ABSTRACT
Children with trisomy 18 tend to develop hepatoblastoma. Since the introduction of appropriate management for organ malfunction, individuals with trisomy 18 have come to have a longer life expectancy. However, the predisposition to hepatoblastoma becomes a significant issue for the quality of a case. Here, we present a rare multifocal hepatoblastoma involving predominantly Couinaud segments 5 and 7 in a 10-month-old boy with trisomy 18. Though the first-line cisplatin monotherapy resulted in unsatisfactory tumor shrinkage, the second-line neoadjuvant chemotherapy administrating irinotecan and vincristine gave rise to significant tumor reduction in volume, leading to the completion of partial resection of the liver without the microscopic residual disease. The patient has been free from recurrence for 44 months. Because anatomical right hepatectomy can cause circulatory instability, including acute onset of pulmonary hypertension in trisomy 18 patients, physicians should balance treatment benefits and potential adverse effects. Our successful experience utilizing a combination of efficacious and less cardiotoxic neoadjuvant chemotherapy followed by the partial hepatectomy encourages physicians to treat a patient with trisomy 18 and tackle hepatoblastoma with a genetic background.
Subject(s)
Hepatoblastoma , Liver Neoplasms , Male , Child , Humans , Infant , Hepatoblastoma/therapy , Hepatoblastoma/drug therapy , Liver Neoplasms/pathology , Trisomy 18 Syndrome/therapy , Trisomy 18 Syndrome/drug therapy , Hepatectomy/adverse effects , Trisomy , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
INTRODUCTION: MEFV is the gene responsible for familial Mediterranean fever. It encodes pyrin, which controls inflammation. Besides, previous studies have reported that some germline MEFV variants were associated with tumour susceptibility. MATERIALS AND METHODS: The loci of 12 germline MEFV variants were genotyped in 153 Japanese children with cancer, and the frequencies of these variants among the patient groups were compared with those in the general Japanese population. Additionally, the relationship between these variants and clinical data, including relapse and death, was investigated. RESULTS: Minor allele frequencies did not differ between patients and the general population, or between sex, age at diagnosis, and diagnosis among patients. P369S/R408Q associated with significantly lower relapse-free survival in all patient analyses and in patients with solid tumours. Additionally, although the results were not significant, E148Q/L110P was likely to associate with worse relapse-free survival in patients with solid tumours. DISCUSSION/CONCLUSION: Despite several limitations, this study provided the novel insight that the germline MEFV variants are associated with the clinical outcome of paediatric cancer.
Subject(s)
Cytoskeletal Proteins , Neoplasms , Child , Cytoskeletal Proteins/genetics , Genetic Predisposition to Disease , Germ Cells , Humans , Japan/epidemiology , Mutation , Neoplasms/genetics , Prognosis , Pyrin/geneticsABSTRACT
BACKGROUND: Clonal evolution of malignancy is a complex process related to intratumoral heterogeneity, as recent studies have also demonstrated in rhabdomyosarcoma. The purpose of this study is to present a distinct clonal feature of a case with anaplastic embryonal type rhabdomyosarcoma (ERMS) using molecular analysis. METHODS: A five-year-old girl developed a metastatic pelvic tumor. We cultured neoplastic cells isolated from the biopsy sample. Next, to characterize the current case, we analyzed the biopsy sample, autopsy sample, and established cell line using combined modalities, including histopathological, cytogenetic, and molecular assay. We also undertook the backtrack mutation-specific polymerase chain reaction to reveal clonal composition. RESULTS: The histology of the biopsy sample was consistent with ERMS with focal anaplasia. We established a permanently growing cell line, ICH-ERMS-1, from the biopsy sample. On molecular analysis, the biopsied tissue revealed a missense mutation at codon 245 of TP53. In contrast, the autopsy tumor tissue and the cell line established from the biopsied tissue showed a missense mutation at codon 248. A backtrack study using mutation-specific polymerase chain reaction detected a TP53 codon 248 mutation in the original biopsy sample. All the specimens examined had a missense mutation at PTPN11 codon 69. CONCLUSIONS: This study highlights intratumoral heterogeneity and distinct clonal change related to the functional context in our anaplastic ERMS case, supporting the concept of intratumoral heterogeneity and clonal evolution. It requires further case collection to reveal whether p14ARF-p53-MDM2 tumor suppressor pathway alteration, considered a late event in ERMS tumorigenesis, is responsible for anaplasia in ERMS.
