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Chieh-Lung Cheng,
Hsin-An Hou,
Ming-Cheng Lee,
Chieh-Yu Liu,
Jie-Yang Jhuang,
Yan-Jun Lai,
Chung-Wu Lin,
Huan-Yuan Chen,
Fu-Tong Liu,
Wen-Chien Chou,
Chien-Yuan Chen,
Jih-Luh Tang, Ming Yao,
Shang-Yi Huang,
Bor-Sheng Ko,
Shang-Ju Wu,
Woei Tsay,
Hwei-Fang Tien
[show abstract]
[hide abstract]
ABSTRACT: Alterations of galectin-3 expression are often seen in cancers and may contribute to tumorigenesis, cancer progression and metastasis. The studies concerning clinical implications of galectin-3 expression in patients with acute myeloid leukemia (AML) are scarce. We investigated the expression of LGALS3, the gene encoding galectin-3, in the bone marrow (BM) mononuclear cells from an original cohort comprising 280 adults with primary non-M3 AML. Higher LGALS3 expression was closely associated with older age, French-American-British M4/M5 subtypes, CD14 expression on leukemic cells and PTPN11 mutation, but negatively correlated with CEBPA mutation and FLT3-ITD. Compared to patients with lower LGALS3 expression, those with higher expression had lower complete remission rates, higher primary refractory rates and shorter overall survival. This result was validated in an independent validation cohort. A scoring system incorporating higher LGALS3 expression and eight other risk factors, including age, white blood cell count, cytogenetics, and gene mutations, into survival analysis proved to be very useful to stratify AML patients into different prognostic groups (P<0.001). In conclusion, BM LGALS3 expression may serve as a new biomarker to predict clinical outcome in AML patients and galectin-3 may serve as a potential therapeutic target in those patients with higher expression of this protein.
Blood 02/2013; · 9.90 Impact Factor
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Shang-Ju Wu,
Chien-Ting Lin,
Sheng-Yi Huang,
Fen-Yu Lee,
Ming-Chi Liu,
Hsin-An Hou,
Chien-Yuan Chen,
Bor-Sheng Ko,
Wen-Chien Chou, Ming Yao,
Jih-Luh Tang,
Woei Tsay,
Hwei-Fang Tien
[show abstract]
[hide abstract]
ABSTRACT: Chronic lymphocytic leukemia (CLL) is much less prevalent in Taiwan than in the West, but we have recently addressed the distinctly increasing incidence of CLL in Taiwan. We sought to find out whether there is any difference in cytogenetic abnormalities (CA) of CLL between the West and the East. We analyze the CA, by conventional cytogenetics (CG) and fluorescence in situ hybridization (FISH), and their clinical significance in 83 Taiwanese CLL patients and compared the data to those of Western countries. Thirty-five patients (42.2 %) possessed CG-CA and 58 (69.9 %) FISH-CA. By either CG or FISH, deletion of 17p or 11q was associated with poorer overall survival (OS) (P < 0.001 and P = 0.008, respectively), whereas isolated 13q deletion was associated with better OS (P = 0.050). Trisomy 3 by CG was found in five patients; all of them were in Binet A stage but had strikingly poor OS (P < 0.001). This prognostic impact was independent from the other CA and Binet stages. We conclude that, though the disease incidence is much different, the CA of CLL in Taiwan are similar to those in the West. The combined CG and FISH analysis is able to predict the patients' prognosis. The clinical significance of trisomy 3 warrants further validation.
Annals of Hematology 02/2013; · 2.62 Impact Factor
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ABSTRACT: The prognostic implication of immunophenotyping in acute myeloid leukemia (AML) patients with NPM1 mutation remains unclear.
Ninety-four of 543 AML patients diagnosed with NPM1 mutation between 1987 and 2007 were studied. The expression of surface antigens on leukemic cells was evaluated with respect to clinical manifestations and outcomes. In order to validate the prognostic effect of the immunophenotypic cluster, another 36 patients with NPM1 mutation diagnosed between 2008 and 2010 were analyzed.
