Yi Yang Chen

Frequencies, clinical characteristics, and outcome of somatic CALR mutations in JAK2-unmutated essential thrombocythemia

Calreticulin (CALR) mutations were recently identified in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) devoid of JAK2 and MPL mutations. We evaluated the clinical, laboratory, and molecular features of a Taiwanese population of patients with ET. Among 147 ET patients, CALR mutations were detected in 33 (22.5xa0%), JAK2V617F in 94 (63.9xa0%), and MPL mutations in 4 (2.7xa0%). Sixteen (10.9xa0%) patients were negative for all three mutations (CALR, JAK2V617F, and MPL; triple negative). Interestingly, one patient with the type 2 CALR mutation also harbored a low allele burden (0.025xa0%) of JAK2V617F mutation. Furthermore, we found a novel CALR mutation, with the resultant protein sharing an identical amino acid sequence to the type 6 CALR mutant. Compared to those with JAK2 mutation, CALR-mutated ET patients were characterized by younger age, lower leukocyte count, higher platelet count, and decreased risk of thrombosis. CARL mutations had a favorable impact on thrombosis-free survival (TFS) for ET patients, whereas the respective TFS outcomes were similarly poorer in JAK2-mutated ET and PV patients. Multivariate analysis confirmed that younger age (<60xa0years), presence of CALR mutations, and a lower platelet count (<1,000u2009×u2009109/L) were independently associated with a longer TFS in ET patients. The current study demonstrates that CALR mutations characterize a special group of ET patients with unique phenotypes that are not discrepant from those seen in Western countries.

Incidence and risk factors for central venous access port-related infection in Chinese cancer patients

BACKGROUND/PURPOSEnCytotoxic chemotherapy via central venous access ports is an important part of the standard treatment for most cancers, but it is accompanied with the risk of infections. This study aimed to analyze the incidence and risk factors for central venous access port-related infection (CPI) among Chinese patients receiving cytotoxic chemotherapy.nnnMETHODSnBetween January 1, 2002 and December 31, 2005 a total of 1391 cancer patients with 1449 totally implantable central venous access ports were evaluated. The log-rank test and Cox proportional hazards model were used for the analyses of risk factors.nnnRESULTSnThe overall CPI incidence rate was 0.21 per 1000 catheter-days. Hematological malignancies and head and neck cancer were associated with an increased risk of CPI (hazard ratio 4.00 and 4.11, respectively, both pxa0<xa00.001) and less infection-free catheter longevity (pxa0<xa00.001) compared with other cancer types. Chemotherapy in an adjuvant setting was associated with a lower risk of infection than for patients in a nonadjuvant setting (pxa0<xa00.001). The most common pathogens isolated from CPI were Pseudomonas aeruginosa and Candida.nnnCONCLUSIONnInfection remains to be a challenging issue for totally implantable central venous ports. Implementation of an insertion bundle for the prevention of central line-associated bloodstream infections is warranted, especially for those patients with hematological and head and neck cancers, as well as for patients receiving chemotherapy in the metastatic settings.

Validation of an enhanced International Prognostic Index (NCCN-IPI) in an Asian cohort of patients with diffuse large B cell lymphoma.

To the EditorFor more than 20 years, the International Prognostic Index(IPI) has been used as the standard for risk stratification inpatientswithdiffuselargeB celllymphoma(DLBCL)receiv-ing chemotherapy with CHOP regimen (cyclophosphamide,doxorubicin, vincristine, and prednisone [1].The advent of rituximab (R) changes the landscape oftreatment for the disease and significantly improves theclinical outcome [2, 3], but it also deduces the power ofimpacts of IPI on the prognostic prediction in these pa-tients [4]. There are pressing needs for newer strategiesto better subcategorize DLBCL patients in the rituximabera. Recently, collaborators from North America exploredtheir database containing DLBCL patients treated withR-CHOP and proposed a new prognostic model [5].The new National Comprehensive Cancer Network(NCCN) IPI was developed based on the clinical charac-teristics of 1650 patients from the USA. Validation wasdone using another independent cohort of more than1100 patients from the British Columbia. Reports usingthe same prognostic stratification from various geograph-ic regions have been published since [6, 7],yetitre-mains unclear if these results can be extrapolated to dif-ferent ethnic populations.We reviewed our database and identified 100 DLBCLpatients who received R-CHOP-like chemotherapy at ourinstitute during the last decade. Baseline characteristicswere collected, and the survival outcome analysis wasperformed using the old IPI model and the new NCCN-IPI model, respectively. The mean age was 63.8 years(standard deviation, 15.9 years). There were 56 male pa-tients. Forty-six patients had stage 3 or 4 disease.Extranodal involvement in major organs (bone marrow,CNS, liver/GI tract, or lung) was seen in 44 patients.Fifty-three patients had elevated levels of lactatedehydrogenase.According to the old IPI risk categorization, therewere 35, 28, 20, and 17 patients each in the four dif-ferent risk subgroups (low-, low-intermediate [LI], high-intermediate [HI], and high). The respective numberswere 11, 43, 32, and 14 in the NCCN-IPI model. TheKaplan–Meier curves for progression-free survival (PFS)and overall survival (OS) were plotted with subgroupstratification based on IPI and NCCN-IPI, respectively(Fig. 1). With regard to PFS, patients in the fourNCCN-IPI groups showed a distinctive clinical outcome(Fig. 1b), whereas patients subcategorized by the old IPIexhibited a less discriminative survival pattern,