Subject(s)
Rhabdomyosarcoma, Alveolar , Rhabdomyosarcoma, Embryonal , Rhabdomyosarcoma , Child, Preschool , Clonal Evolution , Female , Humans , Mutation , Polymerase Chain Reaction , Rhabdomyosarcoma, Embryonal/diagnosis , Rhabdomyosarcoma, Embryonal/geneticsABSTRACT
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 RateABSTRACT
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, GeneticABSTRACT
We present two infants with KMT2A(MLL)-gene-R-associated BCP-ALL, who received HLA haploidentical PBSCT after RIC. The patients developed ALL at age 6 months and 3 months, respectively. Case 1 underwent PBSCT at the second CR with detectable KMT2A-AFF1(MLL-AF4) fusion gene transcript at 11 months of age, and Case 2 at the first CR without KMT2A-MLLT1(MLL-ENL) fusion gene transcript at 8 months of age. Both patients received G-CSF-mobilized unmanipulated peripheral blood mononuclear cells from their HLA haploidentical mothers after administration of FLU, MEL, and ATG. Tacrolimus, methotrexate, and mPSL were administered as prophylaxis against GVHD. Engraftment was rapidly obtained with complete chimerism in both patients. Acute adverse events included acute GVHD in Case 1 and bacterial sepsis in Case 2. At last clinical check at age 5 years and 4 years, respectively, both patients were recurrence-free and attained normal growth and development. We conclude that PBSCT from an HLA haploidentical mother with non-TBI and non-BU regimen seems feasible and efficacious, offering favorable life quality for infants.
Subject(s)
Peripheral Blood Stem Cell Transplantation/methods , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Transplantation Conditioning/methods , Transplantation, Haploidentical , Biomarkers, Tumor/genetics , Female , Gene Rearrangement , Histone-Lysine N-Methyltransferase/genetics , Humans , Infant , Myeloid-Lymphoid Leukemia Protein/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/geneticsSubject(s)
Abnormalities, Multiple , Anemia, Pernicious , Hematologic Diseases , Vestibular Diseases , Abnormalities, Multiple/diagnosis , Anemia, Pernicious/complications , Anemia, Pernicious/diagnosis , Face/abnormalities , Hematologic Diseases/complications , Hematologic Diseases/diagnosis , Humans , Mutation , Phenotype , Vestibular Diseases/complications , Vestibular Diseases/diagnosisABSTRACT
The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Genotype , Mercaptopurine/administration & dosage , Pharmacogenetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Pyrophosphatases/genetics , Adolescent , Age Factors , Alleles , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Female , Gene Frequency , Genetic Association Studies , Humans , Infant , Male , Methyltransferases/genetics , Polymorphism, GeneticABSTRACT
BACKGROUND: Management of the adverse effects of chemotherapy is essential to improve outcome of children with leukemia. Some genetic polymorphisms can predict treatment-related toxicity, and be used individually in dose modification of 6-mercaptopurine (6-MP) and methotrexate (MTX) in maintenance therapy for childhood acute lymphoblastic leukemia (ALL). We investigated associations between clinical course and candidate gene polymorphisms less evaluated in Japanese patients. METHODS: Fifty-three children who received maintenance chemotherapy were enrolled in this study. The scheduled dose of oral 6-MP was 40 mg/m(2) daily and that of oral MTX was 25 mg/m(2) weekly. The doses were adjusted according to white blood cell count (target range, 2.5-3.5 × 10(9) /L) and aspartate aminotransferase and alanine aminotransferase level (< 750 IU/L). Eight polymorphisms in six candidate genes, TPMT, ITPA, MRP4, MTHFR, RFC1, and SLCO1B1, were genotyped using the Taqman PCR method. Clinical course was reviewed retrospectively from medical records. RESULTS: The average dose of 6-MP was lower in the patients with at least one variant allele at SLCO1B1 c.521 T > C than in the patients with wild homozygous genotype. The other analyzed polymorphisms were not associated with toxicity, 6-MP, or MTX dose. CONCLUSIONS: Polymorphism of SLCO1B1 c.521 T > C could be a strong predictor of 6-MP dose reduction in maintenance chemotherapy in childhood ALL.