Ninety-four patients with NPM1 mutations and complete immunophenotyping data were enrolled for a hierarchical cluster analysis and the result was correlated with clinico-laboratory characteristics. Clustering analysis divided the patients with NPM1 mutations into the following two groups: group I, CD34(-)/CD7(-), but with variable expression of HLA-DR; and group II, HLA DR(+)/CD34(+)/CD7(+). With a median follow-up of 53 months, the group II patients had a significantly shorter relapse-free survival (RFS, median: 3 vs. 23 months, p = 0.006) and overall survival (OS, median: 11 vs. 40 months, p = 0.02) than group I patients. Multivariate analysis of variables, including clinico-laboratory data and other gene mutations revealed that the immunophenotypic cluster is an independent prognostic factor (RFS, p = 0.002; OS, p = 0.024). In order to confirm the prognostic effect of the immunophenotypic cluster, another 36 patients with NPM1 mutation diagnosed between 2008 and 2010 were validated. Hierarchical cluster analysis also showed two distinct clusters, group I patient showed significant better RFS (p = 0.021), and OS (p = 0.055). In total, we stratified 130 NPM1-mutant patients, by FLT3-ITD mutation and immunophenotypic cluster into distinct prognostic groups (RFS, p < 0.001 and OS, p = 0.017).
Among NPM1-mutated AML, the antigen expression pattern of HLADR(+) CD34(+) CD7(+) is associated with a poor prognosis, independent to the FLT3-ITD mutation.
BMC Cancer 01/2013; 13:107. · 3.01 Impact Factor
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Chien-Yuan Chen,
Aristine Cheng,
Shang-Yi Huang,
Wang-Huei Sheng,
Jia-Hau Liu,
Bo-Sheng Ko, Ming Yao,
Wen-Chien Chou,
Hui-Chi Lin,
Yee-Chun Chen,
Woei Tsay,
Jih-Luh Tang,
Shan-Chwen Chang,
Hwei-Fang Tien
[show abstract]
[hide abstract]
ABSTRACT: Perianal infection is a common problem for patients with acute leukemia. However, neutropenia and bleeding tendency are relatively contraindicated to surgical intervention. The epidemiology, microbiology, clinical manifestations and outcomes of perianal infection in leukemic patients are also rarely discussed.
The medical records of 1102 adult patients with acute leukemia at a tertiary medical center in Taiwan between 2001 and 2010 were retrospectively reviewed and analyzed.
The prevalence of perianal infection was 6.7% (74 of 1102) in adult patients with acute leukemia. Twenty-three (31%) of the 74 patients had recurrent episodes of perianal infections. Patients with acute myeloid leukemia had higher recurrent rates than acute lymphoblastic leukemia patients (p = 0.028). More than half (n = 61, 53%) of the perianal infections were caused by gram-negative bacilli, followed by gram-positive cocci (n = 36, 31%), anaerobes (n = 18, 15%) and Candida (n = 1, 1%) from pus culture. Eighteen patients experienced bacteremia (n = 24) or candidemia (n = 1). Overall 41 (68%) of 60 patients had polymicrobial infection. Escherichia coli (25%) was the most common micro-organism isolated, followed by Enterococcus species (22%), Klebsiella pneumoniae (13%), and Bacteroides species (11%). Twenty-five (34%) of 74 patients received surgical intervention. Acute leukemia patients with surgically managed anal fistulas tended to have fewer recurrences (p = 0.067). Four (5%) patients died within 30 days after diagnosis of perianal infection. Univariate analysis of 30-day survival revealed the elderly (≧ 65 years) (p = 0.015) and patients with shock (p<0.001) had worse outcome. Multivariate analysis showed septic shock to be the independent predictive factor of 30-day crude mortality of perianal infections (p = 0.016).
Perianal infections were common and had high recurrence rate in adult patients with acute leukemia. Empirical broad-spectrum antibiotics with anaerobic coverage should be considered. Shock independently predicted 30-day crude mortality. Surgical intervention for perianal infection remains challenging in patients with acute leukemia.
