, academics, policy experts also a medical consultant to the Cable he was awarded an MSc in Medical Dr. Naftali Busakhala is the founder News Network (CNN). Otis Brawley serves Statistics from the London School of and chairman of the department of You will find in our list of Senior Research Fellows scientists at the top of their field of study. You will find academics from the bona on the Board of Regents of the Uniformed Hygiene (1988). His MD focused on the Hematology and Oncology at Moi fide most exacting academic institutions. You will find ministers of health, university presidents but also a sociologist who has Services University of the Health Sciences. application of survival models to a variety Teaching and Referral Hospital, the devoted her life to improving the lives of her fellow citizens. Patient advocates are also proud Senior Research Fellows working He has served as a member of the Food of complex problems in renal medicine. teaching hospital for Moi University in along side women and men whose body of work lies withing the pharmaceutical industry. and Drug Administration Oncologic Drug Paul Burton is a Chartered Statistician Nairobi. Under his leadership, the depart- Advisory Committee, the Centers for (Royal Statistical Society), a member of ment has expanded rapidly from about From day one, Professor Peter Boyle and his leadership team recognized that, in the words of St. Exupéry, a profession is at its best Disease Control and Prevention Breast the Royal College of Physicians (UK), and 50 patient visits to over 8000 patient only because of the women and men who labour in it. and Cervical Cancer Early Detection holds professorships within the Faculties visits per year. Collaborations have been and Control Advisory Committee and of Public Health in universities both in the formed with Indiana University, Brown Chaired the NIH Consensus Panel on UK and Australia. He is on the Specialist University, University of Massachusetts, Clement Adebamowo of the American Society of Clinical France for further training in breast and the Treatment of Sickle Cell Disease. Register for Public Health Medicine. and University of Toronto. Dr. Busahkala Oncology; Chairman of the National reconstructive surgery obtaining an AFSA Among numerous other awards, he was In recent years, his research work has is now the Co-Director of the Chandaria Clement Adebamowo, born in Lagos, Health Research Ethics Committee of in breast and reconstructive surgery and a Georgia Cancer Coalition Scholar and increasingly focused on activities that Cancer and Chronic Diseases Center, in graduated BM ChB Hons from the Nigeria; Member of the Expert Advisory microsurgery. After returning to Oman, received the Key to St. Bernard Parish for promote and facilitate the construction Eldoret Kenya. University of Jos, Nigeria. He trained in Panel on Clinical Practice Guidelines and Adil established the SQUH Breast unit, a his work in the U.S. Public Health Service of major infrastructural research projects Surgery and Oncology at the University Research Methods and Ethics of the World unique service in the region. This breast in the aftermath of Hurricane Katrina. in population-based biomedicine. He College Hospital Ibadan, Nigeria and at Health Organization (WHO); Country PI of one-stop clinic, introduced multidisci- Harvard University where he earned a the Partnership for Cohort Development plinary practices to Oman, and the first DSc. He is a Fellow of the West African and Training (PaCT); and Nutrition ever breast reconstruction surgery in College of Surgeons and the American Epidemiology Transition Collaboration Oman. Adil regularly organises interna- College of Surgeons; Director of Office (NET). His research interests are non- tional conferences in Oman and is invited of Strategic Information, Research and communicable diseases epidemiology, worldwide to participate and speak at Training, Institute of Human Virology, AIDS-associated malignancies, and global health conferences. Adil Aljarrah Nigeria; President of the Society of Bioethics. is also the founder of the Oman Breast Oncology and Cancer Research of Cancer Society (OBCS). Nigeria; Convener of the Nigerian Research Consortium; Director of the Adil Aljarrah Center for Bioethics, Nigeria; Director of Otis W. Brawley the West African Framework Program Adil Aljarrah, graduated from the on Global Health; and an Associate University la-Sapienza with honours. Otis Brawley, a graduate of University Professor of Epidemiology, University of He completed his general surgery and of Chicago, Pritzker School of Medicine, Maryland, Baltimore. He is Editor in Chief breast surgery residency in Scotland completed a residency in internal of Bioethics Online Journal (BeOnline®), obtaining a fellowship in general surgery medicine at University Hospitals of Cancer in Africa Online Journal (CIAO®), FRCS (Glasgow) and FRCSI (Ireland). Adil Cleveland, Case-Western Reserve Associate Editor of Frontiers in Oncology, then started intensive research in breast University, and a fellowship in medical and Contributing Editor to many other cancer epidemiology at Edinburgh Breast oncology at the National Cancer Institute. journals. Clement is Honorary Professor, Unit and the University of Edinburgh As the chief medical and scientific officer University of Dundee, UK; current Chair obtaining a postgraduate MD from and executive vice president of the of the International Affairs Committee Edinburgh University. He then moved to American Cancer Society, Otis Brawley,

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of Milano-Bicocca. Prof. Corrao currently Oncology) from the Faculty of Medicine, promising medical technologies across at Louisiana State University (LSUHSC) Mark Clanton Giovanni Corrao carries out his research activity at the University Paris XI. He joined INSERM Europe and lives between France and the School of Public Health and Professor of Laboratory of Healthcare Research and (French National Institute for Health UK. Pathology in the LSU School of Medicine In 2006, Mark Clanton served as Giovanni Corrao became research Pharmaco-epidemiology, Department and Medical Research), and worked in where she has been on the faculty in Deputy Director of the National Cancer assistant at the Faculty of Medicine, of Statistics and Quantitative Methods, Villejuif (Institute of Cancerology and the LSUHSC since 1980. She also serves Institute, under NCI Director Andrew University of Turin, in 1984. In 1988 he University of Milano-Bicocca. His main Immunogenetics) and Lyon (Léon Bérard Kenneth Fleming as Senior Consultant Epidemiologist to von Eschenbach. His duties included was upgraded to Associate Professor research interest is on methodological Cancer Centre) where he was Director the Louisiana Office of Public Health. providing senior executive oversight at the Faculty of Medicine, University issues of clinical research and in the of an Immunology and Experimental Kenneth Fleming is a pathologist with Dr. Fontham’s major area of research is of the NCI Cancer Center Core Grant of L’Aquila, where he stayed until 1993. design, analysis and interpretation of Oncology INSERM Research Unit. His a special expertise in the liver. He cancer epidemiology, with an interest Program. The Director and staff of the He is currently Full Professor in Medical statistical models for both observational focus is on human melanoma, exposure graduated from Glasgow University in tobacco and nutrition-related cancers Office of Cancer Centers reported to Statistics, University of Milano-Bicocca. studies and clinical trials. More recently, to ultraviolet radiation and skin cancer in 1968 and after training posts in and gastric carcinogenesis. She has him during this time and he engaged in and the chairman of the Italian College he has focused on statistical methods and prevention. He was a founding member Pathology in Glasgow and Oxford, conducted studies of lung cancer and executive problem solving and senior of Medical Statistics Professors. From epidemiological designs in pharmaco- of the EORTC Melanoma Group. He is a received his DPhil from Oxford University environmental tobacco smoke, including level sign-off for this program on behalf 2005 to 2009 he was the President of epidemiology and outcome research, member of the International Task Force in 1980 and his Fellowship of the Royal the largest early study of lung cancer of the Director of the NCI. Mark currently the Italian Society of Medical Statistics and on the use of electronic archives in on Skin Cancer Screening and Prevention College of Pathologists in 1988.He has in non-smoking women that provided serves on three cancer center external and Clinical Epidemiology. From 2009 to this area. He is currently the coordinator that evaluates the national skin cancer extensive experience of successful lead- some of the critical information leading advisory boards (EAB) including the 2012 he was the Dean of the Faculty of for the University of Milano-Bicocca on 6 screening in Germany. He is currently ership and management in academia to the classification of second-hand University of Kansas Cancer Center. He Statistical Science, University of Milano- collaborative research projects in the field President of the Specialized Experts with various positions in Oxford and smoke as a human carcinogen. Dr. chairs the EAB at the NCI Cancer Center Bicocca. He is the founding Editor of the of pharmaco-epidemiology supported Committee on Physical Agents of the nationally, including appointment Fontham has published extensively on Support Grant (CCSG) designated journal Epidemiology, Biostatistics and from the European, Italian Medicines French National Agency for Health Safety. as the inaugural Head of the Medical stomach cancer and its risk factors, with University of Hawaii Cancer Center Public Health. Since 2003 he has been the Agency, and Italian Health Ministry. He was awarded the Order of Merit of the Sciences Division at the University of studies of the high-risk populations in and serves as member of the NCI CCSG coordinator of the postgraduate course French Republic (Knight, 1978). Oxford from 2000 to 2008. He is currently the Andes Mountains of Colombia. Her designed Siteman Cancer Center in St. program in Biostatistics, University of Honorary Consultant in Pathology for current research includes the study of Louis. Dr. Clanton provides advice and Milano-Bicocca. He currently teaches Jean-François Doré the Oxford Radcliffe Hospitals NHS Trust innovative approaches to cervical cancer feedback in the public health areas of Medical statistics, Methodology of Mark Dumenil and Associate Head for Academic Affairs screening in hard to reach women, and tobacco control, healthcare disparities, clinical and epidemiological research Jean-François Doré, born in 1940 in of the Oxford Post-Graduate Deanery. In studies of the long-term human health cancer prevention and control as well and Pharmaco-epidemiology, Fécamp, France, graduated LSc Nat Born in London, Mark moved to France addition, he is leading the development effects of the exposures resulting from as general advice on the overall perfor- Biostatistics, and Medical statistics. He from the Faculty of Sciences, University in 1981 and directed his career to inter- of a MMed in Pathology in Zambia and the Gulf of Mexico Oil Spill. She has mance of the cancer center against NCI is currently the vice-coordinator of the of Paris, and obtained a Doctorate national healthcare with an interest in has developing involvement in fostering served as a member of the NCI Board of CCSG expectations. PhD program of Public Health, University in Human Biology (Experimental introducing medical devices technology increased educational capacity in several Scientific Counselors. She was Treasurer that make a difference to patients’ lives east and central African countries. He and on the Board of Directors of the across Europe. With nearly 30 years was made an honorary Fellow of the American College of Epidemiology of experience in a variety of international Royal College of Physicians in 2007 which she is a Fellow. She was a member leadership roles at CR Bard Inc., Johnson and was appointed the first Director of the inaugural Editorial Board of Cancer and Johnson Inc., and CMA Microdialysis for International Activities of the Royal Epidemiology Biomarkers and Prevention AB, Mark has developed strong connec- College of Pathologists in November as Assistant Editor; Chairman of the tions with leading clinical, regulatory and 2011. His main research and clinical Scientific Editorial Board of the North well as market access specialists across interest has been in liver disease and American Association of Central Cancer Europe. In 1996 Mark joined the Ethicon he has over 150 publications in learned Registries; and a contributing author for Division of J&J and was offered a leader- journals on aspects of liver pathology both the Surgeon General’s Report and ship role in developing a new surgical and on molecular biology and pathology. International Agency for Cancer Research oncology business. This was later merged Carcinogenesis Monograph series. She with urology where he was made Vice is recipient of the Alton Ochsner Award President Europe for Oncology and Elizabeth Fontham Relating Tobacco and Health, the C.L. Urology. Today he leads an international Brown Award for Leadership Excellence healthcare consultancy based in Paris Elizabeth Fontham is the Founding Dean in Tobacco Prevention; the Leadership dedicated to introducing successfully and Professor of Epidemiology Emeritus and Distinguished Service Award of

iPRI 141 iPRI - International Prevention Research Institute — About Us iPRI

the American College of Epidemiology; Centre for Epidemiology of the National developed a Project of Quality control of in 2011, and served as President of the Scientific Director of the Engineer School and the Pfizer Award for Excellence Institute of Health of Italy, where he Digital Mammography in Breast Cancer Peter Johnstone American Radium Society in 2010, and CPE-Lyon, Michel Jourlin is currently in Research, Education and Patient served for 32 years. Donato Greco Screening which is currently used in President of the Society for Integrative Full Professor at the University of Saint- Care. served for four years as Director of the several National Screening Programs. Peter Johnstone was raised in Gresham, Oncology in 2007. Etienne and develops his research at the Department of Disease Prevention in the Oregon. He graduated from the CNRS Laboratory Hubert Curien. Italian Ministry of Health where he was he United States Naval Academy in 1979, Sara Gandini led Influenza Pandemic preparedness. As Geoffrey Hamilton-Fairley completing a Master of Arts degree Michel Jourlin National Epidemiologist at ISS he investi- in Communication from Oklahoma Dan Krewski Sara Gandini has a degree in Statistics gated hundreds of epidemics worldwide Geoffrey Hamilton-Fairley’s entrepre- University in 1985 and an MD degree Michel Jourlin was born in Saint-Etienne, (University of Bologna), an MSc in including the ECDC response to the 2009 neurial career started in 1982 when from the Uniformed Services University France, and graduated in Mathematics Dr. Krewski is Scientific Director of the Biometry (University of Reading) and H1N1 pandemic evaluation (May-July he founded a number of companies in of the Health Sciences in 1989. He at the University of Lyon 1. After McLaughlin Centre for Population Health a PhD in Cancer Studies (University of 2009). Donato Greco has worked exten- the media sector. In 1988 he joined the completed Residency in Radiation obtaining his PhD in Pure Mathematics, Risk Assessment at the University of Birmingham). She is a senior investigator sively with WHO and the European board of Abingdon as CEO and subse- Oncology subsequently at the National he turned his research towards Image Ottawa, and Professor in the School in the division of Epidemiology and Center for Disease Control. Today he quently became sole owner. Abingdon Cancer Institute. In December, 2007, Processing. His most important contri- of Epidemiology, Public Health and Biostatistics, at the European Institute serves as consultant in communicable had a number of quoted and unquoted Dr. Johnstone was named Chair and bution is the development of the LIP Preventive Medicine. He holds a Natural of Oncology in Milan (Italy). She has diseases surveillance, prevention and risk investments in a variety of sectors; William A. Mitchell Professor of Radiation (Logarithmic Image Processing) Model, Research Council of Canada Research conducted extensive research in cancer communication. He has authored more Property, Corporate Finance, Unit Trusts, Oncology at Indiana University (IU). He which offers a particularly efficient Chair in Risk Science, focusing on risk epidemiology, including systematic than 150 scientific publications and has an ITV franchise (TVS) and a few early was named President and Chief Executive framework for Biomedical and Industrial assessment and management of a wide reviews and meta-analyses, with the been teaching epidemiological methods technology companies – perhaps the Officer of the IU proton center in August, Image Processing, due to its strong range of technological and other risk goal of better understanding cancer in Italian universities for many years. most noteworthy being Fortronic which 2008, and director of IU cyclotron opera- physical and mathematical proper- issues. From 2007 to 2012, he served as aetiology. Her main interest is now Donato Greco has been awarded the developed the first magnetic strip plastic tions in January, 2010. Dr. Johnstone was ties added to its consistency with the Associate Scientific Director of PrioNet melanoma epidemiology and the role of Italian Gold Medal for Public Health. card swipe technology. In 1998 he selected to the ACR Board of Chancellors Human Visual System. After ten years as Canada. Dr Krewski also serves as Chief Vitamin D in cancer epidemiology. She launched Premium TV (PTV) securing a is the lead organizer of a multicentre contractual joint venture with Eurosport Italian trial on Vitamin D supplementa- André-Robert Grivegnée to create “British Eurosport”. As CEO of tion for melanoma patients. Since 2008 PTV Geoffrey Hamilton-Fairley insti- she has been lecturer at the Italian André-Robert Grivegnée is Head of the gated and oversaw the highly complex Melanoma Intergroup Master and for Cancer Prevention and Screening Clinic development of the largest integrated statistical courses at the European at Jules Bordet Institute in Brussels. broadband and internet sports broad- Institute of Oncology. In December 2011 As a radiologist, he is Head of the casting platform in the world. Over she was unanimously elected as new Senology Unit in the same Institution. the past ten years Mr Hamilton-Fairley President-elect of EuroSkin. Sara Gandini He is Professor at the Free University of has increasingly focussed his time and has authored or co-authored over 50 Brussels (Université Libre de Bruxelles). energies on the health sector. Geoffrey publications and she acts as referee He is involved in Breast Screening Hamilton-Fairley has dedicated the past 5 of several international peer reviewed Programs in Belgium and at the European years to the development of Oncimmune journals, such as JNCI and JCO. In 2008 Level and is Past-President of the Brussels Ltd, serving as its Executive Chairman. she received the Bruno Martinetto Award Program for Breast Cancer Screening. The company has a unique technology for Research in Chemoprevention. He is administrator of the Association for detecting the immune response to against respiratory diseases (FARES). His cancer at a very early stage in a cancer’s Curriculum Vitae includes 102 articles development - up to 4 years before Donato Greco and more than 200 presentations at current screening technologies. national and international societies Donato Greco was born in Naples, and and symposia. He participated in seven graduated in medicine with a specialisa- European Research projects and is tion in infectious diseases, public health, currently involved in a Project on Breast epidemiology, and biostatistics. He Cancer Risk Evolution. He is an active founded and later directed the National member of the EORTC Imaging group. He

