A study of ruxolitinib response-based stratified treatment for pediatric hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a lethal disorder characterized by hyperinflammation. Recently, ruxolitinib (RUX), targeting key cytokines in HLH, has shown promise for HLH treatment. However, there is a lack of robust clinical trials evaluating its efficacy, especially its utility as a frontline therapy. In this study (www.chictr.org.cn, ChiCTR2000031702), we designed ruxolitinib as a first-line agent for pediatric HLH and stratified the treatment based on its early response. Fifty-two newly diagnosed patients were enrolled. The overall response rate (ORR) of ruxolitinib monotherapy (day 28) was 69.2% (36/52), with 42.3% (22/52) achieving sustained complete remission (CR). All responders achieved their first response to ruxolitinib within 3 days. The response to ruxolitinib was significantly associated with the underlying etiology at enrollment (P = .009). Epstein-Barr virus (EBV)-HLH patients were most sensitive to ruxolitinib, with an ORR of 87.5% (58.3% in CR). After ruxolitinib therapy, 57.7% (30/52) of the patients entered intensive therapy with additional chemotherapy. Among them, 53.3% (16/30) patients achieved CR, and 46.7% (14/30) patients dominated by chronic active EBV infection-associated HLH (CAEBV-HLH) developed refractory HLH by week 8. The median interval to additional treatment since the first ruxolitinib administration was 6 days (range, 3-25 days). Altogether, 73.1% (38/52) of the enrolled patients achieved CR after treatment overall. The 12-month overall survival (OS) for all patients was 86.4% (95% confidence interval [CI], 77.1% to 95.7%). Ruxolitinib had low toxicity and was well tolerated compared with intensive chemotherapy. Our study provides clinical evidence for ruxolitinib as a frontline agent for pediatric HLH. The efficacy was particularly exemplified with stratified regimens based on the early differential response to ruxolitinib. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR2000031702.

The plasma-soluble CSF1R level is a promising prognostic indicator for pediatric Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm characterized by the clonal proliferation of Langerhans-like cells. Colony-stimulating factor 1 receptor (CSF1R) is a membrane-bound receptor that is highly expressed in LCH cells and tumor-associated macrophages. In this study, a soluble form of CSF1R protein (sCSF1R) was identified by plasma proteome profiling, and its role in evaluating LCH prognosis was explored. We prospectively measured plasma sCSF1R levels in 104 LCH patients and 10 healthy children using ELISA. Plasma sCSF1R levels were greater in LCH patients than in healthy controls (p < .001) and significantly differed among the three disease extents, with the highest level in MS RO+ LCH patients (p < .001). Accordingly, immunofluorescence showed the highest level of membrane-bound CSF1R in MS RO+ patients. Furthermore, the plasma sCSF1R concentration at diagnosis could efficiently predict the prognosis of LCH patients treated with standard first-line treatment (AUC = 0.782, p < .001). Notably, dynamic monitoring of sCSF1R levels could predict relapse early in patients receiving BRAF inhibitor treatment. In vitro drug sensitivity data showed that sCSF1R increased resistance to Ara-C in THP-1 cells expressing ectopic BRAF-V600E. Overall, the plasma sCSF1R level at diagnosis and during follow-up is of great clinical importance in pediatric LCH patients.

Efficacy of ruxolitinib for HAVCR2 mutation-associated hemophagocytic lymphohistiocytosis and panniculitis manifestations in children.

Frequent germline mutations of HAVCR2, recently identified in subcutaneous panniculitis-like T-cell lymphoma (SPTCL), are associated with an increased risk of hemophagocytic lymphohistiocytosis (HLH). However, SPTCL-HLH represents a challenge because of the difficulties in treatment with poor survival. Its malignant nature, specifically harbouring HAVCR2 mutations, has also been questioned. To better understand its pathology and treatment, we analysed the clinical data of six patients diagnosed at our centre. The median age at onset was 10.5 years (range, 0.8-12.4). Five patients presented with skin lesions of subcutaneous nodules/plaques and/or ulceration. All patients developed HLH; notably, one infant only had HLH without skin involvement. Histopathologically, only two patients were diagnosed with SPTCL and three were reported as panniculitis with no sufficient evidence of lymphoma. Genetically, germline homozygous mutation of HAVCR2 (p.Y82C) was identified in all patients, with a median diagnosis time of 4.6 months. All patients initially received corticosteroids, immunosuppressants or chemotherapy, achieving unfavourable responses. Strikingly, they responded well to ruxolitinib targeting inflammatory cytokines, allowing rapid disease resolution and/or long-term maintenance of remission. The excellent efficacy of ruxolitinib highlights this disease as an inflammatory condition instead of neoplastic nature and indicates novel agents targeting key inflammatory pathways as an encouraging approach for this disease entity.

