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  • 1
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    Azacitidine Pre-Treatment Followed by Reduced-Intensity Stem Cell Transplantation in Patients with Higher-Risk Myelodysplastic Syndrome
    S. Karger AG ; 2015
    In:  Acta Haematologica Vol. 134, No. 1 ( 2015), p. 40-48
    Details
    In: Acta Haematologica, S. Karger AG, Vol. 134, No. 1 ( 2015), p. 40-48
    Abstract: Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine the role of AZA before allogeneic stem cell transplantation (allo-SCT), we conducted a prospective study of AZA pre-treatment followed by allo-SCT in patients with higher-risk MDS. Twenty-one patients who were scheduled for their third to sixth cycle of AZA pre-treatment followed by allo-SCT were enrolled. AZA pre-treatment was interrupted early in 3 patients (14.3%) because of leukaemic transformation or death. The overall response rate to AZA pre-treatment was 57.1%. There were 2 cases of complete remission, 1 case of partial remission, and 9 cases of haematologic improvement. Fourteen patients (66.7%) received the planned allo-SCT and 5 patients were alive at the last follow-up. Three-year progression-free survival (PFS) and 3-year overall survival (OS) in the 14 patients who received allo-SCT were 30.0% (95% CI 3.3-56.7) and 42.9% (95% CI 17.1-68.7), respectively. PFS and OS were not influenced by response to AZA pre-treatment (p 〉 0.05). In this study, AZA had a role as a bridge therapy to prevent leukaemic transformation prior to selection of a donor for allo-SCT and showed low toxicity. It may be considered in patients with higher-risk MDS.
    Type of Medium: Online Resource
    ISSN: 0001-5792 , 1421-9662
    URL: Article
    DOI: 10.1159/000368711
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2015
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  • 2
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    Multicenter Retrospective Analysis of Second Allogeneic HSCT Outcomes for Hematologic Malignancies in Korea.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 4298-4298
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4298-4298
    Abstract: Abstract 4298 Background Increasing number of autologous or allogeneic HSCT in Korea in this decade resulted in increasing requirement for second allogeneic hematopoietic stem cell transplantation (HSCT) as a result of the recurrence of primary disease or graft failure. Since Dec 2008, second HSCT has been approved by Korean government to be covered by national health insurance reimbursement system. However, there is no available data on the transplant outcomes following second allogeneic HSCT in Korea. Accordingly, the current study attempted to analyze the outcome of second allogeneic HSCT retrospectively. Methods Transplant data were collected retrospectively from 8 transplant centers in Korea. Inclusion criteria are as follows. 1) Age equal or over 15 years old, 2) Hematologic malignancies excluding aplastic anemia, PRCA, PNH or solid tumor, 3) Patients who underwent second alloHSCT receiving cord blood transplantation (CBT). Results Sixty four pts were included with following diagnoses: AML (n=28), ALL (n=5), CML (n=3), lymphoma (n=22), myeloma (n=5), and others (n=1). The median age was 37 (range 16-65). The first transplantation had been performed with autologous (59.4%) or allogeneic (40.6%) donors. The donors for second HSCT were HLA-identical sibling 32(47%), unrelated 28(49%), or haploidentical donor 2(4%). Conditioning regimen included TBI-based myeloablative 6(9%), non TBI myeloablative 19(30%), or reduced intensity regimen 38(60%). With median 16 months of follow up (range, 3 to 93 months), 40 pts died of transplant related toxicity (n=28; 70%), recurrence of primary disease (n=9; 22.5%) or other (n=3; 7.5%). After second HSCT, 56% were in complete remission, 38% in partial remission, and 6% were refractory. The 1- and 2- year overall survival rate was 42% and 29%, respectively. Conclusion The patients received non TBI conditioning regimens were shown longer survival. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.4298.4298
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 3
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    Replication of New Genomic Classification System in Acute Myeloid Leukemia with Normal Karyotype
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 2876-2876
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2876-2876