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Risk Scientist and CEO of Risk Sciences as a leading authority in cancer aetiology in Johannesburg, South Africa. He worked for the EUROCAT Central Registry NIH-funded program to detect gene(s) for In 2013 he was also appointed Medical International, a Canadian company and epidemiology. Presently, he is held academic appointments in in Brussels, as a lecturer in epidemiology familial pancreatic cancer (PACGENE). He is Advisor to QuarterWatch: Monitoring established in 2006 in partnership Professor of Epidemiology at the School the Department of Medicine at in Nottingham University, as an epide- a member of the American Gastrointestinal FDA MedWatch Reports, Institute for with the U. of Ottawa to help public of Medicine at the University of Milan. the University of Chicago and then miologist in the International Agency Association, of the American Pancreatic Safe Medication Practices. From 2002 and private sector clients in under- Dr. La Vecchia serves as an editor for served as Chair of the Department of for Research on Cancer in Lyon, and as Association, and of the Panc4 Consortium, to 2012 he was Senior Advisor to the standing, managing, and communi- numerous clinical and epidemiologic Gastrointestinal Medical Oncology Professor of Epidemiology at Aberdeen an international group of investigators Director of the Eunice Kennedy Shriver cating risk. Prior to 1998, Dr. Krewski journals. He is among the most renowned and Digestive Diseases at University University, during which he spent a associated with case-control studies of National Institute of Child Health and held several research and management and productive epidemiologists in the of Texas M.D. Anderson Cancer Center sabbatical year at the Office of Genomics pancreatic cancer who have agreed to Human Development, National Institutes positions in Health Canada, including field with over 1,840 peer-reviewed until his appointment as Vice President and Disease Prevention, CDC, Atlanta. His pool their data for cooperative studies. of Health. He has also been the Medical as Director of Risk Management and papers in the literature and is among the for Cancer Prevention and Population current research includes empirical work Director of the March of Dimes, Dean of Senior Branch Advisor for Health Risk most highly cited medical researchers Sciences. He retired from MD Anderson on potential biases in genetic associa- the Graduate School of Public Health at Assessment. While with Health Canada, in the world, per ISIHighlyCited.com, Cancer Center in November 2007 and tion studies, harmonization of biobanks, Melinda Magyari the University of Pittsburgh, Director Dr. Krewski laid the groundwork for the developer and publisher of the was appointed as Professor Emeritus. the potential value of germline genetic of Human Risk Assessment at the FDA the Departmental Decision-Making Science Citation Index (h index, 125). He has served as Chair of the American profiling in prediction of risk for chronic Melinda Magyari, born in Transylvania, National Center for Toxicological Research Framework for Identifying, Assessing, Dr. La Vecchia is an Adjunct Professor of Cancer Society’s National Advisory Task disease, the potential value of informa- obtained her medical degree from the and on the faculty of the University of and Managing Health Risks. Dr. Krewski Medicine at Vanderbilt Medical Center Force on Colorectal Cancer, founding tion on family history in predicting risk University of Southern Denmark. In Arkansas for Medical Sciences, University served as Chair of the National Research and the Vanderbilt-Ingram Cancer co-chair of the National Colorectal for chronic disease, potential value of 2008 she specialised in neurology and of Pittsburgh, and Columbia University. Council’s Committee on Toxicity Testing Center. Dr. La Vecchia is a temporary Cancer Roundtable, President of the information on HPV and other factors in obtained her PhD at the University During this time, he has also served in the and Assessment of Environmental advisor at the World Health Organization International Society of Gastrointestinal management of women with low-grade of Copenhagen in 2014. Dr. Magyari US Public Health Service, with deploy- Agents. More recently, Dr. Krewski was in Geneva, and a registered journalist Carcinogenesis and founding Chair of the cervical abnormalities, and etiology of is currently the Head of The Danish ments for medical and public health closely involved in the US Environmental in Milan. He was Adjunct Associate World Gastroenterology Organization cleft lip and palate. Multiple Sclerosis Registry and a support. In his research, he has led drug Protection Agency’s NexGen project that Professor of Epidemiology at Harvard Foundation whose mission is to raise consulting neurologist at the Danish development in paediatrics and obstet- proposed a new framework for the next School of Public Health between 1996 funds for the training of gastroenterolo- Multiple Sclerosis Centre, at Copenhagen rics, including safety signal identifica- generation of risk science in 2014. He also and 2001 and Professor of Epidemiology gists in low-resource countries. He was Albert Lowenfels University Hospital, Rigshospitalet. tion and evaluation. He has also led the chaired the US Health Effects Institute at the University of Lausanne (2000- co-editor, with Peter Boyle, of the “World Dr. Magyari’s major research area is in development of methods in risk assess- Diesel Epidemiology Panel evaluating 14), was Senior Research Fellow at the Cancer Report” published by IARC/WHO Albert Lowenfels has made major contri- multiple sclerosis epidemiology, with an ment for reproductive and develop- epidemiological evidence on diesel International Agency for Research on in December 2008. He currently serves on butions in the field of alcohol as a cause interest in gender differences in multiple mental endpoints. Currently his research exhaust emissions from a risk assessment Cancer IARC/WHO between 2006 and the editorial board of the Journal of the of common chronic conditions. Initially sclerosis. Her current research includes explores approaches to understand drug perspective. Dr. Krewski is a Fellow of the 2008, and Head of the Department of National Cancer Institute. His research trained as a surgeon, he has pursued studies on the risk factors, comorbidities use, effectiveness, safety and risk-benefit Society of Risk Analysis and the American Epidemiology at the Mario Negri Institute interests include molecular markers for a second career in gastrointestinal and the social consequences of multiple communications, as well as environ- Statistical Association, and a lifetime between 2007 and 2014. Dr. La Vecchia’s detection of colorectal cancer and better disease epidemiology with a focus on sclerosis and observational studies on mental impacts on population health. National Affiliate of the US National main fields of interest include cancer methods for enhancing public awareness the role of alcohol. His special areas of treatment effect and safety of disease Dr. Mattison earned a BA (Chemistry and Academy of Sciences. He currently serves epidemiology and the risk related to of colorectal cancer prevention. His interest, as represented in more than modifying drugs. She participates exten- Mathematics) from Augsburg College in on the Scientific Advisory Committee diet, tobacco, oral contraceptive use and public health interests lie in enhancing 200 peer-reviewed publications, include sively in several international multiple Minneapolis, an MS Chemistry from the of the Council of Canadian Academies, occupational or environmental exposure medical care in developing countries. alcohol-related illnesses, epidemiology sclerosis databases. Massachusetts Institute of Technology which provides science advice to the to toxic substances; and analysis of of pancreatic cancer, and the relation and a MD from the College of Physicians federal government on a wide range temporal trends and geographical distri- between benign and malignant digestive and Surgeons, Columbia University. of issues of national and international bution of mortality from cancer, cardio- Julian Little tract disease. He is currently Professor Donald Mattison His clinical training in Obstetrics and importance. vascular diseases, perinatal and other of Surgery and Professor of Community Gynaecology was at the Sloane Hospital selected conditions. Julian Little, PhD holds a Canada Research and Preventive Medicine at New York Donald Mattison has had a distinguished for Women in the Columbia Presbyterian Chair in Human Genome Epidemiology, Medical College. He is also Senior Advisor career in medicine and public health. Medical Center in New York. His training Carlo La Vecchia and is a Professor in (and Chair of) in the Department Epidemiology and In 2012 he was concurrently appointed in Pharmacology and Toxicology was Bernard Levin the Department of Epidemiology and Biostatistics at the European Institute Chief Medical Officer and Senior Vice at the National Institutes of Health, Carlo La Vecchia received his medical Community Medicine at the University of Oncology in Milan, Consultant in the President of Risk Sciences International Bethesda, MD. He has published more degree from the University of Milan and a Professor Bernard Levin earned his of Ottawa. His PhD, from Aberdeen Department of Community and Preventive and Associate Director of the McLaughlin than 200 peer reviewed articles. In 1997, MSc in clinical epidemiology from Oxford medical degree from the University University, was on problems of ascer- Medicine at Weill-Cornell Medical College Centre for Population Health Risk he was elected a Fellow of the American University. He is recognized worldwide of the Witwatersrand Medical School tainment of congenital anomalies. He in Qatar, and External Advisor for a Assessment at the University of Ottawa. Association for the Advancement of

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Science, in 1999, a Fellow of the New obesity and physical activity as risk DARTS research study, has published York Academy of Medicine, in 2000 a factors of non-communicable diseases. over 170 original papers and has member of the Institute of Medicine, in attracted over £20 million in peer 2005 Distinguished Alumni of Augsburg reviewed grant funding. He is the College and in 2009 a Fellow of the Royal William R. Miller principal investigator on many clinical Society of Medicine. studies of new therapeutics of diabetes William R. Miller is an Emeritus Professor as well as genetics of diabetes, including at the University of Edinburgh. He the Wellcome Trust United Kingdom Case Jean-Claude Mbanya completed his BSc and PhD degrees at Control Collection for Type 2 Diabetes the University of Leeds before receiving that is recruiting 15,000 individuals. He is Jean Claude Mbanya is Professor of a DSc from the University of Edinburgh. also the principal investigator of Medicine and Endocrinology at the William R. Miller is past Chairman of the Generation Scotland, a study of the Faculty of Medicine and Biomedical Scientific Advisory Board of the Breast genetic health in 50,000 Scots. He was Sciences, University of Yaoundé I, Director Cancer Campaign, past Chairman of the awarded the RD Lawrence Award by Biotechnology Center and Coordinator British Breast Group, and was Secretary Diabetes UK in 2003, the Saltire Society Doctoral School of Life, Health and to the British Association for Cancer Scottish Science Award in 2005 and is a Environmental Sciences, University of Research. He is a member of various Fellow of the Royal Society of Edinburgh, Yaoundé 1 and Adjunct Professor of editorial boards, including the British Scotland’s national academy of science Medicine, Endocrinology Diabetes, Journal of Cancer, New Directions in and letters. He was appointed by the Organization for Research and Training in first isotropic-resolution 3D microscope, PMA clearances. He is trained in financial at the University of Technology. He is Endocrine Treatment of Breast Cancer, Minister for Health and Community Care Cancer (AORTIC); Past Director of INCTR addressing the world’s number one accounting, and his companies have also Consultant Physician and Director and The Breast. Miller has published to be Lead Clinician for diabetes in in Cameroon; Permanent Secretary of cancer killer. This breakthrough tech- passed rigorous government audits with of the National Obesity Centre at the more than 250 articles and made more Scotland (2002-2006) and led a national the European and African Congress in nology has the potential to save tens of high marks. In the States of Washington University Teaching Hospital in Yaoundé. than 100 presentations at national and programme of quality improvement in Oncology since 2001; Local PI in several millions of lives. Previously, Dr. Nelson and Arizona, Dr. Nelson changed the He is Past President of the International international societies and symposia. His diabetes care. He is also the eHealth research protocols in Yaounde in Kaposi was the founder, President and CEO of State Ethics Law and re-wrote the State Diabetes Federation. He initially studied research interests include cell biology Director of NHS Tayside and chairs the sarcoma, Breast cancer, CML and AIDS- NeoPath, Inc., a company dedicated Intellectual Property Policy, respec- in Cameroon where he obtained his and tumour endocrinology of breast Translational Medicine Research related malignancies. to eradicating cervical cancer by tively, to facilitate more streamlined MD and trained at the University of cancer. He currently organises and runs Collaboration Steering Group, unique inventing and developing the FocalPoint. and successful technology transfer. Dr. Newcastle upon Tyne where he obtained scientific meetings and editing proceed- £50 million collaboration between all The technology is now standard of care Nelson holds 145 issued patents and a PhD and later became a Member of ings - most notably ‘Controversies in Medical Schools in Scotland and the Alan Nelson throughout the world and is credited with has published 120 peer-reviewed papers the Royal College of Physicians. He is a Breast Cancer’, an annual symposium pharmaceutical giant Wyeth. Recently he saving over 100,000 women’s lives. Dr. in the field of biomedical imaging. He Fellow of the Royal College of Physicians, which is now in its ninth year. has been appointed as a Chairman of Alan Nelson, PhD, is the founder, Nelson was on the tenured faculty at UW received his PhD in Physics/Biophysics London and Doctor philosophiae honoris The Wellcome Trust Expert Review Group Chairman and CEO of VisionGate, Inc., where he directed the graduate Medical from the University of California, Berkeley. causa, University of Oslo. Prof. Mbanya – Genetics, Genomics and Population founder and Chairman of Nortis, Inc., Imaging Program. Before joining UW, he He is driven to have impact. also currently serves on several inter- Andrew Morris Research. founder and President of the Predictive was an associate professor appointed national scientific and WHO advisory Health Analytics Institute (PHAIT), and jointly at MIT and Harvard where he held groups, including the Expert Advisory Andrew Morris is the Professor of Diabetic the former Executive Director of the the W.M. Keck Foundation endowed chair Twalib Ngoma Panel on Chronic Degenerative Diseases Medicine and Head of Planning and Paul Ndom Biodesign Institute at Arizona State and directed the graduate Radiological and Diabetes and the WHO African Development in the College of Medicine University where he also served as full Sciences Program. He has decades of Twalib Ngoma is one of Africa’s foremost Advisory Committee on Health Research Dentistry and Nursing at the University of Paul Ndom was born in Cameroon professor of Bioengineering and of senior executive experience in the lead- radiation oncologists with special and Development. He is a recipient of Dundee. He leads a translational research and graduated MD from the Faculty of Physics. He holds an appointment as ership, management and accountability interest in cancer control. He trained at several international awards. His major team that focuses on the epidemiological Medicine (CUSS), University of Yaounde. an Associate Member of the Arizona of large complex programs, using profes- the Christie Hospital in Manchester and interests include diabetes and other non- and molecular aetiological basis of He is Associate Professor of Medicine at Cancer Center with the University of sional project management, and he is Beatson Oncology Centre in Glasgow in communicable diseases epidemiology diabetes and its complications. He also the University of Yaounde I, in charge of Arizona. In 2001, he founded VisionGate certified in quality systems regulations, the 1980’s and then went back to his and prevention, integration of diabetes has a major interest in how managed training in oncology; Head of Medical to develop groundbreaking technology including ISO-9001 and FDA QSRs and home country, Tanzania, where he care in the health care system of devel- clinical networks can improve patient Oncology Service in Yaounde General for lung cancer screening using a non- GMP. He brings an in-depth knowledge became the Executive Director of the oping countries, diabetes complications, care across geographical boundaries. He Hospital since 1997; President of the NGO invasive sputum test analyzed on a new and experience in translational work and Ocean Road Cancer Institute. He was also leads the internationally acclaimed SOCHIMIO; Past President of the African device called the Cell-CT, the world’s clinical trials for FDA 510(k) and Class III the Director of INCTR’s Tanzania office

