The predictive utility of cytokines, procalcitonin and C-reactive protein among febrile pediatric hematology and oncology patients with severe sepsis or septic shock.

Severe sepsis and septic shock are life-threatening for pediatric hematology and oncology patient receiving chemotherapy. Th1/Th2 cytokines, C-reactive protein (CRP), and procalcitonin (PCT) are all thought to be associated with disease severity. The aim of this study was to prospectively verify the utility of Th1/Th2 cytokines and compare them with PCT and CRP in the prediction of adverse outcomes. Data on patients were collected from January 1, 2011, to December 31, 2020. Blood samples were taken for Th1/Th2 cytokine, CRP, and PCT measurements at the initial onset of infection. Severe infection (SI) was defined as severe sepsis or septic shock. Th1/Th2 cytokine levels were determined by using flow cytometric bead array technology. In total, 7,735 febrile episodes were included in this study. For SI prediction, the AUCs of IL-6, IL-10 and TNF-α were 0.814, 0.805 and 0.624, respectively, while IL-6 and IL-10 had high sensitivity and specificity. IL-6 > 220.85 pg/ml and IL-10 > 29.95 pg/ml had high odds ratio (OR) values of approximately 3.5 in the logistic regression. Within the subgroup analysis, for bloodstream infection (BSI) prediction, the AUCs of IL-10 and TNF-α were 0.757 and 0.694, respectively. For multiorgan dysfunction syndrome (MODS) prediction, the AUC of CRP was 0.606. The AUC of PCT for mortality prediction was 0.620. In conclusion, IL-6 and IL-10 provide good predictive value for the diagnosis of SI. For children with SI, IL-10 and TNF-α are associated with BSI, while CRP and PCT are associated with MODS and death, respectively.

Spectrum and clinical features of gene mutations in Chinese pediatric acute lymphoblastic leukemia.

PURPOSE: The 5-year survival rate of children with acute lymphoblastic leukemia (ALL) is 85-90%, with a 10-15% rate of treatment failure. Next-generation sequencing (NGS) identified recurrent mutated genes in ALL that might alter the diagnosis, classification, prognostic stratification, treatment, and response to ALL. Few studies on gene mutations in Chinese pediatric ALL have been identified. Thus, an in-depth understanding of the biological characteristics of these patients is essential. The present study aimed to characterize the spectrum and clinical features of recurrent driver gene mutations in a single-center cohort of Chinese pediatric ALL. METHODS: We enrolled 219 patients with pediatric ALL in our single center. Targeted sequencing based on NGS was used to detect gene mutations in patients. The correlation was analyzed between gene mutation and clinical features, including patient characteristics, cytogenetics, genetic subtypes, risk stratification and treatment outcomes using χ2-square test or Fisher's exact test for categorical variables. RESULTS: A total of 381 gene mutations were identified in 66 different genes in 152/219 patients. PIK3R1 mutation was more common in infants (P = 0.021). KRAS and FLT3 mutations were both more enriched in patients with hyperdiploidy (both P < 0.001). NRAS, PTPN11, FLT3, and KMT2D mutations were more common in patients who did not carry the fusion genes (all P < 0.050). PTEN mutation was significantly associated with high-risk ALL patients (P = 0.011), while NOTCH1 mutation was common in middle-risk ALL patients (P = 0.039). Patients with ETV6 or PHF6 mutations were less sensitive to steroid treatment (P = 0.033, P = 0.048, respectively). CONCLUSION: This study depicted the specific genomic landscape of Chinese pediatric ALL and revealed the relevance between mutational spectrum and clinical features of Chinese pediatric ALL, which highlights the need for molecular classification, risk stratification, and prognosis evaluation.

