Clinical Characteristics of Peripheral Lymphocyte Subtypes in Chronic Active Epstein-Barr Virus Infection.

BACKGROUND: We aimed to analyze the clinical characteristics of peripheral Epstein-Barr virus (EBV)-infected lymphocyte subtypes in children with chronic active EBV infection (CAEBV). METHODS: The levels of peripheral EBV infection of CD4+ T cells, CD8+ T cells, and CD56+ natural killer (NK) cells were determined by flow cytometry and quantitative polymerase chain reaction (qPCR) in patients with CAEBV from July 2017 to July 2022. RESULTS: In total, 112 children with CAEBV were evaluated. Of these, CD4+ type, CD8+ type, and CD56+ type were defined in 44, 21, and 47 patients, respectively. Patients with CD8+ T-cell type had a significantly higher frequency of rash, while hepatomegaly was more common in patients with CD4+ T-cell type. Generally, patients with CD8+ T-cell type had the lowest overall survival rate (P = .017). Patients treated with chemotherapy and hematopoietic stem cell transplantation (HSCT) had a better prognosis (P = .001). In multivariate analysis, rash, hemophagocytic lymphohistiocytosis, CD8+ T-cell type, and no decrease of plasma EBV-DNA after treatment were independent indicators of poor prognosis (P = .002, .024, .022, and .012, respectively). CONCLUSIONS: In children with CAEBV, rash was more frequent in patients with CD8+ T-cell type, whereas patients with CD4+ T-cell type were more likely to develop hepatomegaly. Patients with CD8+ T-cell type had a poor prognosis despite receiving chemotherapy or further HSCT.

Molecular Engineering to Regulate the Pseudo-Graphitic Structure of Hard Carbon for Superior Sodium Energy Storage.

Resin-derived hard carbons have shown great advantages in serving as promising anode materials for sodium-ion batteries due to their flexible microstructure tunability. However, it remains a daunting challenge to rationally regulate the pseudo-graphitic crystallite and defect of hard carbon toward advanced sodium storage performance. Herein, a molecular engineering strategy is demonstrated to modulate the cross-linking degree of phenolic resin and thus optimize the microstructure of hard carbon. Remarkably, the resorcinol endows resin with a moderate cross-linking degree, which can finely tune the pseudo-graphitic structure with enlarged interlayer spacing and restricted surface defects. As a consequence, the optimal hard carbon delivers a notable reversible capacity of 334.3 mAh g-1 at 0.02 A g-1, a high initial Coulombic efficiency of 82.1%, superior rate performance of 103.7 mAh g-1 at 2 A g-1, and excellent cycling durability over 5000 cycles. Furthermore, kinetic analysis and in situ Raman spectroscopy are performed to reveal the electrochemical advantage and sodium storage mechanism. This study fundamentally sheds light on the molecular design of resin-based hard carbons to advance sodium energy for scale-up applications.

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.

Ruxolitinib-based regimen in children with primary hemophagocytic lymphohistiocytosis.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare immune disorder and hematopoietic stem cell transplan- tation (HSCT) is the only potentially curative treatment. Given the high pre-HSCT mortality of pHLH patients reported in the HLH-2004 study (17%), more regimens to effectively control the disease and form a bridge with HSCT are needed. We conducted a retrospective study of pHLH children treated by ruxolitinib (RUX)-based regimen. Generally, patients received RUX until HSCT or unacceptable toxic side-effect. Methylprednisolone and etoposide were added sequentially when the disease was suboptimally controlled. The primary end point was 1-year overall survival. Twenty-one pHLH patients (12 previously treated and 9 previously untreated) were included with a median follow-up of 1.4 years. At last follow-up, 17 (81.0%) patients were alive with a 1-year overall survival of 90.5% (95% confidence interval: 84.1-96.9). Within the first 8 weeks, all patients had an objective response, of which 19 (90.5%) achieved complete response (CR) and two (9.5%) achieved partial response (PR) as a best response. Seventeen (81.0%) patients received HSCT, of which 13 (76.5%) had CR, three (17.6%) had PR and one (5.9%) had disease reactivation at the time of HSCT. Fifteen (88.2) patients were alive post- HSCT. Notably, eight (38.1%) patients received zero doses of etoposide, suggesting the potential of RUX-based regimen to reduce chemotherapy intensity. Patients tolerated RUX-based regimen well and the most frequently observed adverse events were hematologic adverse events. Overall, RUX-based regimen was effective and safe and could be used as a bridge to HSCT for pHLH children.

