Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine ... more Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine the role of AZA before allogeneic stem cell transplantation (allo-SCT), we conducted a prospective study of AZA pre-treatment followed by allo-SCT in patients with higher-risk MDS. Twenty-one patients who were scheduled for their third to sixth cycle of AZA pre-treatment followed by allo-SCT were enrolled. AZA pre-treatment was interrupted early in 3 patients (14.3%) because of leukaemic transformation or death. The overall response rate to AZA pre-treatment was 57.1%. There were 2 cases of complete remission, 1 case of partial remission, and 9 cases of haematologic improvement. Fourteen patients (66.7%) received the planned allo-SCT and 5 patients were alive at the last follow-up. Three-year progression-free survival (PFS) and 3-year overall survival (OS) in the 14 patients who received allo-SCT were 30.0% (95% CI 3.3-56.7) and 42.9% (95% CI 17.1-68.7), respectively. PFS and OS were not...
To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed ... more To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed incidences and prognostic impacts of mutations in c-KIT, WT1, CEBPA, CBL, and a number of epigenetic genes in CBF AML. Seventy one and 21 AML patients with t(8;21) and inv(16) were enrolled in this study, respectively. NPM1, CEBPA, c-KIT, IDH1/2, DNMT3A, EZH2, WT1, and CBL mutations were analyzed by direct sequencing. Patients were categorized with respect to c-KIT and WT1 mutation status, and both clinical features and prognoses were compared. The incidences of FLT3 internal tandem duplication (ITD), NPM1, CEBPA, IDH1/2, DNMT3A, EZH2, and CBL mutations were low (≤5%) in CBF AML patients. However, c-KIT and WT1 mutations occurred frequently (10.9% and 13.8%, respectively). t(8;21) patients with c-KIT mutations showed significantly shorter overall survival (OS) and disease free survival (DFS) periods than those without mutations (P<0.001, for both); however, although the limited number...
The genetic variant rs16754 of Wilms tumor gene 1 (WT1) has recently been described as an indepen... more The genetic variant rs16754 of Wilms tumor gene 1 (WT1) has recently been described as an independent prognostic factor in AML patients. It is of great interest to test whether WT1 single nucleotide polymorphism can be used as a molecular marker in other types of cancer, to improve risk and treatment stratification. We performed sequencing analysis of exons 7 and 9 of WT1, which are known mutational hotspots, in a total of 73 patients with BCR-ABL1-negative myeloproliferative neoplasm (MPN) and 93 healthy controls. No previously reported WT1 mutations were identified in the present study. In Korean patients with BCR-ABL1-negative MPN, WT1 genetic variant rs16754 had no significant impact on clinical outcomes. We observed a significant difference in the allelic frequencies of WT1 rs16754 in Koreans between BCR-ABL1-negative MPN cases and healthy controls. Individuals carrying variant G alleles of WT1 rs16754 showed a relatively low prevalence of BCR-ABL1-negative MPN, compared with those carrying wild A alleles of WT1 rs16754 (Hazard ratio 0.10-0.65, P < 0.05). Therefore, possession of the variant G allele of WT1 rs16754 may reduce the risk of developing BCR-ABL1-negative MPN.
Congenital leukemia is very rare, and its prevalence according to recently published papers is fr... more Congenital leukemia is very rare, and its prevalence according to recently published papers is from 1 to 5 per million live births. This can be often diagnosed in postpartum throughout bone marrow biopsy, showing abnormal proliferation of immature blasts and granulocytic precursors. Hepatosplenomegaly is the most common feature which is found during perinatal examinations, that diagnosing is difficult during perinatal period. Hepatosplenomegaly can occur not only in congenital leukemia but in many other cases such as infection which is the most common cause. In other words, congenital leukemia is the one of the rare causes of hepatosplenomegaly. However, this case shows the fetus with the features of hepatosplenomegaly during perinatal period and being diagnosed as congenital leukemia associated with acquired AML1 gene duplication in postpartum through bone marrow biopsy. Due to its rare instance, we are to describe the case with a review of literatures.
We performed customer satisfaction surveys for physicians and nurses regarding clinical laborator... more We performed customer satisfaction surveys for physicians and nurses regarding clinical laboratory services, and for outpatients who used phlebotomy services at a tertiary care unit level to evaluate our clinical laboratory and phlebotomy services. Thus, we wish to share our experiences with the customer satisfaction survey for clinical laboratory and phlebotomy services. Board members of our laboratory designed a study procedure and study population, and developed two types of questionnaire. A satisfaction survey for clinical laboratory services was conducted with 370 physicians and 125 nurses by using an online or paper questionnaire. The satisfaction survey for phlebotomy services was performed with 347 outpatients who received phlebotomy services by using computer-aided interviews. Mean satisfaction scores of physicians and nurses was 58.1, while outpatients' satisfaction score was 70.5. We identified several dissatisfactions with our clinical laboratory and phlebotomy servi...
We evaluated the incidence, clinical characteristics, and prognostic impact of calreticulin (CALR... more We evaluated the incidence, clinical characteristics, and prognostic impact of calreticulin (CALR) mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients. In all, 48 ET and 14 PMF patients were enrolled, and the presence of CALR mutations was analyzed by direct sequencing. Patients were classified into three subgroups according to Janus kinase 2 (JAK2) V617F and CALR mutation status, and their clinical features and prognosis were compared. CALR mutations were detected in 15 (24.2%) patients, and the incidence increased to 50.0% in 30 JAK2 V617F mutation-negative cases. These included 11 patients with three known mutations (c.1092_1143del [seven cases], c.1154_1155insTTGTC [three cases], and c.1102_1135del [one case]) and 4 patients with novel mutations. ET patients carrying CALR mutation were younger, had lower white blood cell counts, and experienced less thrombosis during follow-up than those carrying JAK2 V617F mutation, while both patient groups showed similar clinical features and prognosis. In ET patients without JAK2 V617F mutation, CALR mutation did not significantly affect clinical manifestation and prognosis. In conclusion, CALR mutation analysis could be a useful diagnostic tool for ET and PMF in 50% of the cases without JAK2 V617F mutations. The prognostic impact of CALR mutations needs further investigation.
