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.
The aim was to describe transfusion practice in critically ill patients at an international level and evaluate the effects of red blood cell (RBC) transfusion on outcomes in these patients.
This was ...a pre-planned sub-study of the Intensive Care Over Nations audit, which involved 730 ICUs in 84 countries and included all adult patients admitted between 8 May and 18 May 2012, except admissions for routine postoperative surveillance.
ICU and hospital outcomes were recorded. Among the 10,069 patients included in the audit, data related to transfusion had been completed for 9553 (mean age 60 ± 18 years, 60% male); 2511 (26.3%) of these had received a transfusion, with considerable variation among geographic regions. The mean lowest hemoglobin on the day of transfusion was 8.3 ± 1.7 g/dL, but varied from 7.8 ± 1.4 g/dL in the Middle East to 8.9 ± 1.9 g/dL in Eastern Europe. Hospital mortality rates were higher in transfused than in non-transfused patients (30.0% vs. 19.6%, p < 0.001) and increased with increasing numbers of transfused units. In an extended Cox proportional hazard analysis, the relative risk of in-hospital death was slightly lower after transfusion in the whole cohort (hazard ratio 0.98, confidence interval 0.96-1.00, p = 0.048). There was a stepwise decrease in the hazard ratio for mortality after transfusion with increasing admission severity scores.
More than one fourth of critically ill patients are transfused during their ICU stay, with considerable variations in transfusion practice among geographic regions. After adjustment for confounders, RBC transfusions were associated with a slightly lower relative risk of in-hospital death, especially in the most severely ill patients, highlighting the importance of taking the severity of illness into account when making transfusion decisions.
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).
Background Primary immunodeficiencies (PIDs) are inherited diseases associated with a considerable increase in susceptibility to infections. It is known that PIDs can also predispose to cancer and ...immune diseases, including allergy, autoimmunity, and inflammation. Objective We aimed at determining the incidence of autoimmunity and inflammation in patients with PIDs. Methods We have retrospectively screened 2183 consecutive cases of PID in the Centre de Référence Déficits Immunitaires Héréditaires registry (CEREDIH; the French national PID registry) for the occurrence of autoimmunity and inflammation. Results One or more autoimmune and inflammatory complications were noted in 26.2% of patients, with a risk of onset throughout the patient's lifetime. The risk of autoimmune cytopenia was at least 120 times higher than in the general population, the risk of inflammatory bowel disease in children was 80 times higher, and the risk of other autoimmune manifestations was approximately 10 times higher. Remarkably, all types of PIDs were associated with a risk of autoimmune and inflammatory complications, although the greatest risk was associated with T-cell PIDs and common variable immunodeficiency. The occurrence of autoimmune disease is a negative prognostic factor for survival. Conclusions Our results provide the basis for a detailed prospective evaluation of autoimmunity and inflammation in the context of PIDs, with a view to accurately assessing these risks and describing the possible effect of medical intervention.
Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We characterize 58 primary human RS ...samples by genome-wide DNA methylation and whole-transcriptome profiling. Our comprehensive approach determines RS DNA methylation profile and unravels a CLL epigenetic imprint, allowing CLL-RS clonal relationship assessment without the need of the initial CLL tumor DNA. DNA methylation- and transcriptomic-based classifiers were developed, and testing on landmark DLBCL datasets identifies a poor-prognosis, activated B-cell-like DLBCL subset in 111/1772 samples. The classification robustly identifies phenotypes very similar to RS with a specific genomic profile, accounting for 4.3-8.3% of de novo DLBCLs. In this work, RS multi-omics characterization determines oncogenic mechanisms, establishes a surrogate marker for CLL-RS clonal relationship, and provides a clinically relevant classifier for a subset of primary "RS-type DLBCL" with unfavorable prognosis.
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.
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.
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).
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.
Refractory chronic immune thrombocytopenia (r‐cITP) is one of the most challenging situations in chronic immune thrombocytopenia (cITP). Pediatric r‐cITP is inconsistently defined in literature, ...contributing to the scarcity of data. Moreover, no evidence is available to guide the choice of treatment. We compared seven definitions of r‐cITP including five pediatric definitions in 886 patients with cITP (median min‐max follow‐up 5.3 1.0–29.3 years). The pediatric definitions identified overlapping groups of various sizes (4%–20%) but with similar characteristics (higher proportion of immunopathological manifestations IM and systemic lupus erythematosus SLE), suggesting that they adequately captured the population of interest. Based on the 79 patients with r‐cITP (median follow‐up 3.1 0–18.2 years) according to the CEREVANCE definition (≥3 second‐line treatments), we showed that r‐cITP occurred at a rate of 1.15% new patients per year and did not plateau over time. In multivariate analysis, older age was associated with r‐cITP. One patient (1%) experienced two grade five bleeding events after meeting r‐cITP criteria and while not receiving second‐line treatment. The cumulative incidence of continuous complete remission (CCR) at 2 years after r‐cITP diagnosis was 9%. In this analysis, splenectomy was associated with a higher cumulative incidence of CCR (hazard ratio: 5.43, 95% confidence interval: 1.48–19.84, p = 7.8 × 10−4). In sum, children with cITP may be diagnosed with r‐cITP at any time point of the follow‐up and are at increased risk of IM and SLE. Second‐line treatments seem to be effective for preventing grade 5 bleeding. Splenectomy may be considered to achieve CCR.