Genetic and clinical characteristics of primary hemophagocytic lymphohistiocytosis in children.

To analyze the genetic variation and prognosis of primary hemophagocytic lymphohistiocytosis (pHLH) in children and the clinical features of isolated central nervous system HLH (CNS-HLH). We retrospectively analyzed the clinical and genetic data of 480 HLH children admitted to our hospital from September 2017 to September 2022. There were 66 patients (13.75%) with pHLH, and the median age was 3.21 years (0.17-12.92 years). Variants in UNC13D (22/66, 33.33%), PRF1 (20/66, 30.30%) and XIAP (11/66, 16.67%) were the most common. More CNS involvement was observed in pHLH patients than in secondary hemophagocytic lymphohistiocytosis (sHLH) patients (50% vs. 25.3%, P = 0.001). Eight pHLH patients had isolated CNS-HLH at onset, which progressed to systemic HLH within 10-30 days to several years. Among them, five patients who underwent hematopoietic stem cell transplantation (HSCT) survived without CNS sequelae, and the three patients who did not undergo HSCT died of disease progression or recurrence. Determination of natural killer (NK) cell cytotoxicity and CD107a levels had low sensitivity and specificity in the diagnosis of pHLH, especially in patients with PRF1 and XIAP mutations. The 3-year overall survival (OS) was significantly lower in pHLH patients than in sHLH patients (74.5% ± 14.7% vs. 89.2% ± 3.53%, P = 0.021) and in patients with CNS involvement than in those without (53.8% ± 26.07% vs. 94.4% ± 10.58%, P = 0.012). There was a significant difference in OS among pHLH patients with different gene variants (P = 0.032); patients with PRF1 variants had poor 3-year OS, and patients with XIAP variants had good 3-year OS (50% ± 28.22% and 100%, respectively). pHLH patients with distinct variants have different prognoses. Isolated CNS-HLH patients are easily misdiagnosed, and HSCT may be beneficial for these patients. Determination of NK cell cytotoxicity and CD107a levels cannot precisely distinguish pHLH from sHLH.

Clinical features and outcomes of 17 children with systemic juvenile xanthogranuloma (sJXG) including five complicated with hemophagocytic lymphohistiocytosis (HLH).

Juvenile xanthogranuloma (JXG) is primarily limited to the skin, and systemic JXG (sJXG) is rarely reported. Reports of sJXG patients with hemophagocytic lymphohistiocytosis (HLH) are particularly rare. Herein, we conducted a retrospective study of children diagnosed with sJXG in the Hematology Centre of Beijing Children's Hospital from Jan. 2016 to Dec. 2021. The clinical features, laboratory parameters, treatments and outcomes of 17 sJXG patients were investigated, including five complicated with HLH. All sJXG-HLH patients had intermittent fever, rash, hepatosplenomegaly, cytopenia and high levels of soluble CD25, but interferon-γ was almost normal. Patients with sJXG-HLH had a younger diagnosis age (P = 0.035) and were more likely to have skin, liver, and spleen involvement than those without HLH (P = 0.029, P = 0.003, P = 0.003, respectively). Corticosteroids and/or ruxolitinib could be used to control the hyperinflammatory status when HLH was diagnosed. The treatment of sJXG varied, including Langerhans cell histiocytosis (LCH)-based chemotherapy and targeted therapy. The overall response rate of sJXG for first-line and second-line chemotherapy was 50.0% (5/10) and 50% (4/8), respectively. Patients with BRAF V600E mutation showed a response to dabrafenib. There was no significant difference in the overall survival and progression-free survival between sJXG patients without and with HLH (P = 0.12 and P = 0.46, respectively). Therefore, LCH-based chemotherapy could serve as an effective treatment for sJXG patients, and dabrafenib, to some extent, showed efficacy in controlling sJXG in patients with BRAF V600E mutation. The prognosis of sJXG-HLH patients seemed to be comparable to patients without HLH.

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.

Ruxolitinib Monotherapy for a Child With HAVCR2 Gene Mutation Associated Subcutaneous Panniculitis-like T-cell Lymphoma: A Case Report.