Background. DNA methyltransferase 3A (DNMT3A) mutation was recently introduced as a prognostic in... more Background. DNA methyltransferase 3A (DNMT3A) mutation was recently introduced as a prognostic indicator in normal karyotype (NK) AML and we evaluated the incidence and prognostic impact of DNMT3A mutations in Korean NK AML patients. Methods. Total 67 NK AML patients diagnosed during the recent 10 years were enrolled. DNMT3A mutations were analyzed by direct sequencing and categorized into nonsynonymous variations (NSV), deleterious mutations (DM), and R882 mutation based on in silico analysis results. Clinical features and prognosis were compared with respect to DNMT3A mutation status. Results. Three novel (I158M, K219V, and E177V) and two known (R736H and R882H) NSVs were identified and the latter three were predicted as DMs. DNMT3A NSVs, DMs, and R882 mutation were identified in 14.9%-17.9%, 10.3%-10.4%, and 7.5% of patients, respectively. DNMT3A mutations were frequently detected in FLT3 ITD mutated patients (P = 0.054, 0.071, and 0.071 in NSV, DMs, and R882 mutation, resp.) but did not affect clinical features and prognosis significantly. Conclusions. Incidences of DNMT3A NSVs, DMs, and R882 mutation are 14.9%-17.9%, 10.3%-10.4%, and 7.5%, respectively, in Korean NK AML patients. DNMT3A mutations are associated with FLT3 ITD mutations but do not affect clinical outcome significantly in Korean NK AML patients.
Children with Down syndrome are predisposed to developing acute leukemia. The most common leukemi... more Children with Down syndrome are predisposed to developing acute leukemia. The most common leukemia associated with Down syndrome is acute megakaryoblastic leukemia (AMKL), and the incidence is approximately 500fold higher than in healthy children (1). Transient myeloproliferative disorder (TMD) is a leukemoid reaction occurring occasionally in Down syndrome newborn infants, and is characterized by the rapid growth of abnormal blast cells expressing megakaryocytic markers. Although most TMD cases resolve spontaneously, AMKL develops in approximately 20% to 30% of TMD cases in the first 4 yr of life, often preceded by a myelodysplastic phase. Recently, acquired mutations in the N-terminal activation domain of the GATA1 gene, encoding a zinc-finger transcription factor that regulates the normal development of the megakaryocytic, erythroid, basophilic/mast cell and eosinophilic lineages, have been reported in TMD and Down syndrome-related AMKL (DS-AMKL) (2). Two isoforms of GATA-1 protein are usually detected: a full-length GATA-1 translated from the first start codon ATG on exon 2, and a 40-kDa shorter form, GATA-1s that initiated from an ATG on exon 3. Most of the mutations in TMD and DS-AMKL were located in the regions including exon 2 and an identical mutation in specimens from TDM and AMKL have been found in Down syndrome patients (3-8). The mutation results in the introduction of a premature stop codon in the gene sequence that encodes the N-terminal activation domain, and a lack of expression of the full-length GATA-1.
The types of metallo-beta-lactamases (MBLs), integrons, and genetic relatedness among Pseudomonas... more The types of metallo-beta-lactamases (MBLs), integrons, and genetic relatedness among Pseudomonas aeruginosa were investigated with a recent high prevalence of imipenem resistance in a Korean hospital. During 2000-2003, a total of 116 non-duplicate imipenem-resistant P. aeruginosa isolates were analyzed by PCR and DNA sequencing to detect of bla (IMP-1), bla (VIM-1), bla (VIM-2), bla (SPM-1), intI 1, intI 2, and intI 3 genes. Among them, MBL-producing isolates were evaluated for genetic relatedness using pulsed-field gel electrophoresis (PFGE) profiles. Of 116 isolates, 21 (18.1%) carried bla (VIM-2) gene with the intI 1 gene. Analysis of VIM-2 procuders by PFGE grouped 21 isolates into eight different clusters. Six of eight cluster I strains, all of four cluster II strains, and all of three cluster III strains were isolated in 2000, 2002, and 2003, respectively. Data concluded that P. aeruginosa carrying bla (VIM-2) with a class 1 integron was the only type among MBLs. A hospital outbreak by VIM-2 producers occurred annually, which could be at least a part of a recent high prevalence of imipenem resistance.