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and a member of the Standing Advisory the obstacles posed by limited resources contribution to nutritional sciences and treatment of malnutrition and the role of EU-Framework Programme. He was also of the French Urologic Association, Group on Nuclear applications (SAGNA) mirror those of his native country. improving the quality of nutritional care nutrition in the care of the critically ill. responsible for Austria’s international European Urologic Association and which advises the IAEA Director General of patients. Ibolya started working as an research infrastructure memberships corresponding member of the American on the Agency’s activities in the applica- ICU dietitian in the late 1970s at Royal like EMBL and EMBC. He progressed Urologic Association. tion of nuclear techniques carried out Ibolya Nyulasi Melbourne Hospital following a period Christian Partensky to become the first full-time Deputy within the programmes of Food and at the Hammersmith hospital in London. Director General for Research in the Agriculture, Human Health, Water Professor Nyulasi is the Head the She was the Australasian editor of the Christian Partensky has been Professor Ministry of Science in Austria and then Chris Robertson Resources, Assessment and Management Department of Nutrition and Dietetics journal Nutrition from 1998 to 2008. She of Digestive Surgery at the Claude to be Scientific Coordinator at the of the Marine and Terrestrial at Alfred Health, Melbourne Australia. was involved with the development of Bernard University of Lyon since 1977 International Agency for Research on Chris Robertson is a statistician whose Environments, and Radioisotope Alfred Health is a multi-campus health Monash University Dietetics course which and Head of the Department of HPB Cancer. From the establishment of long-term research interests have Production and Radiation Technology. service that includes a large quaternary she later led as the course convenor and Surgery at the Edouard Herriot Hospital iPRI in April 2009 to December 2013 focussed on the application and devel- He has a leading role in Tanzania as the teaching hospital with a major trauma, to the successful accreditation of the new of Lyon since from 1981 to 2007. After Markus Pasterk was Chief Operating opment of statistical modelling in local coordinator and Secretary of the burns services and a 45 bed ICU. It also course. In 2003 she was the recipient of 2007, he was either concomitantly or Officer and Vice President, Science, at epidemiology. Since 2002 he has had a steering committee for the development has a comprehensive cancer program grant from the Australia India Council sequentially, consultant for surgery, the International Prevention Research joint appointment as Professor of Public of a National Cancer Control Strategy and including radiotherapy and bone marrow to develop a train the trainer nutrition emeritus professor, member of the Institute. In December 2013 he took Health Epidemiology in the Department Action Plan. After the selection of transplant service. Ibolya is the current education program for disease related French High Health Authority Committee up the key position of Administrative of Mathematics and Statistics at the Tanzania by the International Atomic President of the Australasian Society of and maternal child health nutrition in for Evaluation of Medical Devices and Director at the new BBMRI-ERIC based in University of Strathclyde, Glasgow, Energy Agency to be one of the PACT Enteral and Parenteral Nutrition AuSPEN rural India. She chairs The Alfred Hospital Medical Technologies, and IARC Senior Graz in his native Austria. and also at Heath Protection Scotland Model Demonstration Sites for the devel- a position she has held in the past and is small project committee and the Allied Visiting Scientist. His main area of (HPS). From 1995 to 2001, he was Head opment of multidisciplinary capacity- a life member of the society. She is also Health research committee. Although interest has been pancreatic cancer. of Biostatistics and Vice Director in building projects in cancer control, member of the ESPEN faculty and holds she heads a clinical department, she He is a member of the French Academy Paul Perrin Epidemiology and Biostatistics in the Twalib Ngoma became a PACT Consultant an Adjunct Associate Professor position has a long-standing interest in research of Surgery, of the French Association European Institute of Oncology, Milano. and National Coordinator. As past in the Department of Medicine at Monash and has published 45 papers in peer of Surgery, a senior member of the Paul Perrin has been Professor of Urology Prior to that he was a lecturer and senior President of the African Organization for University, Melbourne. In 2016 she was reviewed journals in collaboration with European Surgical Association and fellow at the University of Lyon since 1981. He lecturer in Mathematics and Statistics Research and Training in Africa, he is also recognised by the European Society researchers across the world. Nyulasi has of the American College of Surgeons. He received his degree in Medicine from the and Modelling Science at Strathclyde addressing the challenges of controlling for Clinical Nutrition and Metabolism a major interest in the identification and was awarded the Order of the French Claude Bernard University in Lyon and University. Presently his main research cancer throughout the continent, where by a Career Achievement Award for her Legion of Honour in 2003. his postgraduate training included an is in statistical modelling of infectious internship and residency in Urology at diseases and in designing epidemio- the Hospices Civils University Hospital. logical studies for disease surveillance Markus Pasterk He was awarded a fellowship with systems. He is currently involved with Roger Barnes in Loma Linda University the Ethics Committee and the Data Markus Pasterk was born in Klagenfurt, in California. He was appointed as Dean Safety Monitoring Committee of the Austria and studied Molecular Biology of the Laennec Medical School and then International Breast Cancer Study Group, at the University of Vienna, where he chaired the Department of International and with the West of Scotland Research received a MSc degree in 1994. Early in Exchanges Program for students for the Ethics Committee. He is also a member his career he decided to transition from Claude Bernard University Lyon 1. He of the Scientific Advisory Group for research to research management. In served as Chief of Urology at the Lyon Interdisciplinary Centre for Human and 2001 Markus Pasterk was promoted University Hospital from 1986 to 2008 Avian Influenza Research (Edinburg Director of the newly created Life and chaired the Department of Surgery University), and of the Scientific Pandemic Sciences Division within the Austrian at the Lyon Sud University Hospital from Influenza Advisory Committee Subgroup Ministry of Science, with responsibili- 2005 to 2011. He is currently Consultant on Modelling for the UK Department of ties of research, in particular genomics, for surgery to the Claude Bernard Health. biotechnology and medical research. University. His main areas of interest are He became the Austrian delegate to the use of ultrasound in urology, evalu- the programme committee of the Life ation of outcomes for the treatments of Sciences, Genomics and Biotechnology BPH and clinical research in the field of for Health Programme of the 6th prostate cancer. He is an active member

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school of medicine, Tel Aviv University and Pharmacology. He has published Hans Joachim Schmoll (2009-2013), and Chairman of the nearly two hundred original research European Society for Clinical Nutrition journal articles, a dozen review articles Prof. HJ Schmoll obtained his medical and Metabolism (ESPEN) (2010-2014). He and four book chapters. Temple Smith degree in 1970 from Hanover Medical has been appointed as associate editor, is also a co-founder of Modular Genetics University. Currently, Prof. Schmoll is the section editor or co-editor in various Inc., a gene engineering company. His Head of the Division of Hematology and journals such as Intensive Care Medicine, research is centred on the application Oncology and Director of the Center for Clinical Nutrition, Clinical Nutrition of various computer science and math- Cell and Gene Therapy, Martin Luther Experimental, Nutrition or JPEN. From ematical methods for the discovery of University, Halle, Germany, and Professor 2002, he has been the Chairman of the syntactic and semantic patterns in of Medicine at Martin Luther University, the Annual Israel Nutrition Week. nucleic acid and amino acid sequences, Germany. He has published over 355 peer His research interests center around and their evolution. These include the review papers with focus on the biology nutrition and metabolism, sepsis, respira- development of new sequence pattern and particular treatment of advanced tory disorders technologies. Dr. Singer extraction tools (PIMA), multi-domain colon and rectal cancer as well as on has supervised more than 50 clinical dissection methods, and protein inverse at York University and a PhD in medical 2007, he is now also the Director of the germcell cancer. He has been leading and academic research theses. He has folding or threading prediction algo- education. She chaired, until 2014, the Division of Clinical Population Sciences Richard Sullivan author of the first European consensus received numerous awards and grants rithms. Temple Smith has carried out paediatric haematology oncology unit Education in Dundee. Frank Sullivan’s guideline for germcell cancer in 2004 and throughout his career. He is co-author of research applications exploiting such at Tygerberg Hospital, Stellenbosch research interests lie mainly in health Richard Sullivan is Director of External of the first international ESMO consensus the teaching modules on Nutrition in the methods on problems ranging from the University, where she founded the informatics and community based trials, Affairs at Kings Health Partners Integrated guideline for diagnosis and treatment of ICU from ESPEN (LLL) and ESICM (PACT) time calibration of HIV and Papilloma African Cancer Institute. At AORTIC, covering the spectrum from record- Cancer Centre and Director of the new colon and rectal cancer in 2011. as well as of the ESPEN 2000 Parenteral viral evolution through the modelling of she is currently the Co-chair of African linkage of electronic health records to KHP Centre for Global OncoPolicy Health, Nutrition in the ICU guidelines. Dr. Singer the 3D structure of the WD repeat protein research, chair of paediatric oncology decision support to the evaluation of a joint partnership with the European has presented over 250 lectures, and had family and that of the translational and chair of African Cancer Economics complex interventions. He has published Institute of Oncology. He is also Visiting Pierre Singer more than 200 invited papers at scientific GTPases. His current focus is on early network. Her activity included the first widely on different types of primary care Professor (Cancer and Public Health) at meetings. He has published more than evolution, for example, that of a novel twinning program in oncology between research notably in the management of Universidad Catolica, Santiago de Chile. Pierre Singer has over 30 years of clinical 125 original articles, 30 review articles, family of apoptotic regulatory proteins, two African countries, cancer education long-term conditions such as diabetes Richard Sullivan qualified in Medicine and academic experience. He was born 23 book chapters, and 175 abstracts. He the Lifeguard family and the ribosomal and research activities, cancer registry as and coronary heart disease in the at St. Marys Hospital, London. Following in France attending medical school at is the editor of a recent book entitled: proteins. well as contributions to various African community. He led the Bell’s trial which training in surgery he undertook a PhD the Louis Pasteur Faculty of Medicine Nutrition in the ICU: Beyond Physiology. National Cancer Control Plans. She serves involved more than half of all general and post-doctoral research in cell signal- of Strasbourg. Since 1995 he has been as an advisor to the Minister of Health in medical practices in Scotland whose ling at University College London. He the Director of the General Intensive Cristina Stefan South Africa and various other African main paper in the NEJM won the BMA then worked in a senior role in the phar- Care Department, Rabin Medical Center, Temple F. Smith committees and groups. research paper of the year in 2009. In the maceutical industry before spending Beilinson Campus, Petach Tikva, Israel. Cristina Stefan is the President-Elect past, Frank Sullivan was Director of the 10 years with Cancer Research UK as Since 2006, Dr. Singer has also been Head Temple Smith graduated with a PhD of AORTIC (African Organisation for East of Scotland Primary Care Research their clinical director. Richard serves on of the Institute of Nutrition Research at in Nuclear Physics from University Research and Training in Cancer). She will Frank Sullivan Network (EastRen) and a member the multiple international advisory boards, Rabin Medical Center, Director of the of Colorado. He is a co-developer be President of AORTIC 2017-2019. She MRC College of experts 2005-2009 and e.g. Charite Comprehensive Cancer Metabolism Laboratory at the Felsenstein of the Smith-Waterman sequence is also past Vice-President of the South Frank Sullivan is a medical graduate of of the Member UK Office for Strategic Centre Berlin, Irish Clinical Oncology Medical Research Center and Professor alignment algorithm, and was one of African Medical Research Council where Glasgow University. Following clinical Co-ordination of Health Research Group, Kings College Marjan Centre of Anesthesia and Intensive Care at the the founders of GenBank at Los Alamos. she was responsible for the strategic training in the West of Scotland, fourteen (OSCHR) E-Health Records Board. More for Conflict Conservation, Pfizer Policy Sackler School of Medicine, Tel Aviv He also founded the Molecular Biology planning of research (with a special focus years as a partner in a practice in Blantyre recently his work has extended to two Advisory Board and is past UK Director University. Dr. Singer was President Computer Research Resource at the on NCDs) as well as education, building during which time he completed a PhD large European projects which extract of the Council for Emerging National of the Israel Society of Intensive Care Dana-Farber Cancer Institute, which later up capacity, providing leadership and and a year’s work in the Seychelles, and link primary care and research data. Security Affairs (CENSA), a Washington- Medicine (2000-2004), Israel Society for became the BioMolecular Engineering assuming accountability for the strategic he was appointed to the NHSTayside He was a co-author of the BMJ series and based national security think-tank. His Clinical Nutrition (ISCN) from 2005-2009. Research Center at the College of and operational planning of the organi- Chair of Research and Development in book on Health Informatics. current research programmes cover More recently, Dr. Singer held positions Engineering at Boston University. At sation. A paediatrician by profession, she General Practice and Primary Care in the the social and political policy of cancer as Chairman of the Department of Boston University he is a professor in the qualified a few years later as an oncologist, University of Dundee. Director of the (OncoPolicy), including e-policy and Anesthesia and Intensive Care, Sackler departments of Biomedical Engineering completing a Masters in Epidemiology Scottish School of Primary Care since global public health challenges in

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transitional, high-risk conflict areas current position is Chief Cancer advisor Federal and State Health Ministers on of complications. In the field of HIV studies. Before 2004, and between 2008- Ministry of Health (since 2000). He has focusing on DR Congo, Afghanistan and for the Victorian Government. He is also cancer matters. infection, he completed studies of the 2011, Dr. Trapido was Professor and Vice published over 170 international publi- Libya. Chair of the Victorian Cancer Agency mother-to-child transmission and new Chair of the Department of Epidemiology cations, edited 2 international, 4 national with responsibility for the translational treatments and gene therapy against and Public Health at the University of textbooks and hundreds of scientific research agenda and funding of cancer Jean-Louis Touraine HIV in the humanized SCID mouse. In Miami Miller School of Medicine. Dr. posters in international congresses. Robert JS Thomas research in Victoria. Robert Thomas has the ethics of transplantation, his work Trapido also led the Southeast Regional been heavily involved in the develop- Professor Touraine has been a Professor includes foetal development and HIV Cancer Information Service, Florida Robert JS Thomas graduated in Medicine ment of cancer reforms within Australia, in Nephrology, Immunology and infection. Finally, in the field of immu- Cancer Data System (Registry), Early Carlos Vallejos Sologuren from the University of Melbourne and has been past President of COSA, Chair Transplantation at the Claude Bernard nology, he has worked on immunological Breast Cancer Detection Program, and trained in surgery at the Royal Melbourne of the National Committee creating the University of Lyon since 1979. From 1986 tolerance, T-cell differentiation, role of the Southeast Comprehensive Cancer Dr. Carlos Vallejos Sologuren is principal Hospital. He commenced surgical Colorectal Cancer Guidelines, and was a to 2012 he was Head of the Department HLA antigens and antigen recognition by Control Coalition. Most of his research has member of AUNA, one of the most practice in Melbourne based at the Royal member of the Ministerial Taskforce on of Transplantation and Clinical T-cells. Professor Touraine has authored been in tobacco control, cancer preven- important private healthcare services in Melbourne Hospital where he was deeply Cancer. He has published over 100 peer Immunology, Hôpital Edouard Herriot. In over 1000 scientific papers and 35 scien- tion and control, health disparities, early Perú. In 1996, he founded the Sociedad involved in the teaching of medical reviewed scientific papers and book the field of immunodeficiency diseases tific books. Since 2007, Professor Touraine detection, and in HIV/AIDS. His recent Peruana de Oncología Médica, being its students. He then became Professor chapters. He was honoured by the RACS his scientific contributions include is an elected member of the French research includes environmental epide- first President until 1997. In 1998, he was and Director of Surgical Oncology at with “Excellence in Surgery Award”. He is the discovery of the Bare Lymphocyte Parliament (Assemblée Nationale) and a miology, working on the health effects re-elected as President of the Sociedad the Peter MacCallum Cancer Centre. He a past Editor-in-Chief of the ANZ Journal Syndrome, the first successful foetal member of The Parliamentary Office for of the Gulf Oil Spill which occurred in the Peruana de Oncología Médica. He was was instrumental in the development of Surgery and has served as Chair of liver stem cell transplants in humans, the Scientific and Technological Assessment. Gulf of Mexico in April 2010. His degrees regional delegate of the “Federation of the discipline of Surgical Oncology in NHMRC panels. He has ongoing research first in utero foetal stem cell transplants include an MS in Public Health from Latinoamericana de Sociedades de Australasia and was responsible for the interests in the molecular pathology into human foetuses, bone marrow and the University of North Carolina, and Cancerología”. In 1999, he created creation of the Surgical Oncology Group of gastrointestinal tumours. He has thymic epithelial cell transplants, and Ed Trapido Master’s and Doctor of Science degrees ONCOSALUD, the largest private onco- within the Royal Australasian College recently been appointed Co-Chairman other studies and treatments. In the field in Epidemiology from Harvard logical services provider in Perú. One of Surgeons. He now holds the title of of The National Cancer Expert Reference of renal and pancreatic transplantation Dr. Ed Trapido is Associate Dean year later, he was elected Principal Distinguished Fellow within the Division Group, a high level group to advise the he is responsible for new immunosup- for Research at the Louisiana State Investigator of Eastern Cooperative of Surgical Oncology at Peter Mac. His pressive therapies and prevention University School of Public Health, Murat Tuncer Oncology Group (ECOG), one of the most Professor and Wendell Gauthier Chair for important scientific organizations in the Cancer Epidemiology, and the Deputy Murat Tuncer is a specialist in Paediatric World. From December 2002 to July Director for Population Science in the Haematology (1991) in Hacettepe 2006, he was the Director General of Stanley S. Scott Cancer Center, and past University Faculty of Medicine. INEN. In July 2003, he was chosen as president of the American College of Between 1997 and 2005, Professor Regional Representative of the European Epidemiology. He also serves as the lead Tuncer was Secretary General of the Society for Medical Oncology (ESMO) for external evaluator for the International National Pediatrics Society, an Executive South America, and became part of the Atomic Energy Agency’s and World Committee member of International Editorial Committee of the Journal of Health Organization’s Program of Action Children’s Centre (ICC) (2002-2008), Oncology. He is the author of the thesis in Cancer Therapy. From 2004-2009, the Union of Middle-Eastern and “Mieloma Múltiple” (1968); and “Leucemia Dr. Trapido was at the U.S National Mediterranean Pediatric Societies (2000- Aguda” (1987). He participated in more Cancer Institute, as Deputy Director for 2005), UNICEF National Committee than 169 research projects related to International Cancer Control in the Office (1999-2005), Turkish Science Academy oncology and published more than 60 of the NCI Director, and before that, Cancer Committee (2003-2009), and a scientific articles and almost 118 Associate Director of the Epidemiology member of the National Cordon Banking abstracts in several books and magazines. and Genetics Research Program within Committee (2003-2008). Professor Tuncer Vallejos Sologuren was Minister of Health NCI’s Division of Cancer Control and currently holds the role of President of Perú, from July 2006 to December Population Sciences. Dr. Trapido also of the Middle East Cancer Consortium 2007. He has received over 46 awards. In co-chaired the Trans-NIH Tobacco and (MECC) (since 2000), and the Asian Pacific 2008, he was elected Vice-President of Nicotine Research Interest Group and Organization for Cancer Prevention the Executive Committee of the World served as the NCI liaison to the post (APOCP); he is presently Director of the Health Organization. In 2010, he was 9/11 World Trade Center first responders’ Cancer Control Department in the Turkish named Director Member of the

