Is Less Chemotherapy Detrimental in Adults with Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) Treated with High-Dose Imatinib? Results of the Prospective Randomized Graaph-2005 Study

Aim: To compare a less intensive regimen based on high-dose imatinib (IM) to an intensive IM/HyperCVAD regimen in adults with Ph+ ALL, in terms of early response and outcome after stem cell transplantation (SCT). Methods: Patients aged 18-60 years with previously untreated Ph+ ALL not evolving from chronic myeloid leukemia were eligible if no contra-indication to chemotherapy and SCT (ClinicalTrials.gov ID, NCT00327678). After a steroid prephase allowing Ph and/or BCR-ABL diagnosis, cycle 1 differed between randomization arms. In arm A (IM-based), IM was given at 800 mg on day 1-28, combined with vincristine (2 mg, day 1, 8, 15, 22) and dexamethasone (40 mg, day 1-2, 8-9, 15-16, and 22-23) only. In arm B (IM/HyperCVAD), IM was given at 800 mg on day 1-14, combined with adriamycin (50 mg/m2, day 4), cyclophosphamide (300 mg/m2/12h, day 1, 2, 3), vincristine (2 mg, day 4 and 11), and dexamethasone (40 mg, day 1-4 and 11-14). All patients received a cycle 2 combining high-dose methotrexate (1 g/m2, day 1) and AraC (3 g/m2/12h, day 2 and 3) with IM at 800 mg on day 1-14, whatever their response. Four intrathecal infusions were given during this induction/consolidation period. Minimal residual disease (MRD) was centrally evaluated by quantitative RQ-PCR after cycle 1 (MRD1) and cycle 2 (MRD2). Major MRD response was defined as BCR-ABL/ABL ratio <0.1%. Then, all patients were to receive allogeneic SCT using related or unrelated matched donor stem cells or autologous SCT if no donor and a major MRD2 response. IM/chemotherapy maintenance was planned after autologous SCT. In the absence of SCT, patients received alternating cycles 1 (as in arm B) and cycles 2 followed by maintenance, like in the published IM/HyperCVAD regimen. The primary objective was non-inferiority of arm A in term of major MRD2 response. Secondary objectives were CR rate, SCT rate, treatment- and transplant-related mortality, relapse-free (RFS), event-free (EFS) and overall (OS) survival. Results: Among the 270 patients randomized between May 2006 and August 2011, 265 patients were evaluable for this analysis (133 arm A, 132 arm B; median age, 47 years; median follow-up, 40 months). Main patient characteristics were well-balanced between both arms. Due to higher induction mortality in arm B (9 versus 1 deaths; P=0.01), CR rate was higher in the less intensive arm A (98% versus 89% after cycle 1 and 98% versus 91% after cycle 2; P= 0.003 and 0.006, respectively). A total of 213 and 205 patients were evaluated for bone marrow MRD1 and MRD2. The rates of patients reaching major MRD response and undetectable MRD were 45% (44% arm A, 46% arm B; P=0.79) and 10% (in both arms) at MRD1 and 66% (68% arm A, 63.5% arm B; P=0.56) and 25% (28% arm A, 22% arm B; P=0.33) at MRD2, respectively. The non-inferiority primary endpoint was thus demonstrated (P= 0.002). Overall, EFS was estimated at 42% (95% CI, 35-49) and OS at 51% (95% CI, 44-57) at 3 years, with no difference between arm A and B (46% versus 38% and 53% versus 49%; P=0.25 and 0.61, respectively). Of the 251 CR patients, 157 (80 arm A, 77 arm B) and 34 (17 in both arms) received allogeneic and autologous SCT in first CR, respectively. Allogeneic transplant-related mortality was similar in both arms (31.5% versus 22% at 3 years; P=0.51). Of the 157 allografted patients, 133 had MRD2 evaluation and 89 had MRD2 <0.1%. In these patients, MRD2 did not significantly influence post-transplant RFS and OS, either when tested with the 0.1% cutoff or as a continuous log covariate. Of the 34 autografted patients, 31 had MRD2 evaluation and, according to the protocol, 28 had MRD2 <0.1%. When restricting the comparison to patients achieving major MRD2 response and with the current follow-up, a trend for better results was observed after autologous as compared to allogeneic SCT (RFS, 63% versus 49.5% and OS, 69% versus 58% at 3 years; P=0.35 and P=0.08, respectively). Conclusions: In adults, the use of TK inhibitors (TKI) has markedly improved the results of Ph+ ALL therapy, now close to those observed in Ph-negative ALL. We demonstrated here that chemotherapy intensity may be safely reduced when associated with high-dose IM. We will further explore this TKI-based strategy using nilotinib prior to SCT in our next GRAAPH-2013 trial. The trend towards a better outcome after autologous compared to allogeneic SCT observed in MRD responders validates MRD as an important early surrogate endpoint for treatment stratification and new drug investigation in this disease.

Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression.

Treg are the main mediators of dominant tolerance. Their mechanisms of action and applications are subjects of considerable debate currently. However, a human microRNA (miR) Treg signature has not been described yet. We investigated human natural Treg and identified a signature composed of five miR (21, 31, 125a, 181c and 374). Among those, two were considerably under-expressed (miR-31 and miR-125a). We identified a functional target sequence for miR-31 in the 3' untranslated region (3' UTR) of FOXP3 mRNA. Using lentiviral transduction of fresh cord blood T cells, we demonstrated that miR-31 and miR-21 had an effect on FOXP3 expression levels. We showed that miR-31 negatively regulates FOXP3 expression by binding directly to its potential target site in the 3' UTR of FOXP3 mRNA. We next demonstrated that miR-21 acted as a positive, though indirect, regulator of FOXP3 expression. Transduction of the remaining three miR had no direct effect on FOXP3 expression or on the phenotype and will remain the subject of future investigations. In conclusion, not only have we identified and validated a miR signature for human natural Treg, but also unveiled some of the mechanisms by which this signature was related to the control of FOXP3 expression in these cells.

A new technique for simultaneous validation of two manual nonmercury auscultatory sphygmomanometers (A&D UM-101 and Accoson Greenlight 300) based on the International protocol.

INTRODUCTION: Auscultatory nonmercury manual devices seem good alternatives for the mercury sphygmomanometers in the clinic and for research settings, but individual internal validation of each device is time-consuming. The aim of this study was to validate a new technique capable of testing two devices simultaneously, based on the International protocol of the European Society of Hypertension. METHODS: The concept of the new technique is to measure blood pressure alternatively by two observers using a mercury sphygmomanometer and by two observers using the A&D UM-101 and Accoson Greenlight 300 devices, connected by Y-tube to obtain simultaneous readings with both nonmercury devices. Thirty-three participants were enrolled (mean age 47.2±14.0 years). Nine sequential blood pressure measurements were performed for each participant. RESULTS: Both devices passed phase 1 using 15 participants. In phase 2.1 (n=33), on a maximum of 99 measurements, the Accoson device produced 81/95/99 measurements within 5/10/15 mmHg for systolic blood pressure (SBP) and 87/98/99 for diastolic blood pressure (DBP). The A&D device produced 86/96/99 for SBP and 94/99/99 for DBP. In phase 2.2 (n=33), 30 participants had at least 2 out of 3 SBP obtained with Accoson device within 5 mmHg of the mercury device, as compared with 29 of 33 participants with the A&D device. For DBP, this was 33 of 33 participants for both devices. CONCLUSION: Both the nonmercury devices passed the International protocol. The new technique of simultaneous device testing using a Y-tube represents a time saving application of the International protocol.

Estimating and explaining the effect of education and income on head and neck cancer risk : INHANCE consortium pooled analysis of 31 case-control studies from 27 countries

Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region, and calendar time, and to explain the association in terms of behavioural risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2·50; 95%CI 2·02- 3·09). Overall one-third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviours; and it remained elevated among never users of tobacco and non-drinkers (OR = 1·61; 95%CI 1·13 - 2·31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviours: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America, and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low vs high household income. The lowest levels of income and educational attainment were associated with more than 2-fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioural risk factors for these cancers, and which varies across cancer sites, sexes, countries, and country income inequality levels. © 2014 Wiley Periodicals, Inc.

