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  • 1
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2016
    In:  Journal of Cancer Research and Clinical Oncology Vol. 142, No. 11 ( 2016-11), p. 2291-2301
    In: Journal of Cancer Research and Clinical Oncology, Springer Science and Business Media LLC, Vol. 142, No. 11 ( 2016-11), p. 2291-2301
    Type of Medium: Online Resource
    ISSN: 0171-5216 , 1432-1335
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
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  • 2
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5245-5245
    Abstract: Objects: Investigate the clinical significance of myeloblasts percentage in the de novo acute myeloid leukemia(AML) with erythroid hyperplasia from a single center of China Methods: We retrospectively collected information regarding clinical characteristics and survival data from de novo101 patients with newly diagnosed AML with erythroid hyperplasia ( 〉 50% erythroid cells) from 2002-2016. The total patients were divided into two groups according to the myeloblasts percentage in total marrow cells. Cases with 〈 20% total myeloblast was defined as low-blast group while cases with 〉 20% total myeloblast was defined as high-blast group. Median follow-up of patients was 10.03 months. Results:1.A total of 101 patients were diagnosed as de novo acute myeloid leukemia with erythorid hyperplasia according to WHO2008 criteria, 70 patients was classified as low-blast group, 31 patients was classified as high-blast group. Compared with high-blast group, in the low-blast group, the median age was older (39.8 vs 33.3, p=0.044), male was predominant (71.4% vs 48.4%, p=0.01). But complete remission (CR) after induction chemotherapy was lower in high-blast group(44.4% vs 57.4%, p=0.019).There were no difference in the white blood count(WBC), chromosome karyotype and incidence of various gene mutations. 2. The median survival time in the low-blast group and high-blast group was 39.19 months and 23.43 months respectively. 3-year overall survival(OS) was 53.1% and 43.4%(p=0.668), 3-year disease free survival(DFS) was 71.4% and 47.8% (p=0.297). 3. Univariable analysis showed that OS of 101 AML patients was correlated with prognosis subtype, remission of induction chemotherapy, transplant and relapse, and not related with myeloblast percentage exceed 20% of total morrow cells or not, WBC, age, gender and induction regimens. DFS of the all patients was correlated with the remission of induction chemotherapy and prognosis subtype. Multivariable analysis showed that OS was only correlated with remission of induction chemotherapy and transplant, DFS was only correlated with remission of induction chemotherapy. Conclusions: In the AML patients with erythroid hyperplasia with 〈 20% total myeloblast, the age was older and CR was higher than that with 〉 20% total myeloblast, but the survival was similar in both patients regardless of myeloblast percentage. The patients who attained CR after induction chemotherapy and received transplantation would get better outcome. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 3
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 23 ( 2019-12-01), p. 7058-7067
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 23 ( 2019-12-01), p. 7058-7067
    Abstract: No study has investigated the precise perioperative dynamic changes in circulating tumor DNA (ctDNA) in any patients with early-stage cancer. This study (DYNAMIC) investigated perioperative dynamic changes in ctDNA and determined the appropriate detection time of ctDNA-based surveillance for surgical patients with lung cancer. Experimental Design: Consecutive patients who underwent curative-intent lung resections were enrolled prospectively (NCT02965391). Plasma samples were obtained at multiple prespecified time points including before surgery (time A), during surgery after tumor resection (time B–time D), and after surgery (time P1–time P3). Next-generation sequencing–based detection platform was performed to calculate the plasma mutation allele frequency. The primary endpoint was ctDNA half-life after radical tumor resection. Results: Thirty-six patients showed detectable mutations in time A. The plasma ctDNA concentration showed a rapid decreasing trend after radical tumor resection, with the average mutant allele fraction at times A, B, C, and D being 2.72%, 2.11%, 1.14%, and 0.17%, respectively. The median ctDNA half-life was 35.0 minutes. Patients with minimal residual disease (MRD) detection had a significant slower ctDNA half-life than those with negative MRD (103.2 minutes vs. 29.7 minutes, P = 0.001). The recurrence-free survival of patients with detectable and undetectable ctDNA concentrations at time P1 was 528 days and 543 days, respectively (P = 0.657), whereas at time P2 was 278 days and 637 days, respectively (P = 0.002). Conclusions: ctDNA decays rapidly after radical tumor resection. The ctDNA detection on the third day after R0 resection can be used as the baseline value for postoperative lung cancer surveillance.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