Favorable clinical outcome and unique characteristics in association with Twist1 overexpression in de novo acute myeloid leukemia

Epithelial–mesenchymal transition (EMT) is a critical process for inducing stem-like properties of epithelial cancer cells. However, the role of EMT inducers in hematological malignancies is unknown. Twist1, an EMT inducer necessary for cell migration, has recently been found to have transcriptionally regulatory activity on the expression of Bmi1, and these two are capable of promoting tumorigenesis in a synergized manner. Knowing that Bmi1 expression is essential for maintenance of leukemic stem cells, we speculate that Twist1 might govern the pathogenesis of acute myeloid leukemia (AML) development as well. We found that upregulated Twist1 increased Bmi1 expression in AML and endued leukemic cells a higher proliferative potential and increased resistance to apoptosis. In primary AML samples, there was strong positive correlation between the expression levels of Twist1 and Bmi1. AML patients whose leukemic blasts harbored overexpressed Twist1 had a more aggressive clinical phenotype, but they were more likely to have a better clinical outcome after standard therapy. In vitro studies confirmed that Twist1-overexpressing leukemic cells were more susceptible to cytarabine, but not daunorubicin, cytotoxicity. Our findings suggest that, in a subset of AML patients, Twist1 has a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.

Clinical characteristics and treatment outcome in a Taiwanese population of patients with Epstein-Barr virus-positive diffuse large B-cell lymphoma.

OBJECTIVEnEpstein-Barr virus-positive diffuse large B-cell lymphoma is a provisional entity in the 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues. Reports on the characteristics and clinical outcome of this disease in different geographic regions showed great disparities.nnnMETHODSnTo define the clinical characteristics as well as the prognostic impact of Epstein-Barr virus infection on diffuse large B-cell lymphoma in Taiwan, we retrospectively investigated the Epstein-Barr virus status of 89 patients with newly diagnosed diffuse large B-cell lymphoma in our institute.nnnRESULTSnUsing a cutoff point of positive nuclear staining of Epstein-Barr virus-encoded RNA-1-in situ hybridization in ≥20% of the examined cells, we identified 15 cases (16.9%) of the entire study cohort as Epstein-Barr virus-positive diffuse large B-cell lymphoma. The clinical and laboratory features were not different between Epstein-Barr virus-positive and -negative diffuse large B-cell lymphoma patients. Univariate analysis showed patients with diffuse large B-cell lymphoma that were either Epstein-Barr virus-positive or had activated B-cell-like features had an inferior overall survival. Older age, advanced stage and lymphoma with activated B-cell-like features or Epstein-Barr virus-encoded RNA positivity were independent prognostic factors affecting overall survival on multivariate analysis. Patients with two or three of these adverse-risk factors were considered high risk and fared far worse than patients with no or only one adverse factor.nnnCONCLUSIONSnTaken together, we demonstrated that a higher frequency of Epstein-Barr virus association was detected in a Taiwanese cohort of diffuse large B-cell lymphoma patients, and Epstein-Barr virus-encoded RNA positivity was shown to add important prognostic value in these patients.

Clinical efficacy and safety of ruxolitinib in the management of myelofibrosis: A single institution experience in Taiwan.

Objective: Myelofibrosis (MF) is a pathologic entity of myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and constitutional symptoms that severely affect the quality of life accompanied with the risk of leukemia development. Conventional treatment is usually ineffective and has limited impact on prolongation of survival. Dysregulated Janus kinase (JAK) signaling is common in MPN. In two randomized controlled trials, ruxolitinib, a potent pan-JAK inhibitor, has been shown to be highly effective in patients with intermediate- and high-risk MF. Method: We retrospectively analyzed the therapeutic outcome of 10 MF patients treated with ruxolitinib in our institute. Basic clinical data, JAK2V617F mutational status and Myelofibrosis Symptoms Assessment Form (MF-SAF) to evaluate disease-related symptoms were recorded initially, and at every visit. Result: Among these patients, only half of the patients harbored JAK2V617F mutation. After treatment with ruxolitinib, all patients had reduction of splenic size and reached nadir by week 24. Nine patients had body weight increment, and four of them had body weight increment more than 10%. Seven patients had their total symptom score reduced by more than 50% after therapy. The efficacy of ruxolitinib was irrelevant to JAK2V617F mutational status. Adverse events were mainly hematological and easily manageable. Discussion and conclusion: Ruxolitinib is both safe and efficacious in a cohort of Asian patients with MF. The efficacy of ruxolitinib is irrelevant to the mutational status of JAK2V617F

Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index.