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International Affairs Committee of the Cancer Hospital of Vietnam. He is Visiting on many international clinical trials years later the University of Trondheim in scientific journals and is co-author of American Society of Clinical Oncology – Tran Van Thuan Professor at the Graduate School of conducted in Vietnam. He is member of awarded him a PhD. In 1996, he became several books. Lars Vatten is a Member ASCO and became member of Cancer Science and Policy, National the advisory council on cancer control of chair of Epidemiology at the Norwegian of The Norwegian Royal Academy of International Education Council of Tran Van Thuan was born in Bac Ninh, Cancer Center of Korea. He is author and the Government of Vietnam. He also has University of Science and Technology, Sciences and in 2010 received the King Molecular Targeted Therapy of Cancer Vietnam and graduated MD, MSC and co-author of many peer-reviewed scien- served on cancer protocol committees for Medical School, a post he still holds. Olav V’s Prize for Cancer Research. (MTTC) as chair under ESMO’s sponsor- PhD from Ha Noi Medical University. tific publications and books, including the Ministry of Health. He is a member of Since 2008 Lars Vatten holds an honorary ship. He returned to the role of He studied at Singapore General 85 articles in oncology. He is a board the steering group in Health and Medical professorship at Bristol University and is Institutional Head of the Instituto Hospital and in 1998, as a clinical fellow, member of the Vietnam Cancer Society Sciences of Vietnam – United States Joint a Visiting Scientist of Harvard School of Jim Vaught Nacional de Enfermedades Neoplásicas completed a clinical training course on and served as scientific committee Committee Meeting. Public Health since 2009. He has a wide (INEN), from February 2008 to January Medical Oncology at Mater Hospital in co-chair of the annual Vietnam National research background, with interests Jim Vaught spent 14 years at the U.S. 2012. In 2011 he was named President of Sydney and undertook a management Cancer Control conference. Dr. Thuan covering the epidemiology of various National Cancer Institute (NCI), most the Latin American Caribbean Society of course for Cancer Control at the United was appointed as Deputy Director of Lars Vatten cancers, cardiovascular diseases and recently as the Chief of the Biorepositories Medical Oncology (SLACOM). In May States National Cancer Institute. Dr. National Cancer Hospital (2007), Director diabetes, as well as complications of and Biospecimen Research Branch 2012 he was named as Visiting Professor Thuan is affiliated with the American of National Cancer Hospital (2016) Lars Vatten was born in Trondheim, pregnancy and their consequences for (BBRB) in the Cancer Diagnosis Program. at the Universidad del Salvador in Society of Clinical Oncology (ASCO) and and as Director of National Institute Norway, studied Medicine at the both the mother and child. He has a He earned a BSc in chemistry from Argentina. the International Union Against Cancer for Cancer Control (2010). Dr. Thuan University of Tromsø and received a particular interest in the developmental the University of Georgia and PhD in (UICC). Van Thuan is Associate Professor led three state-level research projects, Master of Public Health in 1988 from origin of chronic diseases. Lars Vatten biochemistry from the Medical College of Medical Oncology at the National and has been the principal investigator the University of North Carolina. Two has published more than 200 articles of Georgia. His additional training and

iPRI 155 iPRI - International Prevention Research Institute — About Us iPRI

research at Roswell Park Cancer Institute President of Global Health and Agriculture France, working in the Unit of Analytical and the Michigan Cancer Foundation Dan Waitzberg William Wood Policy at PepsiCo where he supported Muhammed Aasim Yusuf Epidemiology. After returning to Moscow were in the areas of chemical carcino- portfolio transformation and led engage- in 1986, he was appointed as Director of genesis and drug metabolism. He has Dan Waitzberg is a gastrointestinal William Wood is a graduate of Harvard ment with major international groups Muhammed Aasim Yusuf is a gastroen- the Institute of Carcinogenesis, which is a been working in the field of bioreposi- surgeon and nutrologist. He received his Medical School. He completed a as well as new African initiatives at the terologist with interest and expertise part of the N. N. Blokhin Russian Cancer tory and biospecimen science for over medical degree from the University of São residency in surgery at the Massachusetts nexus of agriculture and nutrition. He has in therapeutic endoscopy in gastro- Research Centre. Today he is Director of 20 years. In 1999, he was one of the Paulo (FMUSP) in 1974 and completed his General Hospital and a fellowship in headed global health at the Rockefeller intestinal cancer. He graduated from the Department of Epidemiology and founding members of the International residency in surgery at the Hospital das surgical oncology at the National Cancer Foundation, been a Professor of Global the King Edward Medical College, Prevention at the Russian Academy of Society for Biological Environmental Clínicas in 1977. Dr. Waitzberg obtained Institute. He is currently Professor of Health at Yale University, and is a former Lahore, in 1986 and trained in internal Medical Sciences and he is President Repositories (ISBER) and was its second his Masters and PhD in surgery from the Surgery at Emory University School Executive Director for Noncommunicable medicine in Canterbury, and then in of the Russian Cancer Society. David president. He was involved in organizing University of São Paulo, where he also of Medicine in the division of Surgical Diseases and Mental Health of the World Gastroenterology in Birmingham. He Zaridze was and is still member of several and writing parts of the first edition of became an Associate Professor from the Oncology in the Winship Cancer Institute. Health Organization (WHO). At WHO, Dr. received his Membership of the Royal national and international scientific ISBER’s Best Practices for Repositories. Department of Gastroenterology in 1991. He has devoted his research efforts to Yach served as cabinet director under College of Physicians of the UK in 1991, committees, including the European In 2005, Dr. Vaught joined NCI BBRB and Dr. Waitzberg is the Director of Short Bowel oncology, first in the immunology of Director-General Gro Harlem Brundtland, and was elected a Fellow of the Royal Organization for Cancer Research and participated in the development of NCI’s Syndrome Ambulatory, Clinical Director of autoantibodies to tumour-associated where he led the development of WHO’s College of Physicians of Edinburgh in the International Agency for Research on Best Practices for Biospecimen Resources Nutrition Service, Founder and Director antigens, then in clinical trials of the Framework Convention on Tobacco 2000. In 1994, he returned to Pakistan Cancer. In December 2011, he received a and the office’s other strategic initiatives. of Nutrology Residence at Hospital das multimodality treatment of breast cancer. Control and the Global Strategy on Diet to join the commissioning team at title of Visiting Professor of Epidemiology Since 2005 he has served as the NIH repre- Clinicas, University of São Paulo Medical He has served as Chair of the Cancer and and Physical Activity. Dr. Yach established Pakistan’s first tertiary care cancer centre, of Oxford University. He has authored sentative to the Interagency Working School. In addition, he has been Director Leukaemia Group B Breast Committee, the Centre for Epidemiological Research the Shaukat Khanum Memorial Cancer or co-authored over 200 peer-reviewed Group on Scientific Collections, which of the Laboratory of Investigation in the Eastern Cooperative Oncology Breast at the South African Medical Research Hospital Research Centre, in Lahore. publications. Recently he has been was created by the Office of Science and Metabolism and Nutrition in Digestive Committee, the NCI Breast Intergroup, Council. He has authored or co-authored He became Head of the Department appointed as a Deputy Director for Technology Policy. He serves on several Surgery at FMUSP and Founder and and Co-Chair of the NCI Breast Cancer over 200 articles covering the breadth of of Internal Medicine in 1999, and was Research at his Centre. biobank advisory groups including for the Director of GANEP - Nutrição Humana Steering Committee, the Early Breast global health, regularly publishes blog appointed to the position of Medical Telethon-Italy Genetic Biobank Network; since 1981. In GANEP he developed several Cancer Trialists’ Collaborative Group posts, and is cited by the Huffington Post, Director in 2004. His main research and the Stellenbosch University (Cape Town) educational programs in clinical nutrition [Oxford], and BIG-NABCG. He has been The New York Times and The Economist. clinical interests are in gastrointestinal Tongzhang Zheng H3-Africa Governance Advisory Panel; for the classroom and the internet a Governor of the American College of Dr. Yach serves on several advisory boards endoscopy, particularly as applied to and the Biobanques Network (France) including the yearly conference Ganepao. Surgeons, a Director of the American including those of the Clinton Global cancer care. Tongzhang Zheng is Professor of Scientific Board. In addition to ISBER, He is the Head of the Nutritional Support Society of Clinical Oncology, and the Initiative, the New York Academy of Epidemiology (environmental health) at Dr. Vaught is a member of the American Team at the Institute of Cancer of the State Christian Medical Association, a member Sciences, the NIH’s Fogarty International the Yale School of Public Health. He Association for Cancer Research (AACR), of Sao Paulo (ICESP) and Hospital Santa of the Board of Scientific Advisors of Centre, and the Mass General Global David Zaridze received a D.Sc. from Harvard University the American Society for Pharmacology Catarina. He is the Scientific Director of the the NCI, and President of the Society of Health Board. He is Chairman of the in 1990. His research interests have been and Experimental Therapeutics, the Free Educational Portal of Clinical Nutrition Surgical Oncology, the South-eastern Board of Cornerstone Capital and sits David Zaridze was born in Tbilisi, Georgia. environmental pollution and human European Society for Biopreservation for Health Practitioners since 1991, with 65 Surgical Congress, the Georgia Surgical on the Lancet Commission for Planetary He is member of Russian Academy of health, particularly in cancer epidemi- Biobanking and the American Association thousand registered members. His main Association, and the Southern Surgical Health. He is also the Chair of the Medical Sciences and Russian Academy ology and aetiology related to environ- for Clinical Chemistry. He is the author research area is clinical and experimental Association. He has received an honorary World Economic Forum Global Agenda of Natural Sciences. He graduated from mental hormone disruptors, genetic of nearly 70 peer-reviewed articles and nutrition, with special interest in inflamma- doctorate in medicine and surgery from Council on Ageing. His degrees include the Medical Institute in Tbilisi, Georgia susceptibility and gene-environmental book chapters. From 2006 to 2012 he tion, microbiota, molecular biology, and the Universita Politecnica delle Marche, an MBChB from the University of Cape (MD). He received a PhD from the interaction. His research emphasizes the was Senior Editor for Biospecimens and enteral and parenteral therapy, particu- and honorary membership in several Town; BSc (Hons Epi) from the University Institute of Experimental and Clinical role of organochlorine compounds (such Biorepositories for the AACR journal larly immunonutrition and omega-3 fatty colleges and societies. of Stellenbosch; an MPH from the Johns Oncology in Moscow in 1969 and DCc in as PCBs, DDE and other pesticides) in the Cancer Epidemiology, Biomarkers and acids, in the context of malnutrition, Hopkins Bloomberg School of Public 1977 from the Cancer Research Centre in aetiology of several major cancers in the Prevention. In 2012 he became Editor-in- surgery, obesity and cancer. He is member Health; and a DSc (Honoris Causa) from Moscow. Initially trained as pathologist, United States including breast, Chief of Biopreservation and Biobanking, of several clinical nutrition societies all Derek Yach Georgetown University. he has pursued a second career in epide- Non-Hodgkin lymphoma, Hodgkin’s the official journal of ISBER. In 2013 over the world and serves as a member of miology of chronic diseases. He worked diseases, multiple myeloma and Dr. Vaught was the recipient of ISBER’s several editorial boards and has published Dr. Derek Yach has focused his career on in Oxford University with Professor testicular cancer. Zheng has considerable award for Outstanding Achievement in over 130 articles in peer-reviewed journals, advancing global health. He is currently Richard Doll in 1977-78. From 1979 to experience in conducting epidemiolog- Biobanking. 120 in non-peer reviewed journals, more the Executive Director of the Vitality 1985 he was affiliated with International ical studies in China. He is the Principal than 260 book chapters and 10 books. Institute. Prior to that he was Senior Vice Agency for Research on Cancer in Lyon, Investigator (PI) for a National Institutes

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of Health (NIH) training grant studying air Screening Program in Israel, Skin Cancer pollution, temperature changes and Witold Zatoński Awareness Month, as well as multiple human health in 6 different cities with programs to raise awareness and promote different types of air pollution in China. Witold Zatoński, MD, PhD, is a Director early detection and methods of preven- He is also PI for a case-control study of and Professor in the Division of Cancer tion and new means for rehabilitation. Miri liver cancer in China and serves as Epidemiology Prevention at Cancer earned a MA degree in Medical Sociology Co-Investigator for a case-control study Center Institute of Oncology in Warsaw, with distinction at the Tel-Aviv University, of indoor pollution, gene polymorphisms Poland. As founder and President of the and completed the study requirements and risk of lung cancer in Xuanwei Health Promotion Foundation, Professor for the PhD. Additionally, she taught County in China. In 2007 he received an Zatoński has been instrumental in Medical Sociology at Tel Aviv University Honorary MA from Yale University launching numerous health campaigns for about a decade. She is a graduate of implemented in Poland and other areas the Lead Project of the NBCC and of the of Eastern Europe. Professor Zatoński has 92nd St. Y Ford Fellowship Program in New Kurt Zatloukal recently completed work on the HEM York – Developing Community Leaders. – Closing the Gap project, a complex Locally, she is a member of: The Israel Kurt Zatloukal is professor of pathology study examining health inequalities National Health Committee, the Israel at the Medical University of Graz with between eastern and western parts of National Council of Oncology, the National specialisation in molecular pathology, the European Union. At present, Professor Council for Women’s Health, the National focusing on metabolic and neoplastic Zatoński implements project PONS, Council of Health Promotion, and an diseases, mainly of the liver. He was a aimed at establishing an infrastructure for Executive Board Member of Israel Health member of the Bioethics Commission prospective cohort studies of population Consumers coalition. Internationally, at the Austrian Federal Chancellery and health in Poland. Professor Zatoński has Miri has been serving since 1995 as a Austrian representative in the OECD been at the forefront of public health and National Representative of the European taskforce on biological resource centres tobacco control in Poland, Eastern Europe, Breast Cancer Coalition – Europa Donna and the Roadmap Working Group of the and internationally, for over 35 years. (E.D.). From 1992-2002 she served at the European Strategy Forum on Research A passionate activist and researcher, he Executive Board of the European Cancer Infrastructure. Additionally, he acts as has helped promote policy development League (ECL). In July 2006 she was selected member of the steering committee of the through research and dissemination of to serve on the Executive Board of the P3G Consortium. In the context of the research evidence and best practice. In Union for International Cancer Control – Austrian Genome Programme (GEN-AU), 2006 he was awarded the Luther L. Terry UICC. In August 2008, she was selected for Kurt Zatloukal is coordinator of the pan- award for Distinguished Career by the an additional term. The Israeli Association European “Biobanking and Biomolecular American Cancer Society. of Public Relations recently awarded Miri as Resources Research Infrastructure - “Best CEO in Israel” for her innovative and BBMRI”, which is funded by the European creative activities alongside her profound Framework Programme 7. This infrastruc- Miri Ziv management skills, as well as the Nurit ture aims at providing the technical, ethical, Kadatzaki-Roz Award from the University of legal, and financial foundation to become a Miri Ziv is a Medical Sociologist and serves Tel Aviv, for continuing efforts in the fight key resource in biomedical sciences, drug as a consultant for the Israeli medical against cancer. A gold medal of apprecia- development and public health. authorities, providing guidance on issues tion was awarded to Miri Ziv by the Israeli relating to cancer control. One of her Society For Clinical Oncology Radiation main areas of expertise and interest lies in Therapy. Miri was elected as Global Cancer breast cancer advocacy. Miri is active both Ambassador by the American Cancer locally and abroad. She works towards Society to participate in activities at UN initiating and implementing national headquarters and was invited to partici- projects, especially around cancer control. pate in the Israeli delegation to the historic She initiated steps that led to the imple- UN General Assembly High-Level meeting mentation of the National Mammography on NCDs in September 2011.

