DNA methyltransferase inhibitor, 5-azacitidine (AC) is effective in myelodysplastic syndromes (MDS) and can induce re-expression in cancer. We analyzed the methylation of 25 tumor suppressor genes in AC-treated MDS. Hypermethylation of CDKN2B, FHIT, ESR1, and IGSF4 gene was detected in 9/44 patients. In concordance with the clinical response, a lack of or decreased methylation in 4 patients with hematologic improvements and persistent methylation in 4 others with no response was observed. The mRNA expression of CDKN2B, IGSF4, and ESR1 was significantly reduced in MDS. Our results suggest that methylation changes contribute to disease pathogenesis and may serve as marker to monitor the efficacy of treatments.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Azacitidine/*pharmacology/*therapeutic use ; DNA Methylation/*drug effects ; DNA Modification Methylases/antagonists & inhibitors/metabolism ; Enzyme Inhibitors/*pharmacology/*therapeutic use ; Female ; Genes, Tumor Suppressor ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes/*drug therapy/*genetics ; Young Adult

BACKGROUND: Myelodysplastic syndromes (MDS) are clonal hematologic stem cell disorders characterized clinically and morphologically by ineffective hematopoiesis. A consensus-defined French-American-British (FAB) classification and International Prognostic Scoring System (IPSS) for predicting outcome and planning therapy in MDS has been developed, but its prognostic value in a large and independent series remains unproven. So we investigate clinical characteristics and prognosis of MDS, according to French-American-British (FAB) classification and International Prognostic Scoring System (IPSS). METHODS: A retrospective analysis of 50 patients who were diagnosed as myelodysplastic syndrome at Ajou University Hospital was performed from November, 1994 to April, 2003. The patients with secondary MDS were excluded. All patients were classified according to the FAB classification and calculated prognostic scores for IPSS. Patients were evaluated for clinical features and for blood and bone marrow findings at the time of diagnosis, and were followed up for survival and leukemic progression. Survival curves were based on the Kaplan-Meier method. All reported p values less than or equal to 0.05 were regarded as stastistically significant. RESULTS: The peak age was in the fifth decade and the male to female ratio was 1.5:1. RA (36%) was observed most frequently. Thereafter, RAEB-t (26%), RAEB (24%), RARS (12%) and CMML (2%) were observed, respectively. The initial symptoms on admission were fever (24%), dizziness and headache (16%), general weakness (16%), hemorrhage (14%), dyspnea (12%), abdominal pain (4%) and vomiting (4%). Cytogenetic studies were performed in 34 patients with MDS. They were classified as good, intermediate, poor group by chromosome score of IPSS. The median survival was 16.4 months for the good group, 15 months for the intermediate, 10.3 months for the poor. The median survival according to FAB classified groups were RA (33.8 mo), RARS (12.5 mo), RAEB (16.4 mo), RAEB-t (6.7 mo) and CMML (1.3 mo). Survival according to IPSS scoring system were 67.2 months for low, 27.1 months for intermediate-1, 10.3 months for intermediate-2 and 6.0 months for high groups. These data were statistically significant (p<0.05). CONCLUSIONS: In our experiencies, FAB and IPSS classification would be good predictors in clinical outcomes. But, because of the heterogeneity of MDS, large multicenter studies will be needed to define the issue of a new classification for these disorders.
Abdominal Pain ; Anemia, Refractory, with Excess of Blasts ; Bone Marrow ; Classification* ; Cytogenetics ; Diagnosis ; Dizziness ; Dyspnea ; Female ; Fever ; Headache ; Hematopoiesis ; Hemorrhage ; Humans ; Male ; Myelodysplastic Syndromes* ; Population Characteristics ; Prognosis* ; Retrospective Studies ; Stem Cells ; Vomiting

Dermatomyositis (DM) is an uncommon inflammatory myopathy with characteristic rash accompanying, or more often preceding, muscle weakness. There is a well-recognized association between DM and several cancers, such as ovarian cancer, breast cancer, melanoma, colon cancer, and non-Hodgkin lymphoma. We report the first case of cancer of unknown primary site associated with DM. A 62-yr-old woman presented to us with both shoulder painful swelling and facial edema. She was diagnosed previously as cancer of unknown primary site, histologically confirmed with squamous cell carcinoma in a pelvic mass. For the following days, she complained of erythematous face followed by progressive weakness of the proximal muscles of upper and lower limbs. The laboratory tests showed an increased muscle enzyme and acute phase reactants. The electromyogram showed the typical findings of DM. After the treatment with high dose steroid and methotrexate, the proximal motor weakness improved, and she received palliative radiation therapy.
Carcinoma, Squamous Cell/complications/diagnosis/pathology ; Dermatomyositis/*complications/diagnosis/pathology/therapy ; Female ; Humans ; Middle Aged ; Neoplasms, Unknown Primary/*complications/diagnosis/pathology