    Abstract: Introduction Acute myeloid leukemia (AML) is a genetically heterogeneous disease. A recent study (NEJM, 2016) classified 1540 patients into 14 subgroups using mutation information from targeted next generation sequencing data as well as cytogenetic information [1]. The classification criteria of 7 of these subgroups rely solely on mutation information. NK-AML is characterized by its lack of cytogenetic abnormalities. In this study, we attempted to replicate the prognostic stratification in an independent set of NK-AML patients using the NEJM study's genomic classification criteria. Patients and Methods This study included a total of 393 patients who met the following eligibility criteria: 1) age ≥ 15 years; 2) a diagnosis of NK-AML confirmed by conventional cytogenetic analysis; 3) treatment with induction chemotherapy using a standard protocol (a 3-day course of anthracycline with a 7-day course of cytosine arabinoside). The median follow-up duration was 55.1 months (range, 0.7-182.9). Analysis of genetic mutations were performed using targeted sequencing by Illumina Hiseq 2000 (Agilent custom probe set targeting entire exon regions of a myeloid panel consisting of 94 genes). Results We identified driver mutations across 28 genes or genomic regions, with 2 or more driver mutations identified in 15/393 patients (3.8%). Based on the genomic classification criteria, the patients were classified as follows: 136 patients (34.6%) with NPM1 mutations, 42 patients (10.7%) with mutated chromatin modifiers and/or RNA-splicing genes, 6 patients (1.5%) with TP53 mutations, 40 patients (10.2%) with biallelic CEBPA mutations, 8 patients (2.0%) with IDH2-R172 mutations and no other class-defining lesions, 108 patients (27.5%) with driver mutations but no detected class-defining lesions, 38 patients (9.7%) with no detected driver mutations, and 15 patients (3.8%) who met the criteria of more than one genomic subgroup. Of the 393 patients, 325 patients (82.7%) achieved complete remission (CR). CR rates vary depending on the genomic subgroup (75.9%-97.4%). The CR rate for each subgroup was as follows: 86.8% (118/136) of patients with NPM1 mutations61.9% (26/42) of patients with mutated chromatin and/or RNA-splicing genes83.3% (5/6) of patients with TP53 mutations97.5% (38/40) of patients with biallelic CEBPA mutations87.5% (7/8) of patients with IDH2-R172 mutations and no other class-defining lesions75.9% (82/108) of patients with driver mutations but no detected class-defining lesions97.3% (37/38) of patients with no detected driver mutations80.0% (12/15) of patients meeting criteria of more than one subgroup 5-year OS and 5-year relapse incidence (RI) for each subgroup was as follows: 49.3% (95% CI, 40.1-58.5) and 39.8% (95% CI, 30.1-49.2) of patients with NPM1 mutations11.6% (95% CI, 1.4-21.8) and 71.4% (95% CI, 45.7-86.5) of patients with mutated chromatin and/or RNA-splicing genes50.0% (95% CI, 10.0-90.0) and 20.0% (95% CI, 0.4-61.2) of patients with TP53 mutations68.3% (95% CI, 53.4-83.2) and 19.7% (95% CI, 8.5-34.4) of patients with biallelic CEBPA mutations56.3% (95% CI, 17.3-95.3) and 21.4% (95% CI, 0.3-67.3) of patients with IDH2-R172 mutations and no other class-defining lesions26.6% (95% CI, 17.4-35.8) and 53.2% (95% CI, 40.7-64.3) of patients with driver mutations but no detected class-defining lesions29.1% (95% CI, 14.2-44.0) and 43.8% (95% CI, 27.1-59.3) of patients with no detected driver mutations40.0% (95% CI, 15.3-64.7) and 33.3% (95% CI, 9.2-60.3) of patients that meet the criteria of more than one subgroup. The CR rates of the subgroup with mutated chromatin and/or RNA-splicing genes was significantly lower than the rest of the cohort (61.9% vs. 85.2%, p=0.00016). The 5-year OS and 5-year RI of the subgroup were also poorer than the others [61.9% vs. 85.2% in OS (p=0.00016), 71.4% vs. 40.1% in RI (p 〈 0.0001)]. Conclusion Our NK-AML cohort showed similar survival patterns to the cohort in Papaemmanuil et al (NEJM 2016). The subgroup in AML with mutated chromatin and/or RNA-Splicing genes had the poorest prognosis with respect to CR rate and overall survival. This analysis replicates the result of recently published genomic classification and supports its use for categorizing NK-AML patients. Reference [1] Genomic Classification and Prognosis in Acute Myeloid Leukemia. Papaemmanuil E et al. N Engl J Med, 2016 vol. 374 (23) pp. 2209-2221. Figure Figure. Disclosures Jang: Kyowa Hakko Kirin Co., Ltd.: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.2876.2876
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 4