The fallacy of slimming products: a case analysis in Switzerland

Introduction: Many people desire to lose weight. This favors the marketing of "miracle" products with overemphasized slimming capacities. To our knowledge, no study regarding the claimed performances of slimming products has ever been conducted in Switzerland. Objectives: To assess weight loss claims of slimming products available in Switzerland by analyzing their corresponding advertisements. Methods: Between May 2008 and February 2013, 31 advertisements for 13 different slimming products from a single producer were collected. Weight loss claims and text of the advertisement were analyzed. Results: Weight loss claims ranged between 7 and 31 kg, with an estimated daily weight loss ranging between 300 g and 1 kg. 84% of the advertisements targeted women (by including the photograph of a woman), 61% showed a picture of a person before and after using the product, and 51% claimed that the product had improved marital relationships. The terms "natural", "miracle/extraordinary" and "scientific" were present in 92%, 77%, and 31% of the products, respectively. Free gifts were provided to buyers for 69% of the products. Cost was very similar for all 13 products (range: 49 to 59 CHF, with 8 products costing the same amount) and no correlation was found between cost of the product and weight loss claims. No differences were found for weight loss claims according to presence or absence of a picture or of the terms ".natural", ".miracle/extraordinary" and ".scientific" Finally, the yearly costs for advertising such products (French-speaking Switzerland) ranged between 56,000 and 126,000 CHF, suggesting that the gains obtained were higher than this value. Conclusion: In Switzerland, advertisements for slimming products use positive and reassuring terms to attract consumers, which are lured by unreachable, false promises of rapid and easy weight loss. Taking into account the costs of advertising, the gains obtained appear to be significant. Legislation on advertising of such products is urgently needed.

Changes in the risk of death after HIV seroconversion compared with mortality in the general population.

CONTEXT: Mortality among human immunodeficiency virus (HIV)-infected individuals has decreased dramatically in countries with good access to treatment and may now be close to mortality in the general uninfected population. OBJECTIVE: To evaluate changes in the mortality gap between HIV-infected individuals and the general uninfected population. DESIGN, SETTING, AND POPULATION: Mortality following HIV seroconversion in a large multinational collaboration of HIV seroconverter cohorts (CASCADE) was compared with expected mortality, calculated by applying general population death rates matched on demographic factors. A Poisson-based model adjusted for duration of infection was constructed to assess changes over calendar time in the excess mortality among HIV-infected individuals. Data pooled in September 2007 were analyzed in March 2008, covering years at risk 1981-2006. MAIN OUTCOME MEASURE: Excess mortality among HIV-infected individuals compared with that of the general uninfected population. RESULTS: Of 16,534 individuals with median duration of follow-up of 6.3 years (range, 1 day to 23.8 years), 2571 died, compared with 235 deaths expected in an equivalent general population cohort. The excess mortality rate (per 1000 person-years) decreased from 40.8 (95% confidence interval [CI], 38.5-43.0; 1275.9 excess deaths in 31,302 person-years) before the introduction of highly active antiretroviral therapy (pre-1996) to 6.1 (95% CI, 4.8-7.4; 89.6 excess deaths in 14,703 person-years) in 2004-2006 (adjusted excess hazard ratio, 0.05 [95% CI, 0.03-0.09] for 2004-2006 vs pre-1996). By 2004-2006, no excess mortality was observed in the first 5 years following HIV seroconversion among those infected sexually, though a cumulative excess probability of death remained over the longer term (4.8% [95% CI, 2.5%-8.6%] in the first 10 years among those aged 15-24 years). CONCLUSIONS: Mortality rates for HIV-infected persons have become much closer to general mortality rates since the introduction of highly active antiretroviral therapy. In industrialized countries, persons infected sexually with HIV now appear to experience mortality rates similar to those of the general population in the first 5 years following infection, though a mortality excess remains as duration of HIV infection lengthens.

