Effective rescue treatment with vemurafenib of an infant with high-risk Langerhans cell histiocytosis.

INTRODUCTION: The recently identified role of a BRAF somatic mutation in the pathophysiology of Langerhans cell histiocytosis (LCH) offers new therapeutic options. Herein we describe the case of a 10-month-old infant with refractory high-risk LCH successfully treated with vemurafenib. OBSERVATION: The patient first presented with cutaneous LCH at the age of 2 months. The disease remained undiagnosed until she was 6 months old, when it rapidly evolved to a multisystemic high-risk and life-threatening disease, refractory to 2 lines of chemotherapy. BRAFV600E mutation was found at skin biopsy, and targeted therapy with vemurafenib was started when she was 10 months old. The treatment induced a fast and sustained response, but rapid relapse occurred after treatment discontinuation, leading to resumption of treatment, once more resulting in a sustained response. CONCLUSION: Our case highlights the first-line role of dermatologists in establishing the diagnosis of LCH, especially in children, in whom the eruption may be difficult to identify, leading to delayed diagnosis. Targeted therapy with vemurafenib has recently been described in children in this indication and our results support its efficacy, highlighting the need for prolonged treatment and raising the question of maintenance therapy, as well as the necessity for large-scale and long-term studies.

Progress towards molecular-based management of childhood Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing abundant CD1a+ CD207+ histiocytes that lead to the destruction of affected tissues. This disease has a remarkable pleiotropic clinical presentation and most commonly affects young children. Although the current mortality rate is very low for childhood LCH patients (<2%), reactivation frequently occurs after a long period of disease control and the rates of permanent complications and sequelae remain high. Advances in genomic sequencing technologies in this past decade have highlighted somatic molecular alterations responsible for the disease in around 80% of childhood LCH cases. More than half of these cases harbored the BRAFV600E mutation, and most other mutations also concerned proteins involved in the MAPKinase pathway. In addition to improving what is known about the LCH pathology, this molecular knowledge provides opportunities to optimize patient management. The BRAFV600E mutation is associated with more severe presentations of the disease, a high reactivation rate, and a high permanent complication rate; this mutation therefore paves the way for future stratified management approaches. These therapies may be based on the patient's molecular status as well as other clinical characteristics of the disease that are independently associated with undesired events. Moreover, as observed in patients with solid tumors, the BRAFV600E allele can be detected in the circulating cell-free DNA of patients with severe BRAFV600E-mutated LCH. Quantification of the plasmatic BRAFV600E load for this group of patients can precisely monitor response to therapy. Finally, targeted therapies, such as BRAF inhibitors, are new therapeutic options especially designed for refractory multisystemic LCH involving risk organs. However, the long-term efficacy, long-term tolerance, optimal protocol scheme, and appropriate modalities of administration for these innovative therapies for children still need to be defined, a huge challenge.

Higher mortality in patients with right hemispheric intracerebral haemorrhage: INTERACT1 and 2.

BACKGROUND AND PURPOSE: Controversy exists over the prognostic significance of the affected hemisphere in stroke. We aimed to determine the relationship between laterality of acute intracerebral haemorrhage (ICH) and poor clinical outcomes. METHODS: A subsidiary analysis of the INTERACT Pilot and INTERACT2 studies--randomised controlled trials of patients with spontaneous acute ICH with elevated systolic blood pressure (BP), randomly assigned to intensive (target systolic BP <140 mm Hg) or guideline-based (<180 mm Hg) BP management. Outcomes were the combined and separate end points of death and major disability (modified Rankin scale (mRS) scores of 3-6, 6 and 3-5, respectively) at 90 days. RESULTS: A total of 2708 patients had supratentorial/hemispheric ICH and information on mRS at 90 days. Patients with right hemispheric ICH (1327, 49%) had a higher risk of death at 90 days compared to those with left hemispheric ICH after adjustment for potential confounding variables (OR, 1.77 (95% CI 1.33 to 2.37)). There were no differences between patients with right and left hemispheric ICH regarding the combined end point of death or major disability or major disability in the multivariable-adjusted models (1.07 (0.89 to 1.29) and 0.85 (0.72 to 1.01), respectively). CONCLUSIONS: Right hemispheric lesion was associated with increased risk of death in patients with acute ICH. The laterality of the ICH does not appear to affect the level of disability in survivors. TRIAL REGISTRATION NUMBER: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00226096 and NCT00716079.

