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1.  Adult T-Cell Lymphoma/Leukemia Presenting as Isolated Central Nervous System T-Cell Lymphoma 
Case Reports in Hematology  2014;2014:917369.
Adult T-cell leukemia/lymphoma (ATLL) is a T-cell neoplasm, associated with infection by the retrovirus human T-lymphotropic virus type 1 (HTLV-1). Central nervous system (CNS) involved by ATLL is often occurred in advanced disease, such as acute and lymphomatous variants. On the other hand, isolated CNS lymphoma is rare. We repot a 50-year-old woman who presented with multiple infiltrative brain lesions on the magnetic resonance (MR) imaging. Results of initial biopsy of brain tumor indicated CNS vasculitis. The patient received one course of high-dose methotrexate and MR imaging of brain revealed remission of infiltrative lesions. Two years later, new brain lesions were detected. Histopathologic examination of specimens via craniotomy revealed T-cell lymphoma. The patient responded poorly to subsequent chemotherapy, and salvage whole-brain irradiation was performed. Six months later, the patient had hepatosplenomegaly, hypercalcemia, and multiple lymphocytes with a cloverleaf appearance in circulation. Results of flow cytometry analysis of peripheral blood indicated ATLL and antibodies to human T-lymphotropic virus type 1 (HTLV-1) were detected. Clinicians should screen HTLV-1 infection when patients are diagnosed with peripheral T-cell lymphoma. Combined antiviral therapy and intensive chemotherapy may improve the outcomes of ATLL.
doi:10.1155/2014/917369
PMCID: PMC4284927  PMID: 25587470
2.  Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma 
Annals of Hematology  2014;93(8):1371-1380.
Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0–8) and a score ≥4.5 was used for CRBN positivity (CRBN+) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN+ NDMM patients, CRBN− NDMM patients had more international staging system (ISS) III (26 vs. 61 %, respectively; P = 0.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN+ patients than CRBN− patients (LD 79 vs. 33 %, respectively; P = 0.005) (TD 75 vs. 29 %, respectively; P = 0.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN+ for treatment response was 79 and 67 % and 75 and 71 %, respectively. Multivariate analysis showed that CRBN+ was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.
doi:10.1007/s00277-014-2063-7
PMCID: PMC4082140  PMID: 24687382
Cereblon; Immunohistochemistry; Immunomodulatory drugs; Multiple myeloma; Prognosis
3.  Clinicopathologic features and responses to radiotherapy of myeloid sarcoma 
Background
To evaluate clinicopathological features, radiotherapeutic parameters, and their associations with responses to radiotherapy (RT) in patients with myeloid sarcoma (MS).
Methods
We reviewed 20 patients receiving RT for MS lesions (in 43 RT courses) and analyzed the patients’ clinicopathologic features and radiotherapeutic parameters, and their associations with complete responses (CR) to RT using Fisher’s exact test and univariate logistic regression analysis. Generalized Estimating Equation was used to analyze all 43 irradiated lesions and account for the correlations in RT responses among lesions from the same patient.
Results
We found that the underlying hematological diseases of the evaluated patients were acute myeloid leukemia (AML) in 14 patients (70%), chronic myeloid leukemia in 4 patients (20%), myelodysplastic syndrome with AML transformation in one patient (5%), and de novo MS in one patient (5%). Most patients (55%) received RT for MS at the time of relapse following bone marrow transplantation (BMT). The most common cytogenetic abnormality was t(8;21)(q22;q22). The median RT dose of 20 Gy (range 6–35 Gy), administered in 1.5-3.5 Gy fractions, provided a 63% CR rate. RT dose, sex, cytogenetics, and bone marrow status at the time of RT had no significant effect on CR. Younger age (<50 y, P = 0.06), BMT prior to RT (P = 0.05), and underlying AML (P = 0.05) were marginally associated with higher CR to RT.
Conclusions
Our results indicate that a modest RT dose (20-30 Gy) achieves good local control of MS. Age, previous BMT, and underlying hematologic disease can affect RT response.
doi:10.1186/1748-717X-8-245
PMCID: PMC4016483  PMID: 24148102
Chloroma; Granulocytic sarcoma; Myeloid sarcoma; Extramedullary leukemia; Radiotherapy
4.  Improving but Inferior Survival in Patients with Chronic Lymphocytic Leukemia in Taiwan: A Population-Based Study, 1990–2004 
PLoS ONE  2013;8(4):e62930.