PLoS ONE 01/2013; 8(4):e60624. · 4.09 Impact Factor
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Chien-Yuan Chen,
Chan-Hwei Tai,
Aristine Cheng,
Hung-Chang Wu,
Woei Tsay,
Jia-Hau Liu,
Pey-Ying Chen,
Shang-Yi Huang, Ming Yao,
Jih-Luh Tang,
Hwei-Fang Tien
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Clinical characteristics and outcomes of intracranial hemorrhage (ICH) among adult patients with various hematological malignancies are limited. METHODS: A total of 2,574 adult patients diagnosed with hematological malignancies admitted to a single university hospital were enrolled into this study between 2001 and 2010. The clinical characteristics, image reports and outcomes were retrospectively analyzed. RESULTS: A total of 72 patients (48 men and 24 women) with a median age of 56 (range 18 to 86) had an ICH. The overall ICH incidence was 2.8% among adult patients with hematological malignancies. The incidence of ICH was higher in acute myeloid leukemia (AML) patients than in patients with other hematological malignancies (6.3% vs 1.1%, P = 0.001). ICH was more common among patients with central nervous system (CNS) involvement of lymphoma than among patients with CNS involved acute leukemia (P <0.001). Sites of ICH occurrence included the cerebral cortex (60 patients, 83%), basal ganglia (13 patients, 18%), cerebellum (10 patients, 14%), and brainstem (5 patients, 7%). A total of 33 patients (46%) had multifocal hemorrhages. In all, 56 patients (77%) had intraparenchymal hemorrhage, 22 patients (31%) had subdural hemorrhage, 15 patients (21%) had subarachnoid hemorrhage (SAH), and 3 patients (4%) had epidural hemorrhage. A total of 22 patients had 2 or more types of ICH. In all, 46 (64%) patients died of ICH within 30 days of diagnosis, irrespective of the type of hematological malignancy. Multivariate analysis revealed three independent prognostic factors: prolonged prothrombin time (P = 0.008), SAH (P = 0.021), and multifocal cerebral hemorrhage (P = 0.026). CONCLUSIONS: The incidence of ICH in patients with AML is higher than patients with other hematological malignancies. But in those with intracranial malignant disease, patients with CNS involved lymphoma were more prone to ICH than patients with CNS involved acute leukemia. Mortality was similar regardless of the type of hematological malignancy. Neuroimaging studies of the location and type of ICH could assist with prognosis prediction for patients with hematological malignancies.
BMC Medicine 08/2012; 10(1):97. · 6.03 Impact Factor
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Shang-Ju Wu,
Yuan-Yeh Kuo,
Hsin-An Hou,
Li-Yu Li,
Mei-Hsuan Tseng,
Chi-Fei Huang,
Fen-Yu Lee,
Ming-Chih Liu,
Chia-Wen Liu,
Chien-Ting Lin,
Chien-Yuan Chen,
Wen-Chien Chou, Ming Yao,
Shang-Yi Huang,
Bor-Sheng Ko,
Jih-Luh Tang,
Woei Tsay,
Hwei-Fang Tien
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ABSTRACT: Recurrent somatic mutation of SRSF2, one of the RNA splicing machinery genes, has been identified in a substantial proportion of patients with myelodysplastic syndrome (MDS). However, the clinical and biologic characteristics of MDS with this mutation remain to be addressed. In this study, 34 (14.6%) of the 233 MDS patients were found to have SRSF2 mutation. SRSF2 mutation was closely associated with male sex (P = .001) and older age (P < .001). It occurred concurrently with at least 1 additional mutation in 29 patients (85.3%) and was closely associated with RUNX1, IDH2, and ASXL1 mutations (P = .004, P < .001, and P < .001, respectively). Patients with SRSF2 mutation had an inferior overall survival (P = .010), especially in the lower risk patients. Further exploration showed that the prognostic impact of SRSF2 mutation might be attributed to its close association with old age. Sequential analyses in 173 samples from 66 patients showed that all SRSF2-mutated patients retained their original mutations, whereas none of the SRSF2-wild patients acquired a novel mutation during disease evolution. In conclusion, SRSF2 mutation is associated with distinct clinical and biologic features in MDS patients. It is stable during the clinical course and may play little role in disease progression.