Single-nucleotide polymorphisms (SNPs) and haplotypes in the x-ray repair cross-complementing gro... more Single-nucleotide polymorphisms (SNPs) and haplotypes in the x-ray repair cross-complementing group 1 (XRCC1) gene, which is one of the base excision repair genes, are thought to be associated with the risk of non-small cell lung cancer (NSCLC). We genotyped three coding (Arg280His, Arg399Gln, and Gln632Gln) SNPs and six haplotype-tagging SNPs (htSNPs) for 140 advanced NSCLC cases and 217 healthy controls (all Koreans) using unconditional logistic regression analysis, and this was adjusted for age, gender, and the smoking status. The haplotypes were reconstructed according to the genotyping data and the linkage disequilibrium status of these nine SNPs. The minor allele heterozygotes of the rs1001581 htSNP showed an increased risk of NSCLC (adjusted odds ratio = 2.118, p = 0.013), and the minor allele homozygotes of the rs2293036 htSNP showed a decreased risk of NSCLC (adjusted odds ratio = 0.363, p = 0.020). Seven possible haplotypes were demonstrated in this study (haplotype frequency &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1%). The GGGGGGGGG haplotype, which is composed of nine major alleles, showed a protective effect for developing NSCLC (odds ratio = 0.433, p = 0.002); however, the GGGGGGAGG haplotype that contained the minor allele of the rs1001581 demonstrated an increased risk of NSCLC (odds ratio = 1.597, p = 0.044). The above associations were similarly noted for the never smokers, and so the smoking status might modify the associations between the x-ray repair cross-complementing group 1 (XRCC1) genetic variants and the risk of developing NSCLC. On 10-million permutation testing, only the GGGGGGGGG haplotype was significantly associated with a decreased risk of NSCLC in the total group (p = 0.001). This study presents several novel aspects of the genetic susceptibility to develop NSCLC. Larger studies that will focus on the role of the rs1001581 and rs2293036 htSNPs and haplotypes for developing NSCLC are needed in the future.
An 8-year-old boy was diagnosed with precursor B-cell acute lymphoblastic leukemia. After intensi... more An 8-year-old boy was diagnosed with precursor B-cell acute lymphoblastic leukemia. After intensified chemotherapy, he underwent sex-mismatched allogeneic cord blood transplantation. Postcord blood transplantation cytogenetic studies revealed engraftment failure evidenced by switching into the recipient type (XY), and, notably, various complex chromosomal aberrations in the recipient cells. Nonclonal and clonal aberrations including deletions of 7q and 20q were persistently observed. Nonetheless, the patient was clinically stable without evidence of marrow dysplasia or leukemic cells. Del(7q) and del(20q), 2 recurrent chromosomal aberrations in myeloid neoplasia, might represent underlying genomic instability in this patient, not the direct culprits of dysplasia or leukemogenesis.
Currarino syndrome (CS) is a rare autosomal dominant disease that has been described as a triad o... more Currarino syndrome (CS) is a rare autosomal dominant disease that has been described as a triad of partial sacral agenesis, anorectal anomalies, and a presacral mass. Mutations in the HLXB9 gene have been suggested to be the genetic background of CS. In this study, sequence analysis of the HLXB9 gene was performed in two familial and two sporadic Korean patients showing the clinical features of CS, and two mutations in the HLXB9 gene were identified only in the two familial cases. One mutation (R295W) has been reported previously, and the other (H260_Q261delinsLELLELE) is novel. Consistent with previous observations, the phenotypic expression of the mutation carriers in the CS families varies from mild to severe, including the complete triad. This study confirms that familial CS patients in Korea have the same genetic background as other ethnicities and reaffirms the phenotype variability among CS patients with the same mutation.
The purpose of this study was to re-evaluate post-remission therapy outcomes after first remissio... more The purpose of this study was to re-evaluate post-remission therapy outcomes after first remission according to years of patient enrollment in patients with core binding factor acute myeloid leukaemia. We conducted a retrospective study on 138 patients aged less than 60 years diagnosed with core binding factor acute myeloid leukaemia between 1994 and 2006, comparing allogeneic stem cell transplantation and high-dose cytarabine chemotherapy as post-remission treatment options after the first remission. The 5-year probabilities of disease-free survival and overall survival were not different between allogeneic stem cell transplantation and high-dose cytarabine groups. However, 3-year probabilities of disease-free survival (86.7% vs. 67.0%) and overall survival (90.0% vs. 67.3%) showed a trend towards improvement in the allogeneic stem cell transplantation group compared with the high-dose cytarabine group in cohort after 2003 (2003-2006), whereas outcomes were not different in cohort before 2003 (1994-2002). Especially, 3-year probabilities of disease-free survival (95.2% vs. 59.3%, P = 0.008) and overall survival (95.2% vs. 59.6%, P = 0.032) of allogeneic stem cell transplantation group were significantly better than high-dose cytarabine group in cohort after 2003 of acute myeloid leukaemia patients with t(8;21). The relative risk of overall survival with allogeneic stem cell transplantation, compared with high-dose cytarabine chemotherapy, was significantly improved in the cohort after 2003 (0.33; 95% CI, 0.07-1.48) when compared with that before 2003 (1.92; 95% CI, 0.77-4.82). In multivariate analysis in cohort after 2003, allogeneic stem cell transplantation as post-remission therapy was associated with better disease-free survival. Allogeneic stem cell transplantation is currently the more effective post-remission therapy than it was prior to 2003 for core binding factor acute myeloid leukaemia achieving first remission. On the contrary to previous findings, allogeneic stem cell transplantation provides significantly improved outcomes than high-dose cytarabine chemotherapy in acute myeloid leukaemia with t(8;21).