Impact des maladies rhumatismales sur la population âgée en Suisse et sa consommation de soins

Les maladies rhumatismales sont fréquemment observées chez les personnes âgées et ont un impact considérable sur la qualité de vie des personnes en souffrant. Peu d'études suisses sur la situation épidémiologique et sur l'impact de ce type de maladies sur la consommation des services de santé existent. Cette thèse a pour but d'étudier les connaissances actuelles à partir de la littérature suisse et étrangère et d'établir un bilan en Suisse au moyen d'une enquête de population effectuée en 1997. Une revue systématique de littérature a été effectuée. En dépit d'une grande variété des approches méthodologiques rendant délicates les comparaisons géographiques et temporelles, la prévalence des maladies rhumatismales chez les personnes de 65 ans et plus semble être homogène entre pays et stable temporellement. particulièrement dès 1980. Celle-ci est élevée et augmente rapidement avec le très grand âge. De plus, les femmes sont plus fréquemment atteintes que les hommes. Notre revue montre que le recours aux soins ambulatoires (médecins, chiropraticiens, traitements ambulatoires des hôpitaux) lié aux maladies rhumatismales est important. L'impact de ces maladies sur les hospitalisations est, par contre, moins clairement établi. Les nouvelles générations de personnes en souffrant semblent avoir plus recours aux services de santé que les précédentes. Ces maladies sont aussi à l'origine d'une forte consommation d'anti-inflammatoires non-stéroïdiens avec comme conséquence une multitude de complications. En dépit de son efficacité et de son utilité, le recours à l'arthroplastie est sous- utilisé. Notre analyse se base sur une enquête réalisée auprès d'un échantillon représentatif des individus âgés de 15 ans et plus résidant de manière permanente en Suisse en 1997 : la prévalence des maladies rhumatismales en Suisse s'élève à 41 % chez les personnes âgées de 65 ans et plus, dont 48 % chez les femmes et 31 % chez les hommes. Ces prévalences sont inférieures à celles relevées dans la littérature probablement en raison de notre définition relativement restrictive des maladies rhumatismales. Ces dernières augmentent de 50 % le nombre attendu de consultations chez un médecin ou un chiropraticien et de 30 % le nombre attendu d'hospitalisations. Les personnes souffrantes ont. en outre, une probabilité de recours aux services de Soins à domicile 1,7 fois plus élevé que les autres. Aucun impact sur le nombre de traitements ambulatoires en milieu hospitalier n'a été trouvé. Nos résultats sont comparables à ceux relevés dans la littérature internationale et suisse, sauf pour les traitements ambulatoires des hôpitaux. En 1990, sur les 983'400 personnes de 65 ans et plus (recensement fédéral de la population de 1990), 403'200 personnes souffraient de maladies rhumatismales. Quelque 5'334'900 consultations chez un médecin ou un chiropraticien, 4'959'300 consultations chez un médecin et 216'800 hospitalisations étaient imputables aux personnes de 65 ans et plus toutes causes de consultations confondues, dont 1'008'000 consultations chez un médecin/chiropraticien, 927'300 chez un médecin et 98'500 hospitalisations imputables aux maladies rhumatismales. Selon ie scénario (( tendance )) des projections démographiques publiées par l'Office Fédéral de la Statistique. d'ici 2040, le nombre de personnes souffrant de maladies rhumatismales en Suisse risque d'augmenter de 80 % (en supposant que la prévalence reste stable), affectant 726'500 sur 1'772'000 personnes de 65 ans et plus. Cette augmentation est la conséquence de l'accroissement prévu de la population de 65 ans et plus dans la population générale. Le nombre global de consultatiordhospitalisations risque d'augmenter dans les mêmes proportions si le recours aux services de santé reste stable. En effet. en 2040, quelque 9'613'100 consultations chez un médecinichiropraticien, 8'936'200 consultations chez un médecin et 390'700 hospitalisations pourraient être imputables aux personnes de 65 ans et plus. dont 1'8 16'300 consultations chez un médecin/chiropraticien, 1'67 1'000 consultations chez un médecin et 1 90'600 hospitalisations en raison de maladies rhumatismales. Une légère diminution du nombre de personnes atteintes de maladies rhumatismales. ainsi que du recours aux services de santé engendré par ces maladies. est attendue dès 3040. Le nombre de personnes souffrant de maladies rhumatismales et le nombre de consultations/ hospitalisations associées risquant d'augmenter de façon considérable, il est nécessaire de freiner cette progression. Des mesures préventives primaires, secondaires ou tertiaires peuvent diminuer la prévalence des maladies rhumatismales et l'impact de celles-ci sur la consommation des services de santé.