Blood 08/2012; 120(15):3106-11. · 9.90 Impact Factor
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Hsin-An Hou,
Yuan-Yeh Kuo,
Chieh-Yu Liu,
Wen-Chien Chou,
Ming Cheng Lee,
Chien-Yuan Chen,
Liang-In Lin,
Mei-Hsuan Tseng,
Chi-Fei Huang,
Ying-Chieh Chiang, [......],
Chia-Wen Liu,
Jih-Luh Tang, Ming Yao,
Shang-Yi Huang,
Bor-Sheng Ko,
Szu-Chun Hsu,
Shang-Ju Wu,
Woei Tsay,
Yao-Chang Chen,
Hwei-Fang Tien
[show abstract]
[hide abstract]
ABSTRACT: DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. In the present study of 500 patients with de novo AML, DNMT3A mutations were identified in 14% of total patients and in 22.9% of AML patients with normal karyotype. DNMT3A mutations were positively associated with older age, higher WBC and platelet counts, intermediate-risk and normal cytogenetics, FLT3 internal tandem duplication, and NPM1, PTPN11, and IDH2 mutations, but were negatively associated with CEBPA mutations. Multivariate analysis demonstrated that the DNMT3A mutation was an independent poor prognostic factor for overall survival and relapse-free survival in total patients and also in normokaryotype group. A scoring system incorporating the DNMT3A mutation and 8 other prognostic factors, including age, WBC count, cytogenetics, and gene mutations, into survival analysis was very useful in stratifying AML patients into different prognostic groups (P < .001). Sequential study of 138 patients during the clinical course showed that DNMT3A mutations were stable during AML evolution. In conclusion, DNMT3A mutations are associated with distinct clinical and biologic features and poor prognosis in de novo AML patients. Furthermore, the DNMT3A mutation may be a potential biomarker for monitoring of minimal residual disease.
Blood 11/2011; 119(2):559-68. · 9.90 Impact Factor
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ABSTRACT: Superparamagnetic iron oxide (SPIO) nanoparticles show promise as labels for cellular magnetic resonance imaging (MRI) in the application of stem cell-based therapy. However, the unaddressed concerns about the impact of SPIO nanoparticles on stem cell attributes make the feasibility of SPIO labeling uncertain. Here, we show that the labeling of human mesenchymal stem cells (hMSCs) with ferucarbotran can induce epidermal growth factor receptor (EGFR) overexpression. Labeled hMSCs with their overexpressed EGFR were attracted by tumorous EGF and more effectively migrated toward tumor than unlabeled cells, resulting in more potent intrinsic antitumor activity. Moreover, the captured binding of tumorous EGF by overexpressed EGFR of labeled hMSCs blocked EGF/EGFR signaling-derived tumor growth, tumorous angiogenesis, and tumorous VEGF expression also responsible for tumor progression and development. Our results show that the impact of SPIO nanoparticles on stem cell attributes is not necessarily harmful but can be cleverly used to be beneficial to stem cell-based therapy.
ACS Nano 11/2011; 5(12):9807-16. · 10.77 Impact Factor
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Wen-Chien Chou,
Sheng-Chieh Chou,
Chieh-Yu Liu,
Chien-Yuan Chen,
Hsin-An Hou,
Yuan-Yeh Kuo,
Ming-Cheng Lee,
Bor-Sheng Ko,
Jih-Luh Tang, Ming Yao, [......],
Yao-Chang Chen,
Yi-Chang Chang,
Yi-Yi Kuo,
Kuan-Ting Kuo,
Fen-Yu Lee,
Ming-Chi Liu,
Chia-Wen Liu,
Mei-Hsuan Tseng,
Chi-Fei Huang,
Hwei-Fang Tien
[show abstract]
[hide abstract]
ABSTRACT: The studies concerning clinical implications of TET2 mutation in patients with primary acute myeloid leukemia (AML) are scarce. We analyzed TET2 mutation in 486 adult patients with primary AML. TET2 mutation occurred in 13.2% of our patients and was closely associated with older age, higher white blood cell and blast counts, lower platelet numbers, normal karyotype, intermediate-risk cytogenetics, isolated trisomy 8, NPM1 mutation, and ASXL1 mutation but mutually exclusive with IDH mutation. TET2 mutation is an unfavorable prognostic factor in patients with intermediate-risk cytogenetics, and its negative impact was further enhanced when the mutation was combined with FLT3-ITD, NPM1-wild, or unfavorable genotypes (other than NPM1(+)/FLT3-ITD(-) or CEBPA(+)). A scoring system integrating TET2 mutation with FLT3-ITD, NPM1, and CEBPA mutations could well separate AML patients with intermediate-risk cytogenetics into 4 groups with different prognoses (P < .0001). Sequential analysis revealed that TET2 mutation detected at diagnosis was frequently lost at relapse; rarely, the mutation was acquired at relapse in those without TET2 mutation at diagnosis. In conclusion, TET2 mutation is associated with poor prognosis in AML patients with intermediate-risk cytogenetics, especially when it is combined with other adverse molecular markers. TET2 mutation appeared to be unstable during disease evolution.
