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  • American Society of Hematology  (16)
  • 1
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    Retrospective Analysis of Prognostic Factors for Waldenström Macroglobulinemia: A Multicenter Cooperative Study in Japan
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 5028-5028
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 5028-5028
    Abstract: Background: Analysis of prognostic factors and clinical trials of novel agents for Waldenstrӧm macroglobulinemia (WM) are ongoing in Western countries, but few studies of WM have been performed in Japan. As a step toward future investigations, we retrospectively analyzed clinical features and prognostic factors in Japanese patients with WM. Methods: We retrospectively analyzed clinical and laboratory characteristics, treatment and outcomes of 110 patients with WM, IgM-MGUS or lymphoplasmacytic lymphoma (LPL) diagnosed from January 2001 to March 2013 at 12 institutes. Overall survival (OS) was analyzed using Kaplan-Meier methods and survival was compared using log-rank testing. Several clinical characteristics at diagnosis were assessed by Cox regression for uni- and multivariate analysis for OS. Results: Median age at diagnosis was 69 (range, 41-96) years, 73.6% were male, 12.0% had an ECOG performance status 2-4 and 6.4% presented with B-symptoms. Hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia and cold agglutinin disease were shown in 9.1%, 4.5%, 1.8%, 4.5% and 2.7%, respectively. In 94 patients with available CT findings at diagnosis, lymphadenopathy, hepatosplenomegaly, pleural effusion, lung involvement, bone involvement and skin involvement were shown in 41.5%, 14.9%, 8.5%, 4.3%, 4.3% and 6.4%, respectively. Median serum monoclonal protein level was 2.62 g/dl (range, 0.70-9.35 g/dl). Symptomatic WM was present in 76 patients, asymptomatic WM in 23 and IgM-MGUS in 2 according to criteria of the Second International Workshop on WM. Seven patients showed IgG- or IgA-secreting LPL and 2 showed LPL without bone marrow infiltration. In patients with symptomatic WM, international prognostic scoring system for WM (ISSWM) was low in 9.2%, intermediate in 34.2%, high in 39.5% and unknown in 17.1%. Among patients with asymptomatic and symptomatic WM, watchful waiting was performed in 91.3% and 40.0%, respectively, with 61.9% and 36.7% remaining untreated, respectively. Median time to treatment from diagnosis of asymptomatic or symptomatic WM was 240 days (range, 3-1238 days) and 31 days (range, 0-2011 days), respectively. Oral alkylating agents were administered to 34.7% of patients with WM, 19.4% were treated with CHOP or CHOP-like regimen with or without rituximab, 8.2% received fludarabine mono- or combination therapy and 6.1% received rituximab monotherapy. Rituximab-containing therapy was administered as the initial treatment in 33.8% of patients who received treatment. Overall response rate (ORR) (complete + partial response rate) was 48.6%, and patients treated with rituximab-containing therapy displayed higher ORR (64.0%) compared to those with non-rituximab therapy (40.8%). Plasmapheresis was performed in 3.7% of patients. Three patients (2.7%) showed transformation to diffuse large B-cell lymphoma, and 7 (6.4%) developed second primary malignancies. Median follow-up was 38 months, 5-year OS rate for all patients was 74.9% (95% confidence interval (CI) 62.5-83.7) and rates for those with symptomatic WM, asymptomatic WM and other LPL were 66.0% (95%CI 50.6-77.6), 100% and 88.9% (95%CI 43.3-98.4), respectively. Significant differences in survival between risk groups of ISSWM in patients with symptomatic WM were not seen (5-year OS: high, 62.4%; intermediate, 64.3%; low, 75.0%; p=0.86). Although no significant difference in OS was observed compared to initial treatment (p=0.265), patients treated with rituximab during the observation period showed significantly prolonged