Background
Chronic lymphocytic leukemia (CLL) is much less prevalent in Asian countries. Whether there are differences in survival outcomes between the East and West, however, remain unclear.
Methods
The survival data for CLL patients identified in the Taiwan Cancer Registry database between 1990 and 2004, together with corresponding data in the US Surveillance, Epidemiology, and End Results database, were retrieved. The relative survivals (RS, adjusted for the expected survival in the general population) were estimated in patients diagnosed in three 5-year periods of time.
Results
CLL drastically shortened patients’ life expectancy; more importantly, this negative impact in Taiwan was much larger than that in the US: the 5-year RS in Taiwan and US were 59% and 76%, and the 10-year RS, 45% and 56%, respectively. Nevertheless, survival in Taiwan was better in the periods after 1995 (5-year RS, from 53.0% to 60.6%), a time period corresponding to the introduction of the Taiwan National Health Insurance scheme. Such improvement was largely due to decreased mortality in patients younger than 65 (5-year RS, from 53.5% to 69.1%). Despite the improvement, patients’ RS in Taiwan in recent periods remain steadily 15∼20% inferior to that in the US in both younger and older patient groups.
Conclusions
The improved RS in Taiwan implies that therapeutic advances are changing the prognosis of CLL. The stable RS gap between Taiwanese and the US patients suggests the existence of an ethnic difference in CLL patients’ outcomes.
doi:10.1371/journal.pone.0062930
PMCID: PMC3634739  PMID: 23638168
5.  Clinical and Microbiological Characteristics of Perianal Infections in Adult Patients with Acute Leukemia 
PLoS ONE  2013;8(4):e60624.
Background
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.
Method
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.
Result
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).
Conclusion
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.
doi:10.1371/journal.pone.0060624
PMCID: PMC3618431  PMID: 23577135
6.  Hierarchical cluster analysis of immunophenotype classify AML patients with NPM1 gene mutation into two groups with distinct prognosis 
BMC Cancer  2013;13:107.
Background
The prognostic implication of immunophenotyping in acute myeloid leukemia (AML) patients with NPM1 mutation remains unclear.
Methods
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.
Results
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).
Conclusions
Among NPM1-mutated AML, the antigen expression pattern of HLADR(+) CD34(+) CD7(+) is associated with a poor prognosis, independent to the FLT3-ITD mutation.
doi:10.1186/1471-2407-13-107
PMCID: PMC3599624  PMID: 23496932
Acute myeloid leukemia; NPM1 mutation; Immunophenotype; Prognosis
7.  A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment 
PLoS ONE  2012;7(11):e49769.
Somatic Nucleophosmin (NPM1) mutation frequently occurs in acute myeloid leukemia (AML), but its role in leukemogenesis remains unclear. This study reports the first “conventional” knock-in mouse model of Npm1 mutation, which was achieved by inserting TCTG after nucleotide c.857 (c.854_857dupTCTG) to mimic human mutation without any “humanized” sequence. The resultant mutant peptide differed slightly different from that in humans but exhibited cytoplasmic pulling force. Homozygous (Npm1c+/c+) mice showed embryonic lethality before day E8.5, wheras heterozygous (Npm1wt/c+) mice appeared healthy at birth and were fertile. Approximately 36% of Npm1wt/c+ mice developed myeloproliferative disease (MPD) with extramedullary hematopoiesis. Those Npm1wt/c+ mice that did not develop MPD nevertheless gradually developed monocytosis and showed increased numbers of marrow myeloid precursors. This second group of Npm1wt/c+ mice also showed compromised cobblestone area formation, suggesting pathology in the hematopoietic niche. Microarray experiments and bioinformatic analysis on mice myeloid precursor cells and 227 human samples revealed the expression of CXCR4/CXCL12-related genes was significantly suppressed in mutant cells from both mice and humans. Thus, our mouse model demonstrated that Npm1 mutation can result in MPD, but is insufficient for leukemogenesis. Perturbation of hematopoietic niche in mutant hematopoietic stem cells (implied by underrepresentation of CXCR4/CXCL12-related genes) may be important in the pathogenesis of NPM1 mutations.
doi:10.1371/journal.pone.0049769
PMCID: PMC3511491  PMID: 23226219
8.  Intracranial hemorrhage in adult patients with hematological malignancies 
BMC Medicine  2012;10:97.
