Estimating the global prevalence of chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major public health problem. The present study aims to provide a global and regional estimate of the prevalence of COPD based on spirometry according to the two most widely used diagnostic criteria of COPD: fixed ratio (FR) and lower limit of normal (LLN). METHODS: We conducted a systematic review of the literature according to PRISMA guidelines. MEDLINE, Web of Sciences, and Scopus databases were searched to identify studies on the spirometry-based prevalence of COPD in individuals aged 40 years and older. The meta-analysis was performed using MedCalc 19 software. RESULTS: In total, 42 of the 3393 studies reviewed were eligible for inclusion. The overall prevalence of COPD in people aged 40 years and older was 12.64% (95% CI 10.75%-14.65%) and 7.38% (95% CI 5.47% - 9.55%) based on FR and LLN criteria, respectively. By gender, men had a higher prevalence of COPD compared to women (15.47%; 95% CI 12.22%-19.02% for men versus 8.79%; 95% CI 6.94%-10.82% for women). Using the LLN criteria, the prevalence of COPD in both sexes was almost identical (8.67%; 95% CI 8.44%- 8.90% for men and 8.00%; 95% CI 6.42% - 9.73% for women). We reported a high prevalence of COPD among smokers and the elderly by both definitions of airway obstruction. Regional prevalence estimates using the FR definition indicate that the highest COPD prevalence was recorded in the Americas and the lowest was recorded in the Eastern Mediterranean region. Using the LLN definition, the highest prevalence was recorded in the Southeast Asian region and the lowest prevalence was recorded in the American region. The most common COPD stage was stage II, with a prevalence of 50.46%. The results indicate a huge lack of prevalence data in the African and Eastern Mediterranean region. The results were given using a random-effect model due to the high heterogeneity between studies. CONCLUSION: Results show that the prevalence of COPD differs according to the diagnostic criteria used. In addition, management and prevention strategies targeting risk factors for COPD are certainly needed to reduce the global burden of this chronic respiratory disease.

Gender and Body Mass Index Difference in Aerobic Capacity: A Study in Moroccan High School Students.

Different tests are used to evaluate the aerobic capacity of a person. This study aims to investigate the gender and Body Mass Index (BMI) difference in aerobic capacity measured by using shuttle and Spartacus test. The study was conducted on 230 high school students (135 girls and 95 boys) followed their study in public establishment in kenitra city (Morocco). All participants were classified according to their gender (male vs. female) and their BMI (normal weight vs. overweight-obese) and performed the both test of shuttle and Spartacus. Running speed at the last completed stage, run time, maximum heart rate (max HR) max HR and perceived exertion were measured and analyzed. For each test, VO2max was estimated by using the proposed equation. There was significant BMI difference in the measured parameters (p<0.001). Difference in VO2max between male and female remained significant with high-speed level in boys. A significant difference between males and females (p < 0.001) was observed in shuttle test. Participants with normal weight or physical activity had good aerobic capacity. Compared to the Shuttle test, the Spartacus provides a 11.5% higher final speed (11.2 vs. 9.7km/h) and a total test time 2.3 times longer (11.3vs. 4.9 min) (p < 0.001). Our study underlines the interest of the Spartacus test and is preliminary. Indeed, these results must now be replicated in a larger sample of obese adolescents.

Molecular and clinicopathologic characterization of pediatric histiocytoses.

The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E . Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E -mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.

A circulating subset of BRAFV600E -positive cells in infants with high-risk Langerhans cell histiocytosis treated with BRAF inhibitors.

BRAF inhibitors are an effective treatment for BRAFV600E -mutated, risk-organ-positive Langerhans cell histiocytosis (RO+ LCH). However, cell-free BRAFV600E DNA often persists during therapy and recurrence frequently occurs after therapy discontinuation. To identify a pathological reservoir of BRAFV600E -mutated cells, we studied peripheral blood cells obtained from six infants with RO+ multisystem (MS) LCH that received targeted therapy. After cell sorting, the BRAFV600E mutation was detected in monocytes (n = 5), B lymphocytes (n = 3), T lymphocytes (n = 2), and myeloid and plasmacytoid dendritic cells (n = 2 each). This biomarker may offer an interesting tool for monitoring the effectiveness of new therapeutic approaches for weaning children with RO+ LCH from targeted therapy.