Safety of hematopoietic stem cell transplantation from hepatitis B core antibodies-positive donors with low/undetectable viremia in HBV-naïve children.

Scarce data exist on allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in hepatitis B virus (HBV)-naïve recipients from HBV-experienced donors. Long-term follow-up is herein reported for 17 allogeneic HSCT performed in 13 HBV-naïve children from HBc-antibodies-positive donors between 2006 and 2012. Four donors were HBs-antigen-positive, with detectable but low viremia in 2 cases (<2 log10IU/ml). HBV-DNA was undetectable in all transplanted cell products. Recipients' HBV prophylaxis consisted of pre-transplant vaccination, polyvalent immune globulins, specific anti-HBV immune globulins, and/or oral lamivudine in 3, 12, 8, and 8 children, respectively. No case of HBV transmission occurred based on negative close monitoring of recipients' HBV serology and plasma HBV-DNA during a median follow-up of 22 months. In case of undetectable viremia in the donor, prophylaxis with vaccination and/or immune globulins in the recipient seems to be sufficient and lamivudine prophylaxis might be unnecessary to prevent viral transmission. In case of undetectable viremia in the donor, a systematic screening of HBV DNA in the stem cell product might be unnecessary to confirm the low risk of viral transmission. Prior exposure to HBV in the donor should not be considered a contraindication to HSCT.

Graphical tools for model selection in generalized linear models.

Model selection techniques have existed for many years; however, to date, simple, clear and effective methods of visualising the model building process are sparse. This article describes graphical methods that assist in the selection of models and comparison of many different selection criteria. Specifically, we describe for logistic regression, how to visualize measures of description loss and of model complexity to facilitate the model selection dilemma. We advocate the use of the bootstrap to assess the stability of selected models and to enhance our graphical tools. We demonstrate which variables are important using variable inclusion plots and show that these can be invaluable plots for the model building process. We show with two case studies how these proposed tools are useful to learn more about important variables in the data and how these tools can assist the understanding of the model building process.

[The second (main) phase of an open, randomised, multicentre study to investigate the effectiveness of an INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT2): protocol and baseline characteristics of patients included in France]. / La seconde phase d'une étude randomisée, multicentrique évaluant en ouvert l'effet de la réduction intensive de la pression artérielle dans l'hémorragie cérébrale (INTERACT2) : protocole et caractéristiques des patients inclus en France.

RATIONALE AND AIM: The INTERACT pilot study demonstrated the feasibility of the protocol, safety of early intensive blood pressure (BP) lowering, and effects on hematoma expansion within 6hours of onset of intracerebral hemorrhage (ICH). This article describes the design of the second, main phase, INTERACT2. INTERACT2 aims to compare the effects of a management strategy of early intensive BP lowering with a more conservative guideline-based BP management policy in patients with acute ICH. This article also compares the baseline characteristics of the patients included in France with the baseline characteristics of the patients included in the pilot study INTERACT1. DESIGN OF THE STUDY: INTERACT2 is an international, prospective, multicentre, open, assessor-blinded outcome (PROBE), randomised, controlled trial. Patients with a systolic BP greater than 150mmHg are centrally randomised to either to an intensive BP lowering treatment (Systolic BP≤140mmHg within 1hour) or to a conservative treatment strategy (target systolic BP of 180mmHg). A projected 2800 subjects are to be enrolled from approximately 140 centres worldwide to provide 90% power (α 0.05) to detect a beneficial effect of early treatment on the primary outcome. STUDY OUTCOMES: The primary outcome is the combined endpoint of death and dependency according to the modified Rankin Scale (mRS) at 90 days. The key secondary outcome is the primary endpoint in those patients treated within 4hours of ICH. Other predefined secondary outcomes are the separate components of the primary endpoint, grades of physical function on the mRS, health-related quality of life on the EuroQoL, recurrent stroke and other vascular events, days of hospitalisation, requirement for permanent residential care, and unexpected serious adverse events. The study is registered under NCT00716079, ISRCTN73916115, and ACTRN12608000362392. POPULATION: As of early July, 152 patients have been included in France. When compared with the patients randomised in the INTERACT1 pilot study, these patients are older, less likely to have had a previous ICH, more often on antiplatelet or warfarin therapy, have a lower diastolic BP, arere more severe clinically (higher NIHSS) and experience their first ICH.

