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1.
J Pediatr Hematol Oncol ; 41(7): 571-573, 2019 10.
Article in English | MEDLINE | ID: mdl-30124546

ABSTRACT

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive type of extranodal non-Hodgkin lymphoma that carries an unsatisfactory prognosis. Treating refractory PCNSL is challenging because of resistance to conventional cytotoxic and intrathecal chemotherapies. Therefore, novel therapeutic approaches are needed. Here, we report a 12-year-old boy with CD20-positive PCNSL, which was refractory to combination chemotherapy and intravenous rituximab. However, the patient achieved complete remission after repeated intraventricular rituximab administration. The results of this case indicate that intraventricular rituximab is an effective option to treat refractory PCNSL in children.


Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Brain Neoplasms/drug therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Rituximab/administration & dosage , Child , Humans , Infusions, Intraventricular , Male , Neoplasm Recurrence, Local/drug therapy
2.
Haematologica ; 104(1): 128-137, 2019 01.
Article in English | MEDLINE | ID: mdl-30171027

ABSTRACT

Fusion genes involving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remain unknown. We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring MEF2D fusions, including MEF2D-BCL9 (n=10), MEF2D-HNRNPUL1 (n=6), and one novel MEF2D-HNRNPH1 fusion. The incidence of MEF2D fusions overall was 2.4% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial. They frequently showed a cytoplasmic µ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen. Besides up- and down-regulation of HDAC9 and MEF2C, elevated GATA3 expression was also a characteristic feature of MEF2D fusion-positive patients. Mutations of PHF6, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients. MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk. Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as salvage therapy. Interestingly, relapse was frequently associated with the presence of CDKN2A/CDKN2B gene deletions. Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features.


Subject(s)
Heterogeneous-Nuclear Ribonucleoproteins , Oncogene Proteins, Fusion , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Translocation, Genetic , Adolescent , Child , Disease-Free Survival , Female , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , Humans , MEF2 Transcription Factors/genetics , MEF2 Transcription Factors/metabolism , Male , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Survival Rate
3.
Int J Hematol ; 108(1): 98-108, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29589281

ABSTRACT

The survival rate of children with acute lymphoblastic leukemia (ALL) has increased to approximately 90% after substantial progress in risk-oriented treatment strategies. Between 2005 and 2013, the Tokyo Children's Cancer Study Group (TCCSG) conducted a risk-oriented, non-randomized study, L04-16. The principal aim of this study was to assemble background characteristics and treatment outcomes, and gather genetic information on leukemic cells under central diagnosis. This report outlines the background characteristics and treatment outcomes of 1033 children with ALL treated according to a TCCSG platform. The 5-year event-free and overall survival (OS) rates for all children were 78.1 ± 1.3 and 89.6 ± 1.0%, respectively. The OS rate was significantly higher in children with B-cell precursor (BCP)-ALL (91.9 ± 1.0%, n = 916) than in those with T-ALL (71.9 ± 4.3%, n = 117, p < 0.001). In univariate analysis for BCP-ALL, children aged 1-6 years (5y-OS: 94.2 ± 1.0%), with an initial white blood cell count of < 20,000/µL (94.0 ± 1.0%), high hyperdiploidy (95.4 ± 1.6%), ETV6-RUNX1 (97.4 ± 1.2%) or TCF3-PBX1 (96.9 ± 2.1%), and "Day8NoBlasts" (96.4 ± 1.1%) had the best outcomes. Genetic investigation revealed two novel fusion genes within this cohort: ETV6-ZNF385A and ZNF362-TCF4. Our study highlighted the clinical aspects of genomic features of ALL in Japanese children. We provide fundamental information for the further molecular investigation of this disease.


Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Analysis of Variance , Asian People , B-Lymphocytes , Child , Child, Preschool , DNA-Binding Proteins/genetics , Diploidy , Female , Gene Fusion , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Proto-Oncogene Proteins c-ets/genetics , Repressor Proteins/genetics , Survival Rate , T-Lymphocytes , Tokyo , Transcription Factor 4/genetics , Treatment Outcome , ETS Translocation Variant 6 Protein
4.
Clin Case Rep ; 6(1): 125-128, 2018 01.
Article in English | MEDLINE | ID: mdl-29375851

ABSTRACT

We report two male siblings with SDS. They have the same compound heterozygous mutations. Only one of the siblings acquired cytogenetic abnormality of i(7q) 2 years after diagnosis, became transfusion-dependent, and underwent allogeneic hematopoietic stem cell transplantation. These cases indicate that i(7q) is associated with significant cytopenia in SDS patients.