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Activity Report

Invited Lectures and Talks

hroughout 2015 and 2016, iPRI Senior Faculty - more broadly - to specific topics of interest to scien- Tand Faculty were very present in meetings tists, academia and policymakers at the highest worldwide. They were called upon to speak on level. Many additional talks and lectures are already topics ranging from analysis to policy, from disease scheduled for 2017 and 2018.

Peter Boyle • Inquiry into the Nature and Causes of the Health of Nations. University of Strathclyde, Glasgow, United Kingdom, February, 2015 • Disposal of Chemotherapeutic Waste. Rhone Island Senate, Providence, Rhode Island, United States of America, April, 2015 • Challenges in Disease Prevention and Control. Brown University, Providence, Rhode Island, United States of America, April, 2015 • Global Public Health. Athens, Greece, April, 2015 • Population-based Strategies to Reduce Mortality from (genito-urinary) Cancers. Moscow, Russia, June, 2015 • Transforming Cancer Care Through Big Data. Barcelona, Spain, November, 2015 • UKCTOCS: Data Monitoring and Ethics Committee. London, United Kingdom, December, 2015 • Identification of Carcinogens. Monte Carlo, Monaco, February, 2016 • Inequalities in Cancer Care and Outcome. IAPO, London, United Kingdom, April, 2016 • Achieving Cancer Control. National Cancer Institute, Hanoi, Vietnam, October, 2016 • Global Public Health. St Luke’s Week Masterclass, Dublin, Ireland, October, 2016 • Lung Cancer and Smoking. Johannesburg, South Africa, November, 2016

Philippe Autier • Presentation at ICACT Congress. Paris, France, 4–5 February 2015 • Lecture and Strengthening Links with the University. London, United Kingdom, 16–18 March 2015 • Member of the High Council for Health, Ministry of Health for Sunbed Legislation. Brussels, Belgium, 29 March – 1 April 2015 • Posters Presentation at ADA 2015. Boston, United States of America, 4–9 June 2015. Diabetes, diabetes treatments and lung cancer risk. Diabetes, diabetes treatments and lung cancer risk. Diabetes and cancer and impact of therapies: analyses of meta-analyses in 2014. • Member of the High Council for Health, Ministry of Health for Sunbed Legislation. Brussels, Belgium, 17–18 September 2015 • Posters Presentation at ECCO 2015. Vienna, Austria, 25–29 September 2015. Non-tumour risk factors for cutaneous melanoma relapse. The Logic of Cancer Screening • Courses for the Eurocan Platform Summer School in Translational Cancer Research. Albufeira, Portugal, 14–18 October 2015. Screening technologies for early detection • LEXI Study Mortality in Belgium - Marc Arhyn for Cancer in Africa - Conseil Supérieur de la Santé. Brussels, Belgium, 23-28 November 2015 • Conference on Breast Screening. Paris, France, 11-12 January 2016 • Meeting on Early Detection and Screening of Priority Cancers. Cairo, Egypt, 13-16 January 2016 • Member of the High Council for Health, Ministry of Health for Sunbed Legislation. Brussels, Belgium, 4-6 February 2016

iPRI 161 iPRIiPRI - International - International Prevention Prevention Research Research Institute Institute — — 2009 About - 2014 Us iPRI

• German Cancer Congress. Berlin, Germany, 25-27 February 2016 • Invited Talk at the Minisymposium “Cancer Modelling: Discreteness and Heterogeneity”. ECMTB/SMB 2016: 9th • Invited by Tata Memorial Center. Mumbai, India, 28 February – 4 March 2016 European Conference on Mathematical and Theoretical Biology, and Annual Meeting of The Society for Mathematical • Lixisenatide project/Superior Health Council. Brussels, Belgium, 8-12 March 2016 Biology, Nottingham, UK, July 11 - 16, 2016, Tumor heterogeneity: one, none and one hundred thousand • INCA. Paris, France, 13-17 April 2016. Expert testimony for mammography screening • Preventing Overdiagnosis Congress. Barcelona, Spain, 20-22 September 2016. Mammography screening effectiveness and overdiagnosis in the Netherlands. Effectiveness of lung cancer Guillaume Noyel screening with low-dose computed tomography: A systematic review and meta-analysis • Image Processing (ICIP). 2015 IEEE International Conference on, Quebec City, QC, Canada, 29 September 2015, • Member of the Jury for WALInnov 2016, Wallonie’s Universities Meeting. Brussels, Belgium, 5-12 October 2016 Asplünd’s metric defined in the logarithmic image processing (LIP) framework for colour and multivariate images. • Courses for the Eurocan Platform Summer School in Translational Cancer Research. Albufeira, Portugal, 25-28 October 2016 • Poster presentation at the Word Diabetes Congress of the International Diabetes Federation. 30 • General meeting for Episearch at Jules Bordet Institute. Brussels, Belgium, 24-27 November 2016 November - 4 December 2015, Vancouver, Canada. Contrast enhancement of eye fundus images. • Member of the High Council for Health, Ministry of Health for Sunbed Legislation. • CIARP 2016, 21st IberoAmerican Congress on Pattern Recognition. Lima, Peru, 10 November 2016, Brussels, Belgium, 30 November – 2 December 2016 Spatio-colour Asplünd ‘s metric and Logarithmic Image Processing for Colour Images (LIPC) • Ministry of Health, Cancer Cluster in Fernelmont. Brussels, Belgium, 13-14 December 2016

Maria Bota Mathieu Boniol • Poster Presentations at ADA 2015. Boston, United States of America, 4–9 June 2015. Diabetes, • Journée Nationale de la Société Française de Photodermatologie. Angers, France, 13 March 2015, diabetes treatments and lung cancer risk. Diabetes, diabetes treatments and lung cancer risk. Addiction solaire et cabines de bronzage, le point de l’épidémiologiste Diabetes and cancer and impact of therapies: analyses of meta-analyses in 2014. • Société Française de Photobiologie. Journées “Photoprotection”, Paris, France, • Poster Presentations at ADA 2016. Physical activity and change in fasting glucose and HbA1c in randomised controlled 4-5 June 2015, Exposition professionnelle aux UVs solaires trials. A quantitative meta-analysis. Proxy definition of acute pancreatitis for monitoring the side effects of anti- • Table Ronde Société Française de Radioprotection. Paris, France, 1 December 2015, diabetic drugs. Incretin Therapies and Risk of Pancreatitis. Lung cancer risk, diabetes and diabetes treatments. Ultraviolets naturels et artificiels et risque de cancers • 3Rd International Conference on UV And Skin Cancer Prevention. Melbourne, Australia, 7-11 December 2015, Monitoring of UV exposure in France children, adults and outdoor workers Cecile Pizot • 3rd International Conference on UV and Skin Cancer Prevention. Melbourne, Australia, • Poster Presentations at ASCO 2015. Physical activity, hormone replacement therapy 7-11 December 2015, Screening for melanoma: Lessons from the German screening program and breast cancer risk: a meta-analysis of prospective studies • WHO Intersun Programme. 5th International advisory committee meeting, Bruxelles, Belgium, • Poster Presentations at San Antonio Breast Cancer Symposium. San Antonio, United States of America. 1-2 June 2016, Data needed to inform WHO’s position regarding sunbeds 6-10 December 2016. Overview of Breast Cancer Mortality Trends in the World. • 20th European Society for Pigment Cell Research (ESPCR) Meeting. Milan, Italy, 12-15 September 2016, Prognostic value of 25-hydroxyvitamin D3 levels in melanoma patients • 20th European Society for Pigment Cell Research (ESPCR) Meeting. Milan, Italy, 12-15 September 2016, Melanoma mortality worldwide, toward a decreasing burden in the next decades • EUROSKIN 8th International Conference 2016 & Annual Scientific Meeting of the Norwegian Society of Photobiology and Photomedicine (NOFFOF). Bergen, Norway, 3-4 November 2016, Recent data on sunbed use and risk of skin cancer – targets for future research

Alberto d’Onofrio • Micro and Macro Systems in Life Sciences. Będlewo (Poland), 8 - 12 June 2015, Mathematical Epidemiology: Going beyond Statistical Mechanics (apparently…). • Keynote Invited Speaker at the International Conference “Mathematical and Computational Epidemiology of Infectious Diseases – The Interplay Between Models and Public Health Policies”. Erice (Italy), “Ettore Majorana Centre for the Diffusion of Scientific Knowledge”, Human Behavior and the Spread of Infectious Diseases: a challenge for modeling • Scientific Organization of International Conferences/Workshops. August 30 – September 5, 2015 • Ettore Majorana Centre for the Diffusion of Scientific Knowledge. Erice (Italy), August 30 – September 5, 2015, Mathematical and Computational Epidemiology of Infectious diseases – the interplay between models and public health policies

iPRI 163 iPRI - International Prevention Research Institute — About Us iPRI

Publications - Peer Reviewed

‘t Mannetje A, Brennan P, Zaridze D, Szeszenia- Amadou A, Fabre A, Torres-Mejia G, Ortega-Olvera Autier P. [Screening for breast cancer: worries Dabrowska N, Rudnai P, Lissowska J, et al Welding C, Angeles-Llerenas A, McKenzie F, et al Hormonal about its effectiveness]. Revue du praticien. and lung cancer in Central and Eastern Europe therapy and risk of breast cancer in mexican women. 2013a;63(10):1369-77. and the United Kingdom. Am J Epidemiol. PLoS One. 2013c;8(11):e79695. Autier P. Mammography screening and women 2012;175(7):706-14. Amadou A, Torres Mejia G, Fagherazzi G, Ortega C, with symptomatic breast cancer. Nat Rev Clin Oncol. Abedi-Ardekani B, Hainaut P. Cancers of the upper Angeles-Llerenas A, Chajes V, et al Anthropometry, 2013b;10(9). gastro-intestinal tract: a review of somatic mutation silhouette trajectory, and risk of breast cancer in Autier P. Mammography screening before introduc- distributions. Arch Iran Med. 2014;17(4):286-92. Mexican women. Am J Prev Med. 2014b;46(3 Suppl tion of the national breast screening programme in 1):S52-64. Abedi-Ardekani B, Dar NA, Mir MM, Zargar SA, Lone Norway. Int J Cancer. 2013c;132(7):1721-2. MM, Martel-Planche G, et al Epidermal growth Amadou A, Degoul J, Hainaut P, Chajes V, Biessy C, Autier P. Breast cancer: Doubtful health benefit of factor receptor (EGFR) mutations and expression in Torres Mejia G, et al Dietary Carbohydrate, Glycemic screening from 40 years of age. Nat Rev Clin Oncol. squamous cell carcinoma of the esophagus in central Index, Glycemic Load, and Breast Cancer Risk Among 2015a;12(10):570-2. Asia. BMC Cancer. 2012;12:602. Mexican Women. Epidemiology. 2015;26(6):917-24. Autier P. Risk factors and biomarkers of life-threat- Abedi-Ardekani B, Kamangar F, Sotoudeh M, Andreotti G, Birmann B, De Roos AJ, Spinelli J, ening cancers. Ecancermedicalscience. 2015b;9:596. Villar S, Islami F, Aghcheli K, et al Extremely high Cozen W, Camp NJ, et al A pooled analysis of alcohol Tp53 mutation load in esophageal squamous cell consumption and risk of multiple myeloma in the Autier P. Vitamin D status as a synthetic biomarker of carcinoma in Golestan Province, Iran. PLoS One. international multiple myeloma consortium. Cancer health status. Endocrine. 2016a;51(2):201-2. 2011;6(12):e29488. Epidemiol Biomarkers Prev. 2013;22(9):1620-7. Autier P. Efficient Treatments Reduce the Cost- Aggarwal A, Lewison G, Idir S, Peters M, Aldige C, Andrews N, McMenamin J, Durnall H, Ellis J, Efficiency of Breast Cancer Screening. Ann Intern Boerckel W, et al The state of lung cancer research: a Lackenby A, Robertson C, et al Effectiveness of Med. 2016b;164(4):297-8. global analysis. J Thorac Oncol. 2016. trivalent seasonal influenza vaccine in preventing Autier P. Age at cancer diagnosis and interpreta- laboratory-confirmed influenza in primary care in Agostini M, Ferro G, Burstyn I, de Vocht F, Portengen tion of survival statistics. The Lancet Oncology. the United Kingdom: 2012/13 end of season results. L, Olsson A, et al Does a more refined assessment of 2016c;17(7):847-48. Euro Surveill. 2014;19(27):5-13. exposure to bitumen fume and confounders alter Autier P, Boniol M. Caution needed for risk estimates from a nested case-control study of Ariffin H, Hainaut P, Puzio-Kuter A, Choong SS, Chan country-specific cancer survival. The Lancet. lung cancer among European asphalt workers? Occup AS, Tolkunov D, et al Whole-genome sequencing 2011a;377(9760):99-101. Environ Med. 2013;70(3):195-202. analysis of phenotypic heterogeneity and anticipa- tion in Li-Fraumeni cancer predisposition syndrome. Autier P, Boniol M. Mammography screening and Agudo A, Bonet C, Travier N, Gonzalez CA, Vineis P, Proc Natl Acad Sci U S A. 2014;111(43):15497-501. breast cancer mortality--letter. Cancer Epidemiol Bueno-de-Mesquita HB, et al Impact of cigarette Biomarkers Prev. 2012a;21(5):869; author reply 70-1. smoking on cancer risk in the European prospective Aschebrook-Kilfoy B, Ward MH, Zheng T, Holford TR, investigation into cancer and nutrition study. J Clin Boyle P, Leaderer B, et al Dietary nitrate and nitrite Autier P, Boniol M. The incidence of advanced breast Oncol. 2012;30(36):4550-7. intake and non-Hodgkin lymphoma survival. Nutr cancer in the West Midlands, United Kingdom. Eur J Cancer. 2012;64(3):488-92. Cancer Prev. 2012b;21(3):217-21. Ait Ouakrim D, Pizot C, Boniol M, Malvezzi M, Boniol M, Negri E, et al Trends in colorectal cancer mortality Aune D, Deneo-Pellegrini H, Ronco AL, Boffetta P, Autier P, Boniol M. Breast cancer screening: evidence in Europe: retrospective analysis of the WHO Acosta G, Mendilaharsu M, et al Dietary folate intake of benefit depends on the method used. BMC Med. mortality database. BMJ. 2015;351:h4970. and the risk of 11 types of cancer: a case-control 2012c;10:163. study in Uruguay. Ann Oncol. 2011;22(2):444-51. Amadou A, Hainaut P, Romieu I. Role of obesity in the Autier P, Boniol M. Effect of screening mammog- risk of breast cancer: lessons from anthropometry. J Autier P. Breast cancer screening. Eur J Cancer. raphy on breast cancer incidence. N Engl J Med. Oncol. 2013a;2013:906495. 2011a;47:S133-S46. 2013a;368(7):677. Amadou A, Torres-Mejia G, Hainaut P, Romieu I. Autier P. Frequency, digital technology, and the Autier P, Boniol M. Pitfalls in using case-control Breast cancer in Latin America: global burden, efficiency of screening mammography. Ann Intern studies for the evaluation of the effectiveness of patterns, and risk factors. Salud Publica Mex. Med. 2011b;155(8):554-5. breast screening programmes. Eur J Cancer Prev. 2014a;56(5):547-54. 2013b;22(5):391-7. The journey of knowledge Autier P. Glossary of essential terms used in cancer Amadou A, Ferrari P, Muwonge R, Moskal A, Biessy screening. Eur J Cancer. 2011c;47:S171-S75. Autier P, Boniol M. RE: Relationship between C, Romieu I, et al Overweight, obesity and risk of sunbed use and melanoma risk in a large case- Autier P. Risk factors for breast cancer for is fueled by those who dare to explore, premenopausal breast cancer according to ethnicity: control study in the United Kingdom. Int J Cancer. women aged 40 to 49 years. Ann Intern Med. a systematic review and dose-response meta- 2013c;132(8):1959. 2012;157(7):529; author reply 29. while accepting the outcome without prejudice. analysis. Obes Rev. 2013b;14(8):665-78. Evidence matters. iPRI 165 iPRI - International Prevention Research Institute — About Us iPRI