Blood 08/2011; 118(14):3803-10. · 9.90 Impact Factor
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ABSTRACT: Fusarium species are the second leading cause of disseminated mold infections in immunocompromised patients. The high mortality caused by such infections is attributed to the high resistance of Fusarium species to current antifungal agents. We report the first case of disseminated fusariosis after the use of alemtuzumab, an anti-CD52 monoclonal antibody, in a patient who presented with striking cutaneous and oral cavity lesions. Case reports of combination antifungal therapy for disseminated fusariosis in immunocompromised patients were reviewed. Among 19 published cases in the last 10 years plus this patient, the patients in 14 cases (70%) responded positively to combination antifungal therapy. A clinical response was achieved in seven cases before resolution of neutropenia.
Medical mycology: official publication of the International Society for Human and Animal Mycology 03/2011; 49(8):872-8. · 2.13 Impact Factor
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ABSTRACT: Stem cells have offered much promise as delivery vehicles for brain tumor therapy, with the development of modalities to track the tumor tropism of stem cells receiving intense focus. Cellular magnetic resonance imaging (MRI) allows serial high-resolution in vivo detection of transplanted stem cells' tropism toward gliomas in the mouse brain once these cells are internally labeled with iron oxide particles, but has been impeded by low labeling efficiencies. In this study, we describe the use of ferucarbotran and protamine (Fer-Pro) complexes for labeling human mesenchymal stem cells (hMSCs) for MRI tracking of glioma tropism in vivo. We found that Fer-Pro was not toxic and was highly efficient for labeling in vitro. Cell labeling with Fer-Pro promoted the migration of hMSCs toward glioma U87MG cells in vitro, which was mediated by stromal-derived factor-1/CXCR4 (SDF-1/CXCR4) signaling. Fer-Pro-labeled hMSCs could migrate specifically toward gliomas in vivo, which was observed with a clinical 1.5-T MRI system. The efficient labeling of Fer-Pro also allowed a tropic mechanism mediated by SDF-1/CXCR4 signaling to be detected by MRI in vivo. Additionally, the potential intrinsic inhibitory effect of hMSCs on glioma progression was estimated simultaneously. This is the first report to have used a clinical MRI modality to simultaneously study the migration, the therapeutic impact on tumors, and above all the trafficking mechanism of bone marrow-derived mesenchymal stem cells from human in a murine glioma xenograft model. The use of Fer-Pro for stem cell labeling may have potential clinical applications in stem cell guided therapy.
Biomaterials 02/2011; 32(12):3275-84. · 7.40 Impact Factor
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ABSTRACT: To assess the value of soluble triggering receptor expressed on myeloid cells-1 as a biomarker of infection in patients with neutropenic fever comparing with procalcitonin and C-reactive protein.
Prospective, comparative, single-center study.
Hematology ward at a university hospital.
Seventy-five patients with neutropenic fever after chemotherapy for their hematologic malignancies.
None.
