Aiko Suminoe

Oversecretion of IL‐18 in haemophagocytic lymphohistiocytosis: a novel marker of disease activity

We investigated the significance of interleukin (IL)‐18 levels in the pathophysiology of haemophagocytic lymphohistiocytosis (HLH). IL‐18 levels were significantly elevated in all nine patients with active HLH compared with those of healthy controls. Serial determination of IL‐18 levels in three cases, showed a gradual decrease compared with those of IL‐12, interferon (IFN)‐γ or soluble Fas ligand (sFasL) in the course of clinical improvement, and seemed to be elevated until complete disappearance of disease activity. IL‐18 and IFN‐γ (CC 0.711, P = 0.018), and IFN‐γ and sFasL (CC 0.849, P = 0.0049) levels were significantly correlated. On the other hand, correlation between IL‐12 and IFN‐γ, IL‐18 and sFasL, or IL‐18 and IL‐12 was not observed. IL‐18, IFN‐γ and sFasL levels significantly correlated with disease activity such as fever and alanine transaminase (ALT) levels. IL‐18 mRNA expression was enhanced in spleen, but not in peripheral blood mononuclear cells (MNC), bone marrow MNC, liver from patients of active HLH, or the tumour from a patient with lymphoma‐associated haemophagocytic syndrome (LAHS). These results suggest that IL‐18 may play important roles in the pathogenesis of HLH, particularly through induction of Th1 cells. IL‐18 measurement may be useful for the diagnosis and for the detection of smouldering disease activity.

Neutrophil-derived TNF-related apoptosis-inducing ligand (TRAIL): a novel mechanism of antitumor effect by neutrophils.

To detect the novel genes expressed uniquely in neutrophils and elucidate their function, the gene expression pattern was compared by using cDNA microarray containing 240 cytokine genes between the neutrophils and peripheral blood mononuclear cells (PBMCs) obtained from healthy human donors. Twenty-six genes, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were expressed in neutrophils at a level >10 times higher than that seen in phytohemagglutinin-stimulated PBMCs. The amounts of mRNA and protein of TRAIL were quantified by real-time reverse transcription-PCR and ELISA, respectively. TRAIL was expressed in resting neutrophils at the mRNA and protein levels, and its expression was enhanced after stimulation with IFN-γ. Neutrophils expressed TRAIL on the cell surface and released it into the culture media. The cytotoxicity of neutrophil-derived TRAIL against Jurkat cells was determined by flow cytometry using FITC-conjugated annexin V. When Jurkat cells were cultured with neutrophils in the presence of IFN-γ, the number of Jurkat cells undergoing apoptosis increased, and such increase depended on the effector:target ratio. This cytotoxicity was suppressed partially by adding anti-TRAIL antibody to the media. Neutrophils may exert their own antitumor effect by TRAIL. A microarray analysis was found to be a useful tool for detecting novel genes that are suggested to play unknown roles in the neutrophil function.

Long-term use of peripherally inserted central venous catheters for cancer chemotherapy in children

BackgroundPeripherally inserted central venous catheters (PICCs) have been increasingly used in pediatric patients. However, little is known about the incidence and risk of complications when using this device in children with cancer. The purposes of this study are to assess the feasibility of PICCs and to determine the risk factors for PICC-related complications in pediatric patients with various types of malignancies.Patients and methodsWe attempted to place PICCs in 53 patients with a median age of 5 years ranging from 2 months to 20 years. PICCs were used to administer fluid, parenteral nutrition, anticancer agents, antibiotics, and blood products and also for the through-line blood sampling. The duration of catheterization and the incidence of PICC-related complications requiring removal were retrospectively evaluated in association with the diagnosis, sex, age and body weight of the patients, size, insertion site and tip location of the catheters, type of treatment, and duration of leukopenia.ResultsPICCs were successfully placed in 109 of 112 attempts (97.3%) in 53 patients, and they were followed for a total of 11,797 catheter days (median placement, 87 days; range, 3 to 512 days). Fifty five PICCs (50.5%) were removed as a result of PICC-related complications with a rate of 4.66 per 1,000 catheter days. The most common reasons for catheter removal were occlusion (n=18), breakage/leakage (15), and infection (10). More than 70% of such complications occurred more than 30 days after placement. The catheter tip location in the superior vena cava or the right atrium might decrease the risk of complications. Other parameters did not influence the incidence of complications.ConclusionsPICCs were found to provide a reliable access for prolonged intravenous administration and blood sampling in children intensively treated for hematologic and solid malignancies, thus leading to a reduction of physical pain and psychological stress in such patients. However, the long-term placement of PICCs may also be related to an increased risk of complications.

