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Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening entity which is characterized by severe hyperinflammation. Now the HLH-2004 protocol has been widely accepted and clinically used; however, many questions still remain in clinical practice. In this review, we discuss the dilemmas in the diagnosis and treatment of HLH in children. Data sources Original research for articles and literature reviews published in PubMed was carried out using the key term “hemophagocytic lymphohistiocytosis”. Results As the gene sequencing technology progresses, the range of causal mutations and primary HLH has been redefined. The monoallelic variants may contribute to the pathogenesis of the disease. Many conditions without defective cytotoxicity of T or NK cells may lead to HLH, such as primary immunodeficiency (PID) and dysregulated immune activation or proliferation (DIAP). HLH shares overlapping clinical and laboratory characteristics with severe sepsis, but usually the single values are more pronounced in HLH than sepsis. H score is another approach to help the diagnosis of secondary HLH. Specific Th1/Th2 cytokine patterns are very helpful tools to differentiate HLH (reactivation of HLH) from sepsis. Moreover, it also has been used successfully to stratify the therapy intensity. The treatment of HLH should consider underlying diseases, triggers and severity. HLH-94 is recommended for patients who need etoposide-based therapy. Conclusions Dramatic progress has been made during the past decades in understanding the pathophysiology of HLH. However, diagnosis and treatment of HLH remain with many dilemmas because of the heterogeneous nature of the disease. Better understanding new gene defects and more effective diagnostic approaches and salvage regimens are goals for the future.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal disease caused by immune dysregulation. Early initiation of treatment is imperative for saving lives. However, a laboratory approach that could be used to quickly evaluate the HLH subtype and clinical situation is lacking. Our previous studies indicated that cytokines such as interferon (IFN)-γ and interleukin (IL)-10 were helpful for the early diagnosis of HLH and were associated with disease severity. The purpose of this study is to clarify the different cytokine patterns of various subtypes of pediatric HLH and to investigate the role of cytokines in a simple evaluation of disease feature. We enrolled 256 pediatric patients with newly diagnosed HLH. The clinical features and laboratory findings were collected and compared among different subtypes of HLH. A model integrating cytokines was established to stratify HLH patients into different clinical groups. Twenty-seven patients were diagnosed with primary HLH (pHLH), 179 with EBV-HLH, and 50 with other causes. The IL-6, IL-10, and IFN-γ levels and the ratios of IL-10 to IFN-γ were different among EBV-HLH, other infection-associated HLH, malignancy-associated HLH, familial HLH, and X-linked lymphoproliferative disease. Patients with the ratio of IL-10 to IFN-γ >1.33 and the concentration of IFN-γ ≤225 pg/ml were considered to have pHLH, with a sensitivity of 73% and a specificity of 84%. A four-quadrant model based on the two cutoff values was established to stratify the patients into different clinical situations. The HLH subtypes, cytokine levels, treatment regimens, treatment response, and outcomes were different among the four quadrants, with the 8-week mortality from 2.9 ± 2.9% to 21.4 ± 5.5% and the 5-year overall survival from 93.9 ± 4.2% to 52.6 ± 7.1%. Different subtypes of HLH present distinct cytokine patterns. IFN-γ and the ratio of IL-10 to IFN-γ are helpful tools to differentiate HLH subtypes. A four-quadrant model based on these two parameters is a useful tool for a simple evaluation of the HLH situation.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy with poor outcome. Four children with BPDCN treated at our hospital were enrolled. All the four cases presented with cutaneous lesions. Bone marrow and central nervous system was involved in 50% and 25% of patients, respectively. The whole exome sequencing analysis revealed that KMT2 family genes were the most frequently mutated (4/4, 100%), followed by IKZF2 (2/4, 50%). The point mutation p.D348N was found in three patients and one patient had p.C394Y mutation in the KMT2C gene. Translocation of KMT2A-MLLT3 was found in Case 2. Case 1 had complex karyotype, who was induced by acute myeloid leukemia-like regimens. Although he received allogeneic hematopoietic stem cell transplantation twice as well as CD123 chimeric antigen receptor T cell therapy, the disease still progressed and he died 37 months after diagnosis. The other three patients were treated with Interfant-99 protocol. They tolerated the therapy well without significant toxicities and now in complete remission so far with a median follow up time of 9 months. More studies are needed to address the question whether the complex karyotype and KMT2 family genes are the causes of the relapse and refractory in BPDCN.