We evaluated the impact of functional polymorphisms in the vascular endothelial growth factor A (... more We evaluated the impact of functional polymorphisms in the vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor 2 (VEGFR2) genes on the survival of patients with diffuse large B cell lymphoma (DLBCL). Five potentially functional polymorphisms in the VEGFA (rs699947, rs2010963 and rs3025039) and VEGFR2 (rs1870377 and rs2305948) genes were assessed in 494 DLBCL patients treated with rituximab plus CHOP chemotherapy. The associations of genotype and haplotype with overall survival (OS) and progression-free survival (PFS) were analyzed. Of the five polymorphisms, VEGFR2 rs1870377T>A was significantly associated with both OS and PFS; in the dominant model, patients with the AA + TA genotypes had significantly better OS (P = 0.002) and PFS (P = 0.004) than those with the TT genotype. The association between significantly better OS and the AA + TA genotypes was observed separately in patients with low (0-2; P = 0.035) and high (3-5; P = 0.043) International Prognostic Index scores. Multivariate analysis showed that, relative to the AA + TA genotypes, the TT genotype was an independent prognostic factor for poor OS (HR, 1.71; 95% CI, 1.21-2.43; P = 0.002) and PFS (HR, 1.57; 1.13-2.17; P = 0.004). Other independent significant predictors of survival in patients with DLBCL were International Prognostic Index score, age > 60 years, lactate dehydrogenase concentration >normal, extranodal disease >1 and presence of B symptoms. The VEGFR2 rs1870377 polymorphism might affect survival in patients with DLBCL, suggesting that angiogenesis might be related to poor survival in these patients. (Cancer Sci 2012; 103: 497-503)
Bone marrow involvement (BMI) in diffuse large B cell lymphoma (DLBCL) was naively regarded as an... more Bone marrow involvement (BMI) in diffuse large B cell lymphoma (DLBCL) was naively regarded as an adverse clinical factor. However, it has been unknown which factor would separate clinical outcomes in DLBCL patients with BMI. Recently, metabolic tumor volume (MTV) on positron emission tomography/computed tomography (PET/CT) was suggested to predict prognosis in several lymphoma types. Therefore, we investigated whether MTV would separate the outcomes in DLBCL patients with BMI. MTV on PET/CT was defined as an initial tumor burden as target lesion≥standard uptake value, 2.5 in 107 patients with BMI. Intramedullary (IM) MTV was defined as extent of BMI and total MTV was as whole tumor burden. 260.5cm(3) and 601.2cm(3) were ideal cut-off values for dividing high and low MTV status in the IM and total lymphoma lesions in Receiver Operating Curve analysis. High risk NCCN-IPI (p&amp;amp;amp;amp;amp;amp;lt;0.001, p&amp;amp;amp;amp;amp;amp;lt;0.001), bulky disease (p=0.011, p=0.005), concordant subtype (p=0.025, p=0.029), high IM MTV status (p&amp;amp;amp;amp;amp;amp;lt;0.001, p&amp;amp;amp;amp;amp;amp;lt;0.001), high total MTV status (p&amp;amp;amp;amp;amp;amp;lt;0.001, p&amp;amp;amp;amp;amp;amp;lt;0.001), and ≥2CAs in BM (p=0.037, p=0.033) were significantly associated with progression-free survival (PFS) and overall survival (OS) than other groups. In multivariate analysis, high risk NCCN-IPI (PFS, p=0.006; OS, p=0.013), concordant subtype (PFS, p=0.005; OS, p=0.007), and high total MTV status (PFS, p&amp;amp;amp;amp;amp;amp;lt;0.001; OS, p&amp;amp;amp;amp;amp;amp;lt;0.001) had independent clinical impacts. MTV had prognostic significances for survivals in DLBCL with BMI.
We analyzed the relation between platelet aggregation measured by light transmittance aggregometr... more We analyzed the relation between platelet aggregation measured by light transmittance aggregometry (LTA) and platelet reactivity index (PRI) measured by vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. It has been suggested that LTA and VASP-P assay correlate differently according to the level of P2Y12 receptor blockade by thienopyridines. We simultaneously measured platelet function by LTA and VASP-P assay in 466 East Asians undergoing elective percutaneous coronary intervention after a 600-mg clopidogrel loading. High on-clopidogrel platelet reactivity (HPR) was defined by published consensus criteria. The degree of correlation between LTA and the VASP-P assay was different according to PRI levels. The correlation was lower in patients with poor responsiveness (PRI >60%) (n = 216) (0.035 ≤ r(2) ≤ 0.047), which was greater in responsive patients (PRI ≤60%) (n = 250) (0.315 ≤ r(2) ≤ 0.526). Despite a 600-mg loading, East Asians had a high prevalence of HPR (4...
Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine ... more Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine the role of AZA before allogeneic stem cell transplantation (allo-SCT), we conducted a prospective study of AZA pre-treatment followed by allo-SCT in patients with higher-risk MDS. Twenty-one patients who were scheduled for their third to sixth cycle of AZA pre-treatment followed by allo-SCT were enrolled. AZA pre-treatment was interrupted early in 3 patients (14.3%) because of leukaemic transformation or death. The overall response rate to AZA pre-treatment was 57.1%. There were 2 cases of complete remission, 1 case of partial remission, and 9 cases of haematologic improvement. Fourteen patients (66.7%) received the planned allo-SCT and 5 patients were alive at the last follow-up. Three-year progression-free survival (PFS) and 3-year overall survival (OS) in the 14 patients who received allo-SCT were 30.0% (95% CI 3.3-56.7) and 42.9% (95% CI 17.1-68.7), respectively. PFS and OS were not...
To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed ... more To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed incidences and prognostic impacts of mutations in c-KIT, WT1, CEBPA, CBL, and a number of epigenetic genes in CBF AML. Seventy one and 21 AML patients with t(8;21) and inv(16) were enrolled in this study, respectively. NPM1, CEBPA, c-KIT, IDH1/2, DNMT3A, EZH2, WT1, and CBL mutations were analyzed by direct sequencing. Patients were categorized with respect to c-KIT and WT1 mutation status, and both clinical features and prognoses were compared. The incidences of FLT3 internal tandem duplication (ITD), NPM1, CEBPA, IDH1/2, DNMT3A, EZH2, and CBL mutations were low (≤5%) in CBF AML patients. However, c-KIT and WT1 mutations occurred frequently (10.9% and 13.8%, respectively). t(8;21) patients with c-KIT mutations showed significantly shorter overall survival (OS) and disease free survival (DFS) periods than those without mutations (P<0.001, for both); however, although the limited number...
Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine ... more Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine the role of AZA before allogeneic stem cell transplantation (allo-SCT), we conducted a prospective study of AZA pre-treatment followed by allo-SCT in patients with higher-risk MDS. Twenty-one patients who were scheduled for their third to sixth cycle of AZA pre-treatment followed by allo-SCT were enrolled. AZA pre-treatment was interrupted early in 3 patients (14.3%) because of leukaemic transformation or death. The overall response rate to AZA pre-treatment was 57.1%. There were 2 cases of complete remission, 1 case of partial remission, and 9 cases of haematologic improvement. Fourteen patients (66.7%) received the planned allo-SCT and 5 patients were alive at the last follow-up. Three-year progression-free survival (PFS) and 3-year overall survival (OS) in the 14 patients who received allo-SCT were 30.0% (95% CI 3.3-56.7) and 42.9% (95% CI 17.1-68.7), respectively. PFS and OS were not...
To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed ... more To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed incidences and prognostic impacts of mutations in c-KIT, WT1, CEBPA, CBL, and a number of epigenetic genes in CBF AML. Seventy one and 21 AML patients with t(8;21) and inv(16) were enrolled in this study, respectively. NPM1, CEBPA, c-KIT, IDH1/2, DNMT3A, EZH2, WT1, and CBL mutations were analyzed by direct sequencing. Patients were categorized with respect to c-KIT and WT1 mutation status, and both clinical features and prognoses were compared. The incidences of FLT3 internal tandem duplication (ITD), NPM1, CEBPA, IDH1/2, DNMT3A, EZH2, and CBL mutations were low (≤5%) in CBF AML patients. However, c-KIT and WT1 mutations occurred frequently (10.9% and 13.8%, respectively). t(8;21) patients with c-KIT mutations showed significantly shorter overall survival (OS) and disease free survival (DFS) periods than those without mutations (P<0.001, for both); however, although the limited number...
The genetic variant rs16754 of Wilms tumor gene 1 (WT1) has recently been described as an indepen... more The genetic variant rs16754 of Wilms tumor gene 1 (WT1) has recently been described as an independent prognostic factor in AML patients. It is of great interest to test whether WT1 single nucleotide polymorphism can be used as a molecular marker in other types of cancer, to improve risk and treatment stratification. We performed sequencing analysis of exons 7 and 9 of WT1, which are known mutational hotspots, in a total of 73 patients with BCR-ABL1-negative myeloproliferative neoplasm (MPN) and 93 healthy controls. No previously reported WT1 mutations were identified in the present study. In Korean patients with BCR-ABL1-negative MPN, WT1 genetic variant rs16754 had no significant impact on clinical outcomes. We observed a significant difference in the allelic frequencies of WT1 rs16754 in Koreans between BCR-ABL1-negative MPN cases and healthy controls. Individuals carrying variant G alleles of WT1 rs16754 showed a relatively low prevalence of BCR-ABL1-negative MPN, compared with those carrying wild A alleles of WT1 rs16754 (Hazard ratio 0.10-0.65, P < 0.05). Therefore, possession of the variant G allele of WT1 rs16754 may reduce the risk of developing BCR-ABL1-negative MPN.
Congenital leukemia is very rare, and its prevalence according to recently published papers is fr... more Congenital leukemia is very rare, and its prevalence according to recently published papers is from 1 to 5 per million live births. This can be often diagnosed in postpartum throughout bone marrow biopsy, showing abnormal proliferation of immature blasts and granulocytic precursors. Hepatosplenomegaly is the most common feature which is found during perinatal examinations, that diagnosing is difficult during perinatal period. Hepatosplenomegaly can occur not only in congenital leukemia but in many other cases such as infection which is the most common cause. In other words, congenital leukemia is the one of the rare causes of hepatosplenomegaly. However, this case shows the fetus with the features of hepatosplenomegaly during perinatal period and being diagnosed as congenital leukemia associated with acquired AML1 gene duplication in postpartum through bone marrow biopsy. Due to its rare instance, we are to describe the case with a review of literatures.
We performed customer satisfaction surveys for physicians and nurses regarding clinical laborator... more We performed customer satisfaction surveys for physicians and nurses regarding clinical laboratory services, and for outpatients who used phlebotomy services at a tertiary care unit level to evaluate our clinical laboratory and phlebotomy services. Thus, we wish to share our experiences with the customer satisfaction survey for clinical laboratory and phlebotomy services. Board members of our laboratory designed a study procedure and study population, and developed two types of questionnaire. A satisfaction survey for clinical laboratory services was conducted with 370 physicians and 125 nurses by using an online or paper questionnaire. The satisfaction survey for phlebotomy services was performed with 347 outpatients who received phlebotomy services by using computer-aided interviews. Mean satisfaction scores of physicians and nurses was 58.1, while outpatients' satisfaction score was 70.5. We identified several dissatisfactions with our clinical laboratory and phlebotomy servi...
We evaluated the incidence, clinical characteristics, and prognostic impact of calreticulin (CALR... more We evaluated the incidence, clinical characteristics, and prognostic impact of calreticulin (CALR) mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients. In all, 48 ET and 14 PMF patients were enrolled, and the presence of CALR mutations was analyzed by direct sequencing. Patients were classified into three subgroups according to Janus kinase 2 (JAK2) V617F and CALR mutation status, and their clinical features and prognosis were compared. CALR mutations were detected in 15 (24.2%) patients, and the incidence increased to 50.0% in 30 JAK2 V617F mutation-negative cases. These included 11 patients with three known mutations (c.1092_1143del [seven cases], c.1154_1155insTTGTC [three cases], and c.1102_1135del [one case]) and 4 patients with novel mutations. ET patients carrying CALR mutation were younger, had lower white blood cell counts, and experienced less thrombosis during follow-up than those carrying JAK2 V617F mutation, while both patient groups showed similar clinical features and prognosis. In ET patients without JAK2 V617F mutation, CALR mutation did not significantly affect clinical manifestation and prognosis. In conclusion, CALR mutation analysis could be a useful diagnostic tool for ET and PMF in 50% of the cases without JAK2 V617F mutations. The prognostic impact of CALR mutations needs further investigation.
