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3.  N-ras Mutation Detection by Pyrosequencing in Adult Patients with Acute Myeloid Leukemia at a Single Institution 
Annals of Laboratory Medicine  2013;33(3):159-166.
Background
N-ras mutations are one of the most commonly detected abnormalities of myeloid origin. N-ras mutations result in a constitutively active N-ras protein that induces uncontrolled cell proliferation and inhibits apoptosis. We analyzed N-ras mutations in adult patients with AML at a particular institution and compared pyrosequencing analysis with a direct sequencing method for the detection of N-ras mutations.
Methods
We analyzed 90 bone marrow samples from 83 AML patients. We detected N-ras mutations in codons 12, 13, and 61 using the pyrosequencing method and subsequently confirmed all data by direct sequencing. Using these methods, we screened the N-ras mutation quantitatively and determined the incidence and characteristic of N-ras mutation.
Results
The incidence of N-ras mutation was 7.2% in adult AML patients. The patients with N-ras mutations showed significant higher hemoglobin levels (P=0.022) and an increased incidence of FLT3 mutations (P=0.003). We observed 3 cases with N-ras mutations in codon 12 (3.6%), 2 cases in codon 13 (2.4%), and 1 case in codon 61 (1.2%). All the mutations disappeared during chemotherapy.
Conclusions
There is a low incidence (7.2%) of N-ras mutations in AML patients compared with other populations. Similar data is obtained by both pyrosequencing and direct sequencing. This study showed the correlation between the N-ras mutation and the therapeutic response. However, pyrosequencing provides quantitative data and is useful for monitoring therapeutic responses.
doi:10.3343/alm.2013.33.3.159
PMCID: PMC3646189  PMID: 23667841
N-ras; AML; Pyrosequencing; Bone marrow
4.  A case of therapy-related acute myeloid leukemia with inv(16)(p13.1q22) after single low-dose iodine-131 treatment for thyroid cancer 
The Korean Journal of Hematology  2012;47(3):225-228.
Radioiodine is regularly used in the treatment of thyroid cancer to eliminate residual malignant tissue after thyroidectomy and to treat metastasis. Because of the low dose of radioiodine used to treat thyroid cancer patients, leukemia is an uncommon complication of exposure to radioiodine. Here, we present a patient who developed therapy-related acute myeloid leukemia with inv(16)(p13.1q22);CBFβ-MYH11, eosinophilia, and K-ras mutation and who had been treated with very low-dose radioiodine following total thyroidectomy.
doi:10.5045/kjh.2012.47.3.225
PMCID: PMC3464341  PMID: 23071479
Radioiodine; Thyroid cancer; Acute myeloid leukemia; CBFβ-MYH11; Eosinophilia; K-ras
5.  A Case of B-cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-cell Lymphoma and Burkitt Lymphoma in a Korean Child 
Annals of Laboratory Medicine  2012;32(2):162-166.
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) (intermediate DLBCL/BL), is a heterogeneous group with some features resembling DLBCL and others resembling BL. Here, we report a case of intermediate DLBCL/BL in a Korean child. A 2-yr-old male was admitted for evaluation and management of left hip pain. Immunohistochemistry of a biopsy of the femur neck revealed tumor cells positive for CD20, CD10, BCL2, BCL6, and Ki67. A bone marrow (BM) aspirate smear revealed that 49.3% of all nucleated cells were abnormal lymphoid cells, composed of large- and medium-sized cells. Immunophenotyping of the neoplastic cells revealed positivity for CD19, CD10, CD20, and sIg lambda and negativity for CD34, Tdt, and myeloperoxidase (MPO). Cytogenetic and FISH analyses showed a complex karyotype, including t(8;14)(q24.1;q32) and IGH-MYC fusion. Intensive chemotherapy was initiated, including prednisone, vincristine, L-asparaginase, daunorubicin, and central nervous system prophylaxis with intrathecal methotrexate (MTX) and cytarabine. One month after the initial diagnosis, BM examination revealed the persistent of abnormal lymphoid cells; cerebrospinal fluid cytology, including cytospin, showed atypical lymphoid cells. The patient was treated again with cyclophosphamide, vincristine, prednisone, adriamycin, MTX, and intrathecal MTX and cytarabine. The patient died of sepsis 5 months after the second round of chemotherapy.
doi:10.3343/alm.2012.32.2.162
PMCID: PMC3289783  PMID: 22389885
Diffuse large B-cell lymphoma; Burkitt lymphoma; Gray zone lymphoma
6.  Diagnostic Usefulness of the Janus Kinase 2 Mutation in non BCR/ABL Myeloproliferative Disorders 
Background
We investigated the Janus kinase 2 (JAK2) mutation and its diagnostic value in patients suffering with non BCR/ABL myeloproliferative diseases (nMPD) or other reactive conditions.