Clinical outcomes and prognostic risk factors of Langerhans cell histiocytosis in children: Results from the BCH-LCH 2014 protocol study.

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm mainly affecting young children. This study aimed to evaluate the outcomes of 449 pediatric patients enrolled in the BCH-LCH 2014 study. 52.6% of patients were classified with single-system (SS) LCH, 28.1% with multisystem (MS) risk organ negative (RO-) LCH, and 19.4% with MS RO+ LCH. Three hundred ninety-six patients (88.2%) were initially treated with first-line therapy based on the vindesine-prednisone combination. One hundred thirty-nine patients who lacked a response to initial treatment were shifted to second-line therapy, 72 to intensive treatment Arm S1 (a combination of cytarabine, cladribine, vindesine, and dexamethasone), and 67 to Arm S2 (without cladribine). The 5-year overall survival (OS), progression-free survival (PFS), and relapse rates were 98.2% (median: 97.6 months), 54.6% (median: 58.3 months), and 29.9%, respectively. MS RO+ patients had the worst prognosis among the three clinical subtypes. For the patients initially treated with first-line therapy, the 5-year OS, PFS, and relapse rates were 99.2%, 54.5%, and 29.3%, respectively. Patients in Arm S1 had a significantly better prognosis than patients in Arm S2 (5-year PFS: 69.2% vs. 46.5%, p = .042; relapse rate: 23.4% vs. 44.2%, p = .031). Multivariate analysis revealed that early treatment response, the involvement of RO, skin, and oral mucosa, as well as laboratory parameters, including CRP and γ-GT, were independent risk factors for the PFS of LCH. Thus, the prognosis of LCH in children has been improved significantly with stratified chemotherapy, and progression and relapse remained the challenges, especially for RO+ patients.

Characteristics and Treatment Outcomes of Pediatric Langerhans Cell Histiocytosis with Thymic Involvement.

OBJECTIVE: To evaluate the characteristics and treatment outcomes of patients with pediatric Langerhans cell histiocytosis (LCH) with thymic involvement. STUDY DESIGN: We retrospectively described the clinical, biological, and imaging characteristics of a series of 19 patients with pediatric LCH with thymic involvement in our center between September 2016 and December 2019. We further analyzed the treatment response and outcomes of patients treated with chemotherapy or targeted therapy. RESULTS: Thymic involvement was found in 4.4% of a 433-consecutive pediatric LCH cohort; all LCH-thymic involvement presented with multisystem disease. Patients with thymic involvement were typically younger, harboring more lung and thyroid involvement and less bone involvement than those without thymic involvement. Most patients with thymic involvement had alteration of immunocompetence with decreased numbers of T-lymphocyte subsets and immunoglobulin G levels. Overall, 47.1% of patients demonstrated a response after 6 weeks of induction therapy, and 92.3% of the patients who did not respond to the first-line treatment had resolution of thymus after the second-line and/or targeted therapy. The progression/relapse rate showed no difference between patients who shifted to second-line therapy and those to dabrafenib (33.3% vs 25%, P = 1.000). The survival for patients with thymic involvement did not differ from those without thymic involvement. More patients treated with second-line chemotherapy had severe adverse events than those given dabrafenib (88.9% vs 0, P < .001). CONCLUSIONS: Thymic involvement was observed rarely in LCH and had specific clinical characteristics. Chemotherapy could resolve most thymic lesions, and BRAF inhibitors might provide a promising treatment option with less toxicity for infants with BRAF-V600E mutation. TRIAL REGISTRATION: http://www.chictr.org.cn, identifier: ChiCTR2000030457 (BCH-LCH 2014 study); ChiCTR2000032844 (dabrafenib study).

Significance of serum Th1/Th2 cytokine levels in underlying disease classification of childhood HLH.