Ruxolitinib is an alternative to etoposide for patient with hemophagocytic lymphohistiocytosis complicated by acute renal injury: A case report.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by excessive production of inflammatory cytokines and multiple organs injury. Ruxolitinib, an oral selective JAK1/2 inhibitor, has recently shown efficacy and safety in the treatment of secondary HLH, which may be an alternative to intensive chemotherapy. CASE REPORT: We report a case of a 2-year-old boy who presented to our institution with recurrent fever and acute renal failure. We made the diagnosis of Epstein-Barr virus related HLH based on the HLH-2004 protocol, and gave the treatment of ruxolitinib instead of etoposide. MANAGEMENT AND OUTCOME: The patient received dexamethasone and continuous renal replacement therapy due to renal failure, but he still had fever and anuria. Given that the use of etoposide may deteriorate renal function, ruxolitinib was administered instead of etoposide. After 5 days of ruxolitinib treatment, the patient's fever was resolved and renal function also gradually recovered 14 days later. DISCUSSION: Currently, dexamethasone, etoposide and cyclosporine A are the main drugs in HLH treatment. However, cytotoxic chemotherapy can temporally deteriorate organ damage and induce serious myelosuppression, which makes clinicians hesitate to implement these regimens. Ruxolitinib has shown efficacy in treating HLH without much toxicity in clinical trials. Thus, we suggest that ruxolitinib constitutes a treatment option for secondary HLH complicated by severe renal damage which may reduce toxic effects compared with intense chemotherapy.

Minimal Residual Disease-guided Risk Restratification and Therapy Improves the Survival of Childhood Acute Lymphoblastic Leukemia: Experience From a Tertiary Children's Hospital in China.

The minimal residual disease (MRD) has been shown to be very important to evaluate the prognostic significance in childhood acute lymphoblastic leukemia (ALL), but the impact under the current treatment protocol in China has not been fully elucidated. The aim of this study was to investigate the efficacy of MRD-guided risk restratification of ALL. A total of 676 children with ALL were enrolled. In the predictive study group, 476 patients were enrolled with 5-year cumulative incidence of relapse rates of the low-risk (LR), intermediate-risk (IR), and high-risk groups being 11.0%±2.3%, 12.6%±3.3%, and 32.7%±4.9%, respectively. In the intervention study group, 19/200 patients enrolled were reclassified into risk groups according to the MRD levels. The 3-year event-free survival and overall survival were 85.2%±2.9% and 90.6%±2.1%, respectively, which were higher than those of the predictive study group (79.1%±1.9% and 84.7%±1.7%, respectively; P<0.05). The 3-year cumulative incidence of relapse in the LR and IR groups of the intervention study group were 4.2%±3.1% and 6.4%±3.1%, respectively, which were significantly lower than those in the predictive study group (7.2%±1.8% and 11.8%±3.2%, respectively; P<0.05). We conclude that the risk of relapse in the LR and IR groups can be significantly reduced after MRD-guided risk restratification.

Associations between inflammatory cytokines and organ damage in pediatric patients with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal disease characterized by overwhelming inflammation response and multiple organ damage. Most of the clinical and laboratory manifestations of HLH are thought to be related to hypercytokinemia and organ infiltration with lymphocytes and histiocytes. The aim of this study was to investigate the associations between cytokines and various manifestations of HLH. A total of 105 patients diagnosed with HLH were enrolled in this retrospective study. The information including the patients' demographic characteristics, clinical and laboratory findings at presentation and cytokine data were collected. The median age at diagnosis was 2.8years, with 74 patients (70.4%) documented Epstein-Barr virus infection. Hepatomegaly (88.6%), splenomegaly (81.9%), cytopenia (68.6%), elevated ferritin level (93.3%), hypofibrinogenemia (61.9%) and hemophagocytosis (77.3%) were found in more than half of the patients. Interleukin (IL)-6, IL-10 and interferon (IFN)-γ were found to be moderately or significantly elevated in most patients. In the correlation analysis, IFN-γ was closely related to the concentration of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, lactate dehydrase (LDH), triglyceride and fibrinogen, while IL-10 was associated with platelet count. When split the patients into two groups according to the cytokine levels, patients with high IFN-γ presented higher level of ALT, AST, bilirubin, LDH, triglyceride, and fibrinogen, while patients with high IL-10 presented much lower hemoglobin and platelet count. In conclusion, the present study put forward clinical evidence that hypercytokinemia is related to organ damage in HLH. IFN-γ may contribute to liver impairment and coagulation disease, while IL-10 is a cytokine related to cytopenias.

Methotrexate Associated Renal Impairment Is Related to Delayed Elimination of High-Dose Methotrexate.