Methods
We reviewed the clinical records of 83 patients who underwent bone marrow (BM) examinations with suspect of nMPD. The diagnoses of nMPD were made based on the WHO criteria since 2001 and the PVSG criteria before 2001. The JAK2 mutation was examined by PCR in 54 patients whose BM samples were available.
Results
The JAK2 mutation was detected in 25 patients (46%); 12 of 26 patients with essential thrombocythemia (ET), 9 of 12 patients with polycyhtemia vera (PV), one of 7 patients with chronic idiopathic myelofibrosis (CIM) and one patient with unclassifiable MPD. Additionally, JAK2 mutation was detected in each one patient with secondary polycythemia and reactive thrombocytosis. These two patients and two other patients among the JAK2 mutated ET did not meet the WHO PV criteria due to their initial low hemoglobin levels. These patients had liver cirrhosis and hypersplenism due to Budd-Chiari syndrome (1), gastrointestinal bleeding (1) or the initial hemoglobin level was slightly below the level as provided by the criteria, but the level showed a rising pattern despite cytoreductive therapy (2). With the results of the JAK2 mutation available, 4 patients' disease could be re-diagnosed as PV. Finally, the positive rate of the JAK2 mutation was 81% in PV, 48% in ET and 14% in CIM. The presence of JAK2 mutation closely correlated with PV (p=0.001), leukocytosis (p=0.001) and an increased cellularity of BM (p=0.024).
Conclusions
The JAK2 mutation may help differentiate nMPD from secondary cytosis. Therefore, it should be incorporated into the guidelines for the nMPD work-up for making a more accurate diagnosis and administering proper treatment.
doi:10.3904/kjim.2006.21.4.219
PMCID: PMC3891025  PMID: 17249502
Janus kinase 2 mutation; Myeloproliferative disorders; Polycythemia vera; Essential thrombocythemia; Chronic idiopathic myelofibrosis
8.  Usefulness of 18F-FDG PET/CT for the Evaluation of Bone Marrow Involvement in Patients with High-Grade Non-Hodgkin’s Lymphoma 
Purpose
To assess the usefulness of 18F-fluorodeoxyglucose PET/CT in the detection of bone marrow (BM) involvement of high-grade non-Hodgkin’s lymphoma (NHL).
Methods
One hundred twenty patients with newly diagnosed diffuse large B-cell lymphoma or peripheral T-cell lymphoma between January 2007 and June 2011, who received BM trephine biopsy and 18F-FDG PET/CT before chemotherapy, were included in this retrospective study. We reviewed their 18F-FDG PET/CT images and bone marrow biopsy (BMB) results. After reviewing the images, we reviewed the medical records and radiological findings of interesting patients.
Results
There were 23 18F-FDG PET/CT scans in which the marrow was considered to be abnormal (either positive or equivocal), and 97 18F-FDG PET/CT scans were regarded as having negative FDG uptake. Of 120 patients, 100 (83.3 %) had a concordant result of BM interpretation between 18F-FDG PET/CT and BMB, and the remaining 20 patients had discordant results. Among 23 patients with either positive or equivocal 18F-FDG PET/CT scans, 1 of 12 patients with ‘positive’ 18F-FDG PET/CT had a lymphomatous involvement on BMB. In contrast, 10 of 11 patients with ‘equivocal’ BM hypermetabolism were reported as having positive involvement by BMB. Patients with abnormal 18F-FDG PET/CT had significantly higher mSUVhighest than those with normal FDG-PET/CT.