OBJECT: Goal of this research was to investigate values of serum cytokines in childhood HLH with different triggers, with the expectation to find secretion spectrum of 5 main types of underlying diseases. METHOD: 118 newly diagnosed HLH were included, and serum concentrations of 6 cytokines were tested before treatment began. Absolute cytokine levels and ratios between them were then studied in the HLH groups collectively and separately RESULTS: In general, IFN-γ, IL-10 and IL-6 showed differences among 5 HLH groups. Specifically, relative levels of these three cytokines to each other were meaningful in distinguishing 4 types of HLH. Level of IL-6 was higher than those of IFN-γ or IL-10 in HLH driven by Systemic auto-inflammatory disorders (SAIDs) or Langerhans Cell Histiocytosis (LCH), while primary HLH and EBV-HLH shared elevated ratio of IL-10 to IL-6. Although more than one distinctive ratios were found in 3 HLH groups, combination of these parameters didn't offer optimal balance between sensitivity and specificity. CONCLUSION: As a group of easily gained laboratory findings, cytokine levels were reliable in the procedure of roughly classifying HLH cases with the help of patients' clinical phenotype. However, adequate data is still needed to explore the significance of these indicators in identifying one particular underlying disease accurately.

A pilot study of ruxolitinib as a front-line therapy for 12 children with secondary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is an immune-regulatory disorder characterized by excessive production of inflammatory cytokines. The treatment recommendations of the HLH-1994 and HLH-2004 protocols have long been used in HLH therapy, but some patients still do not respond well to or have unacceptable side effects from conventional therapies. It is believed that cytokine-targeted strategies that directly target disease-driving pathways will be promising options for HLH. This prospective study aimed to investigate the efficacy and safety of ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, as a front-line therapy in children with secondary HLH. Twelve newly diagnosed patients without previous treatment were enrolled in this study with a median follow-up of 8.2 (7.1-12.0) months, including 8 cases of Epstein-Barr virus associated HLH (EBV-HLH), 2 cases of autoinflammatory disorder (AID)- associated HLH, and 2 cases of unknown etiology. Patients received oral ruxolitinib dosed on 2.5 mg, 5 mg or 10 mg twice daily depending on the body weight for 28 consecutive days. The overall response rate at the end of treatment (day 28) was 83.3% (10/12), with 66.7% (8/12) in complete response (CR), 8.3% (1/12) in partial response (PR), and 8.3% (1/12) in HLH improvement. Among the patients achieving CR, 87.5% (7/8) maintained CR condition for>6 months, and one patient with EBV-HLH relapsed following CR. For the EBV-HLH subgroup, all 8 patients responded to ruxolitinib, with a CR rate of 75% and a PR rate of 25%. Two patients with AID-associated HLH had quite different responses, with one showing reversal of the HLH abnormalities soon and the other showing no improvement, as did the two cases of unknown etiology. Patients who had no response or discontinued ruxolitinib all responded well to the subsequent HLH-1994 regimen. The expected 6-month event-free survival (EFS) rate was 58.3%±10.2%. No serious adverse effects were reported. Our study provides further support for the possibility of ruxolitinib targeted therapy for secondary HLH in children. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR2000029977.

Successful rescue of a lethal Griscelli syndrome type 2 presenting with neurological involvement and hemophagocytic lymphohistiocytosis: a case report.

BACKGROUND: Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disease caused by mutations in RAB27A gene. It is primarily characterized by a combination of partial albinism, hemophagocytic lymphohistiocytosis (HLH) or other immunodeficiency. However, neurological involvement at onset in GS2 and treatment has rarely been described. CASE PRESENTATION: We describe a 3-year-old boy with GS2 in an Asian Chinese family. He presented with progressive neurological abnormalities following unremitting fever at onset. He developed HLH during the clinical course. A novel homozygous mutation (c.1 A > G) in RAB27A gene was subsequently identified. He was then treated by HLH-1994 protocol combined with ruxolitinib and experienced a dramatic remission. He subsequently underwent a successful haploidentical hematopoietic stem cell transplantation and stayed at a good condition. CONCLUSIONS: We reported an atypical form of GS2 manifesting as severe central nervous system involvement at onset and subsequent HLH, which was successfully rescued in time. This case also highlights the need for early consideration of immunologic and genetic evaluation for HLH in unexplained neuroinflammation in the diagnostic work up.