A total of 137 episodes of neutropenic fever in 75 patients were classified into 75 episodes of documented infections and 62 low likelihood of infection. The level of soluble triggering receptor expressed on myeloid cells-1 was significantly elevated in the group of documented infection. The area under the receiver operating characteristic curve for the diagnosis of infection was 0.719 (95% confidence interval, 0.632-0.806; p < .0001) for soluble triggering receptor expressed on myeloid cells-1, which was larger than the values of 0.501 for procalcitonin (0.465-0.657; p = .218) and 0.491 for C-reactive protein (0.394-0.589, p = .858). The fitted marginal logistic regression model of all episodes contained two statistically significant predictors of infection: soluble triggering receptor expressed on myeloid cells-1 (per 1-pg/mL increase; odds ratio [OR], 1.0002; 95% CI, 1.0001-1.0003; p < .0001) and procalcitonin (per 1-ng/mL increase; OR, 1.0094; 95% CI, 1.0005-1.0184; p = .0002). In a diagnostic panel with soluble triggering receptor expressed on myeloid cells-1 and procalcitonin, the sensitivity and specificity were 88% and 48%, respectively.
Soluble triggering receptor expressed on myeloid cells-1 is better than procalcitonin in the prediction of infection at the onset of neutropenic fever. By applying soluble triggering receptor expressed on myeloid cells-1 and procalcitonin together, low or high risk for infection can be defined at the onset of neutropenic fever.
Critical care medicine 01/2011; 39(5):993-9. · 6.37 Impact Factor
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Wen-Chien Chou,
Huai-Hsuan Huang,
Hsin-An Hou,
Chien-Yuan Chen,
Jih-Luh Tang, Ming Yao,
Woei Tsay,
Bor-Sheng Ko,
Shang-Ju Wu,
Shang-Yi Huang,
Szu-Chun Hsu,
Yao-Chang Chen,
Yen-Ning Huang,
Yi-Chang Chang,
Fen-Yu Lee,
Min-Chih Liu,
Chia-Wen Liu,
Mei-Hsuan Tseng,
Chi-Fei Huang,
Hwei-Fang Tien
[show abstract]
[hide abstract]
ABSTRACT: Mutations in the additional sex comb-like 1 (ASXL1) gene were recently shown in various myeloid malignancies, but they have not been comprehensively investigated in acute myeloid leukemia (AML). In this study, we analyzed ASXL1 mutations in exon 12 in 501 adults with de novo AML. ASXL1 mutations were detected in 54 patients (10.8%), 8.9% among those with normal karyotype and 12.9% among those with abnormal cytogenetics. The mutation was closely associated with older age, male sex, isolated trisomy 8, RUNX1 mutation, and expression of human leukocyte antigen-DR and CD34, but inversely associated with t(15;17), complex cytogenetics, FLT3-internal tandem duplication, NPM1 mutations, WT1 mutations, and expression of CD33 and CD15. Patients with ASXL1 mutations had a shorter overall survival than patients without, but the mutation was not an independent adverse prognostic factor in multivariate analysis. Sequential analyses showed that the original ASXL1 mutations were lost at relapse and/or refractory status in 2 of the 6 relapsed ASXL1-mutated patients studied, whereas 2 of the 109 ASXL1-wild patients acquired a novel ASXL1 mutation at relapse. In conclusion, AML bearing ASXL1 mutations showed distinct clinical and biological features. The ASXL1 mutation status can change during disease evolution in a few patients.
Blood 11/2010; 116(20):4086-94. · 9.90 Impact Factor
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Microsugar Chang,
Jong-Kai Hsiao, Ming Yao,
Li-Ying Chien,
Szu-Chun Hsu,
Bor-Sheng Ko,
Shin-Tai Chen,
Hon-Man Liu,
Yao-Chang Chen,
Chung-Shi Yang,
Dong-Ming Huang
[show abstract]
[hide abstract]
ABSTRACT: Ultrasmall superparamagnetic iron oxide (USPIO) particles are very useful for cellular magnetic resonance imaging (MRI), which plays a key role in developing successful stem cell therapies. However, their low intracellular labeling efficiency, and biosafety concerns associated with their use, have limited their potential usage. In this study we develop a novel system composed of RBC-derived vesicles (RDVs) for efficient delivery of USPIO particles into human bone marrow mesenchymal stem cells (MSCs) for cellular MRI in vitro and in vivo. RDVs are highly biosafe to their autologous MSCs as manifested by cell viability, differentiation, and gene microarray assays. The data demonstrate the potential of RDVs as intracellular delivery vehicles for biomedical applications.