Conclusions
18F-FDG PET/CT and BMB are complementary techniques in assessing the presence of BM involvement in patients with high-grade NHL. The increasing availability of 18F-FDG PET/CT will raise the need for additional biopsy for FDG-avid lesions, especially in patients with negative standard BMBs. 18F-FDG PET/CT can be useful as a decision-making tool for determining whether to perform a standard BMB or targeted biopsy to the FDG-avid lesion as an initial staging procedure. A direct bone biopsy for FDGpositive bone lesions should be included in staging guidelines in future. In 18F-FDG PET/CT-negative cases, BMB is still a powerful procedure, but BMB alone is insufficient for full evaluation of BM.
doi:10.1007/s13139-012-0153-9
PMCID: PMC4043073  PMID: 24900074
18F-FDG PET/CT; Lymphoma; Bone marrow
9.  Cervical Lymphadenopathy Mimicking Angioimmunoblastic T-Cell Lymphoma after Dapsone-Induced Hypersensitivity Syndrome 
Korean Journal of Pathology  2012;46(6):606-610.
A 36-year-old woman presented with erythematous confluent macules on her whole body with fever and chills associated with jaundice after 8 months of dapsone therapy. Her symptoms had developed progressively, and a physical examination revealed bilateral cervical lymphadenopathy and splenomegaly. Excisional biopsy of a cervical lymph node showed effacement of the normal architecture with atypical lymphoid hyperplasia and proliferation of high endothelial venules compatible with angioimmunoblastic T-cell lymphoma. However, it was assumed that the cervical lymphadenopathy was a clinical manifestation of a systemic hypersensitivity reaction because her clinical course was reminiscent of dapsone-induced hypersensitivity syndrome. A liver biopsy revealed drug-induced hepatitis with no evidence of lymphomatous involvement. Intravenous glucocorticoid was immediately initiated and her symptoms and clinical disease dramatically improved. The authors present an unusual case of cervical lymphadenopathy mimicking angioimmunoblastic T-cell lymphoma as an adverse reaction to dapsone.
doi:10.4132/KoreanJPathol.2012.46.6.606
PMCID: PMC3540342  PMID: 23323115
Pseudolymphoma; Dapsone therapy
10.  Tumor cell nuclear diameter and CD30 expression as potential prognostic parameter in patients with extranodal NK/T-cell lymphoma, nasal type 
Extranodal natural killer/T-cell lymphoma, nasal type (nasal ENKTL) is a distinct clinicopathologic entity of lymphoid tumors with variable size and differentiation of tumor cells. Nasal ENKTL is related to infection of the tumor cells with Epstein-Barr virus (EBV) and virtually all cases contain monoclonal episomal EBV DNA and detectable EBV encoded small nuclear RNAs (EBERs). Several clinical factors are known for their relation to the prognosis, but histopathologic prognostic factors of nasal ENKTL have not yet been well established. We evaluated the prognostic value of the longest nuclear diameter of EBER+ tumor cells (NDTC) along with the result of CD30 expression. Twenty two patients with newly diagnosed nasal ENKTL were evaluated regarding clinicopathologic characteristics. NDTC was measured using a computerized image analysis system. The results were expressed as the mean diameter of ≥ 50 cells in a patient. Median of the mean NDTC of the patients was 7.32 μm (5.15-11.27). Patients with larger mean NDTC (≥ 7.35 μm) had a poorer event-free survival (EFS) than those with smaller mean NDTC (<7.35 μm; p = 0.024) and had a tendency of inferior overall survival (OS) (p = 0.08). Patients with CD30 expression had a inferior EFS (p = 0.018) and OS (p = 0.011) compared those without CD30 expression. The NDTC of EBV infected tumor cell and CD30 expression had relation to survival in the current exploratory analysis.
PMCID: PMC3484496  PMID: 23119111
Extranodal NK/T-cell lymphoma; nasal type; epstein-barr virus; CD30; prognosis; nuclear diameter
11.  Simvastatin Improves Flow-Mediated Dilation but Reduces Adiponectin Levels and Insulin Sensitivity in Hypercholesterolemic Patients 
Diabetes care  2008;31(4):776-782.
OBJECTIVE
We hypothesized that simvastatin may reduce adiponectin levels and insulin sensitivity in hypercholesterolemic patients.
RESEARCH DESIGN AND METHODS
This was a randomized, double-blind, placebo-controlled, parallel study. Age, sex, and BMI were matched. Thirty-two patients were given placebo, and 30, 32, 31, and 31 patients were given daily 10, 20, 40, and 80 mg simvastatin, respectively, during a 2-month treatment period.