5.
Pediatr Blood Cancer ; 64(9)2017 Sep.
Article in English | MEDLINE | ID: mdl-28233439

ABSTRACT

Bone marrow samples of newly diagnosed children with chronic-phase chronic myeloid leukemia (CML) were obtained at diagnosis and after imatinib initiation and stained with anti-human CD34, CD38, CD123, CD45RA, cMpl, and lineage antibodies. Flow cytometric analysis revealed that granulocyte macrophage progenitor predominance in CML progenitors at diagnosis and elevated cMpl expression in bone marrow progenitors at 3 months may predict poor outcome in children with chronic-phase CML treated with imatinib. We recommend flow cytometric analysis of bone marrow in the early phase of treatment, as it is a convenient tool that may predict treatment response and guide CML management.


Subject(s)
Antineoplastic Agents/therapeutic use , Flow Cytometry/methods , Imatinib Mesylate/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Adolescent , Bone Marrow Cells/pathology , Child , Child, Preschool , Female , Humans , Male , Neoplastic Stem Cells/pathology , Treatment Outcome
6.
Pediatr Blood Cancer ; 64(3)2017 03.
Article in English | MEDLINE | ID: mdl-27734584

ABSTRACT

BACKGROUND: Thrombomodulin alfa (TM-α) is a new class of anticoagulant drug for patients with disseminated intravascular coagulation (DIC). This study aimed to determine the pharmacokinetics of TM-α and determine the optimal dose in pediatric patients with hematological malignancy and DIC. PROCEDURE: Pediatric patients with hematological malignancy and DIC were administered TM-α at a dose of 0.06 mg/kg (380 U/kg) over 30 min every 24 hr. Blood samples were taken at steady state before the start, immediately after the end, and 24 hr after the start of the sixth administration. Population pharmacokinetic analysis was performed using sparse samples with the nonlinear mixed-effect modeling program NONMEM® , version 7.3. RESULTS: The actual and predicted plasma concentrations of TM-α based on the final population pharmacokinetic model showed a good linear correlation. Clearance and volume of distribution of TM-α were affected by body weight. The clearance of TM-α in pediatric patients with hematological malignancy and DIC was higher than that in adults as previously reported. Six of eight patients did not achieve the target trough concentration at steady state. Furthermore, the pharmacokinetic simulation based on the estimated pharmacokinetic parameters from the final model demonstrated that TM-α administered at a dose of 0.06 mg/kg every 24 hr also failed to achieve the target trough concentration at steady state in the majority of pediatric patients. CONCLUSIONS: Our study shows that further dose adjustment of TM-α is necessary considering the higher clearance per body weight in pediatric patients with hematological malignancy and DIC.


Subject(s)
Disseminated Intravascular Coagulation/drug therapy , Hematologic Neoplasms/drug therapy , Models, Statistical , Thrombomodulin/administration & dosage , Thrombomodulin/metabolism , Adolescent , Adult , Body Weight , Child , Child, Preschool , Disseminated Intravascular Coagulation/epidemiology , Female , Follow-Up Studies , Hematologic Neoplasms/epidemiology , Humans , Japan/epidemiology , Male , Prognosis , Prospective Studies , Young Adult
7.
Haematologica ; 102(1): 118-129, 2017 01.
Article in English | MEDLINE | ID: mdl-27634205

ABSTRACT

Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384 Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusion-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.


Subject(s)
Immunophenotyping , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism , Adolescent , Biomarkers, Tumor , Child , Child, Preschool , Cluster Analysis , Computational Biology/methods , Female , Gene Expression Profiling , Gene Frequency , High-Throughput Nucleotide Sequencing , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Transcriptome , Translocation, Genetic
8.
Int J Hematol ; 105(3): 377-382, 2017 Mar.
Article in English | MEDLINE | ID: mdl-27848185

ABSTRACT

Behçet disease (BD) is rarely seen in children. Its clinical manifestations are believed to differ between pediatric and adult patients. The characteristics of BD complicated by myelodysplastic syndrome (MDS) are well established for adult patients; however, because only a few cases of pediatric-onset BD complicated by MDS have been reported, its clinical characteristics remain unknown. We here retrospectively review pediatric-onset BD complicated by myeloid malignancies in Japan, having identified five such patients. All patients were female and had gastrointestinal involvements, but lacked both major features of BD, i.e., uveitis and association with HLA-B51. All patients had advanced MDS or acute myeloid leukemia and received chemotherapy followed by hematopoietic stem cell transplantation. These five cases suggest that intestinal BD and myeloid malignancies have one or more pathophysiological mechanisms in common.