Subject(s)
Antineoplastic Agents/administration & dosage , DNA, Neoplasm/genetics , Leukemia/drug therapy , Liver-Specific Organic Anion Transporter 1/genetics , Maintenance Chemotherapy/methods , Polymorphism, Genetic , Adolescent , Alleles , Child , Child, Preschool , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Genotype , Humans , Infant , Leukemia/genetics , Leukemia/metabolism , Liver-Specific Organic Anion Transporter 1/metabolism , Male , Retrospective Studies , Time FactorsSubject(s)
Histone-Lysine N-Methyltransferase , Lymphoma, Large B-Cell, Diffuse , Myeloid-Lymphoid Leukemia Protein , Nuclear Proteins , Oncogene Proteins, Fusion , Skin Neoplasms , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Humans , Infant , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Myeloid-Lymphoid Leukemia Protein/genetics , Myeloid-Lymphoid Leukemia Protein/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathologyABSTRACT
The biological heterogeneity of neuroblastoma underscores the need for an in vitro model of each molecularly defined subgroup to investigate tumorigenesis and develop targeted therapies. We have established a permanently growing cell line from a 12-year-old girl who developed a late recurrent stage MS, MDM2-amplified neuroblastoma arising in the liver and performed histological, molecular, cytogenetic, exome, and telomere analyses of the recurrent tumor and the cell line. On histology, the recurrent tumor was immunoreactive for TP53, CDKN1A, and MDM2. A molecular cytogenetic study of the recurrent tumor revealed the amplification of MDM2 but no amplification of MYCN. The established cell line, NBM-SHIM, showed amplification of both MDM2 and MYCN on double-minute chromosomes. A copy number evaluation based on exome data confirmed the finding for MYCN and MDM2 and further identified high ploidy on CDK4 and GLI2 loci in the recurrent tumor and the cell line. The telomere maintenance mechanism on the cell line is unusual in terms of the low expression of TERT despite MYCN amplification and alternative lengthening of telomeres suggested by positive value for C-circle assay and telomere contents quantitative assay. The cell line is unique because it was established from a MYCN-nonamplified, MDM2-amplified, late-relapsed stage MS neuroblastoma, and MYCN amplification was acquired during cell culture. Therefore, the cell line is a valuable tool for investigating neuroblastoma tumorigenesis and new molecular targeted therapies for disrupted ARF-TP53-MDM2 pathway and amplification of MDM2 and CDK4.
Subject(s)
Gene Amplification , N-Myc Proto-Oncogene Protein , Neuroblastoma , Proto-Oncogene Proteins c-mdm2 , Humans , Neuroblastoma/genetics , Neuroblastoma/pathology , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , N-Myc Proto-Oncogene Protein/genetics , Female , Child , Gene Amplification/genetics , Cell Line, Tumor , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Telomere/genetics , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 4/metabolism , Telomere Homeostasis/geneticsABSTRACT
We conducted a pilot study to evaluate the feasibility of reduced-intensity cord blood transplantation (RI-CBT) using a non-total body irradiation (TBI) regimen in adult patients with advanced hematologic malignancies. Seventeen patients with a median age of 58 years (range, 38-74) underwent RI-CBT at Tsukuba Memorial Hospital between April 2004 and November 2005. Preparative regimens were fludarabine 30 mg/m(2) for 6 days, and busulfan 4 mg/kg for 2 days. Tacrolimus was used for prophylaxis of graft-vs-host disease (GVHD). Median numbers of infused total nucleated were 2.6 x 10(7)/kg (range, 2.0-3.3). HLA disparity was found in 2/6 antigens (n=16) and 1/6 antigens (n=1). Underlying diseases progressed despite preparative regimens in four patients. Of the remaining 13 patients, nine patients achieved engraftment at a median of day 18 (range, 17-28). Six of the nine patients with engraftment achieved complete donor-type chimerism by day 100. Six patients were alive in remission at median follow-up of 13.1 months (range, 1.0-19.0). This study demonstrated the feasibility of RI-CBT using a non-TBI regimen in adults. When disease progression is controlled by the preparative regimen, RI-CBT carries a clinically significant graft-vs-tumor effect. Further studies are required to identify patients who benefit from this regimen.