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.
doi:10.1186/1741-7015-10-97
PMCID: PMC3482556  PMID: 22931433
central nervous system (CNS) involvement; cerebral hemorrhage; hematological malignancy; prognosis; neuroimage
9.  Clinical characteristics and outcomes of Mycobacterium tuberculosis disease in adult patients with hematological malignancies 
BMC Infectious Diseases  2011;11:324.
Background
Diseases caused by Mycobacterium tuberculosis (TB) among adult patients with hematological malignancies have rarely been investigated.
Methods
Adult patients with hematological malignancies at National Taiwan University Hospital between 1996 and 2009 were retrospectively reviewed. Patients with positive serology for HIV were excluded. TB disease is diagnosed by positive culture(s) in the presence of compatible symptoms and signs. The demographics, laboratory and, microbiological features, were analyzed in the context of clinical outcomes.
Results
Fifty-three of 2984 patients (1.78%) were diagnosed with TB disease. The estimated incidence was 120 per 100,000 adult patients with hematological malignancies. Patients with acute myeloid leukemia had a significantly higher incidence of TB disease than other subtypes of hematological malignancies (2.87% vs. 1.21%, p = 0.002, odds ratio, 2.40; 95% confidence interval, 1.39-4.41). Thirty-eight patients (72%) with non-disseminated pulmonary TB disease presented typically with mediastinal lymphadenopathy (53%), pleural effusion (47%) and fibrocalcific lesions (43%) on chest imaging. The 15 (28%) patients with extra-pulmonary disease had lower rates of defervescence within 72 h of empirical antimicrobial therapy (13% vs 45%, p = 0.03) and a higher 30-day in-hospital mortality (20% vs. 0%, p = 0.004) compared to those with disease confined to the lungs.
Conclusions
TB disease is not uncommon among patients with hematological malignancies in Taiwan. Patients who received a diagnosis of extra-pulmonary TB suffered higher mortality than those with pulmonary TB alone. Clinicians should consider TB in the differential diagnoses of prolonged fever in patients with hematological malignancies, particularly in regions of high endemicity.
doi:10.1186/1471-2334-11-324
PMCID: PMC3241214  PMID: 22111760
Mycobacterium tuberculosis (TB); Hematological malignancy; Febrile neutropenia
10.  Invasive fungal sinusitis in patients with hematological malignancy: 15 years experience in a single university hospital in Taiwan 
BMC Infectious Diseases  2011;11:250.
Background
Risk factors and outcomes in hematological patients who acquire invasive fungal sinusitis (IFS) are infrequently reported in the modern medical era.
Method
A retrospective study of hospitalized patients with hematological disease was conducted at National Taiwan University Hospital between January 1995 and December 2009.
Results
Clinical characteristics and outcomes with their associated radiographic and microbiological findings were analyzed. Forty-six patients with IFS and 64 patients with chronic non-invasive sinusitis were enrolled as comparsion. IFS developed more commonly in patients with acute myeloid leukemia (AML) and with prolonged neutropenia (absolute neutrophil count less than 500/mm3 for more than 10 days) (p < 0.001). Aspergillus flavus was the most common pathogen isolated (44%). Serum Aspergillus galactomannan antigen was elevated in seven of eleven patients (64%) with IFS caused by aspergillosis but negative for all three patients with mucormycosis. Bony erosion and extra-sinus infiltration was found in 15 of 46 (33%) patients on imaging. Overall, 19 of 46 patients (41.3%) died within 6 weeks. Patients with disease subtype of AML (p = 0.044; Odds Ratio [OR], 5.84; 95% confidence interval [95% CI], 1.02-30.56) and refractory leukemia status (p = 0.05; OR, 4.27; 95% CI, 1.003-18.15) had worse prognosis. Multivariate analysis identified surgical debridement as an independent good prognostic factor (p = 0.047) in patients with IFS.
Conclusions
Patients of AML with prolonged neutropenia (> 10 days) had significantly higher risk of IFS. Early introduction of anti-fungal agent and aggressive surgical debridement potentially decrease morbidity and mortality in high risk patients with IFS.
doi:10.1186/1471-2334-11-250
PMCID: PMC3196720  PMID: 21939544
Invasive fungal sinusitis (IFS) ; hematological disease;  Aspergillus galactomanan
11.  A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma 
British Journal of Haematology  2014;165(6):768-776.
Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.
doi:10.1111/bjh.12819
PMCID: PMC4282031  PMID: 24617454
vorinostat; indolent B-cell non-Hodgkin lymphoma; follicular lymphoma; phase II trial; HAT mutation

Results 1-11 (11)