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    Longitudinal Tracking of MDS Patients Using Next Generation Sequencing Provides a Predictive Measure for Azacitidine Response and AML Progression
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 52-52
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 52-52
    Abstract: Introduction: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by dysplastic changes in one or more cellular lineages causing impaired bone marrow function. One third of patients diagnosed with MDS progress to secondary acute myeloid leukemia (sAML). These patients have significantly worse prognoses than de novo AML patients. Azacitidine (AZA), a hypomethylating agent is commonly used to treat MDS patients as a frontline therapy. Although its survival benefits over supportive care in a randomized trial has been demonstrated, the underlying genetics and clonal dynamics upon AZA response/AML progression have not been well examined. Using next generation sequencing (NGS) technology, we attempted to assess the clinical relevance of somatic mutations and their dynamics as they relate to AZA treatment in MDS patients using longitudinal samples. Patients and Methods: Ninety-five MDS patients (56 lower risk and 39 higher risk MDS based on the revised IPSS scoring system) were enrolled in this study. The median age of the 95 patients is 67 years (range of 31 Ð 84) and median follow-up duration was 747 days (range of 137-3328 days). We performed targeted deep sequencing (entire exon region of a panel of 84 myeloid genes, Agilent custom probe set) on 285 bone-marrow samples including the longitudinal samples taken at diagnosis (n=95) and post-AZA treatment, (median 4 cycles) as well as T-cell fraction (CD3+). We multiplexed and sequenced the samples using an Illumina Hiseq 2000. After read mapping and variant calling, hierarchical clustering, pathway and survival analyses were performed in R. Results: Targeted sequencing on the myeloid gene panel revealed 176 mutations in 68 patients (68/95, 71.6%) with a median of 2 mutations per patient (ranges 2-6). The average on-target coverage for 285 sequenced samples was 1205x. Twenty-five of 44 mutated genes were recurrently mutated. ASXL1 was the most frequently mutated in the cohort (21%), followed by TET2 (15%), DNMT3A (11%), and SRSF2 (11%). Mutated genes were then grouped into 8 biological pathways, defined in The Cancer Genome Atlas (TCGA) AML study. The most frequent biological pathway with mutated genes at diagnosis was DNA methylation (28.4%), followed by spliceosome (25.2%), chromatin modifiers (22.1%), myeloid transcription factors (TFs) (11.6%), activated signaling (11.6%), tumor suppressors (12.6%), and cohesin complex (6.3%). When assessing the differences in patterns of variant allele frequency (VAF), we found significant VAF reduction in responders compared to non-responders (p = 0.007, repeated measures using general linear model, Figure A). Multivariate analyses revealed that mutation burden in different genes and biological pathways have distinct impact on AZA response, AML transformation, and overall survival. Higher bone marrow blast percentage (5%) was associated with all three measures (Figure B). Most significantly, mutations in activated signaling pathway genes are associated with AML progression (p=0.002). In addition, we could not detect decreased VAFs in activated signalling pathway genes even in responders (Figure C-D). Patients with SRSF2 mutations tend to respond to AZA (OR 14.084, p=0.003). Mutations in tumor suppressors (HR 4.825, p 〈 0.001) and myeloid TFs (HR 3.070, p=0.020) were adverse prognostic factors in overall survival. Of interest, mutations in DNA methylation pathway were not independent prognostic factor for AZA response, AML transformation, or overall survival. Conclusion: These data and analyses show that reduction in mutation burden is correlated with AZA response. Mutations in different genes and biological pathways are associated with distinct clinical measures that tumor suppressors and myeloid TFs were identified as poor prognostic factors in terms of OS. Persistent mutation burden in activated signaling pathways is a strong predictor for AML transformation. In summary, longitudinal tracking of MDS patients using NGS may improve criteria for AZA response and early detection of AML progression. Figure 1. Figure 1. Disclosures Jang: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.52.52
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 5