Background. DNA methyltransferase 3A (DNMT3A) mutation was recently introduced as a prognostic in... more Background. DNA methyltransferase 3A (DNMT3A) mutation was recently introduced as a prognostic indicator in normal karyotype (NK) AML and we evaluated the incidence and prognostic impact of DNMT3A mutations in Korean NK AML patients. Methods. Total 67 NK AML patients diagnosed during the recent 10 years were enrolled. DNMT3A mutations were analyzed by direct sequencing and categorized into nonsynonymous variations (NSV), deleterious mutations (DM), and R882 mutation based on in silico analysis results. Clinical features and prognosis were compared with respect to DNMT3A mutation status. Results. Three novel (I158M, K219V, and E177V) and two known (R736H and R882H) NSVs were identified and the latter three were predicted as DMs. DNMT3A NSVs, DMs, and R882 mutation were identified in 14.9%-17.9%, 10.3%-10.4%, and 7.5% of patients, respectively. DNMT3A mutations were frequently detected in FLT3 ITD mutated patients (P = 0.054, 0.071, and 0.071 in NSV, DMs, and R882 mutation, resp.) but did not affect clinical features and prognosis significantly. Conclusions. Incidences of DNMT3A NSVs, DMs, and R882 mutation are 14.9%-17.9%, 10.3%-10.4%, and 7.5%, respectively, in Korean NK AML patients. DNMT3A mutations are associated with FLT3 ITD mutations but do not affect clinical outcome significantly in Korean NK AML patients.
Children with Down syndrome are predisposed to developing acute leukemia. The most common leukemi... more Children with Down syndrome are predisposed to developing acute leukemia. The most common leukemia associated with Down syndrome is acute megakaryoblastic leukemia (AMKL), and the incidence is approximately 500fold higher than in healthy children (1). Transient myeloproliferative disorder (TMD) is a leukemoid reaction occurring occasionally in Down syndrome newborn infants, and is characterized by the rapid growth of abnormal blast cells expressing megakaryocytic markers. Although most TMD cases resolve spontaneously, AMKL develops in approximately 20% to 30% of TMD cases in the first 4 yr of life, often preceded by a myelodysplastic phase. Recently, acquired mutations in the N-terminal activation domain of the GATA1 gene, encoding a zinc-finger transcription factor that regulates the normal development of the megakaryocytic, erythroid, basophilic/mast cell and eosinophilic lineages, have been reported in TMD and Down syndrome-related AMKL (DS-AMKL) (2). Two isoforms of GATA-1 protein are usually detected: a full-length GATA-1 translated from the first start codon ATG on exon 2, and a 40-kDa shorter form, GATA-1s that initiated from an ATG on exon 3. Most of the mutations in TMD and DS-AMKL were located in the regions including exon 2 and an identical mutation in specimens from TDM and AMKL have been found in Down syndrome patients (3-8). The mutation results in the introduction of a premature stop codon in the gene sequence that encodes the N-terminal activation domain, and a lack of expression of the full-length GATA-1.
The types of metallo-beta-lactamases (MBLs), integrons, and genetic relatedness among Pseudomonas... more The types of metallo-beta-lactamases (MBLs), integrons, and genetic relatedness among Pseudomonas aeruginosa were investigated with a recent high prevalence of imipenem resistance in a Korean hospital. During 2000-2003, a total of 116 non-duplicate imipenem-resistant P. aeruginosa isolates were analyzed by PCR and DNA sequencing to detect of bla (IMP-1), bla (VIM-1), bla (VIM-2), bla (SPM-1), intI 1, intI 2, and intI 3 genes. Among them, MBL-producing isolates were evaluated for genetic relatedness using pulsed-field gel electrophoresis (PFGE) profiles. Of 116 isolates, 21 (18.1%) carried bla (VIM-2) gene with the intI 1 gene. Analysis of VIM-2 procuders by PFGE grouped 21 isolates into eight different clusters. Six of eight cluster I strains, all of four cluster II strains, and all of three cluster III strains were isolated in 2000, 2002, and 2003, respectively. Data concluded that P. aeruginosa carrying bla (VIM-2) with a class 1 integron was the only type among MBLs. A hospital outbreak by VIM-2 producers occurred annually, which could be at least a part of a recent high prevalence of imipenem resistance.