BACKGROUND: The occurrence of hemophagocytic lymphohistiocytosis (HLH) in patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) may be due to HAVCR2 gene mutation, leading to T-cell immunoglobulin and mucin domain-containing molecule 3 deficiency, T-cell and macrophage activation, and proinflammatory cytokine production. OBSERVATION: We report a patient with SPTCL and HLH for whom ruxolitinib, used as a novel treatment, showed notable therapeutic effects. CONCLUSIONS: Remission of both HAVCR2 mutation-induced high inflammatory characteristics and significant symptoms post-ruxolitinib administration suggested that patients with SPTCL and HLH may not represent typical lymphoma cases. Ruxolitinib, with its relatively low toxic side effects, can provide favorable outcomes.

Biomarkers in Pediatric Hemophagocytic Lymphohistiocytosis With Central Nervous System Involvement: A Cohort Study.

BACKGROUND: The aim of this study was to analyze the clinical significance of cerebrospinal fluid (CSF) cytokines in hemophagocytic lymphohistiocytosis associated with central nervous system (CNS-HLH). METHODS: CSF cytokine levels, including interferon (IFN)-γ, soluble CD25 (sCD25), interleukin (IL)-6, IL-10, IL-18, and CXCL9 were measured at disease onset and during the treatment. Five newly diagnosed patients with demyelination disease were enrolled for comparison. RESULTS: Sixty-five samples from 36 patients (13 in the CNS group and 23 in the non-CNS group) were detected. Levels of CSF IFN-γ, sCD25, IL-10, IL-18, and CXCL9 in the CNS group were higher than those in the non-CNS group (P=0.038, <0.001, <0.001, 0.005, and <0.001), and levels of CSF sCD25, IL-10, IL-18, and CXCL9 in the CNS group were higher than those in the demyelination group (P=0.001, 0.008, 0.004, and 0.003). There was no significant difference in IL-6 levels among the 3 groups (P=0.339). CSF IFN-γ, sCD25, IL-10, IL-18, and CXCL9 could assist in diagnosing CNS-HLH. The diagnostic efficiency of CSF sCD25, IL-10, and CXCL9 was better, with a cutoff value of 154.64, 1.655, and 19.54 pg/mL, respectively. The area under the curve was >0.9, with sensitivity and specificity >80%. Correlation analysis suggested that in the CNS group, IFN-γ levels in CSF and serum correlated positively (R=0.459, P=0.007), while there was no correlation between CSF CXCL9 and serum IFN-γ (P=0.915). CONCLUSIONS: CSF IFN-γ, sCD25, IL-10, IL-18, and CXCL9 levels were significantly higher in HLH patients with CNS involvement than those without and could predict HLH patients with CNS involvement. CSF CXCL9 might be a more sensitive biomarker to CNS-HLH than IFN-γ, while CSF IL-6 does not seem to play a vital role.

Treatment of children with refractory/relapse high risk langerhans cell histiocytosis with the combination of cytarabine, vindesine and prednisone.

BACKGROUND: The patients with multisystem and risk organ involvement Langerhans cell histiocytosis (MS-RO + LCH) have poor prognosis. The patients with MS-LCH who failed front-line therapy have a high mortality rate and the standard salvage treatment has not been established. The combination of cytarabine (Ara-c), vincristine (VCR) and prednisone might be effective for refractory/relapse MS-RO + LCH, with low toxicity. METHODS: We retrospectively analyzed pediatric refractory/relapse MS-RO + LCH patients treated with the low-dose Ara-c (100mg/m2/d×5days) or high-dose Ara-c (500mg/m2/d×5days) combined with vindesine (VDS) and prednisone in a single center. The efficacy, outcomes and adverse events were analyzed. RESULTS: From January 2013 to December 2016, 13 patients receiving the low-dose Ara-c chemotherapy (LAC) and 7 patients receiving the high-dose Ara-c chemotherapy (HAC) were included in the study. 11 (84.6%) of the 13 patients treated with the LAC regimen and 6 (85.7%) of the 7 patients treated with the HAC regimen had response after four courses of the therapy. All patients in the study were alive during follow-up and the 3-year event-free survival rate (EFS) was 53.7% and 85.7% in the LAC and HAC groups. The most frequent adverse event was Grade 1/2 myelosuppression, which was observed in 38.5% (5/13) and 42.9% (3/7) of the patients receiving the LAC and HAC regimen. CONCLUSIONS: A combination of Ara-c, VDS and prednisone was effective and safe for some patients with refractory/relapse MS-RO + LCH. The high-dose Ara-c regimen was associated with a numerically higher EFS rate.