In the present study, we have combined several atomic-scale computational techniques static lattice optimization, density functional theory (DFT), canonical Monte Carlo (MC), and Gibbs ensemble MC ...(GEMC) with experiment in order to describe the adsorption of water in potassium-exchanged X-type faujasite. Indeed, by applying DFT calculations, we have evidenced a strongly heterogeneous adsorbent surface and classified the preferential adsorption sites at zero loading for water molecules. The sodalite cage was identified as the preferential location. Moreover, by applying the GEMC technique, we have successfully simulated the water adsorption isotherm in the K–X zeolite. Finally, through the canonical MC simulation, we have described the microscopic mechanisms of water adsorption within the K–X zeolite at various uptakes, ranging from low loading (8 H2O/unit cell) to saturation (240 H2O/unit cell). We have evidenced that at low loading, the sodalite cages host the major part of the adsorbed molecules, while at increasing hydration ratio, the water molecules locate more in supercages. At saturation, each sodalite cage accommodates more than three water molecules on average, whereas nearly 90% of water molecules are located within supercages. Finally, at any hydration ratio, the water molecules in supercages coordinate preferentially with potassium cations at crystallographic site III (or III′) rather than at site II. Cations in site II start interacting with water molecules only at uptakes superior to 80 H2O molecules/unit cell, once all cations in site III (or III′) are occupied by at least one water molecule.
Contrast echocardiography improves accuracy and reduces interreader variability on left ventricular (LV) functional analyses in the setting of two-dimensional (2D) echocardiography. The need for ...contrast imaging using three-dimensional (3D) echocardiography is less defined. The aim of this multicenter study was to define the accuracy and interreader agreement of unenhanced and contrast-enhanced 2D and 3D echocardiography for the assessment of LV volumes and ejection fraction (EF).
A multicenter, open-label study was conducted including 63 patients, using intrasubject comparisons to assess the agreement of unenhanced and contrast-enhanced 2D and 3D echocardiography as well as calibrated biplane cine ventriculography with cardiac magnetic resonance for the determination of LV volumes and EF. Each of the imaging techniques used to define LV function was assessed by two independent, off-site readers unaware of the results of the other imaging techniques.
LV end-systolic and end-diastolic volumes were underestimated by 2D and 3D unenhanced echocardiography compared with cardiac magnetic resonance. Contrast enhancement resulted in similar significant increases in LV volumes on 2D and 3D echocardiography. The mean percentage of interreader variability for LV EF was reduced from 14.3% (95% confidence interval CI, 11.7%-16.8%) for unenhanced 2D echocardiography and 14.3% (95% CI, 9.7%-18.9%) for unenhanced 3D echocardiography to 8.0% (95% CI, 6.3%-9.7%; P < .001) for contrast-enhanced 2D echocardiography and 7.4% (95% CI, 5.7%-9.1%; P < .01) for contrast-enhanced 3D echocardiography and thus to a similar level as for cardiac magnetic resonance (7.9%; 95% CI, 5.4%-10.5%). A similar effect was observed for interreader variability for LV volumes.
Contrast administration on 3D echocardiography results in improved determination of LV volumes and reduced interreader variability. The use of 3D echocardiography requires contrast application as much as 2D echocardiography to reduce interreader variability for volumes and EF.
The risk of adverse effects of nitrous oxide (N
O) exposure is insufficiently recognized despite its widespread use. These effects are mainly reported through case reports. We conducted an individual ...patient data meta-analysis to assess the prevalence of clinical, laboratory, and magnetic resonance findings in association with N
O exposure in medical and recreational settings. We calculated the pooled estimates for the studied outcomes and assessed the potential bias related to population stratification using principal component analysis. Eighty-five publications met the inclusion criteria and reported on 100 patients with a median age of 27 years and 57% of recreational users. The most frequent outcomes were subacute combined degeneration (28%), myelopathy (26%), and generalized demyelinating polyneuropathy (23%). A T2 signal hyperintensity in the spinal cord was reported in 68% (57.2-78.8%) of patients. The most frequent clinical manifestations included paresthesia (80%; 72.0-88.0%), unsteady gait (58%; 48.2-67.8%), and weakness (43%; 33.1-52.9%). At least one hematological abnormality was retrieved in 71.7% (59.9-83.4%) of patients. Most patients had vitamin B12 deficiency: vitamin B12 <150 pmol/L (70.7%; 60.7-80.8%), homocysteine >15 µmol/L (90.3%; 79.3-100%), and methylmalonic acid >0.4 µmol/L (93.8%; 80.4-100%). Consistently, 85% of patients exhibited a possibly or probably deficient vitamin B12 status according to the cB12 scoring system. N
O can produce severe outcomes, with neurological or hematological disorders in almost all published cases. More than half of them are reported in the setting of recreational use. The N
O-related burden is dominated by vitamin B12 deficiency. This highlights the need to evaluate whether correcting B12 deficiency would prevent N
O-related toxicity, particularly in countries with a high prevalence of B12 deficiency.
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