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  • Zhang, Yu  (4)
  • Zhou, Hongsheng  (4)
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  • 1
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4139-4139
    Abstract: Abstract 4139 Background Herpesvirus infections of central nervous system (CNS) are associated with encephalitis/myelitis and other neurological syndromes as well as lymphoproliferative diseases in immunocompromised individuals. Diagnosis is mainly based on the detection of virus-DNA in cerebrospinal fluid (CSF). Recently, some studies demonstrate that herpesvirus-associated diseases have increased in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), but these mainly focus on the systematic herpesvirus infections and lack of a large-sample prospective study of CNS herpesvirus infections. Methods The eligibility criteria are as following: (1)The patients after allo-HSCT; (2)The patients who were diagnosed as Epstein-Barr virus (EBV)-associated diseases; (3)The patients with other herpesvirus-associated diseases other than EBV-associated diseases accompanying CNS manifestations; (4)The patients with unexplainable CNS manifestations. According to the criteria aforementioned, fifty-four of 250 patients undergoing allo-HSCT in our single institution between July 2008 and April 2012 were enrolled in this prospective study. Moreover, 18 patients with herpesvirus-DNA-emia who did not develop herpesvirus-associated diseases volunteered to have their CSF monitored (platelet 〉 50×109/L). Herpesvirus-DNA of CSF, blood and other body fluids was monitored by polymerase chain reaction (PCR). Once herpesvirus-associated CNS diseases were considered, immunophenotypic analysis of CSF cells and magnetic resonance imaging scanning of CNS were performed. Results Twenty-four patients were diagnosed as herpesvirus-associated CNS diseases, including 8 EBV encephalitis, 7 EBV-associated CNS post-transplant lymphoproliferative diseases (PTLD), 5 herpes simplex virus type 1(HSV-1) encephalitis, 2 cytomegalovirus (CMV) encephalitis, 1 CMV myelitis and 1 varicella zoster virus(VZV) encephalitis, respectively. The EBV-DNA levels of CSF were significantly higher than that of blood (82457 ± 6126 copies/ml vs. 18517 ± 3906 copies/ml, P=0.030). The virus of CSF was consistent with the virus of blood in all patients except one patient with EBV-associated CNS-PTLD, who was EBV-DNA positive of CSF but CMV-DNA positive of blood. The median time of herpesvirus-associated CNS diseases onset was 79 days post-transplants and 70.8% cases occurred within 100 days post-transplants. The 3-year cumulative incidence of herpesvirus-associated CNS diseases and EBV-associated CNS diseases was 12.8±2.6% and 7.5±2.0%, respectively. With a median follow-up of 198 days after the diagnosis of herpesvirus-associated CNS diseases, 13 patients survived and 11 died. The causes of death were related with herpesvirus in 7 cases and not related with herpesvirus in 4 cases. Conclusions PCR detection of CSF virus-DNA is a sensitive and specific method for diagnosing herpesvirus-associated CNS diseases. EBV-associated CNS diseases are more common than other herpesvirus-associated CNS diseases in the early times of allo-HSCT. The EBV-DNA negative in blood could not exclude EBV-associated CNS diseases. 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: 2012
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    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3012-3012
    Abstract: Aggressive natural killer leukemia (ANKL), previously being classified as large granular lymphocyte (LGL) leukemia or malignant histiocytosis, is a rare subset neoplasm with high aggressive clinical course. Until now, apart from clinical feature, the frequent chromosome aberrations, somatic genes mutations, signal pathway and the optimal treatment regimen are still poor understood. Patient and Methods A retrospective analysis was performed upon review of clinical database, including additional immunohistochemistry (IHC) staining and integrated mutation analysis on reserved samples. Twelve samples of extranodal NK/T-cell lymphoma-nasal type (ENKL-NT) were used in IHC analysis for control. Results A total of 26 cases were collected during 2001 to 2013, including 17 males and 9 females, median age of 28 years old (range 4-76 years old). Most patients presented with acute-onset high swinging fever (n=26), deteriorating jaundice (n=19) and pancytopenia (n=22) at diagnosis. The organ most frequently involved organs were bone marrow (n=25), liver (n=23), spleen (n=22) and gastrointestinal (n=6). Disseminated intravascular coagulopathy (DIC) was present in 15 out of 26 patients, significantly associated with liver involvement and jaundice (p 〈 0.01). Epstein-Barr virus (EBV) viremia was present in 7 of 8 tested cases (5.12x10*,2-5.41x10*,6 copies/mL). The characteristic morphological appearance of ANKL in bone marrow smears were deep purple-red staining granules in cytoplasm and prominent vacuoles located in cytoplasm and/or nucleus. FACS demonstrated ANKL cells were CD2+cCD3+CD7+CD11b+/-CD11c+/-CD29+CD38+/-CD45+CD56+CD86+BCL-2+, CD3-TCR-cCD79a-cMPO-CD5-CD10-CD19-CD25-CD33-CD83-CD123-. Surprisingly, ANKL cells were negative for CD21, an established EBV receptor. Additional IHC on 14 reserved bone marrow samples