Autier P, Boniol M. Response to the letter to the Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and Environmental Agents in Brazil in 2020. PLoS cancer confounded by alcohol use? Ann Oncol. cancer occurrence in humans. Int J Epidemiol. States. J Neurooncol 101:505-507. J Neurooncol. editor sent by J.M. Broeders and S. Moss on our and ill health: a systematic review. Lancet Diabetes One. 2016;11(2):e0148761. 2011a;22(8):1931-32. 2012a;41(3):686-704. 2011;105(2):433-4; author reply 35. article entitled ‘Pitfalls in using case–control Endocrinol. 2014c;2(1):76-89. Bagnardi V, Botteri E, Rota M, Pelucchi C, Bertuccio P, La Vecchia C, Silverman DT, Petersen GM, Boffetta P, Jayaprakash V, Yang P, Asomaning K, Boniol M, Autier P, Gandini S. Melanoma mortality studies for the evaluation of the effectiveness of Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status Corrao G, Rehm J, et al Re: light drinking has Bracci PM, Negri E, et al Cigar and pipe smoking, Muscat JE, Schwartz AG, et al Tobacco smoking as following skin cancer screening in Germany. BMJ breast screening programmes’ that appeared in and ill health--author’s reply. Lancet Diabetes positive public health consequences. Ann Oncol. smokeless tobacco use and pancreatic cancer: an a risk factor of bronchioloalveolar carcinoma of the Open. 2015a;5(9):e008158. the European Journal of Cancer Prevention, issue Endocrinol. 2014d;2(4):275-6. 2013a;24(5):1421-2. analysis from the International Pancreatic Cancer lung: pooled analysis of seven case-control studies of 20 December 2012. European Journal of Cancer Boniol M, Autier P, Boyle P, Gandini S. Cutaneous Case-Control Consortium (PanC4). Ann Oncol. in the International Lung Cancer Consortium (ILCCO). Prevention. 2014a;23(2):148-49. Autier P, Koechlin A, Smans M, Vatten L, Boniol Bagnardi V, Rota M, Botteri E, Scotti L, Jenab M, melanoma attributable to sunbed use: systematic 2011b;22(6):1420-6. Cancer Causes Control. 2011c;22(1):73-9. M. Mammography screening and breast Bellocco R, et al Alcohol consumption and lung review and meta-analysis. BMJ. 2012a;345:e4757. Autier P, Boniol M. Adjunctive ultrasonography cancer mortality in Sweden. J Natl Cancer Inst. cancer risk in never smokers: a meta-analysis. Ann Beverland IJ, Cohen GR, Heal MR, Carder M, Yap C, Boffetta P, Islami F, Vedanthan R, Pourshams for breast cancer screening. The Lancet. Boniol M, Autier P, Perrin P, Boyle P. Variation of 2012g;104(14):1080-93. Oncol. 2011;22(12):2631-9. Robertson C, et al A comparison of short-term and A, Kamangar F, Khademi H, et al A U-shaped 2016a;387(10036):2380. Psa Value in Men at Screening Age, Analysis of the long-term air pollution exposure associations with relationship between haematocrit and mortality Autier P, Boniol M, Smans M, Sullivan R, Boyle P. Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Prostate, Lung, Colorectal and Ovary (Plco) Study Autier P, Pizot C. Meaningless METS: studying the mortality in two cohorts in Scotland. Environ Health in a large prospective cohort study. Int J Epidemiol. Statistical analyses in Swedish randomised trials on Fedirko V, et al Light alcohol drinking and cancer: a (Pd19-04 ). The Journal of Urology2014. p. e547. link between physical activity and health. Bmj. Perspect. 2012a;120(9):1280-5. 2013b;42(2):601-15. mammography screening and in other randomised meta-analysis. Ann Oncol. 2013b;24(2):301-8. 2016b;354:i4200. Boniol M, Autier P, Perrin P, Boyle P. Variation of trials on cancer screening: a systematic review. J R Beverland IJ, Robertson C, Yap C, Heal MR, Cohen Boffetta P, Fontana L, Stewart P, Zaridze D, Szeszenia- Bah E, Carrieri MP, Hainaut P, Bah Y, Nyan O, Taal M. Prostate-specific Antigen Value in Men and Risk of Autier P, Boniol M, Dore JF. Is sunscreen use for Soc Med. 2015b;108(11):440-50. GR, Henderson DEJ, et al Comparison of models for Dabrowska N, Janout V, et al Occupational exposure 20-years of population-based cancer registration High-grade Prostate Cancer: Analysis of the Prostate, melanoma prevention valid for all sun exposure estimation of long-term exposure to air pollution to arsenic, cadmium, chromium, lead and nickel, Autier P, Funck-Brentano E, Aegerter P, Boniol M, in hepatitis B and liver cancer prevention in the Lung, Colorectal, and Ovarian Cancer Screening Trial circumstances? J Clin Oncol. 2011b;29(14):e425-6; in cohort studies. Atmospheric Environment. and renal cell carcinoma: a case-control study from Saiag P. Re: High nevus counts confer a favorable Gambia, West Africa. PLoS One. 2013;8(9):e75775. Study. Urology. 2015b;85(5):1117-22. author reply e27. 2012b;62:530-39. Central and Eastern Europe. Occup Environ Med. prognosis in melanoma patients by S ribero and Balter V, Nogueira da Costa A, Bondanese VP, Jaouen 2011d;68(10):723-8. Boniol M, Cesarini P, Chignol MC, Cesarini JP, Dore JF. Autier P, Boniol M, Perrin P. Prostate-cancer co-workers, published in the International Journal Bi X, Zheng T, Lan Q, Xu Z, Chen Y, Zhu G, et al K, Lamboux A, Sangrajrang S, et al Natural variations [Why indoor tanning must be taxed? A proposal from mortality after PSA screening. N Engl J Med. of Cancer, 2015 (online 21 march 2015). Int J Cancer. Genetic polymorphisms in IL10RA and TNF modify Boffetta P, Hayes RB, Sartori S, Lee YA, Muscat of copper and sulfur stable isotopes in blood of La Securite Solaire, WHO collaborating centre]. Presse 2012d;366(23):2230; author reply 30-1. 2015c;137(12):3006-7. the association between blood transfusion and J, Olshan A, et al Mouthwash use and cancer of hepatocellular carcinoma patients. Proc Natl Acad Sci Med. 2010b;39(12):1236-7. risk of non-Hodgkin lymphoma. Am J Hematol. the head and neck: a pooled analysis from the Autier P, Gandini S, Mullie P. A systematic review: Autier P, Boniol M, Smans M, Sullivan R, Boyle P. U S A. 2015;112(4):982-5. 2012;87(8):766-9. International Head and Neck Cancer Epidemiology Boniol M, Boyle P, Autier P, Ruffion A, Perrin P. influence of vitamin D supplementation on serum Screening mammography: Authors’ response to Barry KH, Zhang Y, Lan Q, Zahm SH, Holford TR, Consortium. Eur J Cancer Prev. 2015. Critical role of prostate biopsy mortality in the 25-hydroxyvitamin D concentration. J Clin Endocrinol Nystrom and Tabar and colleagues. J R Soc Med. Boffetta P. Exploring a cancer biomarker: the Leaderer B, et al Genetic variation in metabolic number of years of life gained and lost within a Metab. 2012e;97(8):2606-13. 2015d;108(11):431-2. example of C-reactive protein. J Natl Cancer Inst. Boffetta P, Hazelton WD, Chen Y, Sinha R, Inoue M, genes, occupational solvent exposure, and risk prostate cancer screening programme. BJU Int. 2010a;102(3):142-3. Gao YT, et al Body mass, tobacco smoking, alcohol Autier P, Boniol M, Boyle P. Estimation of amounts of Autier P, Boniol M, Smans M, Sullivan R, Boyle P. of non-hodgkin lymphoma. Am J Epidemiol. 2012b;110(11):1648-52. drinking and risk of cancer of the small intestine--a valvular heart disease attributable to benfluorex. Eur Observed and Predicted Risk of Breast Cancer Death 2011;173(4):404-13. Boffetta P. Biomarkers in cancer epidemiology: pooled analysis of over 500,000 subjects in the Asia Boniol M, Boyle P, Autier P, Ruffion A, Perrin P. Heart J. 2013d;8 nov. in Randomized Trials on Breast Cancer Screening. an integrative approach. Carcinogenesis. Bassig BA, Zheng T, Zhang Y, Berndt SI, Holford Cohort Consortium. Ann Oncol. 2012b;23(7):1894-8. Reply: Four-hundredfold overestimation of biopsy PLoS One. 2016c;11(4):e0154113. 2010b;31(1):121-6. Autier P, Boniol M, Boyle P. The benefits and TR, Hosgood HD, 3rd, et al Polymorphisms in mortality. BJU Int. 2013a;111(3):E17-8. Boffetta P, McLerran D, Chen Y, Inoue M, Sinha harms of breast cancer screening. Lancet. Autier P, Boniol M, La Vecchia C, Vatten L, Gavin A, complement system genes and risk of non- Boffetta P. Re: The diesel exhaust in miners study: R, He J, et al Body mass index and diabetes in Boniol M, Boyle P, Autier P, Ruffion A, Perrin P. Reply: 2013e;381(9869):800. Hery C, et al Disparities in breast cancer mortality Hodgkin lymphoma. Environ Mol Mutagen. a nested case-control study of lung cancer and Asia: a cross-sectional pooled analysis of 900,000 Comment to “Critical role of prostate biopsy mortality trends between 30 European countries: retrospective 2012;53(2):145-51. diesel exhaust and a cohort mortality study Autier P, Pizot C, Boniol M. Stable incidence of individuals in the Asia cohort consortium. PLoS One. in the number of years of life gained and lost within trend analysis of WHO mortality database. BMJ. with emphasis on lung cancer. J Natl Cancer Inst. advanced breast cancer argues against screening Becker N, Schnitzler P, Boffetta P, Brennan P, Foretova 2011e;6(6):e19930. a prostate cancer screening programme”. BJU Int. 2010a;341:c3620. 2012;104(23):1842-3; author reply 48-9. effectiveness. BMJ. 2014b;349(nov25 10):g6358. L, Maynadie M, et al Hepatitis B virus infection and 2013b;111:E137-45. Bogusz A, Stewart M, Hunter J, Yip B, Reid D, Autier P, Boniol M, Middleton R, Dore JF, Hery C, risk of lymphoma: results of a serological analysis Boffetta P, Autier P. Is breast cancer associated with Autier P, Koechlin A, Boniol M. The forthcoming Robertson C, et al How quickly do hospital surfaces Boniol M, Dore JF, Greinert R, Gandini S, Cesarini Zheng T, et al Advanced breast cancer incidence within the European case-control study Epilymph. J tobacco smoking? BMJ. 2011a;342:d1093. inexorable decline of cutaneous melanoma become contaminated after detergent cleaning? JP, Securite S, et al Re: Exposure to indoor following population-based mammographic Cancer Res Clin Oncol. 2012;138(12):1993-2001. mortality in light-skinned populations. Eur J Cancer. Boffetta P, Islami F. The contribution of molecular Healthcare Infection. 2013;18(1):3. tanning without burning and melanoma screening. Ann Oncol. 2011e;22(8):1726-35. 2015a;51(7):869-78. Behrens T, Kendzia B, Treppmann T, Olsson A, Jöckel epidemiology to the identification of human risk by sunburn history. J Natl Cancer Inst. Bojar I, Biliński P, Boyle P, Zatoński W, Marcinkowski Autier P, Koechlin A, Boniol M, Mullie P, Bolli G, KH, Gustavsson P, et al Lung cancer risk among carcinogens: current status and future perspectives. 2015c;107(5):djv102-djv02. Autier P, Boniol M, Gavin A, Vatten LJ. Breast cancer JT, Wojtyła A. Prevention of female reproductive Rosenstock J, et al Serum insulin and C-peptide bakers, pastry cooks and confectionary makers: the Ann Oncol. 2013a;24(4):901-8. mortality in neighbouring European countries system cancer among rural and urban polish Boniol M, Coignard F, Vacquier B, Benmarhnia T, concentration and breast cancer: a meta-analysis. SYNERGY study. Occup Environ Med. 2013. with different levels of screening but similar access Boffetta P, Kaihovaara P, Rudnai P, Znaor A, Lissowska pregnant women. Ann Agric Environ Med. Gaillot-de Saintignon J, Le Tertre A, et al Health Cancer Causes Control. 2013f;24(5):873-83. to treatment: trend analysis of WHO mortality Bellocco R, Pasquali E, Rota M, Bagnardi V, Tramacere J, Swiatkowska B, et al Acetaldehyde level in spirits 2011;18(1):183-8. impact assessment of artificial ultraviolet radiation database. BMJ. 2011c;343:d4411. Autier P, Tryggvadottir L, Sigurdsson T, Olafsdottir I, Scotti L, et al Alcohol drinking and risk of renal cell from central European countries. Eur J Cancer Prev. from sunbeds on cutaneous melanoma in France. Boniol M. Rapporteur’s report on Session 2: E, Sigurgeirsson B, Jonasson JG, et al Autier et al carcinoma: results of a meta-analysis. Ann Oncol. 2011b;20(6):526-9. BEH. 2012c;18-19. Autier P, Dore JF, Eggermont AM, Coebergh JW. Epidemiological findings. Prog Biophys Mol Biol. Respond to “A Sunbed Epidemic?”. Am J Epidemiol. 2012;23(9):2235-44. Epidemiological evidence that UVA radiation is Boffetta P, Autier P, Boniol M, Boyle P, Hill C, Aurengo 2011;107(3):367-8. Boniol M, Koechlin A, Boniol M, Valentini F, Chignol 2010b;172(7):771-72. involved in the genesis of cutaneous melanoma. Curr Berthiller J, Straif K, Agudo A, Ahrens W, Bezerra Dos A, et al An estimate of cancers attributable to MC, Dore JF, et al Occupational UV exposure in Boniol M, Autier P. Prevalence of main cancer Opin Oncol. 2011d;23(2):189-96. Autier P, Doré JF, Breitbart E, Greinert R, Pasterk Santos A, Boccia S, et al Low frequency of cigarette occupational exposures in France. J Occup Environ French outdoor workers. J Occup Environ Med. lifestyle risk factors in Europe in 2000. Eur J Cancer. M, Boniol M. The indoor tanning industry’s double smoking and the risk of head and neck cancer in Med. 2010;52(4):399-406. 2015d;57(3):315-20. Autier P, Esserman LJ, Flowers CI, Houssami N. Breast 2010a;46(14):2534-44. game. Lancet. 2011;377(9774):1299-301. the INHANCE consortium pooled analysis. Int J cancer screening: the questions answered. Nat Rev Boffetta P, Winn DM, Ioannidis JP, Thomas DC, Little Boniol M, Koechlin A, Swiatkowska B, Sorahan Epidemiol. 2015. Boniol M, Dore JF, Boyle P. Re. Lehrer S, Green S, Stock Clin Oncol. 2012f;9(10):599-605. Azevedo ESG, de Moura L, Curado MP, Gomes Fda J, Smith GD, et al Recommendations and proposed T, Wellmann J, Taeger D, et al Cancer mortality RG (2011) Association between number of cell phone S, Otero U, Rezende LF, et al The Fraction of Cancer Bertuccio P, La Vecchia C, Silverman DT, Petersen guidelines for assessing the cumulative evidence in cohorts of workers in the European rubber contracts and brain tumor incidence in nineteen U.S. Attributable to Ways of Life, Infections, Occupation, GM, Bracci PM, Negri E, et al Reply to Are cohort on joint effects of genes and environments on manufacturing industry first employed since 1975. data on smokeless tobacco use and pancreatic Ann Oncol. 2016;27(5):933-41.