Cutaneous adverse events in children treated with vemurafenib for refractory BRAFV600E mutated Langerhans cell histiocytosis.

BACKGROUND: The somatic BRAFV600E mutation occurs in 38-64% of pediatric cases of Langerhans cell histiocytosis (LCH). Vemurafenib (VMF), a BRAF inhibitor, was approved for refractory BRAFV600E mutated LCH. In adults, VMF causes frequent cutaneous adverse events (CAE) including skin tumors (squamous cell carcinomas, melanomas), but little is known in children. The objective of this study was to evaluate the frequency, clinical spectrum, and severity of CAEs in children treated with VMF for LCH. In addition, a correlation between CAE occurrence and VMF dose, residual plasma levels (RPLs), and efficacy was searched for. PROCEDURE: Multicentric retrospective observational study including patients <18 years treated with VMF alone for refractory BRAFV600E mutated LCH in 13 countries between October 1, 2013 and December 31, 2018. RESULTS: Fifty-seven patients: 56% female, median age 2.1 years (0.2-14.6), median treatment duration 4.1 months (1.4-29.7). Forty-one patients (72%) had at least one CAE: photosensitivity (40%), keratosis pilaris (32%), rash (26%), xerosis (21%), and neutrophilic panniculitis (16%). No skin tumor was observed. Five percent of CAEs were grade 3. None were grade 4 or led to permanent VMF discontinuation. Dose reduction was necessary for 12% of patients, temporary treatment discontinuation for 16%, none leading to loss of efficacy. VMF dose, median RPL, and efficacy were not correlated with CAE occurrence. CONCLUSIONS: At doses used for pediatric LCH, CAEs are frequent but rarely severe and have little impact on the continuation of treatment when managed appropriately. Regular dermatological follow-up is essential to manage CAEs and screen for possible induced skin tumors.

Long-term follow-up of children with risk organ-negative Langerhans cell histiocytosis after 2-chlorodeoxyadenosine treatment.

The nucleoside analogue, 2-chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO-) involvement. However, we lack data on long-term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long-term tolerance. This study included 44 children from the French LCH registry, treated for a RO- LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3-19·7 years) and the median follow-up after was 5·4 years (range, 0·6-15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five-year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five-year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long-term therapy for treating patients with RO- LCH. Appropriate management of induced immune deficiency is mandatory.

Chest computed tomography findings for a cohort of children with pulmonary Langerhans cell histiocytosis.

OBJECTIVE: This study was undertaken to describe the spectrum of lung computed-tomography (CT) findings in children with pulmonary Langerhans cell histiocytosis (PLCH) and to evaluate for this population the CT-scan nodule and cyst scores proposed by adult pulmonologists at diagnosis and during follow-up. METHODS: Among 175 children with PLCH identified in the French national population-based Langerhans cell histiocytosis cohort, 60 were retrospectively selected by the availability of CT for a central review by three pediatric radiologists. These 60 patients are representative of childhood PLCH for almost all clinical aspects, except a lower percentage of risk organ involvement (38% vs 54%; P = 0.05). RESULTS: The 60 children's chest CT scans (n = 218) were reviewed. At diagnosis, 63% of them had nodules, 53% had cysts, and 29% had both. The percentages of patients with nodules or cysts increased from diagnosis to peak disease activity, respectively, from 63% to 73% and from 53% to 66%. The costophrenic angle was involved in 71%. Patients with pneumothorax (25%) had a higher median cyst score. Alveolar consolidation was observed in 34%. Patients with low CT-scan nodule and cyst scores had no long-term pulmonary sequelae. CONCLUSIONS: Well-known characteristics of adult PLCH (nodules and cysts) were observed in children. The chest CT scores proposed by adult pulmonologists could easily be applied to childhood PLCH. Lesions in children, unlike those in adults, are frequently located near the costophrenic angles. Alveolar consolidation might be considered an atypical feature of childhood PLCH.