Clinical features and treatment outcomes of liver involvement in paediatric Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, and liver involvement in LCH is rare. This retrospective study reported the clinical features and prognosis of patients with hepatic LCH. Liver involvement was defined by histopathological findings, liver dysfunction or abnormalities, or ultrasound imaging. A total of 130 patients (14.5%) with hepatic LCH out of 899 in the LCH population were enrolled. Patients with liver involvement had greater frequencies of skin, lung, hearing system, and haematologic system involvement, and hemophagocytic lymphohistiocytosis (P<0.001, 0.001, 0.002, 0.009, and <0.001, respectively). Overall survival and progression-free survival were lower in LCH patients with liver involvement than in those without liver involvement (P<0.001 and <0.001). In patients with liver involvement, the overall survival (OS) and progression-free survival (PFS) rates were lower in patients with cholangitis than in those without cholangitis (P<0.020 and 0.030). For the treatment response, the response rate of hepatic LCH patients to initial first-line therapy (n=89) was 22.5%. However, there was no significant difference in the response rate or recurrence rate between patients who shifted from first-line treatment to second-line treatment (n=29) or to targeted therapy (n=13) (P=0.453 and 1.000). The response rate of hepatic LCH patients who received initial second-line therapy (n=13) was 38.5%. Two of these patients subsequently experienced bone recurrence. The response rate of hepatic LCH patients who received initial targeted therapy (n=16) was 75.0%. Three patients subsequently experienced recurrence, including 2 in the bone and 1 in the liver and skin. A total of 39.3% of patients who received second-line treatment had severe myelosuppression (grade III-IV), and 50.8% had varying degrees of gastrointestinal events, whereas there was no severe toxicity in patients who received first-line treatment and targeted therapy. Four patients underwent liver transplantation because of liver cirrhosis. The patients' liver disease improved within a follow-up period of 18-79 months. This study demonstrated that LCH with liver involvement, especially cholangitis, indicates a poor prognosis. Targeted therapy provides a good treatment response and less toxicity. However, it may relapse after withdrawal. Liver transplantation is still a reliable salvage option for patients with end-stage liver disease.

Resolving Deactivation of Low-Spin Fe Sites by Redistributing Electron Density toward High-Energy Sodium Storage.

Prussian blue (PB) has been an emerging class of cathode material for sodium-ion batteries due to its low cost and high theoretical capacity. However, their working voltage and capacity are substantially restricted due to the deactivation of low-spin Fe sites. Herein, we demonstrate a universal strategy to activate the low-spin Fe sites of PB by hybridizing them with the π-π conjugated electronic conductors. The redistribution of electron density between π-π conjugated conductors and PB effectively promotes the participation of low-spin Fe sites in sodium storage. Consequently, the low-spin Fe-induced plateau is greatly aroused, resulting in a high specific capacity of 148.4 mAh g-1 and remarkable energy density of 444.2 Wh kg-1. In addition, the excellent structural stability enables superior cycling stability over 2500 cycles and outstanding rate performance. The work will provide fundamental insight into activating the low-spin Fe sites of PB for advanced battery technologies.

Clinical characteristics of peripheral lymphocyte subtypes in chronic active Epstein-Barr virus infection.

PURPOSE: To analyze the clinical characteristics of peripheral Epstein-Barr virus(EBV)-infected lymphocyte subtypes in children with chronic active EBV infection(CAEBV). METHODS: The levels of peripheral EBV infection of CD4 + T cells, CD8 + T cells, and CD56 + NK cells were determined by flow cytometry and qPCR in patients with CAEBV from July 2017 to July 2022. RESULTS: A total of 112 children with CAEBV were evaluated in the study. Of them, CD4 + type, CD8 + type, and CD56 + type were defined in 44, 21, and 47 patients, respectively. Patients with CD8 + T-cell type had a significantly higher frequency of rash, while hepatomegaly was more common in patients with CD4 + T-cell type. Generally, patients with CD8 + T-cell type had the lowest overall survival(OS) rate(P = 0.017). As for treatment, patients treated with chemotherapy and hematopoietic stem cell transplantation had a better prognosis(P = 0.001). In multivariate analysis, rash, HLH, CD8 + T-cell type, and no decrease of plasma EBV-DNA after treatment were indicated as independent factors of poor prognosis(P = 0.002, 0.024, 0.022, and 0.012, respectively). CONCLUSION: In children with CAEBV, the rash was more frequent in patients with CD8 + T-cell type, whereas patients with CD4 + T-cell type were more likely to develop hepatomegaly. Patients with CD8 + T-cell type had a poor prognosis despite receiving chemotherapy or further HSCT.