The aim of this study was to identify specific laboratory indices to distinguish Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis (EBV-HLH) in children. In this prospective study, Th1/Th2 cytokines, including IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ, were analyzed in patients with EBV-HLH or sepsis at the onset of disease by flow cytometry. IL-10, IFN-γ, IL-10/IL-6, and IFN-γ/IL-6 were higher and IL-6 was lower in EBV-HLH patients compared to sepsis patient levels. When using the criteria of IL-10 >20.9 pg/mL, IFN-γ >17.9 pg/mL, IL-10/IL-6 >0.5 and IFN-γ/IL-6 >0.7, the sensitivity was 89.8%, 93.2%, 93.2%, and 91.5%, while the specificity was 89.8%, 100%, 94.9%, and 100%, respectively. After treatment of EBV-HLH patients, IL-6, IL-10, TNF-α, and IFN-γ were significantly reduced (IL-6: P<.001; IL-10: P<.001; TNF-α: P=.011; IFN-γ: P<.001). This study showed that IFN-γ, IL-10/IL-6, and IFN-γ/IL-6 are novel specific indicators for differential diagnosis of EBV-HLH. Additionally, IL-6, IL-10, TNF-α, and IFN-γ are useful indices for monitoring the effects of treatment on EBV-HLH. •IFN-γ, IL-10/IL-6 and IFN-γ/IL-6 are new, specific indicators for the differential diagnosis of EBV-HLH.•IL-6, IL-10, TNF-α, and IFN-γ are useful indices for the observation of a curative effect in EBV-HLH.

Background NUP98 rearrangements ( NUP98 -r) are rare but overrepresented mutations in pediatric acute myeloid leukemia (AML) patients. NUP98 -r is often associated with chemotherapy resistance and a particularly poor prognosis. Therefore, characterizing pediatric AML with NUP98 -r to identify aberrations is critically important. Methods Here, we retrospectively analyzed the clinicopathological features, genomic and transcriptomic landscapes, treatments, and outcomes of pediatric patients with AML. Results Nine patients with NUP98 -r mutations were identified in our cohort of 142 patients. Ten mutated genes were detected in patients with NUP98 -r. The frequency of FLT3- ITD mutations differed significantly between the groups harboring NUP98 -r and those without NUP98 -r ( P  = 0.035). Unsupervised hierarchical clustering via RNA sequencing data from 21 AML patients revealed that NUP98 -r samples clustered together, strongly suggesting a distinct subtype. Compared with that in the non -NUP98 -r fusion and no fusion groups, CMAHP expression was significantly upregulated in the NUP98 -r samples ( P  < 0.001 and P  = 0.001, respectively). Multivariate Cox regression analyses demonstrated that patients harboring NUP98 -r ( P  < 0.001) and WT1 mutations ( P  = 0.030) had worse relapse-free survival, and patients harboring NUP98 -r ( P  < 0.008) presented lower overall survival. Conclusions These investigations contribute to the understanding of the molecular characteristics, risk stratification, and prognostic evaluation of pediatric AML patients.