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Bonneux LG, Autier P. [Population-based breast meta-analysis and review. Eur J Cancer Prev. primary cancer in melanoma patients: a compre- clinical utility through additional autoantibody lung cancers in both men and women. Br J Cancer. EpiLymph case-control study. Cancer Causes Control. cancer screening is not worthwhile. Screening has 2014b;23(5):481-90. hensive review of the literature and meta-analysis. J assays. Tumour Biol. 2012;33(5):1319-26. 2010b;102(7):1190-5. 2012;23(1):195-206. little effect on mortality]. Ned Tijdschr Geneeskd. Dermatol Sci. 2014a;75(1):3-9. Boyle P, Ford I, Robertson J, La Vecchia C, Boffetta P, Chatfield-Ball C, Boyle P, Autier P, van Wees Chuang SC, Jenab M, Heck JE, Bosetti C, Talamini R, Coste A, Goujon S, Boniol M, Marquant F, Faure L, 2011;155(35):A3774. Autier P. Essential considerations in the investigation Caini S, Boniol M, Tosti G, Magi S, Medri M, SH, Sullivan R. Lessons learned from the Matsuo K, et al Diet and the risk of head and neck Dore JF, et al Residential exposure to solar ultraviolet Bosetti C, Bertuccio P, Negri E, La Vecchia C, of associations between insulin and cancer risk using Stanganelli I, et al Vitamin D and melanoma and casualties of war: battlefield medicine and its cancer: a pooled analysis in the INHANCE consortium. radiation and incidence of childhood hematological Zeegers MP, Boffetta P. Pancreatic cancer: overview prescription databases. Ecancermedicalscience. non-melanoma skin cancer risk and prognosis: a implication for global trauma care. J R Soc Med. Cancer Causes Control. 2012;23(1):69-88. malignancies in France. Cancer Causes Control. of descriptive epidemiology. Mol Carcinog. 2009c;3:174. comprehensive review and meta-analysis. Eur J 2015;108(3):93-100. 2015;26(9):1339-49. Clarys P, Deriemaeker P, Huybrechts I, Hebbelinck 2012a;51(1):3-13. Cancer. 2014b;50(15):2649-58. Boyle P, Koechlin A, Pizot C, Boniol M, Robertson Chaturvedi AK, Anderson WF, Lortet-Tieulent M, Mullie P. Dietary pattern analysis: a comparison Coste J, Carel JC, Autier P. [The grey realities of popu- Bosetti C, Bertuccio P, Levi F, Chatenoud L, Negri C, Mullie P, et al Blood glucose concentrations and Calais da Silva F, Calais da Silva FM, Goncalves F, J, Curado MP, Ferlay J, Franceschi S, et al between matched vegetarian and omnivorous lation screening]. Rev Epidemiol Sante Publique. E, La Vecchia C. The decline in breast cancer breast cancer risk in women without diabetes: a Santos A, Kliment J, Whelan P, et al Locally Advanced Worldwide trends in incidence rates for oral subjects. Nutr J. 2013;12:82. 2012;60(3):163-5. mortality in Europe: an update (to 2009). Breast. meta-analysis. Eur J Nutr. 2013;52(5):1533-40. and Metastatic Prostate Cancer Treated with cavity and oropharyngeal cancers. J Clin Oncol. Clarys P, Deliens T, Huybrechts I, Deriemaeker Curado MP. Breast cancer in the world: Incidence and 2012b;21(1):77-82. Intermittent Androgen Monotherapy or Maximal 2013;31(36):4550-9. Boyle P, Koechlin A, Bota M, d’Onofrio A, Zaridze DG, P, Vanaelst B, De Keyzer W, et al Comparison of mortality. Salud Publica Mex. 2011;53:372-84. Androgen Blockade: Results from a Randomised Bosetti C, Filomeno M, Riso P, Polesel J, Levi F, Perrin P, et al Endogenous and exogenous testos- Chen D, McKay JD, Clifford G, Gaborieau V, Chabrier nutritional quality of the vegan, vegetarian, semi- Phase 3 Study by the South European Uroncological Curado MP, Boyle P. Epidemiology of head and neck Talamini R, et al Cruciferous vegetables and cancer terone and the risk of prostate cancer and increased A, Waterboer T, et al Genome-wide association vegetarian, pesco-vegetarian and omnivorous diet. Group. Eur Urol. 2014;66(2):232-9. squamous cell carcinoma not related to tobacco or risk in a network of case-control studies. Ann Oncol. prostate specific antigen (PSA): a meta-analysis. BJU study of HPV seropositivity. Hum Mol Genet. Nutrients. 2014;6(3):1318-32. alcohol. Curr Opin Oncol. 2013;25(3):229-34. 2012c;23(8):2198-203. Int. 2016. Cambon-Thomsen A, Thorisson GA, Mabile L, Group 2011a;20(23):4714-23. Cocco P, t’Mannetje A, Fadda D, Melis M, Becker N, BW. The role of a bioresource research impact factor Curado MP, de Souza DL. Cancer burden in Latin Bosetti C, Rosato V, Polesel J, Levi F, Talamini R, Boyle P, Chapman CJ, Holdenrieder S, Murray A, Chen D, Truong T, Gaborieau V, Byrnes G, Chabrier de Sanjose S, et al Occupational exposure to solvents as an incentive to share human bioresources. Nat America and the Caribbean. Ann Glob Health. 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da Costa NM, Hautefeuille A, Cros MP, Melendez de Franciscis S, Caravagna G, Mauri G, d’Onofrio A. extraction and age-related macular degeneration: DNA adduct levels among non-smokers: the Afghanistan: was the BPHS a success? Global Health. Gandini S, Negri E, Boffetta P, La Vecchia C, Boyle P. ME, Waters T, Swann P, et al Transcriptional Gene switching rate determines response to extrinsic the Alienor Study. Invest Ophthalmol Vis Sci. role of multiple genetic polymorphisms and 2016;12(1):71. Mouthwash and oral cancer risk quantitative meta- regulation of thymine DNA glycosylase (TDG) perturbations in the self-activation transcriptional 2014;55(11):7619-27. nucleotide excision repair phenotype. Int J Cancer. analysis of epidemiologic studies. Ann Agric Environ Frullanti E, La Vecchia C, Boffetta P, Zocchetti C. Vinyl by the tumor suppressor protein p53. Cell Cycle. network motif. Scientific Reports. 2016;6:26980. 2013;132(12):2738-47. Med. 2012;19(2):173-80. 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breast cancer mortality in Brazil and correlations in Central and Eastern Europe. Occup Environ Med. chewing nass and prevalence of heart disease: exposure to polycyclic aromatic hydrocarbons and Kim C, Zheng T, Lan Q, Chen Y, Foss F, Chen X, et al Lehrach H, Subrak R, Boyle P, Pasterk M, Zatloukal with social inequalities: ecological time-series study. 2010a;67(1):47-53. a cross-sectional analysis of baseline data plastics. J Occup Environ Med. 2011;53(2):218-23. Genetic polymorphisms in oxidative stress pathway K, Müller H, et al ITFoM – The IT Future of Medicine. BMC Public Health. 2015;15(1):96. from the Golestan Cohort Study, Iran. Heart. genes and modification of BMI and risk of non- Procedia Computer Science. 2011;7:26-29. Heck JE, Moore LE, Lee YC, McKay JD, Hung RJ, Karami Kavanagh K, Robertson C, McMenamin J. 2013c;99(4):272-8. Hodgkin lymphoma. 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Lucenteforte E, La Vecchia C, Silverman D, Petersen use and risk of mortality from digestive diseases: McMenamin J, Andrews N, Robertson C, Fleming and National Disease Burdens Related to Sugar- System and Population-Based Cancer Registry in Parkin DM, Ferlay J, Curado MP, Bray F, Edwards B, GM, Bracci PM, Ji BT, et al Alcohol consumption a prospective cohort study. Am J Gastroenterol. D, Durnall H, von Wissmann B, et al Effectiveness of Sweetened Beverage Consumption in 2010”. Goiania, Goias State, Brazil]. Cad Saude Publica. Shin HR, et al Fifty years of cancer incidence: CI5 I-IX. and pancreatic cancer: a pooled analysis in the 2013b;108(11):1757-65. seasonal 2012/13 vaccine in preventing laboratory- Circulation. 2016a;133(15):e595. 2014;30(2):296-304. Int J Cancer. 2010;127(12):2918-27. International Pancreatic Cancer Case-Control confirmed influenza infection in primary care in the Mani S, Szymanska K, Cuenin C, Zaridze D, Balassiano Mullie P, Boniol M, Autier P. 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European Journal of Dal Maso L, et al History of cholelithiasis and cancer lular carcinoma risk. Br J Cancer. 2013a;108(1):222-8. 2011;22(8):1153-61. carcinoma in Thailand: association with tumors Cancer. 2016;64:83-88. risk in a network of case-control studies. Ann Oncol. Turati F, Garavello W, Tramacere I, Bagnardi V, Rota developing in the absence of liver cirrhosis. PLoS One. Yankelevitz DF, Henschke CI, Yip R, Boffetta P, Shemesh 2012;23(8):2173-8. Stewart M, Bogusz A, Hunter J, Devanny I, Yip B, Reid M, Scotti L, et al A meta-analysis of alcohol drinking 2012;7(6):e37707. J, Cham MD, et al Second-hand tobacco smoke in D, et al Evaluating use of neutral electrolyzed water Taylor-Black SA, Mehta H, Weiderpass E, Boffetta P, and oral and pharyngeal cancers. Part 2: results by never smokers is a significant risk factor for coronary Villar S, Le Roux-Goglin E, Gouas DA, Plymoth A, Ferro for cleaning near-patient surfaces. Infect Control Sicherer SH, Wang J. Prevalence of food allergy in subsites. Oral Oncol. 2010;46(10):720-6. artery calcification. JACC Cardiovasc Imaging. G, Boniol M, et al Seasonal variation in TP53 R249S- Hosp Epidemiol. 2014;35(12):1505-10. New York City school children. Ann Allergy Asthma 2013;6(6):651-7. Turati F, Garavello W, Tramacere I, Pelucchi C, mutated serum DNA with aflatoxin exposure and Immunol. 2014;112(6):554-56.e1. Stott-Miller M, Chen C, Chuang SC, Lee YC, Boccia Galeone C, Bagnardi V, et al A meta-analysis of hepatitis B virus infection. Environ Health Perspect. Yap C, Beverland IJ, Heal MR, Cohen GR, Robertson S, Brenner H, et al History of diabetes and risk of Tewari P, Ryan AW, Hayden PJ, Catherwood M, Drain alcohol drinking and oral and pharyngeal cancers: 2011;119(11):1635-40. C, Henderson DE, et al Association between head and neck cancer: a pooled analysis from the S, Staines A, et al Genetic variation at the 8q24 locus results from subgroup analyses. Alcohol Alcohol. long-term exposure to air pollution and specific Vlaanderen J, Portengen L, Schuz J, Olsson A, Pesch B, international head and neck cancer epidemiology confers risk to multiple myeloma. Br J Haematol. 2013b;48(1):107-18. causes of mortality in Scotland. Occup Environ Med. Kendzia B, et al Effect modification of the association consortium. Cancer Epidemiol Biomarkers Prev. 2012;156(1):133-6. 2012;69(12):916-24. Turati F, Edefonti V, Talamini R, Ferraroni M, of cumulative exposure and cancer risk by intensity 2012;21(2):294-304. Toporcov TN, Znaor A, Zhang ZF, Yu GP, Winn DM, Malvezzi M, Bravi F, et al Family history of liver of exposure and time since exposure cessation: a Yip R, Islami F, Zhao S, Tao M, Yankelevitz DF, Boffetta Suarez MI, Uribe D, Jaramillo CM, Osorio G, Perez JC, Wei Q, et al Risk factors for head and neck cancer cancer and hepatocellular carcinoma. Hepatology. flexible method applied to cigarette smoking and P. Errors in systematic reviews: an example of Lopez R, et al Wnt/beta-catenin signaling pathway in in young adults: a pooled analysis in the INHANCE 2012;55(5):1416-25. lung cancer in the SYNERGY Study. Am J Epidemiol. computed tomography screening for lung cancer. Eur J hepatocellular carcinomas cases from Colombia. Ann consortium. Int J Epidemiol. 2015;44(1):169-85. 2014;179(3):290-8. Cancer Prev. 2014;23(1):43-8. Urayama KY, Jarrett RF, Hjalgrim H, Diepstra Hepatol. 2015;14(1):64-74. Tramacere I, Negri E, Bagnardi V, Garavello W, A, Kamatani Y, Chabrier A, et al Genome-wide Wagner AP, McKenzie E, Robertson C, McMenamin Zatonski WA, Sulkowska U, Manczuk M, Rehm J, Sullivan R, Peppercorn J, Sikora K, Zalcberg J, Rota M, Scotti L, et al A meta-analysis of alcohol association study of classical Hodgkin lymphoma and J, Reynolds A, Murdoch H. Automated mortality Boffetta P, Lowenfels AB, et al Liver cirrhosis mortality Meropol NJ, Amir E, et al Delivering affordable drinking and oral and pharyngeal cancers. Part 1: Epstein-Barr virus status-defined subgroups. J Natl monitoring in Scotland from 2009. Euro Surveill. in Europe, with special attention to Central and cancer care in high-income countries. Lancet Oncol. overall results and dose-risk relation. Oral Oncol. Cancer Inst. 2012;104(3):240-53. 2013;18(15):20451. Eastern Europe. Eur Addict Res. 2010;16(4):193-201. 2011;12(10):933-80. 2010;46(7):497-503. Vaes E, Manchanda R, Nir R, Nir D, Bleiberg H, Wang D, Zheng W, Wang SM, Wang JB, Wei WQ, Liang Zatonski WA, Manczuk M, Sulkowska U, Didkowska J, Sullivan R, Alatise OI, Anderson BO, Audisio R, Autier Tramacere I, Negri E, Pelucchi C, Bagnardi V, Rota Autier P, et al Mathematical models to discriminate H, et al Estimation of cancer incidence and mortality Wojciechowska U, Tarkowski W, et al Epidemiological P, Aggarwal A, et al Global cancer surgery: delivering M, Scotti L, et al A meta-analysis on alcohol between benign and malignant adnexal masses: attributable to overweight, obesity, and physical analysis of health situation development in Europe safe, affordable, and timely cancer surgery. Lancet drinking and gastric cancer risk. Ann Oncol. potential diagnostic improvement using inactivity in China. Nutr Cancer. 2012a;64(1):48-56. and its causes until 1990. Ann Agric Environ Med. Oncol. 2015;16(11):1193-224. 2012a;23(1):28-36. ovarian HistoScanning. Int J Gynecol Cancer. 2011;18(2):194-202. Wang JB, Jiang Y, Wei WQ, Yang GH, Qiao YL, Boffetta P. 2011;21(1):35-43. Sverzellati N, Calabro E, Randi G, La Vecchia C, Tramacere I, Pelucchi C, Bagnardi V, Rota M, Scotti Estimation of cancer incidence and mortality attribut- Zhang Y, Zhu C, Curado MP, Zheng T, Boyle P. Changing Marchiano A, Kuhnigk JM, et al Sex differences in L, Islami F, et al A meta-analysis on alcohol drinking Vaes E, Manchanda R, Autier P, Nir R, Nir D, Bleiberg able to smoking in China. Cancer Causes Control. patterns of bladder cancer in the USA: evidence of emphysema phenotype in smokers without airflow and esophageal and gastric cardia adenocarcinoma H, et al Differential diagnosis of adnexal masses: 2010;21(6):959-65. heterogeneous disease. BJU Int. 2012;109(1):52-6. obstruction. Eur Respir J. 2009;33(6):1320-8. risk. Ann Oncol. 2012b;23(2):287-97. sequential use of the risk of malignancy index and Wang JB, Fan JH, Liang H, Li J, Xiao HJ, Wei WQ, et al Zheng T, Zhang J, Sommer K, Bassig BA, Zhang X, HistoScanning, a novel computer-aided diagnostic Szymanska K, Matos E, Hung RJ, Wunsch-Filho V, Tramacere I, Pelucchi C, Bonifazi M, Bagnardi V, Attributable causes of esophageal cancer incidence Braun J, et al Effects of Environmental Exposures on tool. Ultrasound Obstet Gynecol. 2012;39(1):91-8. Eluf-Neto J, Menezes A, et al Drinking of mate and Rota M, Bellocco R, et al A meta-analysis on alcohol and mortality in China. PLoS One. 2012b;7(8):e42281. Fetal and Childhood Growth Trajectories. Ann Glob the risk of cancers of the upper aerodigestive tract in Health. 2016;82(1):41-99.

iPRI 179 iPRI - International Prevention Research Institute — About Us iPRI

Publications - Books

Boyle P, Ngoma T, Sullivan R, Ndlovu N, Autier P, Stefan S, Fleming K and Brawley OW. The State of Oncology in Africa 2015. iPRI Scientific Publication 4, iPRI, Lyon, France (2016).