Polymorphisms of transforming growth factor-β1 and transforming growth factor-β1 type II receptor genes are associated with acute graft-versus-host disease in children with HLA-matched sibling bone marrow transplantation

The aim of this study was to determine whether the gene polymorphisms of Th1/Th2 and immunoregulatory cytokines were associated with aGVHD in Japanese children receiving allogeneic bone marrow transplantation (allo BMT). We investigated polymorphisms of genes encoding interleukin (IL)-4, IL-4 receptor (IL-4 R), IL-10, transforming growth factor (TGF)-β1, TGF-β1 type II receptor (TGF-β1 RII), interferon (IFN)-γ, IFN-γ type 2 receptor (IFN-γ R2), and IFN regulatory factor (IRF)-1. Sixty-seven patients were treated with alloBMT from HLA-identical siblings, and aGVHD was observed in 38. TGF-β1 codon 10 leucine (Leu) /proline (Pro) polymorphism in donors was associated with the development of aGVHD. Patients having donors with the Pro allele had aGVHD more frequently than those without Pro allele (30/45 vs 8/20, odds ratio = 3.00; P = 0.04). TGF-β1 RII 1167 C/T polymorphism in recipients was also associated with the development of aGVHD. The incidence was significantly higher in recipients with T allele than in those without T allele (21/27 vs 16/35, odds ratio = 4.16; P = 0.01). In conclusion, genetic backgrounds of TGF-β1 and TGF-β1 RII may be involved in the development of aGVHD in HLA-matched sibling BMT in Japanese children.

Immune response after influenza vaccination in children with cancer.

To assess the immune response to inactivated trivalent split influenza vaccine in children with cancer.

Differential mRNA expression of glucocorticoid receptor α and β is associated with glucocorticoid sensitivity of acute lymphoblastic leukemia in children

Sensitivity of leukemic blasts to glucocorticoid is one of the important prognostic factors for pediatric acute lymphoblastic leukemia (ALL). Alternative splicing of the glucocorticoid receptor (GR) gene results in several isoforms. We examined an association of the expression pattern of GR isoforms in leukemic blasts with their sensitivity to glucocorticoid in childhood ALL.

High expression of platelet-derived growth factor and transforming growth factor-β1 in blast cells from patients with Down Syndrome suffering from transient myeloproliferative disorder and organ fibrosis

To determine whether platelet‐derived growth factor (PDGF) and transforming growth factor‐β1 (TGF‐β1) are involved in organ fibrosis in patients with transient myeloproliferative disorder (TMD) in Down syndrome, the expression of PDGF and TGF‐β1 mRNA in blast cells of TMD was investigated using real‐time quantitative reverse transcription polymerase chain reaction. Blasts and liver tissue from TMD patients with hepatic fibrosis showed a significantly elevated expression of PDGF gene. The expression of TGF‐β1 gene was higher in TMD and acute megakaryoblastic leukaemia than in the control group. These results suggest that PDGF in combination with TGF‐β1 plays a role in organ fibrosis of TMD.