Subject(s)
Behcet Syndrome/complications , Intestinal Diseases/complications , Leukemia, Myeloid, Acute/complications , Myelodysplastic Syndromes/complications , Antineoplastic Agents/therapeutic use , Behcet Syndrome/therapy , Child , Child, Preschool , Female , Hematopoietic Stem Cell Transplantation , Humans , Intestinal Diseases/therapy , Japan , Leukemia, Myeloid, Acute/therapy , Myelodysplastic Syndromes/therapy , Retrospective Studies
9.
Pediatr Blood Cancer ; 63(12): 2221-2229, 2016 12.
Article in English | MEDLINE | ID: mdl-27554591

ABSTRACT

BACKGROUND: Donor mixed chimerism (MC) is an increasing problem after hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. PROCEDURE: In this study, a self-administered questionnaire was used to retrospectively compare efficacy and safety in 49 patients undergoing second HSCT (n = 13) or donor lymphocyte infusion (DLI; n = 36) as treatment for MC. RESULTS: The response rate to DLI of patients with secondary graft failure (GF) (25.0%) was significantly lower than that of patients without secondary GF (81.3%; P = 0.041). Among patients undergoing DLI, the rates of successful response were significantly higher in patients having at least 30% donor chimerism (94.1%) than in patients having less than 30% donor chimerism (61.1%; P = 0.041). Furthermore, the rates of successful response were significantly higher in patients receiving larger first or maximum doses of DLI. Sixteen (50.0%) of 32 patients without secondary GF attained complete chimerism after DLI. The cumulative incidence of grade II-IV acute graft-versus-host disease and cytopenia was 37.6 and 26.1%, respectively. CONCLUSIONS: DLI yields promising response rates in most patients with higher donor chimerism levels, whereas second HSCT is more likely to benefit patients with lower donor chimerism levels.


Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Lymphocyte Transfusion , Transplantation Chimera , Adolescent , Adult , Child , Child, Preschool , Graft vs Host Disease/epidemiology , Humans , Infant , Infant, Newborn , Retrospective Studies , Tissue Donors , Transplantation, Homologous
10.
Turk J Haematol ; 33(4): 331-334, 2016 Dec 01.
Article in English | MEDLINE | ID: mdl-27094503

ABSTRACT

Acute megakaryoblastic leukemia (AMKL) in children without Down syndrome (DS) has an extremely poor outcome with 3-year survival of less than 40%, whereas AMKL in children with DS has an excellent survival rate. Recently, a novel recurrent translocation involving CBFA2T3 and GLIS2 was identified in about 30% of children with non-DS AMKL, and the fusion gene was reported as a strong poor prognostic factor in pediatric AMKL. We report the difficult clinical courses of pediatric patients with AMKL harboring the CBFA2T3-GLIS2 fusion gene.


Subject(s)
Leukemia, Megakaryoblastic, Acute/diagnosis , Leukemia, Megakaryoblastic, Acute/genetics , Oncogene Proteins, Fusion/genetics , Biopsy , Bone Marrow/pathology , Combined Modality Therapy , Female , Humans , Immunophenotyping , Infant , Karyotype , Leukemia, Megakaryoblastic, Acute/therapy , Male , Treatment Outcome
11.
J Clin Immunol ; 36(5): 511-6, 2016 07.
Article in English | MEDLINE | ID: mdl-27091139