OS compared to those treated without rituximab (5-year OS rates: 78.9% vs. 45.6%, p=0.036). In univariate analysis, age, pleural effusion, serum albumin, C-reactive protein and serum IgM levels were poor prognostic factors for OS. In multivariate analysis, age 〉 65 years (hazard ratio (HR)=3.294; 95%CI 1.097-9.888, p=0.0336) and pleural effusion (HR=4.55; 95%CI 1.602-12.930, p=0.0045) were identified as significant prognostic factors for OS. Conclusion: Prognostic factors for WM in Western countries may not be applicable to Japanese patients. This study suggested presence of pleural effusion at diagnosis is associated with poor clinical outcomes. Further investigations including histopathological examinations and molecular analyses are required to elucidate prognostic factors in Japan. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.5028.5028
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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    detail.hit.zdb_id: 80069-7
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  • 2
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    Soluble IL-2 Receptor α Is a More Sensitive Diagnostic Biomarker Than β2 Microglobulin and Predicts Survival in Follicular Lymphoma: Retrospective Analysis of 305 Cases
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3034-3034
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3034-3034
    Abstract: Introduction: Soluble-form IL-2 receptor α (sIL-2Rα) has been identified as a significant prognostic biomarker in patients with non-Hodgkin’s lymphoma (NHL) treated using rituximab-containing regimens. However, the clinical significance of sIL-2R is not fully understood, especially in subtypes of NHL, such as follicular lymphoma (FL). In addition to sIL-2Rα, β2-microglobulin (B2M) has been used as a prognostic and diagnostic biomarker of FL. We compared the predictive and diagnostic abilities of sIL-2Rα and B2M for FL. Patients and Methods: We analyzed 305 patients newly diagnosed with FL (Grade1-3a) between January 2001 and July 2012. Levels of sIL-2Rα and B2M were evaluated at diagnosis. The optimal cut-off values of sIL-2Rα and B2M were calculated from receiver operating characteristic (ROC) curves. Overall survival (OS) and progression-free survival (PFS, death from any cause, relapse and refractory disease) were analyzed using Kaplan-Meier methods and survival was compared using log-rank tests. To estimate the survival impact of several factors including sIL-2Rα, B2M, Hb 〈 12g/dl, B symptoms, LDH, bone marrow involvement, bulky disease, extranodal disease and age, we performed multivariate analysis using the Cox proportional hazards model. Results: Median age was 59 years (range: 28-86 years) and the male: female ratio was 1:1. Most (245/305) patients were treated with chemotherapy regimens. Rituximab was concomitantly administered to 227 of these patients (R-Chemo) and 52 of these patients received rituximab maintenance for 2 years. In the 305patients, clinical stage was I in 12.3%, II in 15.1%, III in 24.9%, and IV in 45.9% and the Follicular Lymphoma Prognostic Index was low in 35.7%, intermediate in 27.2% and high in 36.7%. The median follow-up period was 1,516 days (range: 7 - 4,776 days). The median sIL-2Rα value was 1,107.5 U/L (range: 127-20,800 U/L) and the median B2M value was 2.2 mg/L (range: 1.0-10.29). The 3-year OS of the entire population was 87.8% and the 3-year PFS was 65.1%. The percentage of patients whose sIL-2Rα or B2M level was higher than the upper normal limit (520 U/L for sIL-2Rα, 2.0 mg/L for B2M) at diagnosis was higher for sIL-2R (76.8%) than for B2M (54.2%) patients (p 〈 0.0001), indicating that sIL2Rα is more sensitive diagnostic marker for FL than B2M. To estimate the predictive value of sIL-2Rα and B2M for survival, we determined the optimal cut-off levels of sIL-2Rα and B2M using ROC analysis. This analysis showed that sIL-2Rα and B2M values of 1,700 U/L