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    Pharmacogenomics-Based Drug Response Prediction Model for Acute Myeloid Leukemia with Normal Karyotype
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2698-2698
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2698-2698
    Abstract: Abstract 2698 Introduction: AML is a heterogeneous disease characterized by various recurrent cytogenetic abnormalities, which provide the most important prognostic information. Although AML with normal karyotype (AML-NK) constitutes the largest subgroup representing 45–50% of adult AMLs, the prognosis of AML-NK is quite heterogeneous and their clinical outcomes are diverse. Several model capable of identifying non-responders prior to induction treatment has been proposed in AML-NK. While molecular-guided risk assessment (i.e. FLT3/ITD mutation or NPM1 mutation) and stratification are needed to confirm their prognostic significances, it is quite enthusiastic that genetic variations associated with ADMET (adsorption, desorption, metabolism, excretion, and transport) genes predict the responsiveness of anticancer drugs with better predictive power compared to other genomic variations based stratification. It is also expected SNP markers that reside within the loci of these genetic pathways may play an important role to classify responders and non-responders in AML-NK. Methods and materials: A high density SNP genotyping microarray designed by our group (custom PGX chip; Samsung Electronics Co., Suwon, Korea) was evaluated in 139 patients with AML-NK as a discovery set using both custom PGX chip and Affymetrix SNP array 6.0 (Affymetrix Inc., Santa Clara, CA USA). The DNA samples were obtained from the marrow samples at the time of diagnosis. The custom PGx chip included more extensive SNP markers of ADMET genes and cancer-related genes. Genotypes were determined by Birdseed v2 algorithm for Affymetrix SNP 6.0 and by BRLMM-p for custom PGx chip. Genotypes from 906,600 SNPs were obtained in Affymetrix SNP 6.0 chip while custom PGx chip provided genotype information of 90,647 SNPs. Between Affymetrix SNP 6.0 and custom PGx chip, 67,251 SNPs were shared. ADMET and cancer-related SNPs (n=23,396) were only available on custom PGx chip. The predictive model for the achievement of complete remission was developed using Max Test method with leave-one-out LDA cross validation (repeating 10,000 times of permutation test). The analysis compared the data of PGx chip with data from Affymetrix SNP 6.0 microarray. Results: Genotyping results from custom PGx chip was compared to results from Affymetrix SNP 6.0 showing 94.33% of concordance rate. Among the 164,578 SNP markers included in the original design, 90,647 of them were finally chosen to generate reliable genotype calls. Additional SNP markers including missing genotypes were again removed before the construction of prediction model. Finally, the total number of available SNP markers was reduced to 37,676 for the analysis and model contruction. Max Test provided p-values by performing permutation test. Significant SNP markers with p-values less than 0.01 were chosen to construct a prediction model using leave-one-out LDA (linear discriminate analysis) method. The numbers of SNP markers were narrowed down as p-values became more significant (No. of SNPs in p-value): n=329 in p 〈 0.01; n=66 in p 〈 0.001; n=7 in p 〈 0.0001. The selection of SNP markers could be optimized and further narrowed down by extensive search. The accuracy of the model improved as more SNP markers were included in the model: the accuracy reaches 100% when N was 59. Followings are the example of the significant SNP markers included in the genetic predictive model for complete remission after induction therapy for AML-NK: CCDC93, LRP1B, LASS6, ATF2, and PDE11A on chr 2, PDE4D and PPP2R2B on chr 5, PARK2 on chr 6, PTPRD on chr 9, ABCC4 on chr 13, SLC25A21 on chr 14, ABCC1, PRKCB, ITGAX, and CNOT1 on chr 16, and other SNP markers. The biologic significances of these SNP markers are under investigation. Conclusion: The clinical relevance of the predictive model based on pharmacogenomic informations will be further clarified with external replication in the independent cohorts of AML. In patients with AML-NK which has diverse and heterogeneous clinical characteristics, the predictive model could identify non-responders who might benefit from alternative treatments prior to commencement of conventional induction therapy based on idarubicin plus cytarabine. In addition, it will also reduce the risk of adverse events in the non-responders and eventually improve overall survival in AML-NK. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2698.2698
