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.

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.

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.

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.

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.