Subject(s)
Busulfan/administration & dosage , Cord Blood Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Vidarabine/analogs & derivatives , Adult , Aged , Drug Therapy, Combination , Feasibility Studies , Female , Humans , Male , Middle Aged , Myeloablative Agonists/administration & dosage , Pilot Projects , Transplantation, Homologous , Treatment Outcome , Vidarabine/administration & dosage , Whole-Body IrradiationABSTRACT
We performed cytogenetic and molecular cytogenetic analyses of a primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, a rare type of primary cutaneous T-cell lymphoma. G-banded analysis at initial diagnosis and recurrence revealed complex karyotype and clonal evolution reflecting genomic instability that parallels the aggressive clinical course observed. Spectral karyotyping revealed numerous structural abnormalities. SNP array-based analysis of an initial diagnostic sample revealed numerous gains and losses of chromosomal material, including loss of short arm of the chromosome 17, to which TP53 is mapped. The molecular cytogenetics and array data of this case suggest genomic instability, particularly chromosomal instability and haploinsufficiency for TP53, the latter possibly giving rise to alteration of p14ARF-Mdm2-p53 tumor suppressor protein pathway, likely to be associated with unfavorable clinical course.
Subject(s)
CD8 Antigens , Cytogenetic Analysis , Lymphoma, T-Cell, Cutaneous/genetics , Child , Chromosomes, Human, Pair 17/genetics , Female , Genomic Instability , Humans , Polymorphism, Single Nucleotide , Spectral Karyotyping , Tumor Suppressor Protein p53/geneticsABSTRACT
Backgrounds. Outcome of childhood malignancy has been improved mostly due to the advances in diagnostic techniques and treatment strategies. While methotrexate (MTX) related polymorphisms have been under investigation in childhood malignancies, many controversial results have been offered. Objectives. To evaluate associations of polymorphisms related MTX metabolisms and clinical course in childhood lymphoid malignancies. Method. Eighty-two acute lymphoblastic leukemia and 21 non-Hodgkin's lymphoma children were enrolled in this study. Four single nucleotide polymorphisms in 2 genes (MTHFR (rs1801133/c.677C>T/p.Ala222Val and rs1801131/c.1298A>C/p.Glu429Ala) and SLCO1B1 (rs4149056/c.521T>C/p.V174A and rs11045879/c.1865+4846T>C)) were genotyped by Taqman PCR method or direct sequencing. Clinical courses were reviewed retrospectively. Results. No patient who had the AC/CC genotype of rs1801131 (MTHFR) had relapsed or died, in which distribution was statistically different among the AA genotype of rs1801131 (P = 0.004). Polymorphisms of SLCO1B1 (rs11045879 and rs4149056) were not correlated with MTX concentrations, adverse events, or disease outcome. Conclusions. Polymorphisms of MTHFR (rs1801131) could be the plausive candidate for prognostic predictor in childhood lymphoid malignancies.
ABSTRACT
Juvenile myelomonocytic leukemia is a rare malignancy that occurs in pediatric patients. Previous reports, have described leukemic cells may infiltrate many organs, such as the lungs, skin, liver, spleen, and intestines, but not the central nervous system, although central nervous system infiltration remains a point of concern in every patient with acute leukemia. Here, we present one case of a boy with juvenile myelomonocytic leukemia who developed multiple lesions in the brain while undergoing chemotherapy with 6-mercaptopurine and cytarabine. We diagnosed the central nervous system involvement by magnetic resonance imaging, cerebrospinal fluid cytology, and the patient's clinical course. He was treated with a high dose of cytarabine and intrathecal chemotherapy, then with unrelated cord blood stem cell transplantation. He has been in a first complete remission for more than 18 months after cord blood stem cell transplantation without any neurological sequelae. In conclusion, we encountered a boy with juvenile myelomonocytic leukemia who developed central nervous system lesions under standard chemotherapy. We subsequently switched treatment to central nervous system-oriented chemotherapy, which resulted in a good clinical condition and successful cord blood stem cell transplantation.
Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Brain/drug effects , Brain/pathology , Cytarabine/adverse effects , Leukemia, Myelomonocytic, Juvenile/drug therapy , Mercaptopurine/adverse effects , Humans , Infant , Leukemia, Myelomonocytic, Juvenile/pathology , Leukemia, Myelomonocytic, Juvenile/surgery , Male , Stem Cell TransplantationABSTRACT
We report two patients with chronic granulomatous disease (CGD). The first patient presented with granulomatous colitis and pulmonary aspergillosis, and the second patient with liver abscess and restrictive pulmonary disorder. Both patients underwent allogeneic hematopoietic stem cell transplantation, the first from an HLA-matched sibling donor, and the second from an HLA-matched unrelated donor, after preconditioning with fludarabine, anti-thymocyte globulin, cyclophosphamide, and total-body irradiation of 3 Gy. The engraftment was prompt and the regimen-related toxicity was mild. The patients are able to return to their daily lives with full donor chimerism, although the second patient underwent a living-related-donor orthotopic liver transplantation from his mother for chronic liver graft-versus-host disease. The conditioning regimen we used was feasible and applicable to patients with CGD accompanied by inflammatory disease and severe infection.