Cord blood transplantation from HLA‐mismatched unrelated donors as a treatment for children with haematological malignancies

Factors influencing the outcome for 39 children with haematological malignancy who were subjected to a cord blood transplantation (CBT) from genotypically HLA‐mismatched unrelated donors were analysed. This retrospective study included 21 children with acute lymphoblastic leukaemia, 15 with acute myelogenous leukaemia and one each with chronic myelogenous leukaemia, refractory anaemia with myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukaemia (JMML). Those subjected to CBT during the first or second complete remission (CR) and MDS without blasts were assigned to the standard‐risk (SR) group (n = 16). Patients in third or subsequent remission, relapse or partial remission with refractory leukaemia at the time of CBT were considered to be in advanced phase, and placed in the high‐risk (HR) group (n = 11). JMML and the second CR after a relapse (n = 8), or bone marrow failure after a rejection (n = 3), following haematopoietic stem cell transplantation (HSCT) in the first CR were included in the high‐risk group. Kaplan–Meier estimates for neutrophil and platelet recovery were 83·7 ± 12·2 at d 60 and 55·4 ± 16·6% at d 100 respectively. The incidence of grades II–VI acute graft‐versus‐host disease was 58·5 ± 16·8%. The Kaplan–Meier estimate for 3‐year event‐free survival (EFS) was 49·2 ± 16·6. From multivariate analysis, the most important factor influencing EFS was disease status at CBT: SR patients had a 3‐year EFS of 75·0 ± 21·6%, compared with 29·6 ± 20·6% for those with HR disease (P = 0·013, RR 4·746, 95% CI 1·382–16·298). These data confirm that HLA‐mismatched, unrelated CBT is a feasible procedure to cure a significant proportion of children with leukaemia, especially if conducted in a favourable phase of the disease.

Immunotherapy with autologous dendritic cells and tumor antigens for children with refractory malignant solid tumors.

Abstract:  Immature DCs were generated from the peripheral blood monocytes from five children with refractory solid tumors (Ewing sarcoma, synovial sarcoma, neuroblastoma) using GM‐CSF and IL‐4. These DCs were then pulsed with tumor‐specific synthetic peptides or tumor lysates in the presence of the immunogenic protein KLH for 12 h. Pulsed DCs were administered subcutaneously every one or two weeks in an outpatient setting without any toxicity. In one patient with Ewing sarcoma, the residual tumor disappeared following autologous PBSCT and DC therapy, and a complete remission has been maintained for 77 months. In two patients with synovial sarcoma or with neuroblastoma, growth of the tumors was temporally suppressed for one and 10 months, respectively, followed by their exacerbation. A DTH response was detected against KLH in all five patients and against the tumor lysate in one patient. In the patients with a possible DC‐mediated anti‐tumor effect, the number of CD8+ HLA‐DR+ lymphocytes and INF‐γ+CD8+ lymphocytes increased and an elevation of the NK cell cytotoxic activity was observed during and/or after DC therapy. DC‐based immunotherapy may therefore be a feasible, well‐tolerated and promising approach in the treatment of children with refractory malignant tumors.

Neurotrophin-3 Levels in Cerebrospinal Fluid From Children With Bacterial Meningitis, Viral Meningitis, or Encephalitis

Neurotrophin-3 levels were measured in the cerebrospinal fluid of 35 patients with bacterial meningitis, viral meningitis, or encephalitis by two-site enzyme immunoassay. Elevated cerebrospinal fluid levels of neurotrophin-3 were demonstrated in 8 of 18 patients with bacterial meningitis. Follow-up examination of the eight patients at the convalescent stage showed diminished cerebrospinal fluid levels of neurotrophin-3. In contrast, none of the 17 patients with viral meningitis or encephalitis showed an elevation of neurotrophin-3 levels in cerebrospinal fluid. No relationships were observed between neurotrophin-3 levels and cerebrospinal fluid cell numbers, cerebrospinal fluid protein levels, serum C-reactive protein concentrations, or outcome in bacterial meningitis. Since neurotrophin-3 is involved in the survival of neurons and the modulation of the immune system, neurotrophin-3 could play a neuroprotective or immunomodulatory role in bacterial meningitis. (J Child Neurol 2000;15:19-21).