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  • 4
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 20 ( 2017-10-15), p. 6113-6119
    Abstract: Purpose: The prevalence of mutations in cancer susceptibility genes such as BRCA1 and BRCA2 and other cancer susceptibility genes and their clinical relevance are largely unknown among a large series of unselected breast cancer patients in the Chinese population. Experimental Design: A total of 8,085 consecutive unselected Chinese breast cancer patients were enrolled. Germline mutations in 46 cancer susceptibility genes were detected using a 62-gene panel. Results: Pathogenic mutations were identified in 9.2% of patients among the 8,085 unselected breast cancer patients. Of these, 5.3% of patients carried a BRCA1 or BRCA2 mutation (1.8% in BRCA1 and 3.5% in BRCA2), 2.9% carried other breast cancer susceptibility genes (BOCG) and 1.0% carried another cancer susceptibility genes. Triple-negative breast cancers had the highest prevalence of BRCA1/2 mutations (11.2%) and other BOCG mutations (3.8%) among the four molecular subgroups, whereas ER−/PR−HER2+ breast cancers had the lowest mutations in BRCA1/2 (1.8%) and BOCG (1.6%). In addition, BRCA1 mutation carriers had a significant worse disease-free survival [unadjusted hazard ratio (HR) 1.60; 95% confidence interval (CI) 1.10–2.34; P = 0.014] and disease-specific survival (unadjusted HR 1.96; 95% CI, 1.03–3.65; P = 0.040) than did non-carriers, whereas no significant difference in survival was found between BRCA2 mutation carriers and non-carriers. Conclusions: 9.2% of breast cancer patients carry a pathogenic mutation in cancer susceptibility genes in this large unselected series. Triple-negative breast cancers have the highest prevalence of mutations in BRCA1 /2 and other breast cancer susceptibility genes among the four molecular subgroups, whereas ER−/PR−HER2+ breast cancers had the lowest mutations in these genes. Clin Cancer Res; 23(20); 6113–9. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 5
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1301-1301
    Abstract: Background: Imatinib combined with conventional chemotherapy has significantly improved the prognosis of adults with Philadelphia-positive acute lymphoblastic leukemia ( Ph+ ALL ). Nilotinib, the second generation TKIs is approximately 30 fold more potent than imatinib and is active in vitro against multiple BCR/ABL mutations. Here, we report the efficacy and safety of nilotinib combined with multiple reagents chemotherapy in newly diagnosed patients with Ph+ ALL. Methods: Newly diagnosed Ph+ ALL patients aged 15 to 59 and with adequate organ function were recruited. The 4weeks induction cycle consist of vincristine, daunorubicin, cyclophosphamide and prednisone. After achieving hematological complete remission (HCR), patients received 2 years of consolidation and maintenance therapy. Consolidation therapy was including 7 courses of multiple drug chemotherapy or allogeneic/autologous hematopoietic cell transplantation (allo/auto HCT). Nilotinib was the only drug for maintenance therapy. Nilotinib 400mg was given orally twice daily along with combination chemotherapy starting from day 15 of induction until the initiation of conditioning for transplantation, hematological relapse or continuing for 2 years since achievement of hematological complete remission (HCR).Central nervous system (CNS) prophylaxis was performed by intrathecally administering triple agents. The data cut-off day was June 1st 2015. HCR and molecular complete remission (MCR), overall survival(OS), hematologic relapse free survival (HRFS), toxicity, nilotinib concentration in serum and cerebrospinal fluid(CSF) were evaluated. MCR was defined as Bcr-Abl fusion gene becomes negative in bone marrow using quantitative RT-PCR. Results: A total of 30 patients (19 males and 11 females) were enrolled from September 2011 to November 2013. The median age was 40 (range 21-57) years old. The type of BCR breakpoint was minor in 24 patients, major in 2 patients and both in 4 patients. All the 30 patients (100%) and 8 patients (26.7%) achieved HCR and MCR respectively after the induction cycle. Cumulative MCR rate was 80%. 