Haploidentical Hematopoietic Stem Cell Transplantation for XIAP Deficiency: a Single-Center Report.

PURPOSE: X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in the XIAP/BIRC4 gene is a rare inherited primary immunodeficiency also known as X-linked lymphoproliferative syndrome type 2 (XLP2). Hematopoietic stem cell transplantation (HSCT) is currently the only curative strategy available. However, few studies of haploidentical HSCT have been published regarding the outcomes in patients with this syndrome. METHODS: We evaluated the XIAP gene analysis and clinical characteristics of four Chinese patients with XIAP who underwent haploidentical HSCT. RESULTS: The mutations in the two of four patients had not yet been reported in the literature. All of the patients had recurrent hemophagocytic lymphohistiocytosis but did not have a good matched donor and underwent haploidentical HSCT at BCH in China between September 2016 and December 2018. All four patients received antithymocyte globulin with fludarabine-based regimens. Two patients underwent reduced intensity conditioning (RIC), and the other two received modified myeloablative conditioning (MAC) regimens. Three of the four patients survived. Three patients experienced complications with mixed chimerism. One of the four patients who underwent RIC had early graft loss and then developed grade IV acute graft-versus-host disease (GVHD) after donor lymphocyte infusion with bone marrow. The two patients who received MAC survived with no or mild GVHD, even though one of them developed hepatic veno-occlusive disease in the early stage of transplantation. CONCLUSIONS: Haploidentical HSCT may be a treatment option for patients with XIAP deficiency who lack a good matched donor. More studies are needed to determine whether modified MAC with reduced toxicity is more suitable for haploidentical transplantation.

Renormalization group invariance and optimal QCD renormalization scale-setting: a key issues review.

A valid prediction for a physical observable from quantum field theory should be independent of the choice of renormalization scheme--this is the primary requirement of renormalization group invariance (RGI). Satisfying scheme invariance is a challenging problem for perturbative QCD (pQCD), since a truncated perturbation series does not automatically satisfy the requirements of the renormalization group. In a previous review, we provided a general introduction to the various scale setting approaches suggested in the literature. As a step forward, in the present review, we present a discussion in depth of two well-established scale-setting methods based on RGI. One is the 'principle of maximum conformality' (PMC) in which the terms associated with the ß-function are absorbed into the scale of the running coupling at each perturbative order; its predictions are scheme and scale independent at every finite order. The other approach is the 'principle of minimum sensitivity' (PMS), which is based on local RGI; the PMS approach determines the optimal renormalization scale by requiring the slope of the approximant of an observable to vanish. In this paper, we present a detailed comparison of the PMC and PMS procedures by analyzing two physical observables R(e+e-) and [Formula: see text] up to four-loop order in pQCD. At the four-loop level, the PMC and PMS predictions for both observables agree within small errors with those of conventional scale setting assuming a physically-motivated scale, and each prediction shows small scale dependences. However, the convergence of the pQCD series at high orders, behaves quite differently: the PMC displays the best pQCD convergence since it eliminates divergent renormalon terms; in contrast, the convergence of the PMS prediction is questionable, often even worse than the conventional prediction based on an arbitrary guess for the renormalization scale. PMC predictions also have the property that any residual dependence on the choice of initial scale is highly suppressed even for low-order predictions. Thus the PMC, based on the standard RGI, has a rigorous foundation; it eliminates an unnecessary systematic error for high precision pQCD predictions and can be widely applied to virtually all high-energy hadronic processes, including multi-scale problems.

The clinical impact of serum soluble CD25 levels in children with Langerhans cell histiocytosis.

OBJECTIVE: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm with inflammatory characteristics. This study aims to investigate the correlation between sCD25 levels and clinical characteristics, as well as prognosis, in pediatric LCH. METHODS: Serum sCD25 levels were measured in 370 LCH patients under 18 years old using ELISA assays. The patients were divided into two cohorts based on different treatment regimens. We further assessed the predictive value for the prognosis impact of sCD25 in a test cohort, which was validated in the independent validation cohort. RESULTS: The median serum sCD25 level at diagnosis was 3908 pg/ml (range: 231-44 000pg/ml). sCD25 level was significantly higher in multi-system and risk organ positive (MS RO+) LCH patients compared to single-system(SS) LCH patients (p < 0.001). Patients with elevated sCD25 were more likely to have involvement of risk organs, skin, lung, lymph nodes, or pituitary (all p < 0.05). sCD25 level could predict LCH progression and relapse, with an area under the ROC curve of 60.6 %. The optimal cutoff value was determined at 2921 pg/ml. Patients in the high-sCD25 group had significantly worse progression-free survival compared to those in the low-sCD25 group (p < 0.05). CONCLUSION: Elevated serum sCD25 level at initial diagnosis was associated with high-risk clinical features and worse prognosis. sCD25 level can predict the progression/recurrence of LCH following first-line chemotherapy.

Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis.

CONTEXT.­: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children. OBJECTIVE.­: To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH. DESIGN.­: We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients. RESULTS.­: A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor. CONCLUSIONS.­: Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.

Development and application of an LC-MS/MS method for pharmacokinetic study of ruxolitinib in children with hemophagocytic lymphohistiocytosis.

Ruxolitinib (RUX), a small molecule inhibitor of JAK1/JAK2, has been identified as the possible novel targeted agent for the treatment of hemophagocytic lymphohistiocytosis (HLH). However, due to the lack of randomized clinical trials (RCTs), it is extremely difficult to determine the effective therapeutic dose for RUX in HLH patients, especially in pediatric patients. At the same time, the clinical response of pediatric patients to RUX varies greatly among individuals according to several case reports. Therefore, it is imperative to investigate the pharmacokinetic and pharmacodynamic characteristics of RUX in HLH children, and this must be based on a satisfactory method to determine the concentration of RUX. Owing to several limits of published analytical methods, herein, we describe a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) method for monitoring RUX in children's plasma samples. The protein precipitation method using methanol was used for sample cleanup. The analytes were separated by gradient elution in which 2.0 mM ammonium acetate in distilled water and acetonitrile were used as mobile phases. In the positive electrospray ionization (ESI+) mode, the m/z 307.1 → 186.0 and 316.1 → 185.9 ion pair transitions of RUX and RUX-d9 were used for the qualitative and quantitative analysis, respectively. The calibration curves of RUX were linear in the concentration range from 0.5 to 400 ng mL-1. The intra- and inter-batch precision, accuracy, recovery, dilution completeness, and stability of this method were all within acceptable standards, and no matrix effects or residues were found. This method was successfully applied to the clinical pharmacokinetic study of RUX in 32 children with HLH. The pharmacokinetic parameters of HLH children after a single dose of RUX and the steady state plasma concentration after multiple administrations were proposed through this method. Most importantly, it was found that the age and serum creatinine (SCr) of children with HLH had a significant and complex impact on the in vivo process of RUX after the single as well as multiple administrations of RUX.

Clinical features and treatment outcomes of pediatric Langerhans cell histiocytosis with macrophage activation syndrome-hemophagocytic lymphohistiocytosis.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm. A few LCH patients had Macrophage activation syndrome-hemophagocytic lymphohistiocytosis (MAS-HLH), a life-threatening, hyper-inflammatory syndrome. We retrospectively described the clinical-biological characteristics of a series of 28 pediatric LCH patients with MAS-HLH in a single center. We further analyzed the difference in treatment outcomes between second-line chemotherapy (cytarabine and cladribine) and targeted therapy (dabrafenib) for BRAF-V600E-positive patients. RESULTS: LCH patients with MAS-HLH were aged < 2 years, harbored high frequencies of risk organ, skin, or lymph nodes involvement, and most of them carried BRAF-V600E mutation in lesions (88.0%) or plasma (90.5%). Patients were firstly treated with the initial induction first-line therapy (vindesine-steroid combination), and most of them (26/28) failed to control the active MAS-HLH after one six-week course of induction treatment. Then they were shifted to second-line chemotherapy or targeted therapy dabrafenib. BRAF-V600E-mutant patients treated with dabrafenib had prompt resolution of MAS-HLH signs and symptoms with less toxicity than second-line chemotherapy. Moreover, the progression-free survival (PFS) rate for patients given dabrafenib was much higher than those treated with chemotherapy (4 year-PFS: 75% vs. 14.6%, P = 0.034). CONCLUSIONS: LCH patients with MAS-HLH harbored specific clinical-biology characteristics compared to the multisystem LCH without MAS-HLH. The BRAF inhibitor dabrafenib provides a promising treatment option for LCH with MAS-HLH.