Subject(s)
Granulomatous Disease, Chronic/complications , Granulomatous Disease, Chronic/therapy , Hematopoietic Stem Cell Transplantation , Child , Crohn Disease/etiology , Humans , Liver Abscess/etiology , Lung Diseases, Obstructive/etiology , Male , Pulmonary Aspergillosis/etiology , Severity of Illness Index , Transplantation Conditioning , Transplantation, Homologous , Treatment OutcomeABSTRACT
We present a cytogenetically normal neonate who developed transient abnormal myelopoiesis. The blasts showed trisomy 21. In contrast, fibroblasts, and PHA-stimulated peripheral blood demonstrated normal diploid line on extensive karyotyping. Direct sequencing of the DNA derived from the peripheral blood at overt disease revealed splice site mutation in the boundary of GATA1 exon 2. The patient received three courses of chemotherapy leading to complete remission. During the complete remission, there was neither mutation of GATA1 exon 2 nor trisomy 21, confirming somatic nature of both abnormalities. The patient is now free from the disease 12 months after remission. This case emphasizes the significance of trisomy 21 as the cause of transient abnormal myelopoiesis in Down syndrome.
Subject(s)
Down Syndrome/drug therapy , GATA1 Transcription Factor/genetics , Myelopoiesis/drug effects , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/genetics , Antineoplastic Agents/therapeutic use , Cytarabine/therapeutic use , Cytogenetic Analysis , Down Syndrome/complications , Down Syndrome/genetics , Etoposide/therapeutic use , Exons , Humans , Infant, Newborn , Karyotyping , Mutation , Myeloproliferative Disorders/complicationsABSTRACT
A 46-year-old woman with systemic lupus erythematosus was hospitalized for purpura, hematochezia and hematuria. One week after admission, she developed grand mal seizures and coma and was diagnosed with thrombotic thrombocytopenic purpura (TTP) when fragmented red cells were found on the peripheral blood smear. Laboratory findings showed severe ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) deficiency and anti-ADAMTS13 antibodies, which in recent reports have indicated a poor prognosis. She was refractory to methylprednisolone pulse therapy and plasma exchange, but administration of cyclosporine induced remission without adverse effects. We propose that cyclosporine may be an effective treatment for cases of refractory TTP.
Subject(s)
ADAM Proteins/immunology , Antibody Formation/immunology , Cyclosporine/therapeutic use , Lupus Erythematosus, Systemic/diagnosis , Methylprednisolone/therapeutic use , Purpura, Thrombotic Thrombocytopenic/drug therapy , Blood Chemical Analysis , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/drug therapy , Middle Aged , Purpura, Thrombotic Thrombocytopenic/complications , Purpura, Thrombotic Thrombocytopenic/diagnosis , Recurrence , Risk Assessment , Severity of Illness Index , Treatment OutcomeABSTRACT
Human plasma contains at least three forms of adiponectin: a trimer, a hexamer, and a high-molecular-weight (HMW) multimer. We purified HMW adiponectin from human plasma using its affinity to gelatin and obtained monoclonal antibodies against it. On Western blot analysis, the reactivity of these monoclonal antibodies was shown to be restricted to a non-heat-denatured form of adiponectin molecules. On heating, the collagen-like domain of adiponectin molecules became denatured, and thus the trimer form could not be maintained. From these, monoclonal antibodies against HMW adiponectin were suggested to react with the intact trimer of adiponectin. With these monoclonal antibodies, we developed a sandwich ELISA system for quantifying adiponectin in human serum. Its specificity was verified by analysis of serum fractions separated by gel-filtration chromatography, and our ELISA system was found to be HMW adiponectin-specific. With this novel ELISA, the HMW adiponectin concentrations were 8.4 +/- 5.5 microg/ml (mean +/- SD) in healthy women and 6.2 +/- 3.6 microg/ml in healthy men. Also, serum with a lower HMW adiponectin concentration was shown to have a lower HMW ratio (i.e., HMW adiponectin/total adiponectin).