17 patients underwent HCT, 14 patients with alloHCT and 2 patients with autoHCT in first HCR, 1 patient received alloHCT after relapse. 9 patients died from leukemia relapse and 4 patients died post-alloHCT without relapse. The median HRFS and OS were 20.7 and 34 months respectively. The 4 year HRFS rate was 41% and the 4 year OS rate was 48%. The molecular response after induction has no impact on HRFS and OS. Patients achieving MCR had better HRFS (32 vs 8.9 months, p=0.006) but not OS(33.3vs 17.2months, p=0.068) than those patient without MCR. During induction, 23 patients experienced infectious fever including 2 patients with septicemia and 6 patients with pneumonia needing antifungal therapy. Intestinal obstruction occurred in 7 patients during induction and relived by interrupting nilotinib treatment. The incidence of non-hematologic adverse events (AE) over grade 3 during the study was 23% jaundice, 10% rash, 6.7% arthralgia and bone pain, 6.7%headache, 3.3% ALT elevation. No QTc prolongation over 500ms happened. Grade 2 tachycardia and premature ventricular contraction occurred in 2 patients and 1 patient respectively. During the high-dose methotrexate treatment cycle, delaying of methotrexate metabolism happened in 20 patients (66.7%), increasing creatine occurred in 8 patients (26.7%, grade 3 in 3 patients), 1 patient received haemodialysis. Nilotinib serum level reached to stable concentration after 15 days of administration. Only traces of nilotinib was detected in CSF. Conclusion: In this prospective study, combination of nilotinib and cytotoxic drug was shown to be effective and tolerable for adult Ph+ALL. Nilotinib could not penetrate the blood brain barrier. (ChiCTR-ONC-12002469) Disclosures Off Label Use: nilotinib,the 2nd generation TKI, was approved for CML. Wang:Novarits and Bristol-Mayers squibb. G.S.: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 6
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4015-4015
    Abstract: Background: Patients with AML who obtain first complete remission (CR) are subsequently treated with post-remission treatment, including chemotherapy or hematopoietic stem cell transplantation (HSCT). Suitable post-remission treatment in patients with intermediate-risk acute myeloid leukemia (AML) is remaining investigation. Objectives: To retrospectively investigatethe value of allo-HSCT in the patients with intermediate-risk AML. Patients and Methods: From August 2010 to January 2016, newly diagnosed adultpatients (15 to 55 years old) with AML were consecutivelyenrolled in a prospective trial (ChiCTR-TRC-10001202). Patients were assigned HAD containing conventional dose of cytarabine (homoharringtonine, cytarabine (Ara-c), and daunorubicin) induction therapy (Ara-C 100mg/m2, d1-7) or HAD containing intermediate dose Ara-c (Ara-C 100mg/m2, d1-4, 1.0g/m2, q12h, d5-7). All patients who achieved CR received either high dose Ara-c or intermediate dose Ara-c plus anthracyclines. Allo-HSCT was based on therapeutic responseand patients' intention. Patients received 6 courses of consolidation therapy if they did not receive HSCT. Minimal residual disease (MRD) was analyzed by multi-color flow cytometry after induction and consolidation therapy. Results: 181 enrolled patients were intermediate-risk AML (median age 36 years old). The median follow-up was 15.5 (0.5-67.9) months. One patient was lost to follow-up after induction, 180 patients were evaluated. 128 patients (71.1%) achieved CR after one induction cycle, 7 patients (3.9%) were early death, and 45 patients (25.0%) did not achieve CR. Forty patients received allo-HSCT, 33 of them were in CR1. The median time from diagnosis to transplantation was 6.5(3.9-16.0) months. Three years overall survival (OS) of transplantation group was higher than that of chemotherapy group (78.0% vs 48.0%, P = 0.000). Three years relapse-free survival (RFS) was 42.0% and 45.0% for patients in transplantation group and chemotherapy group, respectively (P = 0.196). However, taking transplantation time into account, the outcome was different. If the median transplantation time (6.5 months) was defined as cut-off value, there is no statistically difference of 3 years OS (77.0% vs 69.0%, P=0.182) and 3 years RFS (42.0% vs 53.0%, P=0.320) between transplantation and chemotherapy groups in the patients without relapse within 6.5 months. Twenty-one patients relapsed within 6.5 