Single-nucleotide polymorphisms (SNPs) and haplotypes in the x-ray repair cross-complementing gro... more Single-nucleotide polymorphisms (SNPs) and haplotypes in the x-ray repair cross-complementing group 1 (XRCC1) gene, which is one of the base excision repair genes, are thought to be associated with the risk of non-small cell lung cancer (NSCLC). We genotyped three coding (Arg280His, Arg399Gln, and Gln632Gln) SNPs and six haplotype-tagging SNPs (htSNPs) for 140 advanced NSCLC cases and 217 healthy controls (all Koreans) using unconditional logistic regression analysis, and this was adjusted for age, gender, and the smoking status. The haplotypes were reconstructed according to the genotyping data and the linkage disequilibrium status of these nine SNPs. The minor allele heterozygotes of the rs1001581 htSNP showed an increased risk of NSCLC (adjusted odds ratio = 2.118, p = 0.013), and the minor allele homozygotes of the rs2293036 htSNP showed a decreased risk of NSCLC (adjusted odds ratio = 0.363, p = 0.020). Seven possible haplotypes were demonstrated in this study (haplotype frequency &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1%). The GGGGGGGGG haplotype, which is composed of nine major alleles, showed a protective effect for developing NSCLC (odds ratio = 0.433, p = 0.002); however, the GGGGGGAGG haplotype that contained the minor allele of the rs1001581 demonstrated an increased risk of NSCLC (odds ratio = 1.597, p = 0.044). The above associations were similarly noted for the never smokers, and so the smoking status might modify the associations between the x-ray repair cross-complementing group 1 (XRCC1) genetic variants and the risk of developing NSCLC. On 10-million permutation testing, only the GGGGGGGGG haplotype was significantly associated with a decreased risk of NSCLC in the total group (p = 0.001). This study presents several novel aspects of the genetic susceptibility to develop NSCLC. Larger studies that will focus on the role of the rs1001581 and rs2293036 htSNPs and haplotypes for developing NSCLC are needed in the future.
An 8-year-old boy was diagnosed with precursor B-cell acute lymphoblastic leukemia. After intensi... more An 8-year-old boy was diagnosed with precursor B-cell acute lymphoblastic leukemia. After intensified chemotherapy, he underwent sex-mismatched allogeneic cord blood transplantation. Postcord blood transplantation cytogenetic studies revealed engraftment failure evidenced by switching into the recipient type (XY), and, notably, various complex chromosomal aberrations in the recipient cells. Nonclonal and clonal aberrations including deletions of 7q and 20q were persistently observed. Nonetheless, the patient was clinically stable without evidence of marrow dysplasia or leukemic cells. Del(7q) and del(20q), 2 recurrent chromosomal aberrations in myeloid neoplasia, might represent underlying genomic instability in this patient, not the direct culprits of dysplasia or leukemogenesis.
Currarino syndrome (CS) is a rare autosomal dominant disease that has been described as a triad o... more Currarino syndrome (CS) is a rare autosomal dominant disease that has been described as a triad of partial sacral agenesis, anorectal anomalies, and a presacral mass. Mutations in the HLXB9 gene have been suggested to be the genetic background of CS. In this study, sequence analysis of the HLXB9 gene was performed in two familial and two sporadic Korean patients showing the clinical features of CS, and two mutations in the HLXB9 gene were identified only in the two familial cases. One mutation (R295W) has been reported previously, and the other (H260_Q261delinsLELLELE) is novel. Consistent with previous observations, the phenotypic expression of the mutation carriers in the CS families varies from mild to severe, including the complete triad. This study confirms that familial CS patients in Korea have the same genetic background as other ethnicities and reaffirms the phenotype variability among CS patients with the same mutation.
The purpose of this study was to re-evaluate post-remission therapy outcomes after first remissio... more The purpose of this study was to re-evaluate post-remission therapy outcomes after first remission according to years of patient enrollment in patients with core binding factor acute myeloid leukaemia. We conducted a retrospective study on 138 patients aged less than 60 years diagnosed with core binding factor acute myeloid leukaemia between 1994 and 2006, comparing allogeneic stem cell transplantation and high-dose cytarabine chemotherapy as post-remission treatment options after the first remission. The 5-year probabilities of disease-free survival and overall survival were not different between allogeneic stem cell transplantation and high-dose cytarabine groups. However, 3-year probabilities of disease-free survival (86.7% vs. 67.0%) and overall survival (90.0% vs. 67.3%) showed a trend towards improvement in the allogeneic stem cell transplantation group compared with the high-dose cytarabine group in cohort after 2003 (2003-2006), whereas outcomes were not different in cohort before 2003 (1994-2002). Especially, 3-year probabilities of disease-free survival (95.2% vs. 59.3%, P = 0.008) and overall survival (95.2% vs. 59.6%, P = 0.032) of allogeneic stem cell transplantation group were significantly better than high-dose cytarabine group in cohort after 2003 of acute myeloid leukaemia patients with t(8;21). The relative risk of overall survival with allogeneic stem cell transplantation, compared with high-dose cytarabine chemotherapy, was significantly improved in the cohort after 2003 (0.33; 95% CI, 0.07-1.48) when compared with that before 2003 (1.92; 95% CI, 0.77-4.82). In multivariate analysis in cohort after 2003, allogeneic stem cell transplantation as post-remission therapy was associated with better disease-free survival. Allogeneic stem cell transplantation is currently the more effective post-remission therapy than it was prior to 2003 for core binding factor acute myeloid leukaemia achieving first remission. On the contrary to previous findings, allogeneic stem cell transplantation provides significantly improved outcomes than high-dose cytarabine chemotherapy in acute myeloid leukaemia with t(8;21).