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 6
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    Candidate Pathway Approach of Single Nucleotide Polymorphism On Imatinib Transport/Metabolism Pathway and DNA Repair Enzyme Pathway Associated with Response and Resistance to Imatinib Therapy in Chronic Myeloid Leukemia.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 3284-3284
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    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3284-3284
    Abstract: Abstract 3284 Poster Board III-1 Purpose: Imatinib resistance is a major cause of imatinib treatment failure in chronic myeloid leukemia (CML) patients. In our previous study (Clin Cancer Res, 2009, 15(14):4750–8), SNP markers in the pathways of imatinib metabolism / transport could predict the response and resistance of imatinib therapy in CML. It has been known that organic cationic transporter-1 gene (OCT1, SLC22A1) is regulated by HNF4A (hepatocyte nuclear factor 4-alpha) or by PPARA (peroxisomal proliferators-activated receptor alpha) or PPARD (PPAR-delta). In addition, DNA repair machinery such as NER (nucleotide excision repair) or DSB (double strand break) repair pathway, plays an important role in the action mechanism of imatinib, in which ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5), or XRCC4 (X-ray repair complementing defective repair in Chinese hamster cells 4), were involved. The response to imatinib therapy in chronic myeloid leukemia (CML) is various according to inter-individual variation of drug delivery or metabolism. Thus, the current study investigated SNPs in the candidate genes involved in the imatinib transport/metabolism pathway and DNA repair enzyme pathway, and its association with clinical outcomes following imatinib therapy in CML patients. Methods: In the current study, we investigated 81 SNPs markers involved in the pathways of imatinib transport/metabolism pathway (n=62; ABCB1, ABCG2, CYP1A2, CYP2C9, CYP2C18, CYP2C19, CYP3A4, CYP3A5, AGP, OCT1, PPARA, PPARD, HNF4A) and DNA repair enzyme pathway (n=19; ERCC1/2/4/5, XRCC1/2/4/5). Total of 187 CML patients treated at the Samsung Medical Center, Chonnam National University Hwasun Hospital, or Kyungpook National University Hospital, Korea, were enrolled into the study. The DNAs from peripheral blood samples were genotyped with MALDI-TOF based technique (Sequenom). Results: Among the SNP markers involved in imatinib transport/ metabolism pathway, HNF4A (rs3212172) was significantly associated with high risk of loss of response (LOR; p 〈 0.001) or treatment failure (p=0.013). CYP1A2 (rs762551) was significantly associated with high risk of LOR (p 〈 0.001) or treatment failure (p=0.035). In addition, ERCC5 (rs17655) showed significant association with response (p=0.036 for complete cytogenetic response [CCR], 0.024 for major molecular response [MMR] ) or with resistance (p=0.05 for LOR, 0.025 for treatment failure), while XRCC4 (rs963248) showed significantly consistent association with response to imatinib (p=0.025 for major cytogenetic response [MCR], 0.032 for CCR, 0.008 for MMR, and 0.06 for complete molecular response [CMR] ). External validation is now ongoing and the result will be presented in the meeting. Conclusions: The current study suggested that SNP marker on HNF4A gene, regulator of OCT1 gene expression, could predict the risk of resistance to imatinib therapy, and that SNP markers on ERCC5 or XRCC4, involved in the NER and DSB repair pathway, also could predict the response to imatinib therapy, suggesting a potential involvement of DNA repair machinery in the action mechanism of imatinib in CML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.3284.3284
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 7
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    A multicenter, retrospective analysis of elderly patients with acute myeloid leukemia who were treated with decitabine
    Impact Journals, LLC ; 2018
    In:  Oncotarget Vol. 9, No. 5 ( 2018-01-19), p. 6607-6614
    Details
    In: Oncotarget, Impact Journals, LLC, Vol. 9, No. 5 ( 2018-01-19), p. 6607-6614
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    URL: Article
    DOI: 10.18632/oncotarget.v9i5
    DOI: 10.18632/oncotarget.23823
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2018
