Harbin Institute of Hematology and Oncology

Harbin, China

Harbin Institute of Hematology and Oncology

Harbin, China

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Zhu H.-H.,Peking University | Wu D.-P.,Soochow University of China | Jin J.,Zhejiang University | Li J.-Y.,Nanjing Medical University | And 5 more authors.
Journal of Clinical Oncology | Year: 2013

Purpose This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of an oral tetra-arsenic tetra-sulfide (As4S4) -containing formula named the Realgar-Indigo naturalis formula (RIF) compared with intravenous arsenic trioxide (ATO) as both induction and maintenance therapies for newly diagnosed acute promyelocytic leukemia (APL). Patients and Methods In all, 242 patients with APL were randomly assigned (1:1) to oral RIF (60 mg/kg) or ATO (0.16 mg/kg) combined with all-trans retinoic acid (ATRA; 25 mg/m2) during induction therapy. After achieving complete remission (CR), all patients received three courses of consolidation chemotherapy and maintenance treatment with sequential ATRA followed by either RIF or ATO for 2 years. The primary end point was the rate of disease-free survival (DFS) at 2 years, which was assessed for noninferiority with a 10% noninferiority margin. Results The median follow-up time was 39 months. DFS at 2 years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6% (95% CI,-3.0% to 8.0%). The lower limit of the 95% CI of DFS difference was greater than the-10% noninferiority margin, confirming noninferiority (P < .001). No significant differences were noted between the RIF and ATO groups with regard to the CR rate (99.1% v 97.2%; P<.62) or the overall survival at 3 years (99.1% v 96.6%; P=.18). The rates of adverse events were similar in the two groups. Conclusion Oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients. © 2013 by American Society of Clinical Oncology.

Chen G.,Harbin Medical University | Feng J.,Jiangsu Province Cancer Hospital | Zhou C.,Tongji University | Wu Y.-L.,Guangdong Academy of Medical science | And 20 more authors.
Annals of Oncology | Year: 2013

Background: The OPTIMAL study found that erlotinib improved progression-free survival (PFS) versus standard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). This report describes the quality of life (QoL) and updated PFS analyses from this study.Patients and methods: Chinese patients ≥18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received erlotinib (150 mg/ day; n = 82) or gemcitabine-carboplatin (n = 72). The primary efficacy end point was PFS; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS).Results: Patients receiving erlotinib experienced clinically relevant improvements in QoL compared with the chemotherapy group in total FACT-L, TOI and LCS (P < 0.0001 for all scales). Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 (non-significant). In the updated analysis, PFS was significantly longer for erlotinib than chemotherapy (median PFS 13.7 versus 4.6 months; HR = 0.164, 95% CI = 0.105-0.256; P < 0.0001), which was similar to the previously reported primary analysis. Conclusion: Erlotinib improves QoL compared with standard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Zhou C.,Tongji University | Wu Y.-L.,Guangdong Academy of Medical science | Chen G.,Harbin Medical University | Feng J.,Jiangsu Province Cancer Hospital | And 19 more authors.
The Lancet Oncology | Year: 2011

Background: Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor (TKI) therapy in non-small-cell lung cancer (NSCLC). The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus standard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC. Methods: We undertook an open-label, randomised, phase 3 trial at 22 centres in China. Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin. Patients were randomly assigned (1:1) with a minimisation procedure and were stratified according to EGFR mutation type, histological subtype (adenocarcinoma vs non-adenocarcinoma), and smoking status. The primary outcome was progression-free survival, analysed in patients with confirmed disease who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT00874419, and has completed enrolment; patients are still in follow-up. Findings: 83 patients were randomly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin; 82 in the erlotinib group and 72 in the chemotherapy group were included in analysis of the primary endpoint. Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 [95% CI 10.58-16.53] vs 4.6 [4.21-5.42] months; hazard ratio 0.16, 95% CI 0.10-0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib); the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations (three [4%] of 83 patients) and skin rash (two [2%] patients). Chemotherapy was also associated with increased treatment-related serious adverse events (ten [14%] of 72 patients [decreased platelet count, n=8; decreased neutrophil count, n=1; hepatic dysfunction, n=1] vs two [2%] of 83 patients [both hepatic dysfunction]). Interpretation: Compared with standard chemotherapy, erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability. These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC. Funding: F Hoffmann-La Roche Ltd (China); Science and Technology Commission of Shanghai Municipality. © 2011 Elsevier Ltd.