ABSTRACT

PURPOSE: Autosomal dominant hyper-IgE syndrome (AD-HIES) is included among primary immunodeficiencies, and results from heterozygous mutations in the signal transduction and activator of transcription 3 (STAT3) gene. AD-HIES leads to impaired Th17 cell differentiation and IL-17 production, and is associated with increased susceptibility to bacteria and fungi. It was reported that several patients with AD-HIES were treated with hematopoietic stem cell transplantation (HSCT). The efficacy of HSCT in treating AD-HIES is variable. This study aims to evaluate the long-term clinical and immunological efficacy of HSCT for AD-HIES. METHODS: We have followed for more than 8 years two patients with AD-HIES who were treated with HSCT. Their ability of IL-17 production was evaluated by flow cytometry. RESULTS: Both patients indicated the normal ability of IL-17 production and their serum IgE levels decreased after HSCT. On the other hand, they suffered from pulmonary complications of AD-HIES such as pneumatoceles and bronchiectasis even after HSCT; however, the frequency of infections was decreased. CONCLUSIONS: Although the dysfunction of STAT3 in non-hematological tissues such as the lungs could not be corrected by HSCT, AD-HIES patients with risk factors for pulmonary complications may benefit from immunological correction by HSCT before severe pulmonary complications occur. Future studies should investigate risk factors for pulmonary complications in AD-HIES patients.


Subject(s)
Hematopoietic Stem Cell Transplantation , Interleukin-17/metabolism , Job Syndrome/therapy , Lung/immunology , Postoperative Complications , Adolescent , Adult , Bronchiectasis/etiology , Child , Female , Flow Cytometry , Follow-Up Studies , Humans , Immunoglobulin E/blood , Immunomodulation , Job Syndrome/genetics , Job Syndrome/immunology , Male , Middle Aged , STAT3 Transcription Factor/genetics , Treatment Outcome , Young Adult
12.
Pediatr Blood Cancer ; 63(3): 406-11, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26485422

ABSTRACT

BACKGROUND: The details of leukostasis in children and adolescents with chronic myeloid leukemia (CML) are unknown. This study determined the characteristics of leukostasis in children and adolescents with CML. PROCEDURE: A total of 256 cases from a retrospective study of patients with CML conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group from 1996 to 2011 were analyzed, and of these, 238 cases were evaluated in this study. RESULTS: Leukostasis was diagnosed in 23 patients (9.7%). The median leukocyte count and spleen size below the left costal margin in cases with leukostasis were significantly higher and larger when compared to those in cases without leukostasis (458.5 × 10(9) /l vs. 151.8 × 10(9) /l (P < 0.01), and 13 vs. 5 cm (P < 0.01), respectively). Leukostasis occurred with ocular symptoms in 14 cases, priapism in four cases, and dyspnea, syncope, headache, knee pain, difficulty hearing, and aseptic necrosis of the femoral head in one case each. One case had two leukostasis symptoms simultaneously. Three cases were diagnosed before imatinib became available. Five cases received special treatment, and in the remaining 15 cases, all of these symptoms resolved after treatment with imatinib. CONCLUSIONS: This retrospective study represents the largest series of children and adolescents in which leukostasis of CML has been reported. Our data provide useful insight into the characteristics of leukostasis in recent cases of children and adolescents with CML.


Subject(s)
Leukemia, Myeloid/complications , Leukostasis/etiology , Adolescent , Antineoplastic Agents , Child , Child, Preschool , Female , Humans , Imatinib Mesylate/therapeutic use , Infant , Infant, Newborn , Leukemia, Myeloid/blood , Leukemia, Myeloid/drug therapy , Male , Retrospective Studies , Young Adult
13.
Pediatr Transplant ; 20(2): 271-5, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26511512

ABSTRACT

The clinical outcome of allogeneic HSCT was retrospectively analyzed in eight patients with CHS. In total, six of these eight patients are alive. Four of five patients transplanted with MAC achieved prompt engraftment, and three of the four patients, including two patients with AP before transplant, are alive without disease. In contrast, three patients transplanted with RIC without active AP disease achieved prompt engraftment and survive long term. RIC-HSCT might be an alternative treatment for CHS similar to other types of HLH, at least for patients without active AP disease.


Subject(s)
Chediak-Higashi Syndrome/therapy , Hematopoietic Stem Cell Transplantation , Transplantation, Homologous , Adult , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Lymphohistiocytosis, Hemophagocytic/therapy , Magnetic Resonance Imaging , Male , Retrospective Studies , Transplantation Conditioning , Treatment Outcome , Young Adult
14.
Pediatr Blood Cancer ; 63(4): 701-5, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26670954