This study examined the prevalence of oral microbes in the saliva of oncological patients and healthy subjects. PCR was used to assess the frequency of oral microbes including 3 cariogenic bacteria, 5 periodontopathic bacteria and 4 Candida species in the saliva of 104 oncological patients and 52 healthy subjects. Among these microorganims, Streptococcus mutans, Fusobacterium nucleatum and Candida albicans were most frequently detected in both groups. There were no significant differences in the prevalence of cariogenic bacteria between the patient and healthy groups, whereas significant differences in the frequency of Porphyromonas gingivalis and Tannerella forsythia were observed between the two groups (p < 0.05). The prevalence of all five periodontopathogens was higher in the healthy group than in the patient group. The prevalence of C. albicans in patients was significantly higher than that of healthy group (p < 0.05). In conclusion, there were significant differences in the prevalence of P. gingivalis, T. forsythia and C. albicans between the oncological patient group and healthy group.
Bacteria ; Candida ; Candida albicans ; Forsythia ; Fusobacterium nucleatum ; Humans ; Polymerase Chain Reaction ; Porphyromonas gingivalis ; Prevalence ; Saliva ; Streptococcus mutans

FLT3 mutations are common genetic changes, and are reported to have prognostic significance in acute myeloid leukemia (AML). The FLT3 internal tandem duplication (ITD) and the D835 activating mutation in the tyrosine kinase domain (TKD) were analyzed by polymerase chain reaction (PCR) in the genomic DNA of Korean patients with AML at diagnosis and during follow-up. There were 226 patients with AML enrolled between March 1996 and August 2005. The incidence of ITD and TKD at diagnosis was 13% (29/226) and 3% (6/226). When compared to Western and other Asian patients with AML, Korean patients had a lower frequency by about two-thirds of ITD and TKD. Among the non-M3 cases (N=203), the patients with an ITD had a significantly shorter event-free survival when compared with those without an ITD (p=0.0079). Among 54 relapsed patients, 9 patients had the FLT3 ITD at diagnosis. Six patients demonstrated a reappearance of the ITD and 3 patients remained negative at relapse. One patient, among 45 patients who relapsed, had a negative baseline ITD but acquired a de novo ITD at relapse. There were 101 samples from 93 patients in remission; they were all negative for an ITD. Among 34 patients who failed to achieve a remission, five patients had a persistent ITD and one patient had a de novo ITD. These results support the concept of resistance of FLT3 ITD leukemic clones to chemotherapy. Therefore, effective therapy with FLT3 targeting agents may improve the prognosis of non-M3 AML patients with the FLT3 mutation.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Disease-Free Survival ; Female ; *Gene Expression Regulation, Neoplastic ; Humans ; Infant ; Infant, Newborn ; Korea ; Leukemia, Myeloid, Acute/*genetics ; Male ; Middle Aged ; *Mutation ; Prognosis ; Recurrence ; Remission Induction ; fms-Like Tyrosine Kinase 3/*genetics

SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.
Acetylation/drug effects ; Adolescent ; Adult ; Aged ; Apoptosis/*drug effects ; Cadherins/metabolism ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p15/metabolism ; DNA Methylation/drug effects ; Enzyme Inhibitors/therapeutic use/*toxicity ; Frizzled Receptors/metabolism ; Gene Expression Regulation/drug effects ; HL-60 Cells ; Histone Deacetylase Inhibitors/therapeutic use/*toxicity ; Histone-Lysine N-Methyltransferase/*antagonists & inhibitors/metabolism ; Histones/genetics/metabolism ; Humans ; Hydroxamic Acids/therapeutic use/*toxicity ; K562 Cells ; Leukemia/drug therapy/metabolism/pathology ; Leukemia, Myeloid, Acute/genetics/metabolism/pathology ; Male ; Middle Aged ; Piperazines/therapeutic use/toxicity ; Promoter Regions, Genetic ; Young Adult

Biphenotypic acute leukemia (BAL) is a subtype of leukemia of ambiguous lineage in the World Health Organization classification system. About one third of the cases have the Philadelphia chromosome, and some cases are associated with other structural abnormalities involving 11q23. BAL is known to have a poor prognosis in both children and adults. According to the previously reported BAL cases with positive BCR-ABL fusion gene, most of the BCR-ABL mRNA transcript type was e1a2. So, we describe here a 30-year-old adult BAL case with the karyotype 46,XY,t(9;22)(q34;q11.2) resulting in a very rare b3a2 type of BCR-ABL mRNA transcript.
Adult ; Child ; Classification ; Humans ; Karyotype ; Leukemia ; Leukemia, Biphenotypic, Acute* ; Philadelphia Chromosome ; Prognosis ; RNA, Messenger* ; World Health Organization