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  • 8
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    Efficacy and Safety of Micafungin as An Empirical Antifungal Agent for Febrile Neutropenic Patients with Hematological Diseases.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 4661-4661
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4661-4661
    Abstract: Abstract 4661 Introduction Invasive or possible fungal infection is often fatal and its incidence is increasing in febrile neutropenic patients with hematological malignancies. Thus, empirical antifungal agent should be carefully selected for those patients. Patients and Methods The study was conducted as a prospective multicenter trial to document the efficacy and safety of micafungin (Mycamine®), a class of echinocandin, as an empirical antifungal agent in febrile neutropenic patients. Micafungin was administrated for sustained fever ( 〉 38.4°C) on day 3 - 5 after initiation of empirical antibiotic therapy. The overall success rate according to the composite score (no breakthrough fungal infection, survival for seven days beyond the end of therapy, did not discontinue therapy prematurely, had resolution of fever during the period of neutropenia, and successfully treated a documented base-line fungal infection) and side effects were evaluated. Results A total of 47 patients with AML, ALL, MDS or lymphomas were enrolled. The overall success rate was 61.7% (29/47). Three patients (6.4 %) experienced grade 3/4 elevated aspartate aminotransferase and ten patients (21 %) showed grade 3/4 hyperbilirubinemia and nine of which resolved, and four patients died of septic shock. Patients with young age ( 〈 50 yr) and ALL rather than AML showed a better response to micafungin. Less profoundly neutropenic (≥50 /mm3) patients revealed a better response, as did the patients who recovered from fever or neutropenia. Conclusions Micafungin has been reported to have an excellent efficacy (61.7 %) and safety profile when used as an empirical antifungal agent to treat febrile neutropenic patients with hematological disorders. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.4661.4661
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 9
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    Killer Cell Immunoglobulin-like Receptor Ligand Matching Determines the Post-Transplant High Risk Groups Among Patients with Permissive HLA Mismatch in Unrelated Donor Hematopoietic Cell Transplantation
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 4566-4566
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4566-4566
    Abstract: Background: Human leukocyte antigen (HLA) matching between donor and recipient is a key part of successful allogeneic hematopoietic cell transplantation (allo-HCT). The HCT from the unrelated donor (UD) with one allele/antigen mismatch (MM) can be as beneficial as HCT from perfectly matched donor. For the remaining patients, the donors with permissive mismatches may be the option. In HLA-mismatched transplantation, the patient and donor can also be mismatched for their killer cell immunoglobulin-like receptor (KIR) ligands that recognize allotypic determinants shared by certain HLA class I allele groups. Recent research has accumulated evidence of the role of each HLA locus and KIR ligand MM on clinical outcomes for UD-HCT. However, HCT outcomes of the patients with permissive MM depending on KIR ligand MM (KIR-L-MM) status remain obscure in UD-HCT. In the current study, we identified permissive and nonpermissive MM allele combinations and analyzed the effects of these mismatches in combination of KIR ligand mismatches in patients with acute myeloid leukemia (AML). Methods: A total of 438 patients with AML who underwent allo-HCT from UD from 2007 to 2014 were analyzed. Alleles of patients and donors at the HLA-A, -B, -C, and -DRB1 loci were identified by the high resolution DNA typing. Nonpermissive HLA allele combinations were defined as a significant HLA risk factor for severe acute graft-versus-host disease (aGVHD). KIR-L-MM among patient-donor pairs were searched in the Immuno Polymorphism Database available at www.ebi.ac.uk/ipd/kir. Results: Median age of the patients was 45 (range 15-60) years and 117 patients (40.4%) were female. Eighty-five (19.4%) patients were high risk at the time of HCT. Reduced intensity conditioning was performed in 131 patients (29.9%) and anti-thymocyte globulin was used in 324 patients (74.0%). Primary graft source was peripheral