OBJECTIVEnPatients with hepatitis C virus (HCV) infection have been associated with development of diffuse large B-cell lymphoma (DLBCL), yet its impact on several clinical aspects, including phenotypic characteristics and treatment-related toxicities as well as survival outcome after rituximab-based immunochemotherapy, remains controversial.nnnMETHODSnTo elucidate the characteristics of HCV-positive DLBCL in the context of a new prognostic model, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), we retrospectively analyzed DLBCL patients diagnosed and treated with immunochemotherapy at our institute during the last decade.nnnRESULTSnIn all, HCV infection was identified in 22 (17.7%) of 124 DLBCL patients. Except for being more likely to present with an advanced stage of disease, patients with HCV infection were phenotypically indistinguishable from HCV-negative cases. Multivariate analysis showed 3 factors independently predicted a dismal overall survival (OS) outcome: lower albumin level (<3 g/dL vs. ≥3 g/dL, p<0.001; HR=13.21, 95% CI=2.69-64.98, p=0.001), presence of HCV infection (vs. HCV-negative; HR=9.75, 95% CI=1.97-48.34, p=0.005), and poor NCCN-IPI risk (high-intermediate or high vs. low-intermediate or low; HR=5.56, 95% CI=1.17-26.55, p=0.031).nnnCONCLUSIONSnOur study has demonstrated that HCV infection status and low serum albumin level add important prognostic values to the newly proposed NCCN-IPI model for patients with DLBCL.

Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype in JAK2-mutated myeloproliferative neoplasms

High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by let-7 microRNA through binding to it’s 3′-untranslated region. Transgenic mice expressing Hmga2 with a truncation of its 3′-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the let-7-HMGA2 axis in myeloproliferative neoplasms, we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent let-7a repression. Ton.JAK2.V617F cells treated with a let-7a inhibitor exhibited further escalation of Hmga2 expression, while a let-7a mimic diminished the Hmga2 transcript level. Hmga2 overexpression conferred JAK2-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of let-7a, downregulated the level of Hmga2, and led to increased apoptosis in Ton.JAK2.V617F cells in a dose-dependent manner. In samples from 151 patients with myeloproliferative neoplasms, there was a modest inverse correlation between the expression levels of let-7a and HMGA2. Overexpression of HMGA2 was detected in 29 (19.2%) of the cases, and it was more commonly seen in patients with essential thrombocythemia than in those with polycythemia vera (26.9% vs. 12.7%, P=0.044). Patients with upregulated HMGA2 showed an increased propensity for developing major thrombotic events, and they were more likely to harbor one of the 3 driver myeloproliferative neoplasm mutations in JAK2, MPL and CALR. Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.

Mutant DNMT3A clone evading chemotherapy and infiltrating central nervous system in a patient with molecularly good-risk acute myeloid leukemia.

Dear Editor,Approximately45%ofacutemyeloidleukemia(AML)shownormal karyotype (cytogenetically normal AML (CN-AML))at diagnosis, which are cytogenetically categorized as inter-mediate risk but is clinically heterogenous. The evaluation ofmolecular mutations offers better prognostication for CN-AML patients. Here, we present a case of molecularly good-risk CN-AML who unusually manifested central nervoussystem disease at the time of first remission.A 51-year-old lady was diagnosed with CN-AML (M2)with favorable-risk molecular profile: mutant NPM1,wild-typeMLL-PTD,andnegativeFLT3-ITD.Shereceivedinduc-tionchemotherapywithdaunorubicin(90mg/m

Thrombopoietic cytokines in patients with hepatitis C virus-associated immune thrombocytopenia

Objectives: Complex and multiple mechanisms are involved in the etiology of Hepatitis C virus-associated immune thrombocytopenia (HCV-ITP). Many hematopoietic growth factors affect the thrombopoiesis. The aim of this study was to clarify the interaction of the thrombopoietic factors in patients with HCV-ITP. Methods: We selected 33 patients with HCV-ITP and 17 normal individuals. We compare serum interleukin (IL)-3, IL-6, IL-11, thrombopoietin (Tpo), stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-α (TNFα), and spleen size between these two groups. Results: Our study shows that Tpo, IL-6, and TNFα significantly increased in patients with HCV-ITP compared to the normal population (Tpo:122.577 vs. 40.602; IL-6: 2.175 vs. 0.943; TNFα: 2.460 vs. 1.322). IL-11 was significantly lower in the HCV-ITP group (10.829 vs. 15.042). HCV-ITP patients had a higher spleen index (21.121 vs 13.498, Pu2009=u20090.003). According to regression analysis and multiple linear regression analysis, only IL-11 had a significantly positive correlation with platelet count, while TNFα showed a negative correlation. Discussions: Tpo and IL-6 increased in patients with HCV-ITP, suggesting a positive feedback of low platelet count. TNFα-associated immune response is suspected to have an impact on low platelet count. IL-11 is assumed to directly affect thrombopoiesis. Conclusions: This study is the most comprehensive study to evaluate the interaction between platelet count and the important thrombopoetic factors in patients with HCV-ITP. The thrombopoietic factors clearly play an important role in HCV-ITP.