Incidence and risk factors for clinical neurodegenerative Langerhans cell histiocytosis: a longitudinal cohort study.

Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late-onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND-LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND-LCH. The 10-year cumulative incidence of cND-LCH was 4·1%. cND-LCH typically affected patients previously treated for a multisystem, risk organ-negative LCH, represented in 69·4% of cND-LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND-LCH patients compared to those without cND-LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The 'cND susceptible patients' (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10-year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV600E status added important information among these cND susceptible patients, with the 10-year cND risk of 33·1% if a BRAFV600E mutation was present compared to 2·9% if it was absent (P = 0·002).

Circulating cell-free BRAFV600E as a biomarker in children with Langerhans cell histiocytosis.

The BRAFV600E mutation is reported in half of patients with Langerhans cell histiocytosis (LCH). This study investigated the detection of the BRAFV600E allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAFV600E -mutated LCH were investigated to detect ccf BRAFV600E at diagnosis (n = 48) and during follow-up (n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAFV600E was positive in 15/15 (100%) patients with risk-organ positive multisystem (RO+ MS) LCH, 5/12 (42%) of patients with RO- MS LCH and 3/21 (14%) patients with single-system (SS) LCH (P < 0·001, Fisher's exact test). The positive BRAFV600E load was higher for RO+ patients (mean, 2·90%; range, 0·04-11·4%) than for RO- patients (mean, 0·16%; range, 0·01-0·39) (P = 0·003, Mann-Whitney U test). After first-line vinblastine-steroid induction therapy, 7/7 (100%) of the non-responders remained positive for ccf BRAFV600E compared to 2/4 (50%) of the partial-responders and 0/4 of the complete responders (P = 0·002, Fisher's exact test). Six children treated with vemurafenib showed a clinical response that was associated with a decrease in the ccf BRAFV600E load at day 15. Thus, ccf BRAFV600E is a promising biomarker for monitoring the response to therapy for children with RO+ MS LCH or RO- LCH resistant to first-line chemotherapy.

Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study.

An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ-positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, comprising at least two 5-day courses of Ara-C (1 g/m(2) per day) plus cladribine (9 mg/m(2) per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.

Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30-year nationwide cohort of 1478 patients under 18 years of age.

The French national cohort of children with Langerhans cell histiocytosis (LCH) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15-year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ (RO+) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five-year survival was 96·6% (95% confidence interval: 95·4-97·5%) overall, improving from 92% pre-1998 to 99% post-1998 (P < 0·001 adjusted to disease extent). This change was supported by an increase in 5-year survival from 60% to 92% in the RO+ group. Survival was particularly associated with cladribine and cytarabine among refractory RO+ patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single-system patients, extended therapy duration, and more efficient second-line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent.

Ethnobotanical survey on herbal remedies for the management of type 2 diabetes in the Casablanca-Settat region, Morocco.

BACKGROUND: Morocco faces a substantial public health challenge due to diabetes mellitus, affecting 12.4% of adults in 2023. The Moroccan population makes extensive use of phytotherapy and traditional medicine to address the difficulties this chronic condition poses. The aim of this study is to document the use of medicinal plants in traditional medicine for managing type 2 diabetes in the provinces of the Casablanca-Settat region. METHODS: The study employed a semi-structured questionnaire for data collection. A study was conducted between August 1st and September 30th, 2023, and 244 individuals diagnosed with diabetes were invited to take part in the research, all of whom used at least one medicinal plant to manage type 2 diabetes, by visiting primary healthcare facilities in Morocco. The analysis included the use of Relative Frequency of Citation (RFC) to scrutinize the data. RESULTS: A total of 47 plant species belonging to 25 families were documented. Notably, the Apiaceae, Lamiaceae, and Fabaceae families were frequently mentioned in the context of treating type 2 diabetes in Morocco. Prominent among the cited plant species were Sesamum indicum L., Lepidium sativum L., followed by Foeniculum vulgare Mill., and Rosmarinus officinalis L. Seeds emerged as the plant part most commonly mentioned, with infusion being the prevailing preparation method and oral consumption being the most frequently depicted method of administration. CONCLUSION: This research underscores the practicality of incorporating traditional medicine into the healthcare framework of the Casablanca-Settat region. The findings not only offer valuable documentation but also have a vital function in safeguarding knowledge regarding the utilization of medicinal plants in this locality. Moreover, they provide opportunities to delve deeper into the phytochemical and pharmacological potential of these plants.