Although Methotrexate (MTX) is an effective drug for the treatment of acute lymphoblastic leukemia (ALL), the toxicity remains a significant problem. In this prospective study, fifty-four patients with ALL were enrolled. 3 g or 5 g MTX/m(2) was administered over 24 hours. Serum MTX concentrations were determined in 24, 48, and 96 hours after MTX infusion. Serum creatinine concentrations and creatinine clearance rate (CCR) were determined before and 24 and 48 hours after MTX infusion. A total of 173 courses of MTX infusion were administered. The serum creatinine concentrations did not change much after MTX infusion while the CCR was gradually decreased. MTX clearance status was independently related to CCR decrease, with the risk of 8.07 to develop renal impairment in patients with delayed MTX elimination. Serum creatinine concentration, serum creatinine ratio, CCR, and CCR ratio at 24 hours were all related to MTX elimination delay. Patients with serum creatinine level >35.0 µmol/L, creatinine ratio >1.129, or CCR <100.0 mL/min were more likely to undergo MTX elimination delay. In conclusion, MTX could induce transient renal impairment and compromised renal function will delay MTX clearance. The serum creatinine concentration and the ratio and CCR are useful tools for evaluating MTX elimination status.

[Clinical and laboratory characteristics of chronic active Epstein-Barr virus infection in children].

OBJECTIVE: To study the clinical and laboratory characteristics of chronic active Epstein-Barr virus (EBV) infection (CAEBV) in children and to provide a basis for the diagnosis and treatment of CAEBV. METHODS: The clinical data of 13 children with CAEBV, as well as 15 cases of acute EBV infection (AEBV) as controls, were analyzed, including clinical manifestations, EBV antibodies, EBV DNA, and peripheral blood lymphocyte subsets. RESULTS: Both groups of patients had infectious mononucleosis-like symptoms such as fever, hepatomegaly, splenomegaly, and lymphadenectasis, but CAEBV patients had a longer course of disease and continuous and recurrent symptoms. Compared with the AEBV group, the CAEBV group had a significantly higher EBV DNA load in peripheral blood (P<0.05), a significantly higher VCA-IgG titer (P<0.05), and significantly lower numbers of white blood cells, lymphocytes, B cells, total T cells, CD4+ T cells, and CD8+ T cells in peripheral blood (P<0.05). Among 13 CAEBV patients followed up, 8 cases died, 2 cases showed an improvement, 2 cases had a recurrence, and 1 case was lost to follow-up after being transferred to another hospital. All the AEBV patients were cured and had no recurrence during the one-year follow-up. CONCLUSIONS: The clinical manifestations of CAEBV vary in children. It is difficult to distinguish CAEBV from AEBV early. More attention should be paid to CAEBV because of its severe complications, poor prognosis, and high mortality. Measurement of EBV DNA load, VCA-IgG titer, and lymphocyte subsets in peripheral blood may be helpful in the diagnosis and differential diagnosis of CAEBV.

The impact of neutrophil count on the results of metagenomic next-generation sequencing in immunocompromised febrile children.

Metagenomic next-generation sequencing (mNGS) has revolutionized the detection of pathogens, particularly in immunocompromised individuals such as pediatric patients undergoing intensive chemotherapy and hematopoietic stem cell transplantation. This study aims to explore the impact of neutrophil count on the diagnostic efficacy of mNGS in diagnosing infections in pediatric patients with febrile diseases. We conducted a retrospective analysis of pediatric patients with febrile diseases in the hematology/oncology department from January 2019 to September 2022. The study included 387 patients with 516 febrile episodes. Analyzing data from 516 pediatric cases, our study found that 70.7 % had febrile neutropenia (FN) and 29.3 % had febrile without neutropenia (FWN). mNGS demonstrated a high positive detection rate of 84.9 %, compared to 29.7 % for conventional microbiological tests (CMT). While the positive detection rates of mNGS were similar in both FN and FWN groups, bacterial pathogens were more frequently detected in FN patients. Furthermore, the rate of identifying a "probable" microbial etiology was lower in the FN group (46.8 %) compared to the FWN group (65.6 %, p＜0.001). When analyzing the types of organisms and specimens, the "probable" identification rates were particularly lower for viruses and fungi detected by mNGS, as well as in blood and nasopharyngeal swab samples. These findings underscore the significant influence of neutrophil counts on mNGS results in pediatric febrile patients and highlight the necessity for tailored diagnostic approaches in this population.