and 2.2mg/Lrespectivelywere the most sensitive and specific values for prediction of a 3-year PFS. Using these values, patients were separated into two significantly different groups of sIL-2Rα values ( 〉 1,700 U/L and ≤1,700 (p 〈 0.0001)) and of B2M values ( 〉 2.2 mg/L and ≤ 2.2 mg/L (p=0.0017)). Further, PFS differed significantly between patients with sIL-2Rα values of 〉 520 U/L and ≤520 U/L, 〉 1,000 U/L and ≤1,000 U/L ,and 〉 2,000 U/L and ≤2,000 U/L (p=0.03, 0.0003 and 〈 0.0001, respectively) and also between patients with B2M values of 〉 2.0 mg/L and ≤2.0 mg/L, 〉 2.5 mg/L and ≤2.5 mg/L, 〉 3.0 mg/L and ≤3.0 mg/L (p=0.011, 0.0016 and 0.0184, respectively). Univariate analysis identified several reported prognostic factors, such as clinical stage3-4, B2M 〉 2.2 mg/L, number of nodal site 〉 5, bone marrow involvement, Hb 〈 12 g/dl, performance status 〈 2, number of extranodal site 〉 1, longest diameter 〉 6 cm ( 〈 0.0001, 0.002, 0.0002, 0.0204, 0.0345, 0.0089, 0.0004 and 0.0053, respectively) in addition to sIL-2Rα (p 〈 0.0001). Cox multivariate analysis indicated sIL-2Rα as a significant prognostic factor (p=0.0361), in addition to several other factors (bone marrow involvement, number of extranodal site 〈 2, number of nodal site 〉 5). In the group treated with the R-chemo regimen, the 3-year OS was 86.9% and the 3-year PFS was 64.9%. Within this group, PFS significantly differed between the two groups of sIL-2Rα; 〉 1,700 U/L and ≤1,700 (p 〈 0.0001), and between two groups with different B2M values 〉 2.2 mg/L and ≤ 2.2 mg/L (p=0.0056). Again, multivariate analysis showed that sIL-2Rα ( 〉 1,700 U/L), in addition to several other factors, was associated with poorer prognosis. Conclusion: This study showed that sIL-2Rα is a more sensitive diagnostic biomarker of FL than B2M. In terms of survival, sIL-2R is an important risk factor of FL, not only for all patients with FL, but also in the R-Chemo era. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3034.3034
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
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    Prognostic Importance of Soluble Form IL-2 Receptor á (sIL-2Rá) and Its Relationship with Surface Expression of IL-2Rá of Lymphoma Cell in Diffuse Large B-Cell Lymphoma Treated with Rituximab-Containing Chemotherapy: a Retrospective Analysis of 409 Cases.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1935-1935
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1935-1935
    Abstract: Abstract 1935 Poster Board I-958 Introduction: Several reports have identified soluble-form IL-2 receptor á (sIL-2Rá) as a significant prognostic factor in patients with non-Hodgkin lymphoma treated using chemotherapy, particularly in rituximab-containing regimens. However, the clinical significance of sIL-2R is not fully understood, as only small populations have been studied to date. The rationale for increasing of serum level of sIL-2Rá in non-Hodgkin lymphoma is also unclear. Patients and Methods: We analyzed 409 patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL) between January 2001 and July 2008. Treatment comprised CHOP-like regimen with (R-CHOP-like) or without rituximab. Levels of sIL-2R were evaluated with enzyme-linked immunosorbent assay at diagnosis. Overall survival (OS) and progression-free survival (PFS, death from any cause, relapse and refractory disease) were analyzed using Kaplan-Meier methods and survival was compared using log-rank tests. To estimate the survival impact of several factors, including sIL-2Rá level, PS, LDH, B symptoms, extranodal sites ≥2 and age, we performed multivariate analysis using Cox proportional hazards. In 166 of 409 patients, CD25 (IL-2Rá) expression on tumor cells was evaluated using a lymphoma sample from the lymph node, bone marrow, blood or other extranodal organ by flow cytometry. To estimate CD25 expression of tumor cell, CD45 bright cells (mature lymphocyte gate) were gated