Background Cytokine receptor-like factor 2 (CRLF2) has been shown to play a role in the pathogenesis of acute lymphoblastic leukemia (ALL). Studies have examined the relationship between CRLF2 alterations such as over-expression or deregulation and clinical outcome in childhood ALL, but the results are conflicting. This meta-analysis aimed to explore the association between CRLF2 alterations and survival of pediatric patients with ALL. Methods Electronic databases updated to March 2014 were searched for relevant studies. A meta-analysis was made of twelve studies including 5945 patients to evaluate the prognostic significance of CRLF2 alterations on survival in childhood ALL. Hazards ratios (HRs) with 95% confidence intervals (CIs) were pooled across the studies using a fixed-effects model. Results CRLF2 over-expression in childhood ALL was associated with poor prognosis in terms of relapse-free survival (RFS; HR=1.70, 95% CI=1.28–2.24, P =0.000), event-free survival (EFS; HR=1.78, 95% CI=1.05–3.01, P =0.032), and overall survival (OS; HR=2.28, 95% CI=1.42–3.65, P =0.001). The combined data also suggested that CRLF2 deregulation in childhood ALL was correlated with poor EFS (HR=1.95, 95% CI=1.46–2.61, P =0.000), RFS (HR=2.20, 95% CI=1.53–3.18, P =0.000), and OS (HR=1.89, 95% CI=1.24–2.87, P =0.003). Subgroup analysis on multivariate HRs showed that CRLF2 deregulation independently predicted a poor prognosis for childhood ALL. Conclusions The present meta-analysis reveals that both CRLF2 over-expression and deregulation are associated with poor prognosis in pediatric patients with ALL.

Purpose We performed a prospective study to evaluate the ability of inflammatory cytokines in discriminating gram-negative from gram-positive bacteremia in septic shock. Methods During the study period, the serum inflammatory cytokine levels were measured at the onset of septic shock by flow cytometry in pediatric hematology/oncology patients with septic shock. Results One hundred episodes of septic shock were enrolled. Of 97 episodes of monomicrobial infection, 73.2 % were caused by gram-negative bacteremia and 26.8 % by gram-positive bacteremia. Interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α were closely related to the pediatric index of mortality 2 (PIM2) score and mortality. However, although the PIM2 score and mortality were comparable, the IL-6, IL-10, and TNF-α levels were significantly higher in patients with gram-negative bacteremia (GNB) than those with gram-positive bacteremia (median levels, pg/mL: IL-6: 784.1 vs. 254.4, P  = 0.001; IL-10: 192.2 vs. 19.7, P  < 0.001; TNF-α: 4.2 vs. 2.0, P  < 0.001). Of the three cytokines, IL-10 was the most useful biomarker for GNB prediction in the derivation cohort and a cutoff value of 50 pg/mL showed a sensitivity of 70.8 % and a specificity of 80.0 %, with a positive predictive value of 89.5 %. When this cutoff value was applied to the validation cohort, the sensitivity, specificity, and positive predictive value were 80.9, 75.0, and 90.5 %, respectively. Conclusions Flow cytometry-based inflammatory cytokine measurement is a helpful adjuvant approach for early and quick discrimination of gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock which might be useful for evaluating the severity of shock and the selection and/or timely withdrawal or switch of antibiotics.

Purpose Monitoring of plasma methotrexate (MTX) concentrations allows for therapeutic adjustments in treating childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) with high-dose MTX (HDMTX). We tested the hypothesis that assessment of creatinine clearance (CrCl) and/or serum Cr may be a suitable means of monitoring plasma MTX concentrations. Methods All children in the study had ALL or NHL, were in complete remission, and received HDMTX (3 or 5 g/m 2 )+leucovorin. Plasma MTX concentrations were measured at 24, 48, and 96 h. CrCl was determined at 24 and 48 h. Correlations between 24- and 48-h plasma MTX concentrations and CrCl and serum Cr concentrations were determined. CrCl and serum Cr concentrations were compared over time between children who had delayed and non-delayed MTX elimination. Results A total of 105 children were included. There were significant negative correlations between CrCl at 24 and 48 h and plasma MTX concentrations at 24 (both p  < 0.001) and 48 h (both p  < 0.001). There were significant positive correlations between serum Cr concentrations at both 24 and 48 h and plasma MTX concentrations at 24 (both p  < 0.001) and 48 h (both p  < 0.001). There were 88 (30.2 %) instances of elimination delay. Children with elimination delay had significantly lower CrCl and higher Cr concentrations at 24 and 48 h compared with children without elimination delay (all p  < 0.05). Conclusion Our findings suggest that, with further refinement, assessment of renal function may be a useful means of monitoring plasma MTX concentrations during HDMTX for ALL and NHL.