ABSTRACT

BACKGROUND: In children with acute myeloid leukemia (AML), hematopoietic stem cell transplantation (HSCT) in first remission is indicated for patients with a relatively high risk of relapse. Second HSCT is a curative option; however, few reports have been published about a second HSCT in children for AML with posttransplantation relapse. PROCEDURE: Using the database provided by the Japanese Society of Hematopoietic Cell Transplantation, we analyzed 46 children with AML who underwent a second allogeneic HSCT after achieving a second remission. RESULTS: The median duration from the first to second HSCT was 20 months, and the source of the second HSCT was related bone marrow (BM) in 22, related peripheral blood in 6, unrelated BM in 14, and unrelated cord blood in 4 patients. Twenty-five children eventually died of the following causes: progressive disease in 14 and transplant-related toxicities in 9. The 5-year overall survival rate was 41.7 ± 7.7%. An interval of less than 24 months between the first and second HSCT was a significant poor prognostic factor. CONCLUSIONS: Children with AML who experience a relapse after HSCT in first remission have a good chance of survival with a second HSCT if a second remission is achieved.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid, Acute/surgery , Neoplasm Recurrence, Local/surgery , Adolescent , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/mortality , Male , Prognosis , Retreatment , Retrospective Studies , Time Factors
16.
Int J Hematol ; 98(6): 702-7, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24241962

ABSTRACT

High-dose methotrexate therapy (HD-MTX) has been well established for the treatment of childhood acute lymphoblastic leukemia (ALL). The aims of this study were to investigate whether clinical and pharmacogenetic factors influence plasma MTX concentration and renal dysfunction in patients treated with HD-MTX. In a total of 127 courses of HD-MTX in 51 patients with childhood ALL, influence of clinical and pharmacogenetic factors on plasma MTX concentration and HD-MTX-related renal dysfunction was evaluated. Clinical factors included age, gender, duration of HD-MTX continuous-infusion and duration of pre-hydration before HD-MTX. Pharmacogenetic factors included 5 gene polymorphisms within the MTX pathway genes, namely, SLC19A1, MTHFR, ABCC2 and ABCG2. Short duration of pre-hydration before HD-MTX is the most important risk factor for prolonged high MTX concentration (p < 0.001, OR 6.40, 95 % CI 2.39-17.16) and renal dysfunction (p = 0.013, OR 3.15, 95 % CI 1.27-7.80). The T allele at MTHFR C677T was the risk factor for prolonged high MTX concentration (p = 0.009, OR 5.54, 95 % CI 1.54-19.85), but not for renal dysfunction. We found the influence of MTHFR C677T polymorphism on prolonged high MTX concentration. We reconfirmed the importance of adequate pre-hydration before HD-MTX to prevent prolonged high MTX concentration and MTX-related renal dysfunction.


Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/pharmacokinetics , Kidney/drug effects , Kidney/metabolism , Methotrexate/adverse effects , Methotrexate/pharmacokinetics , Pharmacogenetics , Adolescent , Antimetabolites, Antineoplastic/administration & dosage , Child , Child, Preschool , Female , Humans , Infant , Infusions, Intravenous , Kidney/physiopathology , Male , Methotrexate/administration & dosage , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Multidrug Resistance-Associated Protein 2 , Odds Ratio , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Retrospective Studies
17.
Cancer Chemother Pharmacol ; 72(6): 1335-42, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24121478

ABSTRACT

PURPOSE: The purpose of the study is to establish a simple and relatively inexpensive flow cytometric chemosensitivity assay (FCCA) for leukemia to distinguish leukemic blasts from normal leukocytes in clinical samples. METHODS: We first examined whether the FCCA with the mitochondrial membrane depolarization sensor, 5, 50, 6, 60-tetrachloro-1, 10, 3, 30 tetraethyl benzimidazolo carbocyanine iodide (JC-1), could detect drug-induced apoptosis as the conventional FCCA by annexin V/7-AAD detection did and whether it was applicable in the clinical samples. Second, we compared the results of the FCCA for prednisolone (PSL) with clinical PSL response in 18 acute lymphoblastic leukemia (ALL) patients to evaluate the reliability of the JC-1 FCCA. Finally, we performed the JC-1 FCCA for bortezomib (Bor) in 25 ALL or 11 acute myeloid leukemia (AML) samples as the example of the clinical application of the FCCA. RESULTS: In ALL cells, the results of the JC-1 FCCA for nine anticancer drugs were well correlated with those of the conventional FCCA using anti-annexin V antibody (P < 0.001). In the clinical samples from 18 children with ALL, the results of the JC-1 FCCA for PSL were significantly correlated with the clinical PSL response (P = 0.005). In ALL samples, the sensitivity for Bor was found to be significantly correlated with the sensitivity for PSL (P = 0.005). In AML samples, the Bor sensitivity was strongly correlated with the cytarabine sensitivity (P = 0.0003). CONCLUSIONS: This study showed the reliability of a relatively simple and the FCCA using JC-1, and the possibility for the further clinical application.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzimidazoles , Carbocyanines , Flow Cytometry/methods , Membrane Potential, Mitochondrial/drug effects , Adolescent , Annexin A5/immunology , Cell Line, Tumor , Child , Child, Preschool , Fluorescent Dyes , Humans , Infant , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Reproducibility of Results , Sensitivity and Specificity
18.
Biol Blood Marrow Transplant ; 18(4): 546-56, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22178962