Nanotechnology 06/2010; 21(23):235103. · 3.98 Impact Factor
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Wen-Chien Chou,
Hsin-An Hou,
Chien-Yuan Chen,
Jih-Luh Tang, Ming Yao,
Woei Tsay,
Bor-Shen Ko,
Shang-Ju Wu,
Shang-Yi Huang,
Szu-Chun Hsu,
Yao-Chang Chen,
Yen-Ning Huang,
Yi-Chang Chang,
Fen-Yu Lee,
Ming-Chi Liu,
Chia-Wen Liu,
Mei-Hsuan Tseng,
Chi-Fei Huang,
Hwei-Fang Tien
[show abstract]
[hide abstract]
ABSTRACT: Mutations of nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase gene (IDH1) have been identified in patients with gliomas. Recent genome-wide screening also revealed IDH1 mutation as a recurrent event in acute myeloid leukemia (AML), but its clinical implications in AML are largely unknown. We analyzed 493 adult Chinese AML patients in Taiwan and found 27 patients (5.5%) harboring this mutation. IDH1 mutation was strongly associated with normal karyotype (8.4%, P = .002), isolated monosomy 8 (P = .043), NPM1 mutation (P < .001), and French-American-British M1 subtype (P < .001), but inversely associated with French-American-British M4 subtype (P = .030) and expression of HLA-DR, CD13, and CD14 (P = .002, .003, and .038, respectively). There was no impact of this mutation on patient survival. Sequential analysis of IDH1 mutation was performed in 130 patients during follow-ups. None of the 112 patients without IDH1 mutation at diagnosis acquired this mutation at relapse. In all 18 IDH1-mutated patients studied, the mutation disappeared in complete remission; the same mutation reappeared in all 11 samples obtained at relapse. We conclude that IDH1 is associated with distinct clinical and biologic characteristics and seems to be very stable during disease evolution.
Blood 04/2010; 115(14):2749-54. · 9.90 Impact Factor
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Hsin-An Hou,
Tai-Chung Huang,
Liang-In Lin,
Chieh-Yu Liu,
Chien-Yuan Chen,
Wen-Chien Chou,
Jih-Luh Tang,
Mei-Hsuan Tseng,
Chi-Fei Huang,
Ying-Chieh Chiang,
Fen-Yu Lee,
Ming-Chih Liu, Ming Yao,
Shang-Yi Huang,
Bor-Sheng Ko,
Szu-Chun Hsu,
Shang-Ju Wu,
Woei Tsay,
Yao-Chang Chen,
Hwei-Fang Tien
[show abstract]
[hide abstract]
ABSTRACT: The impact of WT1 mutations in acute myeloid leukemia (AML) is not completely settled. We aimed to determine the clinical implication of WT1 mutation in 470 de novo non-M3 AML patients and its stability during the clinical course. WT1 mutations were identified in 6.8% of total patients and 8.3% of younger patients with normal karyotype (CN-AML). The WT1 mutation was closely associated with younger age (P < .001), French-American-British M6 subtype (P = .006), and t(7;11)(p15;p15) (P = .003). Multivariate analysis demonstrated that the WT1 mutation was an independent poor prognostic factor for overall survival and relapse-free survival among total patients and the CN-AML group. A scoring system incorporating WT1 mutation, NPM1/FLT3-ITD, CEBPA mutations, and age into survival analysis proved to be very useful to stratify CN-AML patients into different prognostic groups (P < .001). Sequential analyses were performed on 133 patients. WT1 mutations disappeared at complete remission in all WT1-mutated patients studied. At relapse, 3 of the 16 WT1-mutated patients who had paired samples lost the mutation and 2 acquired additional mutations, whereas 3 of 110 WT1-wild patients acquired novel mutations. In conclusion, WT1 mutations are correlated with poor prognosis in AML patients. The mutation status may be changed in some patients during AML progression.