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.

Transcriptomic landscape of circulating mononuclear phagocytes in Langerhans cell histiocytosis at the single-cell level.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm caused by aberrant activation of the mitogen-activated protein kinase (MAPK) pathway. Circulating myeloid cells from patients often carry disease-associated mutations and can be differentiated into langerinhigh LCH-like cells in vitro, but their detailed immune-phenotypic and molecular profiles are lacking and could shed key insights into disease biology. Here we recruited 217 pediatric LCH patients and took blood and tissue samples for BRAFV600E analysis. Immune-phenotyping of the circulating Lin-HLA-DR+ immune population in 49 of these patients revealed that decreased frequency of plasmacytoid dendritic cells was significantly linked to disease severity. By single-cell RNA sequencing of samples from 14 patients, we identified key changes in expression of RAS-MAPK-extracellular signal-regulated kinase (ERK) signaling-related genes and transcription factors in distinct members of the mononuclear phagocyte system in the presence of BRAFV600E. Moreover, treatment of patients with the BRAF inhibitor dabrafenib resulted in MAPK cascade inhibition, inflammation prevention, and regulation of cellular metabolism within mononuclear phagocytes. Finally, we also observed elevated expression of RAS-MAPK-ERK signaling-related genes in a CD207+CD1a+ cell subcluster in skin. Taken together, our data extend the molecular understanding of LCH biology at single-cell resolution, which might contribute to improvement of clinical diagnostics and therapeutics, and aid in the development of personalized medicine approaches.

Serum cytokine pattern in children with hemophagocytic lymphohistiocytosis.

This study aimed to compare the serum levels of 34 cytokines of children with hemophagocytic lymphohistiocytosis (HLH) and explored the specific cytokine pattern of HLH subtypes and the relationship between cytokine levels and prognosis. This retrospective study assessed the clinical data and cytokine levels of newly diagnosed children with HLH in Beijing Children's Hospital, Capital Medical University, from January 2017 to December 2021. A total of 101 children were enrolled in the study. The levels of IFN-γ and IL-18 increased in more than 90% of patients, and MIP-1α, SDF-1α, IP-10, IL-6, IL-8, IL-10, IL-1 RA, and TNF-α increased at different levels in more than 50% of patients. The levels of IL-10 in EBV-HLH increased significantly, followed by IFN-γ and IL-18, while IL-10 and IFN-γ in CAEBV-HLH had a slight increase. Except for IL-10, the levels of IL-6, Eotaxin, IL-13, IL-18, IFN-γ, and MIP-1ß in Rh-HLH increased significantly. F-HLH had significantly high IL-10 levels and a slight increase in IL-13. We showed that various cytokines could assist in differentiating HLH subtypes with ROC curve analysis. When IL-10/IL-6 was 1.37, the sensitivity and specificity of diagnosing EBV-HLH were higher than 80% (AUC = 0.837, p < 0.001). The effect of cytokine ratio on classifying HLH subtypes (17/22, 77.3%) was more significant than the single cytokine (5/22, 22.7%). The 3-year overall survival (OS) rate of children with F-HLH was the lowest during the follow-up. The 3-year OS of patients with EBV-HLH and CAEBV-HLH was significantly higher than that with F-HLH (88.1% ± 5.0% vs. 94.1% ± 5.7% vs. 57.1% ± 14.6%, p = 0.017). Cox proportional hazards model revealed that elevated GM-CSF and MCP-1, as well as CNS involvement, were independent risk factors for poor outcomes for patients with HLH. Various cytokines play important roles in HLH. Different subtypes of HLH have their specific cytokines pattern, and the ratio of cytokines may be more significant in differentiating HLH subtypes than the single one. Elevated GM-CSF and MCP-1 could be useful biomarkers for a poor prognosis for patients with HLH.

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.

Systemic juvenile xanthogranuloma: A systematic review.