RESULTS
Simvastatin doses of 10, 20, 40, and 80 mg significantly reduced total cholesterol (mean changes 27, 25, 37, and 38%), LDL cholesterol (39, 38, 52, and 54%), and apolipoprotein B levels (24, 30, 36, and 42%) and improved flow-mediated dilation (FMD) (68, 40, 49, and 63%) after 2 months of therapy compared with baseline (P < 0.001 by paired t test) or compared with placebo (P < 0.001 by ANOVA). Simvastatin doses of 10, 20, 40, and 80 mg significantly decreased plasma adiponectin levels (4, 12, 5, and 10%) and insulin sensitivity (determined by the Quantitative Insulin-Sensitivity Check Index [QUICKI]) (5, 8, 6, and 6%) compared with baseline (P < 0.05 by paired t test) or compared with placebo (P = 0.011 for adiponectin and P = 0.034 for QUICKI by ANOVA). However, the magnitudes of these percent changes (FMD, adiponectin, and QUICKI) were not significantly different among four different doses of simvastatin despite dose-dependent changes in the reduction of apolipoprotein B levels.
CONCLUSIONS
Simvastatin significantly improved endothelium-dependent dilation, but reduced adiponectin levels and insulin sensitivity in hypercholesterolemic patients independent of dose and the extent of apolipoprotein B reduction.
doi:10.2337/dc07-2199
PMCID: PMC2950311  PMID: 18184901
12.  Low Frequency and Variability of FLT3 Mutations in Korean Patients with Acute Myeloid Leukemia 
Journal of Korean Medical Science  2008;23(5):833-837.
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.
doi:10.3346/jkms.2008.23.5.833
PMCID: PMC2580007  PMID: 18955790
FLT3 Mutations; Internal Tandem Duplication; Tyrosine Kinase Domain Mutation; Leukemia, Myeloid, Acute
13.  Neutrophilic Myositis without Cutaneous Involvement as the First Manifestation of Acute Myeloid Leukemia 
Muscle involvement in acute febrile neutrophilic dermatosis is uncommon. Herein, we report a case of acute febrile neutrophilic myositis, without cutaneous involvement, as the first manifestation of acute myeloid leukemia. The patient was a 35-year-old male, referred due to painful swelling of the left upper arm and fever. The overlying skin looked normal, and a muscle biopsy revealed dense infiltrates, predominantly composed of mature neutrophils, edema and tissue necrosis. All culture reports were negative, and he was finally diagnosed as having acute febrile neutrophilic myositis, associated with acute myeloid leukemia. Corticosteroid treatment resulted in the progressive regression of the fever, myalgia and swelling.
doi:10.3904/kjim.2005.20.4.346
PMCID: PMC3891084  PMID: 16491836
Acute febrile neutrophilic dermatosis; Myositis; Acute myeloid leukemia
14.  Association Between FcgammaR IIa and IIIa polymorphism and clinical manifestations in Korean patients with adult-onset Still's disease. 
High-dose intravenous immunoglobulins alter the disease activity of adult-onset Still's disease (AOSD). Because activation status of FcgammaR is possibly dependent on their genetic polymorphisms, we investigated whether the polymorphisms of FcgammaR IIa and IIIa are risk factors, and affect the clinical features of AOSD. Genomic DNA was extracted from 36 patients and from 197 healthy controls. Polymerase chain reaction for FcgammaR IIa and IIIa using the allele-specific primers and direct sequencing of FcgammaR IIIa polymorphic site were performed. The frequencies of FcgammaR IIa/IIIa genotype between patients with AOSD and controls were not different. The allelic frequencies of FcgammaR IIa/IIIa between patients with AOSD and controls were not different, either. However, the FcgammaR IIa-R/R131 genotype was associated with a higher concentration of hemoglobin (p=0.04) and stable liver function (p=0.009) than the other genotypes. The FcgammaR IIIa-F/F176 genotype was associated with significantly lower titers of serum ferritin (p=0.025), and higher serum albumin (p=0.037) and cholesterol (p=0.014) concentrations than the other genotypes. This study suggest that the FcgammaR IIa and IIIa polymorphisms might not be genetic risk factors for AOSD in Korean, but contribute to the activity of disease. FcgammaR IIa-R/R131 and IIIa-F/F176 genotypes, low-binding genotypes for IgG2a and G1, may have more protective effects in acute stage of the disease than the other genotypes.
PMCID: PMC3054835  PMID: 11850593

Results 1-14 (14)