<br/><br/>Rheumatic diseases are frequently observed in elderly people and have an important impact on tlieir life qurlity. There are fe1.v Swiss stuciies on the epiciemio!ogica! situttien and on the impact of such diseases on the use of health services. This thesis aims at studying the current knowledge based on Swiss and international literature and at establishing the situation in Switzerland from a population survey conducted in 1997. A systeinatic literature review lias been carried out. Despite a large range of methods making a comparisoii diffcult, the prevalence of rheumatic diseases seems to be homogeneous in different countries and stable. especially since 1980. It is high and increases rapidly with age. Furthermore, \niorneil suffer more frequently thaii men. Our review shows that the use of ambulatory care linked to rheumatic diseases is important. On the contrary, the impact of such diseases on hospitalization is less clearly established. New generations seem to consult more. Rheumatic diseases are also at the origin of a strong consumptioii of non-steroidal anti- inflammatory drugs \vitIl potential severe consequences. Despite its effectiveness and efficiency, arthroplasty is underused. Our analysis is based 011 a survey of Swiss permanent residents aged 15 or more in 1997. Based on Our analysis, the prevalence of rheumatic diseases in Switzerland is 41 % for elderly people (48 96 for women and 31 % for men). Theses prevalences are smaller than those found in the literature because of our relatively strict definition of rheumatic diseases. The latter diseases increase of about 50 o/o the expected number of consultations (chiropractor included or not) and of about 30 960 the expected number of hospitalizations. The affected persons have a probability of home care use 1.7 times higlier than the others. No impact on the number of outpatient care provided by hospitals has been found. Our results are comparable to those found in the international and Swiss literature, except for hospital outpatient care. In 1990, of 983,400 perçons aged 65 and older, 403,200 persons suffered from rheumatic diseases. 5,334,900 consultations by a physician or a chiropractor, 4,959,300 consultations by a physician and 2 16,800 hospitalizations were attributed to the elderly whatever, the reason of consultation, of which 1,008,000 consultations by a physicianlchiropractor, 927,300 by a physician, and 98,500 hospitalizations are due to rheumatic diseases. According to the "tendance" scenario of demographic projections published by the Swiss Federal Office of Statistics, until 2040 the number of persons suffering from rheumatic diseases will increase of 80 % if the prevalence stays stable, affecting 736,500 of 1,772,000 perçons of 65 and older. This increase is due to the increase of the percentage of persons 65 and older in the population. The global number of consultationshospitalizations will increase similarly if the use of health services stays stable. In 2040, 9,613,l 00 consultations by a physiciaidchiropractor, 8,936,200 Consultations by a physician and 390,700 hospitalizations could be attributed to the persons aged 65 and older, of which 1,816,300 consultations by a physician, 1,671,000 consultations by a physician/chiropractor and 109,600 hospitalizations will be due to the rheumatic diseases. However a small decrease of the number of affected perçons and of the subsequent use of health services is expected after 2040. The number of affected elderly people and the volume of conçultations/hospitalizations are expected to increase and it ir necessx-y to slow down this progression. Preventive interventions, primary, secondary or tertiary, can decrease the prevalence of rheumatic diseases and the impaci on the consumption of health services.