months, only one of them proceeded to allo-HSCT, and 1 year OS was 29.0%. For 45 patients who did not achieve CR after one induction cycle, 3 years OS was much better by allo-HSCT as compared with chemotherapy (85.0% vs22.0%, P = 0.008). In order to evaluate prognosis earlier, we analyzed MRD by flow cytometry after induction, first and second consolidation cycles in those achieving CR after one induction cycle. The patients with once or more MRD positive of three time points had significantly inferior 6 months RFS than those with continuous MRD negative (61.0% vs 92.0%,P = 0.005). Similar trend was observed on 1 year RFS (46.0% vs 76.0%, P = 0.005). Conclusion: According to the actual treatment, the OS of the patients with intermediate-risk AML was improved by allo-HSCT. When transplantation time was considered in the analysis, there was no difference between allo-HSCT and chemotherapy in survival. The patients with poor early response to chemotherapy (those did not achieve CR after one induction cycle) really benefited from allo-HSCT. The patients without continuous MRD negative after induction, first and second consolidation cycles trended to be early relapse, they might be another subgroup benefiting from allo-HSCT. Acknowledgments: This study was supported, in part, by State Key Program of National Natural Science of China (81430004), Foundation for Innovative Research Groups of the NaturalScience Foundation of China (81421002). Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 7
    In: International Journal of Cancer, Wiley, Vol. 138, No. 2 ( 2016-01-15), p. 489-496
    Abstract: What's new? Mutations in the tumor suppressor p53 are often associated with poor outcome in cancer treatment. Here the authors examined the influence of p53 mutations on the success of neoadjuvant chemotherapy in women afflicted by breast cancer. Surprisingly, they found that patients with p53 mutations are more likely to respond to anthracycline/cyclophosphamide‐based neoadjuvant chemotherapy and have a favorable survival. This was not observed with another treatment, paclitaxel, pointing to a possible selection of patients for therapy based on p53 status.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2016
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    detail.hit.zdb_id: 1474822-8
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  • 8
    In: Journal of Infectious Diseases, Oxford University Press (OUP), Vol. 215, No. 1 ( 2017-01-01), p. 56-63
    Type of Medium: Online Resource
    ISSN: 0022-1899 , 1537-6613
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    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 1473843-0
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  • 9
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 12 ( 2019-06-15), p. 3732-3743
    Abstract: Tumor repopulation is known as a major cause of treatment failure and/or tumor recurrence after radiotherapy. The underlying mechanism remains unclear. Our previous study demonstrated that irradiated apoptotic cells mediated tumor repopulation, in which caspase-3 played an important role. Herein, we investigated downstream effectors of caspase-3 involved in this process. Experimental Design: A dominant-negative protein kinase Cδ (DN_PKCδ) mutant that could not be cleaved by caspase-3 and therefore could not be activated by irradiation-induced apoptosis was constructed. DN_PKCδ stably transduced tumor cells were compared with wild-type tumor cells for their growth stimulation effects in in vitro and in vivo tumor repopulation models. Downstream effectors of caspase-3 and PKCδ were investigated. The role of PKCδ was further verified in human colorectal tumor specimens. Results: Inactivation of caspase-3 or caspase-7 attenuated tumor repopulation and weakened PKCδ cleavage. Both DN_PKCδ and PKCδ inhibitors restrained tumor repopulation both in vitro and in vivo. Phosphorylated Akt was attenuated in caspase-3–, caspase-7–, or PKCδ-inactivated tumor cells. Furthermore, expression of vascular endothelial growth factor (VEGF)-A but not hypoxia-inducible factor 1α (HIF1α) was decreased in PKCδ- or Akt-inactivated tumor cells. In addition, inhibition of p-Akt, HIF1α, VEGF-A, or VEGF-A receptor reduced tumor repopulation significantly. Finally, increased nuclear translocation of PKCδ in colorectal tumor specimens was associated with worse patient prognosis. Conclusions: The caspase-3/PKCδ/Akt/VEGF-A axis is involved in tumor repopulation and could be exploited as a potential target to enhance the efficacy of radiotherapy.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 10