We evaluated the impact of functional polymorphisms in the vascular endothelial growth factor A (... more We evaluated the impact of functional polymorphisms in the vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor 2 (VEGFR2) genes on the survival of patients with diffuse large B cell lymphoma (DLBCL). Five potentially functional polymorphisms in the VEGFA (rs699947, rs2010963 and rs3025039) and VEGFR2 (rs1870377 and rs2305948) genes were assessed in 494 DLBCL patients treated with rituximab plus CHOP chemotherapy. The associations of genotype and haplotype with overall survival (OS) and progression-free survival (PFS) were analyzed. Of the five polymorphisms, VEGFR2 rs1870377T>A was significantly associated with both OS and PFS; in the dominant model, patients with the AA + TA genotypes had significantly better OS (P = 0.002) and PFS (P = 0.004) than those with the TT genotype. The association between significantly better OS and the AA + TA genotypes was observed separately in patients with low (0-2; P = 0.035) and high (3-5; P = 0.043) International Prognostic Index scores. Multivariate analysis showed that, relative to the AA + TA genotypes, the TT genotype was an independent prognostic factor for poor OS (HR, 1.71; 95% CI, 1.21-2.43; P = 0.002) and PFS (HR, 1.57; 1.13-2.17; P = 0.004). Other independent significant predictors of survival in patients with DLBCL were International Prognostic Index score, age > 60 years, lactate dehydrogenase concentration >normal, extranodal disease >1 and presence of B symptoms. The VEGFR2 rs1870377 polymorphism might affect survival in patients with DLBCL, suggesting that angiogenesis might be related to poor survival in these patients. (Cancer Sci 2012; 103: 497-503)
Bone marrow involvement (BMI) in diffuse large B cell lymphoma (DLBCL) was naively regarded as an... more Bone marrow involvement (BMI) in diffuse large B cell lymphoma (DLBCL) was naively regarded as an adverse clinical factor. However, it has been unknown which factor would separate clinical outcomes in DLBCL patients with BMI. Recently, metabolic tumor volume (MTV) on positron emission tomography/computed tomography (PET/CT) was suggested to predict prognosis in several lymphoma types. Therefore, we investigated whether MTV would separate the outcomes in DLBCL patients with BMI. MTV on PET/CT was defined as an initial tumor burden as target lesion≥standard uptake value, 2.5 in 107 patients with BMI. Intramedullary (IM) MTV was defined as extent of BMI and total MTV was as whole tumor burden. 260.5cm(3) and 601.2cm(3) were ideal cut-off values for dividing high and low MTV status in the IM and total lymphoma lesions in Receiver Operating Curve analysis. High risk NCCN-IPI (p&amp;amp;amp;amp;amp;amp;lt;0.001, p&amp;amp;amp;amp;amp;amp;lt;0.001), bulky disease (p=0.011, p=0.005), concordant subtype (p=0.025, p=0.029), high IM MTV status (p&amp;amp;amp;amp;amp;amp;lt;0.001, p&amp;amp;amp;amp;amp;amp;lt;0.001), high total MTV status (p&amp;amp;amp;amp;amp;amp;lt;0.001, p&amp;amp;amp;amp;amp;amp;lt;0.001), and ≥2CAs in BM (p=0.037, p=0.033) were significantly associated with progression-free survival (PFS) and overall survival (OS) than other groups. In multivariate analysis, high risk NCCN-IPI (PFS, p=0.006; OS, p=0.013), concordant subtype (PFS, p=0.005; OS, p=0.007), and high total MTV status (PFS, p&amp;amp;amp;amp;amp;amp;lt;0.001; OS, p&amp;amp;amp;amp;amp;amp;lt;0.001) had independent clinical impacts. MTV had prognostic significances for survivals in DLBCL with BMI.
We analyzed the relation between platelet aggregation measured by light transmittance aggregometr... more We analyzed the relation between platelet aggregation measured by light transmittance aggregometry (LTA) and platelet reactivity index (PRI) measured by vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. It has been suggested that LTA and VASP-P assay correlate differently according to the level of P2Y12 receptor blockade by thienopyridines. We simultaneously measured platelet function by LTA and VASP-P assay in 466 East Asians undergoing elective percutaneous coronary intervention after a 600-mg clopidogrel loading. High on-clopidogrel platelet reactivity (HPR) was defined by published consensus criteria. The degree of correlation between LTA and the VASP-P assay was different according to PRI levels. The correlation was lower in patients with poor responsiveness (PRI >60%) (n = 216) (0.035 ≤ r(2) ≤ 0.047), which was greater in responsive patients (PRI ≤60%) (n = 250) (0.315 ≤ r(2) ≤ 0.526). Despite a 600-mg loading, East Asians had a high prevalence of HPR (4...
Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine ... more Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine the role of AZA before allogeneic stem cell transplantation (allo-SCT), we conducted a prospective study of AZA pre-treatment followed by allo-SCT in patients with higher-risk MDS. Twenty-one patients who were scheduled for their third to sixth cycle of AZA pre-treatment followed by allo-SCT were enrolled. AZA pre-treatment was interrupted early in 3 patients (14.3%) because of leukaemic transformation or death. The overall response rate to AZA pre-treatment was 57.1%. There were 2 cases of complete remission, 1 case of partial remission, and 9 cases of haematologic improvement. Fourteen patients (66.7%) received the planned allo-SCT and 5 patients were alive at the last follow-up. Three-year progression-free survival (PFS) and 3-year overall survival (OS) in the 14 patients who received allo-SCT were 30.0% (95% CI 3.3-56.7) and 42.9% (95% CI 17.1-68.7), respectively. PFS and OS were not...
To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed ... more To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed incidences and prognostic impacts of mutations in c-KIT, WT1, CEBPA, CBL, and a number of epigenetic genes in CBF AML. Seventy one and 21 AML patients with t(8;21) and inv(16) were enrolled in this study, respectively. NPM1, CEBPA, c-KIT, IDH1/2, DNMT3A, EZH2, WT1, and CBL mutations were analyzed by direct sequencing. Patients were categorized with respect to c-KIT and WT1 mutation status, and both clinical features and prognoses were compared. The incidences of FLT3 internal tandem duplication (ITD), NPM1, CEBPA, IDH1/2, DNMT3A, EZH2, and CBL mutations were low (≤5%) in CBF AML patients. However, c-KIT and WT1 mutations occurred frequently (10.9% and 13.8%, respectively). t(8;21) patients with c-KIT mutations showed significantly shorter overall survival (OS) and disease free survival (DFS) periods than those without mutations (P<0.001, for both); however, although the limited number...
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