The effect of the plasma methotrexate concentration during high-dose methotrexate therapy in childhood acute lymphoblastic leukemia.

Two hundred and thirty-one acute lymphoblastic leukemia (ALL) children with 1376 high-dose methotrexate (HD-MTX) courses (3-5 g/m2) were enrolled to analyze the influence of the plasma MTX concentration (CMTX) in ALL. The 24-h target peak CMTX (C24h) was set at 33 µmol/l for low-risk (LR) and 65 µmol/l for intermediate/high-risk (IR/HR) groups. The median C24h was 42.0 µmol/l and 69.7 µmol/l for LR and IR/HR groups, respectively. MTX excretion delay was observed in 14.6% of courses, which was more frequent in IR/HR groups (56.9% vs. LR group 40.2%, p = .014) and T-ALL patients (82.6% vs. B-ALL 47.1%, p = .001). MTX-related toxicities were more common in courses with MTX excretion delay. However, survival between the patients who failed to reach the target C24h or not, with or without MTX excretion delay, was comparable. These findings suggest that, owing to the effectiveness of risk stratification chemotherapy, CMTX does not exert an independent influence on the prognosis of childhood ALL.

Low-dose decitabine for refractory thrombocytopenia following allogeneic hematopoietic stem cell transplantation in children: A pilot study.

Refractory thrombocytopenia is a critical complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is not sensitive to conventional treatment and often leads to lower overall survival and disease-free survival. Previous studies have showed the efficacy and safety of low-dose decitabine for adults' refractory prolonged isolated thrombocytopenia in hematologic malignancy after allo-HSCT. However, clinical data on pediatric patients or non-hematologic malignancies are lacking. Herein, we evaluated the safety and efficacy of low-dose decitabine in nine children with persistent thrombocytopenia after HSCT. Patients received decitabine at 3.5 mg/m2, 5 mg/m2 or 10 mg/m2 respectively for three to five consecutive days according to underlying diseases and hyperplastic state of bone marrow. Six patients reached sustained platelets count more than 100 × 109/L, two patients achieved platelet transfusion independence. The total response rate was 88.8 % (8/9). One patient died from severe infection because of persistent agranulocytosis longer than 3 weeks. In conclusion, the present study supports the safety and efficacy of low-dose decitabine for treatment of refractory thrombocytopenia after allogeneic HSCT in children.

Ruxolitinib Treatment of Steroid-Refractory Graft-versus-Host Disease in Children: A Case Series and Review of the Literature.

BACKGROUND: Ruxolitinib has been increasingly used in the treatment of steroid-refractory graft-versus-host disease (SR-GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. However, there are limited data on the use of ruxolitinib in children. OBJECTIVE: This study aimed to assess the efficacy and toxicity of ruxolitinib in the treatment of SR-GVHD in children. PATIENTS AND METHODS: Data of patients who suffered from SR-GVHD after allo-HSCT and received ruxolitinib treatment between June 2018 and December 2020 at our center were analyzed retrospectively. The characteristics of patients, the dosage of ruxolitinib, the response, toxicity, and the survival data were collected. RESULTS: A total of 14 pediatric patients were diagnosed with SR-GVHD after allo-HSCT and received ruxolitinib. The age of the patients ranged from 3 months to 12 years old. The dosage of ruxolitinib ranged from 2.5 mg twice daily to 7.5 mg twice daily, mainly according to patient weight. The total overall response rate (ORR) was 64.3% (9/14), with 63.6% (7/11) in aGVHD and 67% (2/3) in cGVHD. Of the 14 patients, adverse effects were observed in 9 patients (64.3%), including cytopenia, infection, and elevated alanine aminotransferase. In addition, seven reports on the treatment of SR-GVHD in children with ruxolitinib were included for systematic analysis, with the ORR ranging from 45 to 87% in aGVHD and 70-91% in cGVHD. CONCLUSION: Given its effectiveness and safety, ruxolitinib could be used to treat SR-GVHD in children after HSCT.

Minimal residual disease detection by next-generation sequencing of different immunoglobulin gene rearrangements in pediatric B-ALL.