blood stem cells (n=369, 84.2%) and median 6.0 x 106/kg cells were infused. Severe aGVDH occurred in 43 patients (9.8%) and chronic GVHD (cGVHD) in 193 (44.1%). With median follow-up duration of 19 (range, 2-96) months, treatment-related mortality (TRM) occurred in 111 patients (25.3%), relapse in 119 (27.2%) and death in 214 (48.9%). Two-hundred sixty-four patients (60.3%) were HLA full matched in the 4 loci. Mismatches in HLA-A loci observed in 64 patients, HLA-B in 35, HLA-C in 98, and HLA-DRB1 in 60. Five nonpermissive MM pairs in 33 patients were identified as donor/patient pair: A*02:06/A*02:01, C*03:03/C*08:01, C*08:01/C03:04, C*08:01/C*15:02, and DRB1*04:03/DRB1*04:05. Among 98 patients with HLA-C loci MM, 16 patients showed KIR ligand MM (KIR-L-MM) as GvH direction, which was observed in the permissive MM group. Severe aGVHD occurred in 30.4%, 22.4%, 13.4%, and 10.8% in nonpermissive, permissive MM and KIR-L-MM, permissive MM and KIR-L-M, and full match group, respectively (p=0.003). The 3-year overall survival (OS) rate was inferior in permissive MM and KIR-L-MM group (30.0%) compared to full match (53.5%), permissive MM and KIR-L-M (51.8%), and nonpermissive (42.4%) group (p=0.067). The 3-year TRM was higher in permissive MM and KIR-L-MM group (57.5%) than full match (21.0%), permissive MM and KIR-L-M (27.7%), and nonpermissive (33.3%) group (p=0.006). In the multivariate analysis, high risk at HCT (HR 2.087, p 〈 0.001), severe aGVHD (HR 3.851, p 〈 0.001), and cGVHD (HR 0.321, p 〈 0.001) were identified as variables affecting the OS. The following variables adversely affected on TRM: permissive MM and KIR-L-MM group (HR 2.699, p=0.007), severe aGVDH (HR 2.204, p=0.001), and cGVHD (HR 2.052, p 〈 0.001). Non-permissive MM (HR 7.487, p=0.001) and CD34+ cells 〉 6x106/kg (HR 4.113, p=0.017) were high risk factors on severe aGVHD. Conclusion: Permissive MM for HLA could be further classified into high risk groups with regard to TRM by KIR-L matching in UD-HCT. The evaluation of KIR-L matching is warranted to reduce unfavorable outcomes among the patients with permissive MM in UD-HCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.4566.4566
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 10
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    Low Expression of Bax Predicts Poor Prognosis in Patients with Locally Advanced Esophageal Cancer Treated with Definitive Chemoradiotherapy
    American Association for Cancer Research (AACR) ; 2007
    In:  Clinical Cancer Research Vol. 13, No. 14 ( 2007-07-15), p. 4146-4153
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 14 ( 2007-07-15), p. 4146-4153
    Abstract: Purpose: The present study evaluated the prognostic significance of apoptosis-related proteins, p53, Bcl-2, Bax, and galectin-3 in patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy. Experimental Design: A total of 63 patients with locally advanced esophageal cancer (squamous cell carcinoma: 62; adenocarcinoma: 1; stages II-IV) were treated with definitive chemoradiotherapy using 5-fluorouracil and cisplatin combined with radiotherapy. Pretreatment tumor biopsy specimens were analyzed for p53, Bcl-2, Bax, and galectin-3 expression by immunohistochemistry. Results: High expression of Bax, p53, Bcl-2, and galectin-3 was observed in 67%, 47%, 24%, and 29% of patients, respectively. The median overall survival (OS) of total patients was 14 months with 16% of 3-year OS. High expression of p53, Bcl-2, and galectin-3 did not show correlation with clinicopathologic characteristics, including patient outcome. Low expression of Bax was significantly correlated with lack of clinical complete response (P = 0.023). Low expression of Bax was also associated with poor OS (median, 8 months versus 16 months; P = 0.0008) in univariate analysis. In multivariate analysis, low expression of Bax was the most significant independent predictor of poor OS (P = 0.009), followed by low dose intensity of cisplatin and lack of clinical complete response. Conclusions: Low expression of Bax was significantly associated with the poor survival of patients with locally advanced esophageal cancer treated with chemoradiotherapy using 5-fluorouracil and cisplatin. Immunohistochemical staining for Bax with a pretreatment biopsy specimen might be useful to select the optimal treatment options for these patients.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-06-3063
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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