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1672-1672
    Abstract: Background: Minimal residual disease (MRD) based on quantitativeRT-PCR has become an important prognostic factor for leukemia. There are few cohort based studies to investigate prognostic factors for t(8;21) AML, especially after MRD is integrated. Objectives: To retrospectively investigatethe prognostic factors in t(8;21) AML when MRD is integrated. Patients and Methods: From August 2010 to January 2016, newly diagnosed adultpatients (15 to 55 years old) with AML were consecutively enrolled in a prospective trial(ChiCTR-TRC-10001202). Patients were assigned standard dose HAD (homoharringtonine,cytosine arabinosine(Ara-c), and daunorubicin) induction therapy or HAD containing intermediate dose Ara-c. All patients who achieved CR received either high dose or intermediate dose Ara-c. Allogeneic SCT was based on c-Kit mutation and patients' intention. Patients received 6 courses of consolidation therapy if they did not receive transplantation. MRD based on quantitative RT-PCR was performed after induction therapy and each consolidation therapy. Results: 113 enrolled patients were t(8;21) AML (median age 33 years old).108 patients (95.6%) achieved CR. Six of them receivedallogeneicstem-cell transplantation in CR1.The median follow-up is 14.6(0.6-59.2) months. Three years relapse-free survival (RFS) and overall survival (OS) is 57.2% and 71.8%, respectively. Analyses of prognostic factors were performed. In univariate analysis, high WBC count (cut-off value at 25X109/L) (P=0.007), c-Kit mutation (P=0.017), and MRD positive during therapy (P=0.001)were adverse prognostic factors for RFS. But Age (cut-off value at 45 years old) (P=0.957), gender (P=0.418), induction regimen (P=0.055), and consolidation regimen (P=0.311) were not prognostic factors for RFS. MRDpositive during therapy (P=0.004) was the only adverse prognostic factors for OS. High WBCcount (P=0.824), c-Kit mutation (P=0.052), Age (P=0.596), gender (P=0.714), induction regimen (P=0.222), and consolidation regimen (P=0.299) were not prognostic factors for OS. In multivariate analysis, WBC count and MRD were independent prognostic factors for RFS. And MRD was the only prognostic factors for OS. MRD tests were performed in 83 patients after induction and during consolidation therapy. All of tests were positive in 37 (44.6%) patients. 46 (55.4%) patients achieved negative at least one of tests. The cumulative MRD negative was 3.6%, 15.7%, 34.9%, 39.8%, 47.0%, 50.6%, 55.4% after induction therapy, the first, the second, the third, the forth, the fifth, and the sixth consolidation therapy, respectively. Patients with negative MRD had better 3 years RFS (78.6% vs. 32.1%, P=0.001) and OS (85.3% vs. 55.2%, P=0.004) than patients with positive MRD. C-Kit mutation analysis was performed in 105 patients. 27(25.7%) patients had c-Kit mutation and 78(74.3%) patients had wild type c-Kit. 3 years RFS in patients with wild type c-Kit is superior to that in patients with c-Kit mutation (57.5% vs. 35.8%, P=0.017). There was no statistically difference between wild type and mutated c-Kit in 3 years OS (73.6% vs. 42.4%, P=0.052). MRD became negative during consolidation therapy in 66.1% (39/59) patients with wild type c-Kit, which is significantly higher than patients with mutated c-Kit (27.8%, 5/18, P=0.004). But there was no significant difference in RFS or OS between MRD negative and positive in c-Kit mutated patients (P=0.847 for RFS, P=0.11 for OS). To evaluate prognosis earlier, we analyzed MRD after induction therapy. MRD after induction therapy was performed in 76 patients. MRD decreased to ≤0.1%, 〉 0.1% to≤1%, and 〉 1% in 15 (19.7%), 45 (59.2%), and 31(40.8%) patients, respectively.Patients with MRD ≤1% after induction therapy had favorable 3 years RFS (75.4% vs. 29.7%, P=0.004) and OS (77.9% vs. 53.3%, P=0.013) compared with patients with MRD 〉 1% after induction therapy.In multivariate analysis, in addition to c-Kit mutation and WBC count, MRD after induction therapy was still an independent prognostic factor for RFS. And MRD was the only prognostic factors for OS. Conclusion: MRD is an independentprognostic factor for OS and RFS for patients with t(8;21). Acknowledgments: This study was supported, in part, by State Key Program of National Natural Science of China (81430004), Foundation for Innovative Research Groups of the Natural Science Foundation of China (81421002) Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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