OBJECTIVE: To perform a systematic review to investigate the available literature regarding systemic juvenile xanthogranuloma (SJXG) and report the population characteristics, clinical manifestation, therapy, and outcome. REVIEW METHODS: A search of PubMed, Embase, and Cochrane Library for all articles published between 1981 and 2022 was performed with variations and combinations of the following search terms: extracutaneous, visceral, systemic, and juvenile xanthogranuloma (JXG). Data extracted included demographics, organ involvement, treatment, outcome, and permanent sequelae. RESULTS: A total of 103 articles encompassing 159 patients met the inclusion criteria. The median onset age was 9 months, with a male predominance (61%). The distribution of major involved organs varied by age, and younger onset age was associated with more organ involvement. The most commonly involved site was the central nervous system (CNS) (40.9%), followed by the liver (31.4%), the lung (18.9%), and the eye (18.2%). At the termination of follow-up, 93 patients (58.5%) were alive with no disease, 56 (35.2%) were alive with disease, and 10 (6.3%) were dead of disease. There was a significant difference in outcome between patients with and without spleen involvement (p = .0003), and patients with spleen involvement suffered a higher risk of death. Permanent sequelae mainly comprised CNS symptoms and ocular manifestations. CONCLUSIONS: SJXG can involve varying numbers and combinations of extracutaneous sites. There is no standard therapy for SJXG and clinicians should choose individualized therapy modalities.

Clinical Significance of Plasma Soluble MICB in Children With EBV-associated Hemophagocytic Lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal systemic inflammation disease in children. The most common cause is Epstein-Barr virus (EBV) infection. MHC class I polypeptide-related sequence B (MICB) is a membrane protein inducibly expressed upon cellular stress, viral infection, or malignant transformation, thus marking these cells for clearance through natural killer group 2 member D-positive lymphocytes. MICB can be released into plasma through several mechanisms, reducing NK cell cytotoxicity. METHODS: We conducted clinical research on HLH patients and cell research in vitro. In the retrospective clinical part, 112 HLH patients (including EBV-HLH group and non-EBV-HLH group), 7 infectious mononucleosis patients, and 7 chronic active EBV infection patients were treated in Beijing Children's Hospital, affiliated with Capital Medical University, from January 2014 to December 2020, were enrolled in this study. Real-time quantitative polymerase chain reaction, standard enzyme-linked immunosorbent assay methods, and lactate dehydrogenase release tests were used to examine the expression of MICB mRNA, the soluble MICB (sMICB) levels, and the activity of NK cells in those patients. In vitro research, MICB overexpression-vector virus, MICB knockdown-vector virus, and empty-vector virus were transfected into two kinds of target cells, such as K562 and MCF7. The level of sMICB and NK cell killing activity between other groups was compared. Finally, we compared NK92 cell killing activity in different concentrations of sMICB. RESULTS: In clinical studies, compared with the non-EBV-HLH group, the EBV-HLH group had lower NK cell killing activity ( P < 0.05). The level of sMICB in the EBV-HLH group was significantly higher than in non-EBV-HLH, infectious mononucleosis, and chronic active EBV infection patients ( P ＜0.05). A high level of sMICB was associated with poor treatment response and poor prognosis ( P ＜0. 05). Cellular studies showed that an increased level of membrane MICB could positively correlate with the killing activity of NK92 cells ( P ＜0. 05), and a high level of sMICB (1250 to 5000pg/ml) could reduce the killing activity of NK92 cells ( P < 0.05). A high level of sMICB (2500pg/ml) could increase the release of cytokines from NK92 cells. CONCLUSION: The expression level of sMICB in EBV-HLH patients increased, and a high level of sMICB at the initial onset indicated a poor treatment response. The killing activity of NK cells in EBV-HLH patients decreased more significantly. The high level of sMICB may inhibit the killing activity but increase the release of cytokines of NK92 cells.

Optical micro mechanical accelerometer with double grating: design and simulation.

A double-grating-based optical micro mechanical accelerometer with differential detection structure is reported in order to enhance the optical scale factor. A theoretical model is established based on the multi-slits Fraunhofer diffraction model. According to the calculation and analysis, the normalized optical scale factor is improved from 5.491E6 with the single-side detection structure to 10.98E6 with the differential detection structure. Mechanical sensitivity with 4.04 nm/g and natural frequency with 7756.8 Hz of the optical accelerometer are shown by finite element simulation. The results of simulations show a novel scheme for an optical micro mechanical accelerometer with high resolution, to the best of our knowledge. Furthermore, micro-opto-electro-mechanical system fabrication flow is given in this work, which provides a reference for other kinds of optical sensors.