While the prognostic role of immunoglobulin heavy chain locus (IGH) rearrangement in minimal residual disease (MRD) in pediatric B-acute lymphoblastic leukemia (B-ALL) has been reported, the contribution of light chain loci (IGK/IGL) remains elusive. This study is to evaluate the prognosis of IGH and IGK/IGL rearrangement-based MRD detected by next-generation sequencing in B-ALL at the end of induction (EOI) and end of consolidation (EOC). IGK/IGL rearrangements identify 5.5% of patients without trackable IGH clones. Concordance rates for IGH and IGK/IGL are 79.9% (cutoff 0.01%) at EOI and 81.0% (cutoff 0.0001%) at EOC, respectively. Patients with NGS-MRD < 0.01% at EOI or <0.0001% at EOC present excellent outcome, with 3-year event-free survival rates higher than 95%. IGH-MRD is prognostic at EOI/EOC, while IGK-MRD at EOI/EOC and IGL-MRD at EOI are not. At EOI, NGS identifies 26.2% of higher risk patients whose MRD < 0.01% by flow cytometry. However, analyzing IGK/IGL along with IGH fails to identify additional higher risk patients both at EOI and at EOC. In conclusion, IGH is crucial for MRD monitoring while IGK and IGL have relatively limited value.

[Effectiveness of immunosuppressive therapy for childhood aplastic anemia and its predictive factors].

OBJECTIVE: To evaluate the effectiveness of immunosuppressive therapy (IST) for childhood aplastic anemia (AA) and its predictive factors. METHODS: The medical data of 110 children with AA who received IST between February 2003 and November 2009 were retrospectively studied. Of these patients, 83 were diagnosed as severe AA (SAA) and 27 were non-SAA. The former group was treated with antithymocyte globulin (ATG) + ciclosporin (CSA) +prednisone + androgens and the latter with CSA + prednisone + androgens. RESULTS: Total response rates in the SAA and non-SAA groups were 69.9% and 70.4%, respectively. Univariate analysis showed that disease duration, CD34+ cell level in bone marrow (BM) and the expression of CD4+CD25+ regulatory T cell in BM were related to the severity of disease but not correlated with treatment response. Age, disease duration and proportions of CD3+ and CD8+ T cells in BM were predictive factors for response to IST. Multivariate analysis revealed that patients aged more than 10 years and patients with a CD8+ cell proportion in BM of over 25% had hazard ratios of 3.36 and 3.59 for treatment failure respectively. CONCLUSIONS: IST is effective in the treatment of childhood AA. Age, disease duration and the proportion of CD8+ T cell in BM are predictive factors for response to IST.

Integration of Interleukin-6 Improves the Diagnostic Precision of Metagenomic Next-Generation Sequencing for Infection in Immunocompromised Children.

The performance of metagenomic next-generation sequencing (mNGS) in identifying pathogens in immunocompromised children was not very clear. The purpose of this study is to assess the performance of mNGS in this population and to investigate whether the integration of serum cytokines and mNGS assay could improve diagnostic accuracy. We retrospectively collected the clinical data of pediatric patients who suffered febrile diseases and underwent mNGS determination simultaneously in the department of hematology/oncology between January 2019 and March 2021. Specimens were sent for conventional microbiological test (CMT), mNGS, and serum cytokine measurement in parallel. A total of 258 episodes of febrile diseases were enrolled, mNGS was positive in 224 cases, while CMT was positive in 78 cases. mNGS and CMT were both positive in 70 (27.1%) cases and were both negative in 26 (10.1%) cases. There were 154 (59.7%) cases positive by mNGS only while 8 (3.1%) were positive by CMT only. It was common that two or more pathogens were simultaneously detected by mNGS in a single specimen, with only 61 tests identified a single organism. Whether the organisms reported by mNGS were the microbiological etiology of infection was evaluated. Of the 224 cases with positive mNGS results, 135 (58.4%), 30 (13.0%), and 59 (28.6%) were considered as "probable," "possible," and "unlikely," respectively. Patients with high IL-6 (≥ 390 pg/ml) were likely to be bacterial infection. Although mNGS reported mixed pathogens, 84.6% (33/39) and 83.3% (10/12) of patients presenting high IL-6 were confirmed as bacterial infection in the training and validation cohort, respectively. In conclusion, mNGS analysis demonstrates promising diagnostic potential in rapidly identifying clinically relevant pathogens. Given the detection of many clinically irrelevant organisms, the integration of IL-6 improves the precision of mNGS results interpretation.