Jin J.,Zhejiang University | Wang J.-X.,Peking Union Medical College | Chen F.-F.,Zhejiang University | Wu D.-P.,Soochow University of China | And 23 more authors.
The Lancet Oncology | Year: 2013

Background: Homoharringtonine-based induction regimens have been widely used in China for patients with acute myeloid leukaemia. However, their efficacy has not been tested in a multicentre randomised controlled trial in a large population. We assessed the efficacy and safety of homoharringtonine-based induction treatment for management of newly diagnosed acute myeloid leukaemia. Methods: This open-label, randomised, controlled, phase 3 study was done in 17 institutions in China between September, 2007, and July, 2011. Untreated patients aged 14-59 years with acute myeloid leukaemia were randomly assigned (by a computer-generated allocation schedule without stratification) to receive one of three induction regimens in a 1:1:1 ratio: homoharringtonine 2 mg/m2 per day on days 1-7, cytarabine 100 mg/m2 per day on days 1-7, and aclarubicin 20 mg/day on days 1-7 (HAA); homoharringtonine 2 mg/m2 per day on days 1-7, cytarabine 100 mg/m2 per day on days 1-7, and daunorubicin 40 mg/m2 per day on days 1-3 (HAD); or daunorubicin 40-45 mg/m2 per day on days 1-3 and cytarabine 100 mg/m2 per day on days 1-7 (DA). Patients in complete remission were offered two cycles of intermediate-dose cytarabine (2 g/m2 every 12 h on days 1-3). The primary endpoints were the proportion of patients who achieved complete remission after two cycles of induction treatment and event-free survival in the intention-to-treat population. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-TRC-06000054. Findings: We enrolled 620 patients, of whom 609 were included in the intention-to-treat analysis. 150 of 206 patients (73%) in the HAA group achieved complete remission versus 125 of 205 (61%) in the DA group (p=0·0108); 3-year event-free survival was 35·4% (95% CI 28·6-42·2) versus 23·1% (95% CI 17·4-29·3; p=0·0023). 133 of 198 patients (67%) in the HAD group had complete remission (vs DA, p=0·20) and 3-year event-free survival was 32·7% (95% CI 26·1-39·5; vs DA, p=0·08). Adverse events were much the same in all groups, except that more patients in the HAA (12 of 206 [5·8%]) and HAD (13 of 198 [6·6%]) groups died within 30 days than in the DA group (two of 205 [1%]; p=0·0067 vs HAA; p=0·0030 vs HAD). Interpretation: A regimen of homoharringtonine, cytarabine, and aclarubicin is a treatment option for young, newly diagnosed patients with acute myeloid leukaemia. Funding: Chinese National High Tech Programme, Key Special Research Foundation of the Ministry of Science and Technology of China, National Nature Science Foundation of China, National Clinical Key Specialty Construction Project. © 2013 Elsevier Ltd.

PubMed | Sun Yat Sen University, Peking Union Medical College, The First Peoples Hospital of Shanghai, Zhengzhou University and 11 more.
Type: Journal Article | Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2016

The aim of this study is to investigate the epidemiology, diagnosis, treatment and risk factors of multiple myeloma patients with invasive fungi disease (IFD) in China. We analyzed multiple myeloma (MM) patients receiving chemotherapy in a prospective multicenter study. Basic characteristics, the diagnosis, and treatment of IFD were recorded. A total of 395 MM patients were enrolled, who received a total of 443 chemotherapy courses. Among them, 17 IFDs were diagnosed during one chemotherapy course. Fourteen of these were possible IFD and 3 were probable IFD. Ten of the 14 patients with possible IFD had lung infection. Thirty eight (8.6%) patients received antifungal prophylaxis, and 47.4% of them were administered with fluconazole. Patients who had a history of IFD or underwent a combined therapy with two antibiotics for over 7days and with a history of granulocytopenia or ductus venosus insertion were more likely to be treated with antifungal prophylaxis. All of first-line antifungal therapies were monotherapy. Eleven (84.6%) cases were treated with azoles. The median time of initial antifungal therapy was 8days. The general condition of two patients with probable IFD and 10 patients (90.9%) with possible IFD improved, while 1 patient with possible IFD died. Multivariate analysis revealed that history of IFD is an independent risk factor of IFD. The present multicenter study suggests that the incidence of IFD per chemotherapy courses in MM patients is 3.8% and most patients are labelled as having possible IFD. Fluconazole is the most common antifungal agent for prophylaxis and voriconazole for therapeutic treatment. Previous IFD is a probable independent risk factor of IFD in MM patients receiving chemotherapy.