Thymus and mediastinal node involvement in childhood Langerhans cell histiocytosis: long-term follow-up from the French national cohort.

BACKGROUND: Mediastinal involvement (MI) in Langerhans cell histiocytosis (LCH) has been rarely reported. Here, we describe the clinical, radiological, and biological presentation, and the outcome of childhood LCH with MI. METHOD: From the French LCH register, which includes 1,423 patients aged less than 18 years, we retrieved the medical charts of patients with mediastinal enlargement detected on chest X-rays. RESULTS: Thirty-seven patients were retrieved, including 18 males; median age of diagnosis was 0.7 years, and median follow-up time was 6.2 years. The prevalence of MI varied with the age at diagnosis, ranging from 7% below 1 year old to less than 1% at >5 years. Thirteen cases (35%) were diagnosed because of MI-related symptoms, including respiratory distress (N = 4), superior venous cava syndrome (N = 2), and/or cough and polypnea (N = 10). CT scans performed in 32 cases at diagnosis showed tracheal compression (N = 5), cava thrombosis (N = 2), and/or calcification (N = 16). All patients presented multi-system disease at LCH diagnosis, and 35/37 were initially treated with vinblastine and corticosteroids. Death occurred in five cases, due to MI (N = 1) or hematological refractory involvement (N = 4). The overall 5-year survival was 87.1%, and immunodeficiency was not detected as a sequel. CONCLUSIONS: MI in LCH mainly occurs in young children, and diagnosis was based on CT showing thymus enlargement and calcifications.

[Epidemiological profile and diagnostic and evolutionary features of TB patients at the Diagnostic Centre for Tuberculosis and Respiratory Diseases in Settat, Morocco]. / Profil épidémiologique, aspects diagnostiques et évolutifs des patients tuberculeux au centre de diagnostic de la tuberculose et des maladies respiratoires de Settat, Maroc.

Introduction: tuberculosis is a public health problem in Morocco. This study aims to examine the epidemiological profile as well as the evolutionary and diagnostic features of tuberculosis in Settat, Morocco. Methods: we conducted a retrospective descriptive and analytical study of data from the medical records of TB patients managed at the Diagnostic Centre for Tuberculosis and Respiratory Diseases in Settat, Morocco from 1st January 2015 to 31 December 2019. Results: we identified 1270 cases of tuberculosis. Lung involvement was more common than extrapulmonary involvement. Ganglionic tuberculosis mainly occurred in patients with extrapulmonary tuberculosis. Severe forms included tuberculous meningitis (10 cases) and miliary tuberculosis (10 cases). Diagnosis was bacteriologically confirmed in the majority of patients (84.09%). Extreme ages and female sex were mainly affected by extrapulmonary tuberculosis. Recovery was reported in 35.12% of patients and its rate was higher in pulmonary TB patients than in extrapulmonary TB patients (62.18% vs 0.37%; P<0.001). Patients with pulmonary tuberculosis (19.33% vs 10.81%; P<0.001) were mainly lost to follow-up. Death occurred to almost the same extent in patients with pulmonary and extrapulmonary tuberculosis (2.52% vs. 2.56%). Conclusion: efforts on all fronts are still needed if the country is to achieve the goal of eliminating TB by 2030.

Childhood Langerhans cell histiocytosis with severe lung involvement: a nationwide cohort study.