Effectiveness of motorcycle protective clothing: riders' health outcomes in the six months following a crash.

BACKGROUND: Little is known about the contribution of protective clothing worn in motorcycle crashes to subsequent health-related outcomes, impairment and quality of life. METHODS: A prospective cohort of 212 adult motorcyclists were recruited following presentations to hospitals or crash repair services in a defined geographic area in Australia between June 2008 and July 2009. Data was obtained from participant interviews and medical records at baseline, then by mailed survey two and six months post-crash (n=146, 69%). The exposure factor was usage of protective clothing classified as full protection (motorcycle jacket and pants), partial protection (motorcycle jacket) and unprotected (neither). Outcomes of interest included general health status (Short Form SF-36), disability (Health Assessment Questionnaire) treatment and recovery progress, quality of life and return to work in the six months post-crash. Odds ratios (OR) were estimated for categorical outcomes using multiple logistic regression to assess differences in outcomes associated with levels of protection adjusted for potential confounders including age, sex, occupation, speed and type of impact. Non-parametric procedures were used for data that was not normally distributed. RESULTS: Compared to unprotected riders, both fully and partially protected riders had fewer days in hospital and reported less pain immediately post-crash; at two months both protection groups were less likely to have disabilities or reductions in physical function. By six months there were no significant differences in disability or physical function between groups, but both protection groups were more likely to be fully recovered and returned to pre-crash work than unprotected riders. Fully protected riders achieved better outcomes than either partially or unprotected riders on most measures. There were few significant differences between the full and partial protection groups although the latter showed greater impairment in physical health two months post-crash. CONCLUSIONS: We found strong associations between use of protective clothing and mitigation of the consequences of injury in terms of post-crash health and well-being. Given this evidence it seems likely that the use of protective clothing will confer significant benefits to riders in the event of a crash.

Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials.

OBJECTIVE: To quantify the relative risk reductions achieved with different regimens to lower blood pressure in younger and older adults. DESIGN: Meta-analyses and meta-regression analyses used to compare the effects on the primary outcome between two age groups (<65 v > or =65 years). Evidence for an interaction between age and the effects of treatment sought by fitting age as a continuous variable and estimating overall effects across trials. PRIMARY OUTCOME: total major cardiovascular events. RESULTS: 31 trials, with 190 606 participants, were included. The meta-analyses showed no clear difference between age groups in the effects of lowering blood pressure or any difference between the effects of the drug classes on major cardiovascular events (all P> or =0.24). Neither was there any significant interaction between age and treatment when age was fitted as a continuous variable (all P>0.09). The meta-regressions also showed no difference in effects between the two age groups for the outcome of major cardiovascular events (<65 v > or =65; P=0.38). CONCLUSIONS: Reduction of blood pressure produces benefits in younger (<65 years) and older (> or =65 years) adults, with no strong evidence that protection against major vascular events afforded by different drug classes varies substantially with age.

Patients' preferences for adjuvant chemotherapy in early breast cancer: what makes AC and CMF worthwhile now?