Boyle P, Sullivan R, Zielinski C, Brawley OW. The State of Oncology. Lyon, France: International Prevention Research Institute; 2013.

Boyle P, Gray N, Henningfield J, Seffrin J, Zatoński W.Tobacco: Science, Policy and Public Health - 2nd Edition: Oxford University Press; 2010.

Boyle P, Boffetta P, Lowenfels AB, Harry Burns OB, Zatonski W, Rehm. J. Alcohol: Science, Policy and Public Health: Oxford University Press; 2013.

Boyle P, Autier P, Adebamowo C, Anderson BO, Babwe RA, Ashtoon LP, et al World Breast Cancer Report. Lyon, France: International Prevention Research Institute, 2012.

d’Onofrio A, Gandolfi A.Mathematical Oncology 2013: Birkhauser Science; 2014.

Hainaut P, Olivier M, Wiman KG. p53 in the Clinics: Springer- Verlag New York; 2013.

Simpson CR, Lone N, Kavanagh K, Ritchie LD, WorldBreast Cancer Report 2012 Robertson C, Sheikh A, et al Seasonal Influenza Vaccine Effectiveness (SIVE): an observational retrospective World Breast Cancer Report 2012 cohort study – exploitation

Breast cancer has been known and written about of a unique community-based for millennia and has been the subject of research national-linked database to into its treatment and causes for centuries. determine the effectiveness of Despite all this interest and activity, breast cancer remains a major and growing threat to global the seasonal trivalent influenza Public Health. vaccine; 2013. 1-46 p. This Report set out to take a broad look at the global situation of breast cancer currently Soliman A, Schottenfeld D, Boffetta. (2012) from both the treatment and prevention perspectives. While there is much good news, P. Cancer Epidemiology: Low- and there are also some deeply disturbing aspects Middle-Income Countries and Special which require urgent attention. Breast cancer is a major global problem which requires much more Populations: Oxford University Press; attention particularly in view of the disparities 2013. 442 p. which exist and the rapidly increasing incidence and death rates. Zheng T, Boffetta P, Boyle P.Epidemiology Major themes running throughout the World Breast Cancer Report 2012 are the global and Biostatistics. Lyon, France: International nature of breast cancer; the rapid increase in Prevention Research Institute; 2011. incidence; disparities in awareness and response to symptoms among women; disparities in the availability of diagnostic facilities and treatment options and availability; and major disparities in breast disease cancer outcome. iPRI 181

An iPRI Scientific Publication

IPRI iPRI - International Prevention Research Institute — About Us iPRI

2015 - 2016 PhD Examinations, Jurys and Student Supervision • Pierre Guilbert, one year. Implementation of fast algorithms for image processing

2016 Under the Supervision of Mathieu Boniol • Sabina Stefan, 6 months intership. Image quality assessment and cataract detection for eye fundus images.

2016 • Brian Køster, PhD – “Development and validation of scale and questionnaire for evaluation of the UV exposure of the Danes as a Under the Supervision of Maria Bota scientific tool to reduce the prevalence of skin cancer in Denmark.”, University of Southern Denmark, Denmark • Claudine Backes, PhD (ongoing - half thesis defended in 2016) – “Solar UV Modelling – Anatomical distribution prediction for 2012 skin cancer prevention”, University of Lausanne, Switzerland • Nada Assi, Master of Engineering (6 months internship, co-supervision with Philippe Autier) – “Evaluating the effectiveness of • Isabelle Hoorens, PhD -“Preventive landscape of skin cancer in Belgium. A clinical and health economical analysis.”, Ghent breast cancer screening in Sweden”, INSA Lyon, France University, Belgium • Referee for the application of Professor Robyn Lucas for a nomination to the Australian Academy of Health and Medical Sciences, Australia (ongoing) Under the Supervision of Alice Koechlin

2014 2015 • Miruna Dragomir, Master of Engineering – “Reverse causality in the association between vitamin D and melanoma survival”, INSA • Matteo Franchi, PhD candidate – “Meta-analyses of multiple outcomes”, University of Milano-Bicocca, Milan, Italy. Lyon, France • Francois Bergey, Master of Engineering – “Modelling biases in epidemiological studies with low risk.”, INSA Toulouse , France • Pascal Caillet, PhD – “Usage des bases de données de l’Assurance Maladie dans la pratique de la pharmacoépidémiologie: exemple des pharmacothérapies de l’ostéoporose.”, Université Claude Bernard, Lyon 1, France Visitors 2013 • Referee for the application of Dr Robyn Lucas for a promotion at grade of full professor of Australian National University, Australia. 2015 2012 • Isabelle Chaillol, PhD – “Mesure de l’exposition au rayonnement ultraviolet solaire pour les études épidémiologiques.”, Université January Claude Bernard, Lyon 1, France • Maria Trojano, University of Bari “Aldo Moro”, Bari, Italy • Eva Hatzmann, Genzyme, Naarder, The Netherlands • Maura Pugliatti, University of Sassari, Sassari, Italy • David Byrne, Pathwell, Dublin, Ireland • Tomas Olsson, Karolinska Hospital • Hans Lehrach, Inst.f. Molekulare Genetik, Berlin, Germany Under the Supervision of Alberto d’Onofrio (Solna), Stockholm, Sweden • Kurt Zatloukal, Medical University of Graz, Graz, Austria • Melinda Magyari, Danish Multiple Sclerosis • Derek Yach, Vitality Institute, New York, 2014 Center, Copenhagen, Denmark New York, United States of America • Dario Domingo, Master of Science in Mathematics – “Bounded Noises: new theoretical developments, and applications in • Eva Havrdova, First Medical Faculty Charles • Twalib Ngoma, Ocean Road Cancer Institute, Pharmacokinetics”, University of Pisa, Pisa, Italy. Advisors: Alberto d’Onofrio and Prof Franco Flandoli. University in Prague, Praha, Czech Republic Dar es Salaam, United Republic of Tanzania • Francois Bergey, Master of Engineering – “Modelling biases in epidemiological studies with low risk.”, INSA Toulouse , France • Kjell-Morten Myhr, University of Bergen, Bergen, Norway • Juhaeri Juhaeri, Sanofi, Bridgewater, New (co=advisor with Prof. M. Boniol) • Stéphanie Tcherny-Lessenot, Sanofi, Chilly-Mazarin, France Jersey, United States of America • Stephanie Jurgensen, Genzyme Corporation, • Kenneth Fleming, K.Fleming Consultancy Cambridge, Massachussets, United States of America Limited, Oxford, United Kingdom Under the Supervision of Guillaume Noyel February European Project • Donato Greco, Roma, Italy • David Byrne, Pathwell, Dublin, Ireland • Coordinator of the European Project Eye-Light - Eye fundus colour images enhancement service for Diabetic Retinopathy diagnosis (www.i-pri.org/eye-light). The project has received funding from the European Union’s Horizon 2020 research and March innovation programme under grant agreement No 717108. • David Owens, Cardiff University School of • Nadia Ait-Aissa, Sanofi Groupe, Paris, France Medicine, Cardiff, United Kingdom • Catherine Levy, Sanofi, Paris, France

iPRI 183 iPRI - International Prevention Research Institute — About Us iPRI

• Dan Krewski, University of Ottawa, Ottawa, Ontario, Canada • Fadi El Karak, Saint Joseph University • Robert Thomas, Health Victoria Government, • Donato Greco, Roma, Italy • Chris Robertson, University of Strathclyde, of Beirut, Beirut, Lebanon Melbourne, Victoria, Australia Glasgow, Scotland, United Kingdom • Hugo Fry, Sanofi Pasteur MSD, Lyon, France • Donato Greco, Roma, Italy December • Benoît Soubeyrand, Sanofi Pasteur MSD, Lyon, France • Guy Courbebaisse, Institut National des April Sciences Appliquées, Villeurbanne, France • Evan Lee, Eli Lilly export S.A, Veyrier-Geneva, Switzerland • Twalib Ngoma,Ocean Road Cancer Institute, • Stéphanie Tcherny-Lessenot, Sanofi, Chilly-Mazarin, France Dar es Salaam, United Republic of Tanzania • Philippe Truffinet, Sanofi, Chilly-Mazarin, France • Enrico Pira, University of Turin, Turin, Italy 2016 • Eva Havrdova, First Medical Faculty Charles • Tom Sorahan, University of Birmingham, University in Prague, Prague, Czech Republic Birmingham, United Kindom January • Melinda Magyari, Danish Multiple Sclerosis • Carlo la Vecchia, University of Milan, Milan, Italy • Robert Thomas, Health Victoria Government, • Pietracaprina Massimo, European Center, Copenhagen, Denmark • Jürgen Wellmann, Institute of Epidemiology and Social Melbourne, Victoria, Australia Institute of Oncology, Milan, Italy Medicine University of Muenster, Muenster, Germany • Nyulasi Ibolya, Alfred Hospital, Melbourne, Australia • Orrechia Robert, European Institute of Oncology, Milan, Italy • Maria Guilia Marini, Foundation ISTUD, Milan, Italy • Jean-Pierre Armand, Institut May Claudius Regaud,Toulouse, France • Philippe Vanhems, HCL - Groupement • Mitra Elahi, HCL - Groupement Hospitalier Hospitalier Edouard Herriot, Lyon, France Edouard Herriot, Lyon, France February • Murat Tuncer, Hacettepe University, Sihhiye, Ankara, Turkey June • Harry Burns, University of Strathclyde, • Robert Thomas, Health Victoria Government, March Glasgow, Scotland, United Kingdom Melbourne, Victoria, Australia • Irene Leigh, University of Dundee, Dundee, • Nathalie Schmidely, Bristol-Myers Squibb, Scotland, United Kingdom New-York, New-York, United States of America July • Michael Lees, Bristol-Myers Squibb, New-York, • Twalib Ngoma, Ocean Road Cancer Institute, • Bruno Buonono, Universita’ degli Studi di New-York, United States of America Dar es Salaam, United Republic of Tanzania Napoli “Federico II”, Napoli, Italy April August • Christian Partensky, Former Professor of Surgery • Evi Farazi, University of Nicosi, Nicosia, Cyprus at Edouard Herriot Hospital, Lyon, France

September May • Evi Farazi, University of Nicosi, Nicosia, Cyprus • Witold Zatonski, Health Promotion • Michel Jourlin, Saint-Etienne, France • Christian Partensky, Edouard Herriot Hospital, Lyon, France • Donato Greco, Roma, Italy Foundation, Nadarzyn, Poland • Hugo Fry, Sanofi Pasteur MSD, Lyon, France • Romualdas Gurevicius, Institute of Hygiene,Health June • David Khougazian, Sanofi Pasteur MSD, Lyon, France Information Center, Linius, Lithuania • Pascal Formizyn, Mines St-Etienne, Saint-Etienne, France • Melinda Magyari, Danish Multiple Sclerosis • Andrea Rappagliosi, Sanofi Pasteur MSD, Lyon, France • Donato Greco, Roma, Italy Center, Copenhagen, Denmark • Stephen Lockhart, Sanofi Pasteur MSD, Lyon, France • Harry Burns, Glasgow, Scotland, United Kingdom • Christelle Saint Sardos, Sanofi Pasteur MSD, Lyon, France • Kjell-Morten Myhr, University of Bergen, Bergen, Norway July • Emmanuel Audusseau, Sanofi Pasteur MSD, Paris, France • Pietro Iaffaldano, University of Bari Aldo Moro, Bari, Italy • Twalib Ngoma, Ocean Road Cancer Institute, • Masamba Léo, Queen Elizabeth Central • Marc Tiltman, Sanofi Pasteur MSD, Lyon, France • Melinda Magyari, Danish Multiple Sclerosis Dar es Salaam, United Republic of Tanzania Hospital, Blantyr,Malawi • Benoît Soubeyrand, Sanofi Pasteur MSD, Lyon, France Center, Copenhagen, Denmark • Trapido Edward, LSU Health Sciences Center, • Jackson Orem, Uganda Cancer, Institute, Kampala, Uganda • David Zaridze, Russian N. N. Blokhin Cancer • Pierrette Seeldrayers, CHU of Charleroi,Charleroi, Belgium New Orleans, Louisiana, United States of America • Abdelgawad Tamer, Pfizer, New-York, Research Center, Moscow, Russia • Stéphanie Tcherny-Lessenot, Sanofi, Chilly-Mazarin, France • Otis Brawley, American Cancer Society, Atlanta, New-York, United States of America • Philippe Truffinet, Sanofi, Chilly-Mazarin, France Georgia, United States of America • Chaudhuri Sarbani, Pfizer, New-York, • Tuncer Murat, Turkish Ministry of New-York, United States of America October Health Sihhiye, Ankara, Turkey • Chavane Léonardo, Jhpiego - Ordem dos Médicos • Irene Leigh, University of Dundee, London, United Kingdom • Irene Leigh, University of Dundee, London, United Kingdom de Moçambique, Maputo, Mozambique

iPRI 185 iPRI - International Prevention Research Institute — About Us iPRI

• Elkadi Hatem, Pfizer, Dubaï, United Arab Emirates • Stefan Cristina, South African Medical Research • Wamboga Joshua, UAPO, Kampala, Uganda Council, Cape-Town, South Africa • Visagie Atétia, Pfizer, Sandton, South Africa • Robert Thomas, Health Victoria Government, Melbourne, Victoria, Australia

September • Robert Thomas, Health Victoria Government, • Stéphanie Tcherny-Lessenot, Sanofi, Chilly-Mazarin, France Melbourne, Victoria, Australia • Pietro Iaffaldano, University of Bari Aldo Moro, Bari, Italy • Melinda Magyari, Danish Multiple Sclerosis • Lorenza Scotti University of Milan-Bicocca, Milan, Italy Center, Copenhagen, Denmark • Pierrette Seeldrayers, CHU of Charleroi, Charleroi, Belgium • Kjell-Morten Myhr, University of Bergen, Bergen, Norway • Philippe Truffinet, Sanofi, Chilly-Mazarin, France

October • Cristina Stefan, South African Medical Research • Irene Leigh, University of Dundee, Dundee, Council, Cape Town, South Africa Scotland, United Kingdom • Benoît Soubeyrand, Sanofi Pasteur MSD, Lyon, France

November • Nguyen Thi Xuyen, former Vice Minister,Vietnam • Dinh Viet Chung, Vietnam National National Cancer Hospital, Hanoi, Vietnam Cancer Hospital, Hanoi, Vietnam • Tran Van Thuan, Vietnam National • Dao Van Tu, Vietnam National Cancer Cancer Hospital, Hanoi, Vietnam Hospital, Hanoi, Vietnam

December • Virginia Acha,United Kingdom, The Association of the British Pharmaceutical Industry, London, United Kingdom

iPRI 187 In 1995, 500 internally displaced people were forced to relocate from Khorog to Dushanbe, in Tajikistan. It was a long journey with multiple unexpected obstacles including rebels, a storm, washed out roads, hundreds of cows blocking the road, illness and even a child gone missing.

Most striking of all was their motivation to move on. They knew they could not turn back. They left so much behind. And yet, the promise of new beginings was enough to give them hope.

If we are to overcome our global public health challenges, we must be focussed on moving forward. We must be committed to working together, well above the political or corporate fray. And, we must collectively strive to be truthful in our determina- tion of causes and outcomes by always favoring evidence over conjecture.

IDP convoy on the road from Khorog to Dushanbe

International Prevention Research Institute

We cannot promise that we will get to the destination, but what 95 Cours Lafayette iPRI can promise is that we will keep moving forward, along the 69006 Lyon road to better health, as though we had no choice but to keep going, and because we choose to have faith in better days. France

Will you join us on the journey? +33472171199 www.i-pri.org [email protected] iPRI