BRAF V600E Mutation in Cell-Free DNA, Rather than in Lesion Tissues, at Diagnosis Is An Independent Prognostic Factor in Children with Langerhans Cell Histiocytosis.

The aim of this study was to investigate the prognostic significance of BRAFV600E in cell-free (cf) DNA (cfBRAFV600E) and lesion tissues (ltBRAFV600E) in pediatric Langerhans cell histiocytosis (LCH). This study included a total of 140 patients with successfully detected cfBRAFV600E and ltBRAFV600E at diagnosis. Treatment response at week 6 was correlated with both cfBRAFV600E and ltBRAFV600E Moreover, the patients with positive cfBRAFV600E had a much lower 3-year progression-free survival (PFS) rate and a higher progression/reactivation rate than those with negative cfBRAFV600E (47.1% ± 7.6% vs. 78.4% ± 5.1%, P < 0.0001; 44.6% vs. 19.0%, P = 0.001, respectively). However, no significant difference was found in the 3-year PFS rate or progression/reactivation rate between patients with positive and negative ltBRAFV600E (P = 0.348 and 0.596, respectively). In addition, after patients were divided into group A (both cfBRAFV600E and ltBRAFV600E positive, n = 56), group B (ltBRAFV600E positive and cfBRAFV600E negative, n = 28), and group C (both cfBRAFV600E and ltBRAFV600E negative, n = 56), there was a significant difference in the 3-year PFS rate and progression/reactivation rate among the three groups (47.1% ± 7.6%, 92.9% ± 6.1%, and 72.2% ± 6.1%, P < 0.001; 44.6%, 3.6%, and 26.8%, P < 0.001, respectively). In the multivariate analysis, cfBRAFV600E and age at diagnosis remained independent prognostic factors for 3-year PFS in childhood LCH. Therefore, cfBRAFV600E was more closely associated with important clinical characteristics, treatment response at week 6, and prognosis than ltBRAFV600E.

Effectiveness and Safety of Dabrafenib in the Treatment of 20 Chinese Children with BRAFV600E-Mutated Langerhans Cell Histiocytosis.

PURPOSE: We sought to investigate the effectiveness and safety of dabrafenib in children with BRAFV600E-mutated Langerhans cell histiocytosis (LCH). MATERIALS AND METHODS: A retrospective analysis was performed on 20 children with BRAFV600E-mutated LCH who were treated with dabrafenib. RESULTS: The median age at which the patients started taking dabrafenib was 2.3 years old (range, 0.6 to 6.5 years). The ratio of boys to girls was 2.3:1. The median follow-up time was 30.8 months (range, 18.9 to 43.6 months). There were 14 patients (70%) in the risk organ (RO)+ group and six patients (30%) in the RO- group. All patients were initially treated with traditional chemotherapy and then shifted to targeted therapy due to poor control of LCH or intolerance to chemotherapy. The overall objective response rate and the overall disease control rate were 65% and 75%, respectively. During treatment, circulating levels of cell-free BRAFV600E (cfBRAFV600E) became negative in 60% of the patients within a median period of 3.0 months (range, 1.0 to 9.0 months). Grade 2 or 3 adverse effects occurred in five patients. CONCLUSION: Some children with BRAFV600E-mutated LCH may benefit from monotherapy with dabrafenib, especially high-risk patients with concomitant hemophagocytic lymphohistiocytosis and intolerance to chemotherapy. The safety of dabrafenib is notable. A prospective study with a larger sample size is required to determine the optimal dosage and treatment duration.

Associations between PRF1 Ala91Val polymorphism and risk of hemophagocytic lymphohistiocytosis: a meta-analysis based on 1366 subjects.