Clinical and Genetic Characteristics of IKZF1 Mutation in Chinese Children With B-Cell Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a malignancy associated with altered lymphoid precursor hyperplasia and accompanied with different genetic mutations. Few studies have been reported on the association between gene mutations and clinical features of IKZF1 mutation in children with B-cell ALL (B-ALL). We investigated clinical and genetic characteristics in 200 newly diagnosed pediatric B-ALL through multiplex ligation-dependent probe amplification (MLPA) and targeted next-generation sequencing (NGS) method. We found that IKZF1 mutations, including large segment deletions, small insertions or deletions (InDels) and single nucleotide variations (SNVs), were detected in 22 patients with a positive mutation rate of 11.0%. IKZF1 mutation was significantly associated with higher WBC count (19.38 × 109/L vs. 5.80 × 109/L, p = 0.002). Compared with IKZF1 wild-type cases, a higher frequency of IL7R gene mutation was discovered in IKZF1 mutant cases (9.1% vs. 0.0%, p = 0.012). Patients with IKZF1 mutation were less sensitive to glucocorticoid induction than patients without IKZF1 mutation (63.6% vs. 9.0%, p < 0.001). On the 15th day of induction, minimal residual disease (MRD) > 10-3 level were higher in IKZF1 mutant patients than wild-type patients (45.5% vs. 22.3%, p = 0.018). In conclusion, our study reveals the association between genetic mutations and clinical features in Chinese children with B-ALL, which might contribute to molecular classification, risk stratification and prognosis evaluation, and provide new ideas for targeted therapy in ALL.

Hemophagocytic lymphohistiocytosis caused by STAT1 gain-of-function mutation is not driven by interferon-γ: A case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory syndrome caused by many genetic defects. STAT1 is a DNA-binding factor that regulates gene transcription. HLH caused by STAT1 gain-of-function (GOF) mutations has rarely been reported and its clinical manifestations and mechanisms are not clearly defined. CASE SUMMARY: A 2-year-old boy presented to our hospital with recurrent fever for > 20 d. The patient had a personal history of persistent oral candidiasis and inoculation site infection during the past 2 years. Hepatosplenomegaly was noted. Complete blood cell count showed severe anemia, thrombocytopenia and neutropenia. Other laboratory tests showed liver dysfunction, hypertriglyceridemia and decreased fibrinogen. Hemophagocytosis was found in the bone marrow. Chest computed tomography showed a cavitary lesion. Tests for fungal infection were positive. Serum T helper (Th) 1/Th2 cytokine determination demonstrated moderately elevated levels of interleukin (IL)-6 and IL-10 with normal interferon (IFN)-γ concentration. Mycobacterium bovis was identified in bronchoalveolar lavage fluid by polymerase chain reaction. Genetic testing identified a heterozygous mutation of c.1154C>T causing a T385M amino acid substitution in STAT1. Despite antibacterial and antifungal therapy, the febrile disease was not controlled. The signs of HLH were relieved after HLH-94 protocol administration, except fever. Fever was not resolved until he received anti-tuberculosis therapy. Hematopoietic stem cell transplantation was refused and the patient died six months later due to severe pneumonia. CONCLUSION: Patients with STAT1 GOF mutation have broad clinical manifestations and may develop HLH. This form of HLH presents with normal IFN-γ level without cytokine storm.

High CD38 expression in childhood T-cell acute lymphoblastic leukemia is not associated with prognosis.