ABSTRACT

Cathepsin (Cathepsin) S, L, and B proteases mediate antigen presentation on major histocompatibility complex (MHC) class II by degrading the invariant chain Ii, which blocks peptide loading. The ability of the Cathepsin S inhibitor LHVS (morpholinurea-leucine-homophenylalanine-vinylsulfone phenyl) to impede antigen presentation has led its development as a therapy for autoimmune diseases. There is substantial evidence that donor T cell recognition of host minor histocompatibility antigens (miHA) and subsequent destruction of host tissue mediates graft-versus-host disease (GVHD). We hypothesized that enzymes involved in antigen presentation may play a role in the development of GVHD. Using the C57BL/6 → BALB.B minor mismatch acute GVHD (aGVHD) model, we found that the cathepsin S activity of spleens from allogenetically transplanted mice were significantly increased 1 week after transplantation compared with syngeneic mice. Although LHVS decreased T cell priming responses against both single OVA antigen and miHA in vitro, LHVS did not reduce the severity of aGVHD. In fact, LHVS exacerbated a CD4(+)-T cell-dependent model of GVHD similar to chronic GVHD. This suggests that cytokines rather than T cells may mediate much of the damage in the aGVHD model and that therapeutics based on inhibition of antigen presentation for GVHD must be approached with caution.


Subject(s)
Antigen Presentation/drug effects , Bone Marrow Transplantation , CD4-Positive T-Lymphocytes/drug effects , Cathepsins/antagonists & inhibitors , Dipeptides/administration & dosage , Graft vs Host Disease/drug therapy , Sulfones/administration & dosage , Animals , Antigen Presentation/immunology , CD4-Positive T-Lymphocytes/immunology , Cathepsins/immunology , Enzyme Inhibitors/administration & dosage , Female , Graft vs Host Disease/immunology , Histocompatibility Antigens Class II/immunology , Injections, Intraperitoneal , Major Histocompatibility Complex/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Minor Histocompatibility Antigens/immunology , Spleen/cytology , Spleen/drug effects , Spleen/immunology , Transplantation, Homologous
19.
Anticancer Drugs ; 23(4): 417-25, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22205153

ABSTRACT

The efficacy of 5,7-dimethoxyflavone (DMF), a methylated analog of chrysin, as a therapeutic agent to treat acute lymphoblastic leukemia (ALL) was investigated. Using a panel of ALL cell lines, the IC50 (half-maximal inhibitory concentration) of DMF varied between 2.8 and 7.0 µg/ml. DMF induced G0/G1 cell cycle arrest, concomitant with a decreased expression of phosphorylated retinoblastoma-associated protein 1. DMF increased the rate of apoptosis, although it was apparent only after a long period of exposure (96 h). The accumulation of oxidative stress was not involved in the growth-inhibitory effects of DMF. As DMF reduced the intracellular levels of glutathione, the combination effects of DMF with other anticancer drugs were evaluated using the improved Isobologram and the combination index method. In the simultaneous drug combination assay, DMF antagonized the cytotoxicity of 4-hydroperoxy-cyclophosphamide, cytarabine, vincristine, and L-asparaginase in all tested ALL cells. This study demonstrated that DMF, a methylated flavone, was an effective chemotherapy agent that could inhibit cell cycle arrest and induce apoptosis in ALL cell lines. However, combination therapy with DMF and other anticancer drugs is not recommended.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Asparaginase/pharmacology , E2F1 Transcription Factor/drug effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclophosphamide/analogs & derivatives , Cyclophosphamide/pharmacology , Cytarabine/pharmacology , Drug Interactions , Drug Screening Assays, Antitumor , Flavonoids/pharmacology , Humans , Inhibitory Concentration 50 , Vincristine/pharmacology
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