BACKGROUND: Studies of women who had adjuvant chemotherapy for early breast cancer 10-20 years ago showed that many judged small benefits sufficient to make it worthwhile. Indications, regimens and supportive care have changed. We sought the preferences of contemporary women who received similar chemotherapy. PATIENTS AND METHODS: Ninety-seven consecutive consenting women who completed adjuvant chemotherapy for early breast cancer 3-34 months previously were interviewed. Preferences were elicited with a structured, scripted interview using the trade-off method. Women were presented with four hypothetical scenarios based on known life expectancies (5 and 15 years) and survival rates (65% and 85% at 5 years) without adjuvant chemotherapy. RESULTS: Improvements of an additional year in life expectancy or 3% in survival rates were judged sufficient to make adjuvant chemotherapy worthwhile by 68-84% of women. Half the women judged 1 day or 0.1% sufficient to make adjuvant chemotherapy worthwhile. Recollections of better well-being during adjuvant chemotherapy, having dependants and having a friend or relative who died from cancer were independently associated with judging smaller benefits sufficient to make adjuvant chemotherapy worthwhile (all P < 0.05). CONCLUSIONS: Preferences were highly variable, but the benefits judged sufficient to make adjuvant chemotherapy worthwhile were even smaller than those found in previous studies. Preferences were influenced by factors other than direct benefits and harms of chemotherapy.

A Swiss population-based assessment of dietary habits before and after the March 1996 'mad cow disease' crisis.

OBJECTIVE: To assess differences in dietary habits in the general population of Geneva, Switzerland, after the 1996 (BSE) crisis. DESIGN: Repeated population-based survey during 1993, 1994, 1995 and 1996. SETTING: The Bus Santé 2000 epidemiological observatory of Geneva, Switzerland. SUBJECTS: A representative sample of 1190 men and 1154 women. MAIN OUTCOME MEASURE: Dietary habits assessed by a semi-quantitative food frequency questionnaire. RESULTS: The proportion of women who reported not having eaten beef was 7.7% in 1993-1995 and went up to 14.6% in 1996 (age-adjusted difference +6.4%, 95% CI +2.4 to +10.4). Among men, the proportion of non-beef-eaters remained constant (5%). There was a sharp increase of women who did not eat liver (+14.7%, +9.1 to +20.3) but less so in men (+2 5.1%, -0.7 to +10.8). Among women who ate meat, the amount of beef intake decreased by 120 g/month (95% CI -208 to -36). While chicken intake increased (+44 g/month, -2 to 88), overall intake of meat (including poultry but not fish) declined by 204 g/month (or 2.7 kg per year). In men the decrease in beef intake was not statistically significant (-48 g/month, -172 to 80), but consumption of chicken increased (+2 56g/month, +8 to +104). Fish intake was stable in both genders. The reduction in intake of animal protein (-3.5 g/day) in women and of retinol intake in both sexes (women -77 micrograms/day; men -56 micrograms/day) was statistically significant. CONCLUSIONS: The BSE crisis coincided with spontaneous differences in food habits, especially in women, that may have nutritional consequences at the population level.

Relation of smoking to breast cancer by estrogen receptor status.

It has been suggested that smoking is associated with estrogen-negative breast cancer but not with estrogen-positive breast cancer. A population-based case-control study was conducted in Geneva, Switzerland, to determine the relation of passive and active smoking to breast cancer when the referent unexposed category consisted of women unexposed to active and passive smoke. The 242 patients with breast cancer (cases), in whom estrogen receptor (ER) status was determined on biopsy material, were compared with 1,059 women free of breast cancer (controls). Lifetime history of active and passive smoking was recorded year by year, between age 10 and the date of interview. Prevalence rates of ER+ tumors were 74.7% in pre-menopausal women and 74.2% in post-menopausal women. Post-menopausal active smokers had a lower prevalence of ER+ tumors (70.0%, p = ns). Among pre-menopausal women, the age-adjusted ORs of breast cancer with having smoked an average of > or = 20 cigarettes per day (cpd) during lifetime were 2.7 for ER- tumors and 2.6 for ER+ tumors. Among post-menopausal women, corresponding ORs were 5.7 for ER- tumors and 2.4 for ER+ tumors. Smoking was related to both ER- and ER+ breast cancer in pre- and post-menopausal women, but the strength of the association appeared to be greater for ER- tumors among post-menopausal women.

Community-based surveillance of cardiovascular risk factors in Geneva: methods, resulting distributions, and comparisons with other populations.