BACKGROUND: Lung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed. METHODS: Among 1482 children (< 15 years) registered in the French LCH registry (1994-2018), 111 (7.4%) had lung involvement. This retrospective study included data for 17 (1.1%) patients that required one or more intensive care unit (ICU) admissions for respiratory failure. RESULTS: The median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease. First-line vinblastine-corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine: n = 7; etoposide-aracytine: n = 3; targeted therapy n = 2). A total of 6 children (35%) died (repeated pneumothorax: n = 3; diffuse micronodular lung infiltration in the context of multisystem disease: n = 2; following lung transplantation: n = 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging. CONCLUSIONS: Severe lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy.

Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study.

PURPOSE: Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION: VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000-2004.

INTRODUCTION: Childhood Langerhans cell histiocytosis (LCH) is a rare and poorly understood multisystemic disease. The French National Registry of Childhood Hematopoietic Malignancies (NRCH) has recorded LCH cases of all subtypes since 2000. The present study describes the data on LCH collected on a national scale over a 5-year period. MATERIALS AND METHODS: The cases were children aged less than 15 years, diagnosed with LCH of any type between 2000 and 2004, and residing in mainland France at the time of diagnosis. Completeness was evaluated by capture-recapture after cross-checking against the database compiled by the French Langerhans Cell Histiocytosis Study Group. RESULTS: Two hundred fifty-eight cases of LCH were registered. The completeness of the NRCH was estimated to be 97%. The annual incidence rate was 4.6/10(6) children aged less than 15 years and the sex ratio was 1.2. Bone and skin were the most commonly involved organs at diagnosis. The incidence rate decreased with age from 15.3/10(6) before 1 year to 2.0/10(6) after 10 years. The disease was mainly unifocal (2.6/10(6)) and rarely disseminated (0.6/10(6)), but disseminated forms predominated in infants. The overall 2-year survival rate was 99% (95%CI: [97; 100]). About 30% of the LCH cases were enrolled in a clinical trial at first onset. No case was treated by radiotherapy. CONCLUSION: This study evidenced the main features of LCH incidence in the overall population and was consistent with previous studies. The NRCH thus appears to be a very promising tool for further elucidation of LCH.

BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy.

PURPOSE: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined. PATIENTS AND METHODS: BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. RESULTS: Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). CONCLUSION: In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.

Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group.

BACKGROUND AND OBJECTIVES: The two main complications of severe chronic neutropenia are fatal sepsis and myelodysplasia/acute leukemia (MDS/AL). Granulocyte colony-stimulating factor (G-CSF) therapy has significantly reduced the frequency and severity of infections, but its possible influence on the risk of malignancy is not known. DESIGN AND METHODS: The French Severe Chronic Neutropenia (SCN) Registry has prospectively collected data since 1994 on 231 patients with various forms of SCN, namely severe congenital neutropenia (n=101), cyclic neutropenia (n=60), glycogen storage disease type Ib (GSDIb) (n=15) and Shwachman-Diamond syndrome (SDS)(n=55). The median overall follow-up is 11.1 years. Parameters of exposure to G-CSF therapy, such as the time averaged dose, follow up after first use of G-CSF, and the cumulative dose, have been recorded. RESULTS: Eight septic deaths occurred, of which 6 among patients with severe congenital neutropenia and 2 in patients with cyclic neutropenia; none of these 8 patients was receiving G-CSF therapy. No septic deaths occurred during G-CSF therapy. Thirteen cases of MDS/AL were recorded. The cumulative incidence of MDS/AL was 2.7% (SD 1.3%) at 10 years and 8.1% (SD 2.7%) at 20 years. INTERPRETATION AND CONCLUSIONS: Risk factors for MDS/AL were the diagnostic category, the severity of neutropenia, younger age at diagnosis, and strong exposure to G-CSF. MDS/AL only occurred in patients with severe congenital neutropenia and SDS. Owing to their particular susceptibility to infections, patients with severe congenital neutropenia had the strongest exposure to G-CSF; the risk of leukemia increased with the degree of G-CSF exposure in this subgroup.