BACKGROUND: The presence of FLT3 internal tandem dupulication (FLT3/ITD) in patients with acute myeloid leukemia (AML) with normal karyotype was investigated in order to evaluate its clinical and prognostic significance. METHODS: The FLT3/ITD was studied by PCR assay in bone marrow samples obtained from 123 patients at diagnosis. Ninety patients who received intensive induction chemotherapy were evaluated. RESULTS: Of total 123 patients, forty-seven (38.2%) demonstrated the aberrant FLT3/ITD. Patients with FLT3/ITD had significantly higher leukocyte counts at presentation than did patients without FLT3/ITD (P=0.04). By multivariate analysis, the FLT3/ITD was an independent prognostic factor of leukemic-free survival (LFS) (P=0.01) in AML patients with normal karyotype. CONCLUSION: This study demonstrated that the presence of the FLT3/ITD was a significant factor for poor prognosis in AML patients with normal karyotype.
Bone Marrow ; Diagnosis ; Humans ; Induction Chemotherapy ; Karyotype* ; Leukemia, Myeloid, Acute* ; Leukocyte Count ; Multivariate Analysis ; Polymerase Chain Reaction ; Prognosis

BACKGROUND: Nucleophosmin (NPM1) gene and fms-like tyrosine kinase 3 gene-internal tandem duplication (FLT3-ITD) mutations are the most frequent mutations in patients with cytogenetically normal (CN)-AML. We analyzed the prognostic impact of these mutations and their interactions in adults with CN-AML. METHODS: NPM1 mutation (NPM1mut) and FLT3-ITD mutation (FLT3-ITD+) were analyzed by GeneScan and PCR assays of bone marrow samples obtained from 121 adult patients with CN-AML (age< or =60 years at diagnosis). RESULTS: The incidence of FLT3-ITD+ was higher in the NPM1mut group than in the wild-type NPM1 gene (NPM1wt) group. The patients were divided according to their mutation status into the NPM1mut/FLT3-ITD (isolated NPM1mut), NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD-, and NPM1wt/FLT3-ITD+ (isolated FLT3-ITD+) groups. The isolated NPM1mut group showed significantly better clinical outcomes in terms of relapse rate, 5-year relapse-free survival (RFS), and overall survival (OS) than the other groups. In contrast, the isolated FLT3-ITD+ group had a higher relapse rate and shorter RFS and OS than the other groups. The 5-year RFS rate was much higher among the patients who underwent allogeneic stem cell transplantation (alloSCT) than among those treated with high-dose cytarabine chemotherapy (HDAC) only as consolidation therapy in the isolated NPM1mut group and the NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD- group. CONCLUSION: Adult patients with CN-AML carrying isolated NPM1mut and isolated FLT3-ITD+ exhibit different clinical outcomes than those with NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD-. Although isolated NPM1mut leads to favorable clinical outcomes of CN-AML, the role of alloSCT in such patients remains to be considered.
Adult ; Bone Marrow ; Cytarabine ; fms-Like Tyrosine Kinase 3 ; Humans ; Incidence ; Leukemia, Myeloid, Acute ; Lifting ; Nuclear Proteins ; Polymerase Chain Reaction ; Recurrence ; Stem Cell Transplantation

Rituximab is a chimeric monoclonal antibody that specifically targets the CD20 molecule on the B cell surface. Although rituximab was originally introduced for the treatment of lymphoid neoplasms such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), it is now emerging as an effective and relatively safe therapeutic option for the patients with refractory immune thrombocytopenic purpura (ITP). We report here on a case of life-threatening toxic epidermal necrolysis (TEN) that was related with the use of rituximab in a patient with refractory ITP. The patient developed extensive erythematous papules and bullous lesions on his whole body associated with fever and visual disturbance during the second cycle of rituximab. The rituximab was discontinued and high dose intravenous immunoglobuline and steroid were administrated. Four weeks later, he fully recovered without any sequelae. A review of the literature reveals this to be the first reported case of TEN associated with rituximab injection in Korea.
Antibodies, Monoclonal, Murine-Derived ; Blister ; Epidermal Necrolysis, Toxic ; Fever ; Humans ; Immunoglobulins ; Korea ; Leukemia, Lymphocytic, Chronic, B-Cell ; Lymphoma, Non-Hodgkin ; Purpura, Thrombocytopenic, Idiopathic ; Rituximab