BACKGROUND: Perforin (PRF1) gene mutation can cause the onset of hemophagocytic lymphohistiocytosis (HLH). It has reported that PRF1 Ala91Val polymorphism was related with HLH risk. In the meta-analysis, we aim to evaluate the association between PRF1 Ala91Val polymorphism and HLH risk. METHODS: We accomplished a meta-analysis of six published case-control studies including 391 patients with HLH and 975 controls. We evaluated the quality of each study through Newcastle-Ottawa Scale (NOS). Data analysis was performed with Stata software. RESULTS: In general, all studies were of high quality (NOS score higher than 7). There were statistically significant between the PRF1 Ala91Val polymorphism and HLH risk though the pooled analysis [for Ala/Val vs. Ala/Ala: pooled odds ratio (OR) = 3.22, 95% confidence interval (CI) 1.08-9.56, P = 0.035, random model; for Ala/Val + Val/Val vs. Ala/Ala: pooled OR = 2.96, 95% CI 1.14-7.69, P = 0.025, random model]. Furthermore, sensitivity analysis also revealed a relationship between PRF1 Ala91Val polymorphism and HLH risk (for Ala/Val vs. Ala/Ala: pooled OR = 5.236, 95% CI 2.72-10.08, P < 0.000, I2 = 12.1%, Pheterogeneity = 0.332; for Ala/Val + Val/Val vs. Ala/Ala, pooled OR = 4.856, 95% CI 2.66-8.85, P < 0.000, I2 = 5.9%, Pheterogeneity = 0.373). Funnel plot and Egger's test did not indicate obvious published bias (P = 0.841 for Ala/Val vs. Ala/Ala; P = 0.284 for Ala/Val + Val/Val vs. Ala/Ala). CONCLUSION: This meta-analysis indicated that PRF1 Ala91Val polymorphism affects the factor for developing HLH and future studies of PRF1 Ala91Val on the onset of HLH will be guaranteed.

Significance of serum ferritin level in hemophagocytic lymphohistiocytosis diagnosis.

INTRODUCTION: The threshold of serum ferritin (SF) level listed in diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH) of HLH-2004 has a low specificity. The goal of this research was to evaluate the role of admission SF in HLH diagnostic procedure and to find an appropriate threshold for a HLH suspected cohort with fever. METHODS: All patients admitted to Beijing Children's Hospital during the period of September 1, 2015 and July 31, 2016 with fever and SF tested at admission were included in this study. The significance of SF in HLH diagnosis and its relationships with HLH-relevant clinical characteristics were studied. RESULTS: Among 357 patients, 39 HLH cases were diagnosed (24 EBV-related HLH, 13 unknown etiologies triggered HLH, and two familial HLH). The best cutoff value of admission SF was 934 ng/mL, with sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) being 87.2%, 88.4%, 47.9%, and 98.3%, respectively. Compared to 500 ng/mL, specificity and PPV of the new SF standard in HLH diagnose increased by 11.7% and 14.0%, which indicated improvements in diagnostic ability of "non-HLH" and in veracity of "HLH" identification. Among four HLH patients whose admission SF was between 500 ng/mL and 934 ng/mL, HLH diagnosis was guaranteed by other laboratory results in two patients; however, possible misdiagnosis was made in the rest two patients. CONCLUSION: Elevated cutoff value of admission SF level seems to be more appropriate for distinguishing HLH in patients with fever. The exact cutoff value of SF level at diagnosis needs to be determined.

Apoptotic mechanisms in rabbits with blast-induced acute lung injury 1.

PURPOSE: To investigate the apoptotic mechanisms in rabbits with blast-induced acute lung injury (ALI). METHODS: A total of 40 rabbits were randomly divided into a blank control group (A, n=10) and an experimental group (EXP, n=30). Explosion-induced chest-ALI models were prepared and sampled at different time points (4, 12, and 24h after modeling, T1-T3) to test the lung dry weight/wet weight ratio (W/D) and arterial oxygen pressure (PaO2), apoptosis of lung tissue by the TUNEL assay, and Caspase-3, Bax, and Bcl-2 levels by immunohistochemical analysis. Furthermore, lung tissue was sampled to observe pathological morphology by microscopy. RESULTS: Under a light microscope, Group EXP exhibited obvious edema in the pulmonary interstitial substance and alveoli, a large number of red blood cells, inflammatory cells, and serous exudation in the alveolar cavity, as well as thickening of the pulmonary interstitial fluid. Compared to Group A, the W/D ratio was significantly increased in Group EXP (P<0.01), while PaO2 was significantly reduced (P<0.01). The apoptosis index was significantly increased (P<0.01), and caspase-3 and Bax/Bcl-2 levels were increased (P<0.01). CONCLUSION: Apoptosis plays an important role in the occurrence and development of acute lung injury in rabbits by participating in lung injury and promoting the progression of ALI.