Blood 04/2010; 115(25):5222-31. · 9.90 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Superparamagnetic iron oxide (SPIO) nanoparticles are very useful for monitoring cell trafficking in vivo and distinguish whether cellular regeneration originated from an exogenous cell source, which is a key issue for developing successful stem cell therapies. However, the impact of SPIO labeling on stem cell behavior remains uncertain. Here, we show the inhibitory effect of Ferucarbotran, an ionic SPIO, on osteogenic differentiation and its signaling mechanism in human mesenchymal stem cells. Ferucarbotran caused a dose-dependent inhibition of osteogenic differentiation, abolished the differentiation at high concentration, promoted cell migration, and activated the signaling molecules, beta-catenin, a cancer/testis antigen, SSX, and matrix metalloproteinase 2 (MMP2). An iron chelator, desferrioxamine, suppressed all the above Ferucarbotran-induced actions, demonstrating an important role of free iron in the inhibition of osteogenic differentiation that is mediated by the promotion of cell mobilization, involving the activation of a specific signaling pathway.
Toxicology and Applied Pharmacology 03/2010; 245(2):272-9. · 4.45 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Recently, dynamic contrast-enhanced magnetic resonance imaging has been shown to be a non-invasive technique that provides global and functional imaging of bone marrow angiogenesis in acute myeloid leukemia. To assess the clinical implication of changes in angiogenesis shortly after induction chemotherapy, dynamic contrast-enhanced magnetic resonance imaging was performed prospectively before treatment (day 0) and on day 7 in 80 patients with de novo acute myeloid leukemia. We demonstrated that a post-therapeutic reduction in Peak (negative DeltaPeak) compared with the day 0 value was significantly associated with a higher chance of achieving complete remission, and better overall and disease free survival (P=0.022, 0.003 and 0.007, respectively). Cox's multivariate analysis also identified negative DeltaPeak value as an independent good prognostic factor for overall and disease free survival. Our findings provide evidence that the change of Peak on day 7 relative to pre-treatment levels may be a relevant biomarker for early identification of patients who may fail conventional induction chemotherapy (ClinicalTrials.gov Identifier: NCT00172562).
Haematologica 03/2010; 95(8):1420-4. · 6.42 Impact Factor
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Jih-Luh Tang,
Hsin-An Hou,
Chien-Yuan Chen,
Chieh-Yu Liu,
Wen-Chien Chou,
Mei-Hsuan Tseng,
Chi-Fei Huang,
Fen-Yu Lee,
Ming-Chih Liu, Ming Yao,
Shang-Yi Huang,
Bor-Sheng Ko,
Szu-Chun Hsu,
Shang-Ju Wu,
Woei Tsay,
Yao-Chang Chen,
Liang-In Lin,
Hwei-Fang Tien
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ABSTRACT: Somatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.
Blood 10/2009; 114(26):5352-61. · 9.90 Impact Factor
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ABSTRACT: Hepatosplenic T γ/δ lymphoma is a rare entity of peripheral T cell lymphoma. Three of 386 patients with non-Hodgkin's lymphoma in our institute were found to have this subtype of lymphoma. All had chromosomal abnormalities of isochromosome 7q and trisomy 8. The clinical and hematological features of these three patients are reported. All were males with ages ranging from 23 to 29 years. Initial presentation comprised purpura and variable degree of hepatosplenomegaly. None had superficial lymphadenopathy. Hematologically, they showed pictures resembling immune related thrombocytopenia and/or hemolytic anemia. Examination of the bone marrows revealed hypercellularity with increased number of megakaryocytes and erythroid cells and various degrees of abnormal lymphoid cell infiltration. The histopathologic section of the spleen from one patient who underwent splenectomy revealed abnormal cell infiltration in the sinusoids of the red pulp. Lymphoma cells showed T γ/δ lymphoid immunophenotype (CD3+ CD2+ CD4- CD8-, TCR δ -1+, and β F1-). The platelet counts were elevated transiently after initial treatment with corticosteroids, but the condition soon deteriorated. All died of refractory lymphoma five to nine months after diagnosis. Review of the literature, showed that only four other cases have been reported until now and although no cytogenetic data were available for these patients, they had very similar clinical pictures as those in this series. It is suggested that hepatosplenic T y/8 lymphoma represents a rare, but distinct, clinicopathological and cytogenetic entity.
06/2009; 22(5-6):495-500.