revealed ANKL cells were strongly positive for LMP2A (n=14), LMP1 (n=11) and EBER (n=10). In ENKL-NT, LMP2A and LMP1 were moderately positive in 5 and 4 out of 12 cases, respectively. EBERs were detected in all ENKT-NT cases. Moreover, IHC analysis showed ANKL cells were strongly stained by CDK6 (n=13), MDM2 (n=14), CD44 (n=13), IFN-γ (n=14), slightly stained by CDK4 (n=2), negative for SH2 domain-containing inositol 5’-phosphatase-1 (SHIP-1), which is responsible for 2B4-mediated inhibition in NK cells. In ENKL-NT samples, CDK6 (n=11), MDM2 (n=9) and CD44 (n=8) were positive; furthermore, SHIP-1 was slightly positive in 4 samples. Chromosome aberrations were present in 7 patients, including dup1(q22q25), inv(3)(p21p25), del(3)(p13), t(3;11)(q21;q23), i(7)(q10), del(7)(q32), del(14)(q24), der(15)t(7;15)(q10;q10), -8, -12,+13,-18,+19,-22. Multiple somatic mutations were detected in 7 cases, including TET2 (D1938E, S69R, V292L, E1207D, G1391C, T1393K, Y1998X), FBXW7 (S427L,Q428K, D431E, R505C, Q508K, G517V, D775Y), CEBPA (E57D, N292K, S85I), FLT3 (M837I, E604X), KRAS (G77R, Q22H, G13D), PAX5 (P93T, A111S), PHF6 (R15S, S155X, V5F), DNMT3A (P602H, H613D), EGFR (E736X, S155X), IDH2 (K166M),SH2B3 (E190X), c-Kit (G812C), JAK1 (D775Y), NOTCH1 (A1701S). Only 1 out of 10 patients obtained partial remission after anthracycline-based or platinum-based regimens (CHOP, CHOP-Bleomycin, CDOP, EPOCH, HyperCVAD and ESHAP). Notably, two cases rapidly achieved durable complete remission after L-asparaginase-containing regimen (CHOP/PEG-L-asp and VDLP). Two patients received allogeneic hematopoietic stem cell transplantation, one maintained durable remission and another died of invasive pulmonary infection before engraftment. The median overall survival of 26 cases was only 7.5 days (range 2-330 days). Conclusions ANKL is Trojan story about EBV and NK cells, being presented with strong evidence of EBV infection/transformation, highly aggressive clinical course and prominent chromosome/genomic instability, which deserves more research efforts to dissect the role of EBV, molecular cytogenetics make-up, signaling pathway of LMP1/LMP2A-PI3K/AKT-CDK6-MDM2 and optimal regimen such as L-asp-contained protocol for this rare leukemia subset. Disclosures: Zhou: Guangzhou Pearl River of Science & Technology New Star (No. 2011J2200069 to HS.Zhou): Research Funding. Liu:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 5518-5518
    Abstract: Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib in treatment of chronic myeloid leukemia (CML) patients, the allogeneic hematopoietic stem cell transplantation (allo-HSCT) scene in CML has changed dramatically. This retrospective cohort study was designed to compare medical outcomes of Imatinib mesylate and allo-HSCT for patients with CML in chronic phase. Patients and Methods From February 2002 to February 2012, 198 patients treated consecutively at the Nanfang Hospital,Southern Medical University were assigned to two groups according to treatment with imatinib or allo-HSCT. One hundred fifteen cases of imatinib group were given imatinib at an initial dose of 400mg daily and the dose was then adjusted according to the patient´s blood and therapy response. All the patients were evaluated for hematologic, cytogenetic and molecular response every 1-3months. Eighty-three cases of allo-HSCT group received myeloablative preconditioning regimen, and methotrexate (MTX) and cyclosporine A (CsA) were used for graft-versus-host disease(GVHD), parts combined with mycophenolate mofetil (MMF) and antihuman thymocyte globulin(ATG). The primary end points of the study were complete cytogenetic response (CCyR), relapse rate, overall survival (OS) and progression-free survival (PFS) after therapy. Results In total, 59 (68.9%) patients treated over 12 months achieved a CCyR after 12 months in imatinib group, while 67 (95.7%) patients in allo-HSCT group. The relapse rates were 14.8% (n=17) in imatinib group and 10.8% (n=9) in allo-HSCT group (P=0.456). Ten-year cumulative OS rates were 93.9% in imatinib group and 77.1% in allo-HSCT group(P=0.015) and ten- year cumulative PFS rates of two groups were 86.1% vs.88.0%(P=0.508). For Sokal rating stratified analysis, the ten-year OS rates of two groups were 96.4% vs.68.0% (P = 0.049) for high-risk patients,92.6% vs. 57.1% (P = 0.019) for intermediate-risk patients , while the ten-year PFS rates of two groups were 89.3% vs. 88.0% for high-risk patients (P = 0.942), 70.4% vs. 85.7% for intermediate-risk patients (P = 0.405).The ten-year OS rates and PFS rates were not significant difference for low-risk patients. The cumulative OS rates of two groups were 94.7% vs. 73.5%(P=0.019)for the patients who were not less than 30 years old,and the cumulative PFS rates of two groups were 84.2% vs. 94.1% respectively (P=0.147). Conclusion Imatinib mesylate treatment is superior to allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in chronic phase. 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: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: PLoS ONE, Public Library of Science (PLoS), Vol. 8, No. 10 ( 2013-10-4), p. e77805-
    Type of Medium: Online Resource
    ISSN: 1932-6203
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2013
    detail.hit.zdb_id: 2267670-3
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