OBJECTIVES: This paper presents the results of an ongoing community-based surveillance program of cardiovascular risk factors in Geneva, Switzerland, using percentiles with their associated 95% confidence intervals and compares the Genevan results with published data from international surveys reporting percentiles. METHODS: A random survey of adults ages 35 to 74 years was conducted from 1993 to 1994. Confidence intervals for percentiles based on parametric and non-parametric methods are given. RESULTS: The distribution of total cholesterol was shifted upward with increasing age. The median reached a maximum at 55-64 years among men (5.7 mmol/L) and at 65-74 years among women (5.9 mmol/L), and remained relatively stable thereafter. In both genders, systolic and, less so, diastolic blood pressure increased progressively with advancing age. The median daily energy intake among men declined from 2,390 kcal at age 35-44 years to 2,169 kcal at age 65-74 years, while among women it remained stable at about 1,900 kcal. In both males and females, the relative intake of saturated fat was stable throughout life (14 to 13%). The median body mass index (BMI) was about 25 kg/m2 across all age groups among men, but increased with age among women, with a peak of 23.6 kg/m2 occurring at ages 65-74 years. Compared with U.S. and western European surveys, Genevan men and women had lower total plasma cholesterol and Genevan women tended to have lower BMIs. CONCLUSIONS: Percentiles with their associated precision appear particularly well suited for international comparison of surveillance data. They could be used in the future to monitor shifts in distributions resulting from mass prevention strategies.

Passive smoking, active smoking, and education: their relationship to weight history in women in Geneva.

OBJECTIVES: This study was undertaken to determine the relationship of education and tobacco smoke to lifetime weight history in women. METHODS: Information on passive smoking, active smoking, and weight history was collected from 928 women aged 29 to 74 years selected from the general population of Geneva, Switzerland. Multivariate analysis of variance was performed for weight, weight at age 20, and weight changes since age 20. RESULTS: Education was inversely related to weight at age 20, current weight, and weight gain since age 20. The least educated group had a current weight of 4 kg more than the most educated group. Differences across smoking categories were small: passive smokers had the highest current weight (63.4 kg) and former active smokers had the lowest (60.4 kg). Weight gain since age 20 tended to be smaller in former and current active smokers (5.5 to 7.2 kg) than in passive smokers (8.3 to 10.4 kg) and those never exposed (9.1 kg). CONCLUSIONS: In this sample, education was an important predictor of women's current weight and weight history. Passive and active smoking had little long-term effect on weight.

Relation of breast cancer with passive and active exposure to tobacco smoke.

Studies on passive smoking have consistently shown a tendency toward an increased risk of breast cancer, while studies an active smoking have failed to demonstrate an association. This apparent contradiction may stem from not separating passive smokers from the unexposed when assessing the effect of active smoking. a population based case-control study was conducted in Geneva, Switzerland, between January 1992 and October 1993 to determine the relation of passive and active smoking to breast cancer when the referent unexposed category consisted of women unexposed to active and passive smoke. The 244 patients with breast cancer (cases) were compared with 1.032 women free of breast cancer (controls). The lifetime history of active and passive smoking was recorded year by year, between the age of 10 and the date of the interview. The adjusted odds of breast cancer for ever active smokers, compared with women unexposed to either passive or active smoke, were 2.2 (95% confidence interval (CI) 1.0-4.4) for an average lifetime consumption of 1-9 cigarettes per day, 2.7% (95% CI 1.4-5.4) for 10-19 cigarettes per day, and 4.6 (95% CI 2.2-9.7) for 30 or more cigarettes per day. Among passive smokers, the adjusted odds ratio was 3.2 (95% CI 1.6-6.3) for being exposed for the equivalent of 2 hours per day for 25 years. The odds ratios were adjusted for known or postulated risk factors of breast cancer, including alcohol and saturated fat intake. There was no evidence of strong selection, detection, or recall biases. Active and passive exposure to tobacco smoke may increase the risk of breast cancer. Additional studies are needed to decide whether the association is causal. Further elucidation of this relation would benefit not only the prevention of breast cancer but also the the prevention of other smoking-related diseases in women.