BACKGROUND: Prognostic factors are not well exploited in childhood T-cell acute lymphoblastic leukemia (T-ALL). OBJECTIVE: The aim of this study was to analyze the prognostic role of CD38 as well as minimal residual disease (MRD) and other biological factors in T-ALL. METHODS: Immunophenotyping of bone marrow (BM) at diagnosis and MRD levels were determined using a standard panel of antibodies by 4-colour flow cytometry. A total of 96 children with T-ALL were enrolled. RESULTS: The results showed that 97.9% of T-ALL patients were positive for CD38 with a median level of 85.3%. CD38-high group had a worse early treatment response than the CD38-low group. However, CD38 levels were not associated with prognosis, albeit CD38-high group had a worse 5-year event free survival rate (55.1% vs. 66.6%, P> 0.05) and a higher 5-year cumulative incidence of relapse (35.6% vs. 19.8%, P> 0.05). Very high MRD levels (> 10%) were related to the worse survival. Neither flow cytometry based minimal residual disease (MRD) levels nor CD38 expression levels showed significant relation to the hazard of relapse (P> 0.05). CONCLUSIONS: We conclude that T-ALL has a high level of CD38 expression which is not associated with prognosis. Very high MRD level (> 10%) is related to the worse survival, however, FCM based MRD detection does not convey a significant prognostic value.

[Efficacy of chemotherapy using 10-hydroxycamptothecin on recurrent or refractory neuroblastoma in children].

OBJECTIVE: The patients with recurrent or refractory neuroblastoma have a very poor prognosis and high mortality. 10-hydroxycamptothecin (HCPT) is a new agent extracted from comptotheca acuminate, a native plant. It has been shown to be very effective in some solid tumors such as gastric and colon cancers, lung cancers and ovary cancers. However, its efficacy in neuroblastoma has not been determined. This study aimed to investigate the therapeutic effects of HCPT in the treatment of recurrent or refractory neuroblastoma in children. METHODS: Ten children with recurrent neuroblastoma and two children with refractory neuroblastoma were treated with HCPT. Of them, 5 children with recurrent neuroblastoma were treated with HCPT alone, and the other 7 patients received combination chemotherapy of HCPT plus other agents. The HCPT alone treatment group was injected with HCPT (7.5 mg/m2 daily) for 14 consecutive days. The combination chemotherapy group was alternately treated with the modified new protocol A1 (cyclophosomide 1 200 mg/m2 on day 1, etoposide 100 mg/m2 on days 1-5, HCPT 5 mg/m2 on days 1-3, cisplatin 90 mg/m2 on day 4) and the modified protocol B (ifosfomide 1.5 g/m2 on days 1-5, HCPT 5 mg/m2 on days 1-3, carboplatin 450 mg/m2 on day 2). RESULTS: Four patients (33.3%) achieved partial remission and 8 patients (66.7%) had stable disease. The median remission duration was 3.5 months (2-5 months). HCPT treatment as a single agent resulted in mild side effects. Myelosuppression and digestive disorders were found as the main adverse events in the combined chemotherapy group. No chemotherapy related deaths were found. CONCLUSIONS: HCPT is safe and effective in the treatment of recurrent or refractory neuroblastoma. The toxicities of HCPT are tolerable. The long-term efficacy of HCPT warrants further research.

Early diagnostic and prognostic significance of a specific Th1/Th2 cytokine pattern in children with haemophagocytic syndrome.

The haemophagocytic syndrome (HPS) is a rare but frequently fatal disorder of immune regulation caused by hypercytokinemia. Using cytometric bead array technique, the serum T-helper cell type 1 (Th1) and 2 (Th2) cytokines including interferon-gamma (IFN-gamma), tumour necrosis factor (TNF), interleukin (IL)-10, IL-6, IL-4 and IL-2 were determined in 24 children with de novo HPS and 87 children as control. The median levels of serum IFN-gamma, IL-10 and IL-6 in the acute phase of HPS were 901.7, 879.0 and 63.8 pg/ml, respectively, significantly higher than those after remission, and in the healthy volunteers and patients with viral infection. IL-4 was slightly elevated while IL-2 and TNF were within normal range in acute phase. Patients with bacterial sepsis showed an extremely high level of IL-6 and moderate level of IL-10, whereas IFN-gamma was only slightly elevated. Five patients were diagnosed with HPS according to the Th1/Th2 cytokine pattern 3-13 d earlier than they fulfilled the relevant diagnostic criteria. IL-10 level >2000 pg/ml was an unfavorable prognostic factor for HPS treatment response (P = 0.033) and outcome (P = 0.009). We conclude that the significant increase of IFN-gamma and IL-10 and a slightly increased level of IL-6 is an early, specific and prognostic cytokine pattern for childhood HPS.