2 pages minimum I will give a article to read and instructions as follow

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ATLG (Neovii) formulation might also profit from these more in-depth analyses of pharmacokinetics and pharmacodynamics, perhaps resulting in more individualised rabbit ATLG (Neovii) dosing for different HSCT settings. In-depth immune-reconstitution monitoring should also be part of these studies to better understand the effect of rabbit ATLG exposure on functional immune reconstitution. Furthermore, immune monitoring also helps to improve understanding of the differences in survival between matched and mismatched donor recipients for the two ATLG doses tested in Locatelli and colleagues’ Article.

In conclusion, randomised trials studying different ATLG doses, as presented by Locatelli and colleagues, are timely and highly warranted in children. We have learned that in children receiving a myeloablative HSCT for a malignancy, less ATLG is more survival, particularly for children receiving HSCT from a mismatched unrelated donor. Future studies should focus on analyses of pharmacokinetics and pharma codynamics to further fine tune the dosing and in turn improve survival chances in these vulnerable children.

Jaap Jan Boelens Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, 3512 EA, Netherlands [email protected]

I declare no competing interests.

1 Storb R, Gluckman E, Thomas ED, et al. Treatment of established human graft-versus-host disease by antithymocyte globulin. Blood 1974; 44: 56–75.

2 Storek J, Mohty M, Boelens JJ. Rabbit anti-T cell globulin in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2014; 21: 959–70.

3 Kröger N, Solano C, Wolschke C, et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. New Eng J Med 2016; 374: 43–53.

4 Bacigalupo A, Lamparelli T, Barisione G, et al. Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant 2006; 12: 560–65.

5 Walker I, Panzarella T, Couban S, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol 2016; 17: 164–73.

6 Locatelli F, Bernardo ME, Bertaina A, et al. Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2017; published online July 10. http://dx.doi.org/10.1016/ S1470-2045(17)30417-5.

7 Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol 2015; 2: e194–203.

8 Admiraal R, Nierkens S, de Witte MA, et al. Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis. Lancet Haematol 2017; 4: e183–e191.

9 Admiraal R, Lindemans CA, van Kesteren C, et al. Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation. Blood 2016; 128: 2734–41.

The science of precision prevention of cancer

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Precision medicine has been proposed as a new frontier to tackle the emergence of non-communicable diseases. According to one definition, “Precision medicine is a revolutionary approach for disease prevention and treatment that takes into account individual differences in lifestyle, environment, and biology.”1 Prevention is mentioned side-by-side with treatment. However, what is precision prevention? How can it be conceptualised? In this Comment, we raise some key considerations relating to the development of a science of precision prevention of cancer.

First, although some definitions clearly indicate that the term precision refers to an application to individuals, on occasion it is used more narrowly, with reference to molecules—ie, a drug that is tailored to a particular

underlying molecular change in a tumour, which happens to reside within a given individual patient. However, although an effect might be established at the molecular level, it is usually limited in scope and could give the false impression of a curative or preventive power that is absent when transferred into practice. Availability of the tools should not be confused with achievement of the goal. Consequently, the ‘precision’ in precision prevention should refer to the individuals who are the target of the intervention.

Second, consideration of inter-individual variability in prevention is hardly new—eg, a focus on more susceptible subgroups has been discussed for decades in relation to cancer screening. In addition, a focus on high- risk individuals because of their genetic background

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has been repeatedly proposed—eg, screening for phenylketonuria in newborns, which permits simple dietary preventive actions. In this context, perhaps the most promising example involves the genotypic selection of individuals based on prostaglandin pathway studies for aspirin chemoprevention in patients with colorectal neoplasia.2 This example illustrates how complex the application of precision to prevention can be, because, at a molecular level, aspirin is unlikely to exert its effects through a single pathway, but rather through several, either independently or in combination.2 Multiple pathways complicate the identification of individuals who might benefit because their status (genetic or phenotypic) would ideally need to be assessed in relation to each molecular target. Such additional assessments would dilute the promises of precision prevention, especially in terms of cost- effectiveness.

Third, as Geoffrey Rose pointed out a long time ago,

a large number of people at a small risk might give rise to more cases of disease than the small number who are at a high risk.3 This problem is not trivial and is related to the frequent gap between individual and population benefit. Rose called it the prevention paradox: “A preventive measure which brings much benefit to the population offers little to each participating individual.”3 The opposite is also true: a useful intervention for a single individual might be irrelevant at the population level. This idea is captured well by the concept of number needed to treat (NNT)—ie, how many people need to be treated to avoid a death or other outcomes. The NNT depends on the efficacy of the intervention and on the frequency of the outcome. For a frequent outcome, the NNT will be lower—ie, fewer individuals need to be treated to obtain a success—thus explaining the quantitative advantage of restricting the intervention to high-risk individuals because the frequency of the outcome is higher among these individuals. However, for relatively rare outcomes (as is the case for many cancers), the NNT might be quite high, and might be even higher if screening is needed to identify susceptible people.

Fourth, prevention carries the risk of being medicalised. The lure of mirroring precision therapy with precision prevention should not be allowed to distract from the many opportunities for prevention at the population level.4 It would be ironic if the benefit of

a much needed shift to redress the imbalance between cancer prevention and treatment were to be replaced by a dominant search for a medical solution for all impending ills, combined with a resulting imbalance between the emphasis on the population and high-risk groups.

The message is especially important in low-income and middle-income countries, where even the implementation of preventive interventions with a strong evidence base are frustrated by major resource constraints and other barriers.5,6 Indeed, examples already exist, even in low-income countries, in which affordable and applicable screening tests for high-risk individuals might be combined with cheap and effective drugs to reduce the cancer burden in a cost-effective manner.7,8 However, without careful consideration being given to equitable access, more sophisticated medical interventions for treatment or prevention pose the risk of exacerbating social inequalities in health, rather than helping to resolve them.

To take the field forward, the development of a science of precision prevention of cancer is needed to avoid both an underestimate of the challenges and the risks of falling into conceptual traps.

Paolo Vineis, *Christopher P Wild MRC-PHE Center for Environment and Health, School of Public Health, Imperial College, London, UK (PV); and International Agency for Research on Cancer, 69008 Lyon, France (CPW) [email protected]

We declare no competing interests.

1 National Institutes of Health. The future of health begins with all of us. 2017. https://allofus.nih.gov/about/about-all-us-research-program (accessed May 4, 2017).

2 Drew DA, Cao Y, Chan AT. Aspirin and colorectal cancer: the promise of precision chemoprevention. Nat Rev Cancer 2016; 16: 173–86.

3 Rose G. Sick individuals and sick populations. Int J Epidemiol 2001; 30: 427–32.

4 Stewart BW, Bray F, Forman D, et al. Cancer prevention as part of precision medicine: ‘plenty to be done’. Carcinogenesis 2016; 37: 2–9.

5 Vineis P, Wild CP. Global cancer patterns: causes and prevention. Lancet 2014; 383: 549–57.

6 Bray F, Jemal A, Torre LA, Forman D, Vineis P. Long-term realism and cost-effectiveness: primary prevention in combatting cancer and associated inequalities worldwide. J Natl Cancer Inst 2015; 107: djv273.

7 Lemoine M, Shimakawa Y, Njie R, et al. Acceptability and feasibility of a screen-and-treat programme for hepatitis B virus infection in The Gambia: the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study. Lancet Glob Health 2016; 4: e559–67.

8 Nayagam S, Conteh L, Sicuri E, et al. Cost-effectiveness of community-based screening and treatment for chronic hepatitis B in The Gambia: an economic modelling analysis. Lancet Glob Health 2016; 4: e568–78.

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