Lu Z.,Sun Yat Sen University | Jin Y.,Sun Yat Sen University | Qiu L.,Harbin Institute of Hematology and Oncology | Lai Y.,Sun Yat Sen University | Pan J.,Sun Yat Sen University
Cancer Letters | Year: 2010

T315I Bcr-Abl in chronic myelogenous leukemia (CML) is the most notorious point mutations to elicit acquired resistance to imatinib. In the present study, we investigated the effect of celastrol on CML cells bearing wild-type Bcr-Abl or T315I-mutant. The results revealed that celastrol potently downregulated the protein levels of Bcr-Abl, and inhibited the growth in CML cells in vitro and in nude mouse xenografts regardless of Bcr-Abl mutation status. Celastrol induced mitochondrial-dependent apoptosis. In conclusion, celastrol exhibits potent activity against CML cells bearing wild-type Bcr-Abl or -the T315I-mutant. © 2009 Elsevier Ireland Ltd. All rights reserved.

Qin T.,University of Houston | Castoro R.,University of Houston | El Ahdab S.,University of Houston | Jelinek J.,University of Houston | And 8 more authors.
PLoS ONE | Year: 2011

Purpose: The DNA methylation inhibitor 5-aza-2′-deoxycytidine (DAC) is approved for the treatment of myelodysplastic syndromes (MDS), but resistance to DAC develops during treatment and mechanisms of resistance remain unknown. Therefore, we investigated mechanisms of primary and secondary resistance to DAC in MDS. Patients and Methods: We performed Quantitative Real-Time PCR to examine expression of genes related to DAC metabolism prior to therapy in 32 responders and non-responders with MDS as well as 14 patients who achieved a complete remission and subsequently relapsed while on therapy (secondary resistance). We then performed quantitative methylation analyses by bisulfite pyrosequencing of 10 genes as well as Methylated CpG Island Amplification Microarray (MCAM) analysis of global methylation in secondary resistance. Results: Most genes showed no differences by response, but the CDA/DCK ratio was 3 fold higher in non-responders than responders (P<.05), suggesting that this could be a mechanism of primary resistance. There were no significant differences at relapse in DAC metabolism genes, and no DCK mutations were detected. Global methylation measured by the LINE1 assay was lower at relapse than at diagnosis (P<.05). On average, the methylation of 10 genes was lower at relapse (16.1%) compared to diagnosis (18.1%) (P<.05).MCAM analysis showed decreased methylation of an average of 4.5% (range 0.6%-9.7%) of the genes at relapse. By contrast, new cytogenetic changes were found in 20% of patients. Conclusion: Pharmacological mechanisms are involved in primary resistance to DAC, whereas hypomethylation does not prevent a relapse for patients with DAC treatment. © 2011 Qin et al.

Liu G.,CAS Institute of Zoology | Ma H.,CAS Institute of Zoology | Qiu L.,Harbin Institute of Hematology and Oncology | Li L.,CAS Institute of Zoology | And 3 more authors.
Immunology and Cell Biology | Year: 2011

CD4 +CD25 + regulatory T cells (Treg cells) are important in maintenance of peripheral tolerance. The direct effect of CD4 +CD25 + Treg cells on macrophages was studied using a mouse model in which syngeneic CD4 +CD25 + Treg cells were adoptively transferred into the peritoneal cavity of SCID mice. Peritoneal macrophages in mice transferred with CD4 +CD25 + Treg cells expressed significantly higher levels of CD23, CD47 and CD206 and less CD80 and major histocompatibility complex class II molecules as compared with those mice that received either CD4 -CD25 + T cells or no cells. Macrophages of mice injected with CD4 +CD25 + Treg cells displayed a remarkably enhanced phagocytosis of chicken red blood cells, and arginase activity together with an increased interleukin-10 (IL-10) production, whereas they showed a decreased antigen-presenting ability and nitric oxide production. Furthermore, CD4 +CD25 + Treg cells and CD4 +CD25 + T cells showed strong antagonistic effects on macrophage polarizations in vivo. Blocking arginase, IL-10 and/or transforming growth factor-Β (TGF-Β) partially but significantly reversed the effects of CD4 +CD25 + Treg cells to induce M2 macrophages in vivo suggesting that CD4 +CD25 + Treg cells have the ability to induce M2 macrophages at least in part through arginase, IL-10 and TGF-Β pathways. Thus, we have provided the in vivo evidence to support the unknown pathways for CD4 +CD25 + Treg cells to regulate innate immunity by promoting the differentiation of M2 macrophages as well as by inhibiting M1 macrophage induction by CD4 +CD25 - T cells in mice. CD4 +CD25 + Treg cells efficiently induced M2 macrophage differentiation in mice, offering the in vivo evidence to support the role of CD4 +CD25 + Treg cells in regulating innate immunity. © 2011 Australasian Society for Immunology Inc. All rights reserved.

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