and considered positive if positivity was seen in 〉 20% of the population excluding CD4-positive cells) using three-color flow cytometry. Results: Median age was 68 years (range, 17-91 years), males/females 1.18, and 28.9% of patients were treated with CHOP-like regimen and 60.2% with R-CHOP-like regimen. Clinical stage was I in 24.4%, II in 24.2%, III in 13.1%, and IV in 38.8%. International Prognostic Index (IPI) was Low in 33.5%, LI in 23.5%, HI in 18.7% and H in 24.3%. Median follow-up for CHOP-like and R-CHOP-like groups was 924 days (range, 16-2878 days) and 799 days (range, 29-2688 days), respectively. Median sIL-2Rá value was 1360 U/L (range, 170-59,500 U/L). For the entire population, CR rate was 71.9%, 3-year OS was 67.6% and PFS was 58.8%. OS differed significantly between sIL-2R 〉 1000 U/L and ≤1000 U/L, between 〉 2000 U/L and ≤2000 U/L and between 〉 3500 U/L and ≤3500 U/L, (p 〈 0.001, 〈 0.001, 〈 0.001, respectively). PFS also differed at each sIL-2Rá point (p 〈 0.001, respectively). The sIL-2Rá value correlated moderately or well with other prognostic factors, such as LDH, PS ≥2, B symptoms, ≥2 extranodal lesions, age and clinical stage by Spearman correlation analysis (r=0.579, 0.258, 0.404, 0.474, respectively). Multivariate analysis showed sIL-2Rá as a significant prognostic factor, in addition to several factors. In a group treated with R-CHOP-like regimen, 3-year OS was 74.5% and PFS was 68.8%. OS again differed significantly between sIL-2Rá 〉 1000 U/L and ≤1000 U/L, between 〉 2000 U/L and ≤2000 U/L and, between 〉 3500 U/L and ≤3500 U/L (p 〈 0.001, respectively). PFS was also significant at each sIL-2Rá value. The higher the level of IL-2R, the worse the 3-year OS at each sIL-2R value (63.6%, 60.1%, 53.2%, respectively). However, we could not identify statistical significance of sIL-2 level by multivariate analysis. IL-2Rá usually functions as a cytokine receptor on cell surface, called CD25. To show the importance of CD25 expression in lymphoma cells on serum level of soluble form IL-2Rá, we compared sIL-2Rá levels in CD25-positive and -negative cases. CD25-positive cases showed significantly higher sIL-2Rá level than CD25-negative cases among the overall population. After defining two group according to clinical stage (I+II and III+IV), sIL-2Rá level was higher in the CD25-positive group than in the CD25-negative group for the stage III+IV group (p=0.001), but this difference was not seen for the stage I+II group (p=0.390). This trend was also seen in the case of IPI, L+LI (p=0.642) and HI+H (p=0.0016)). These results suggest that one rationale for increasing level of sIL-2Rá in DLBCL is removing from tumor cell like other cytokine receptor. Conclusion: In terms of survival and relapse, sIL-2R remains an important risk factor of DLBCL, not only in CHOP-like regimens, but also in the R-CHOP era. The survival rate of patients with sIL-2Rá 〉 3500 U/L is extremely poor even if treated with R-CHOP (53.2%). We showed that one rationale for increasing level of serum sIL-2Rá level in DLBCL is to remove from the tumor cell surface. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1935.1935
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 4
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    The Polymorphisms of Base Excision Repair Genes Influence the Prognosis of Multiple Myeloma
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3981-3981
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3981-3981
    Abstract: Abstract 3981 Background: The DNA in human cells is oxidatively damaged by various endogenous biochemical processes or exogenous stimuli. Base excision repair (BER) systems have important role for repairing oxidative DNA damage, and known to influence the carcinogenesis and the response to anti-cancer treatments. Although previous studies have shown that defective DNA repair is associated with an increased risk of hematologic malignancies including leukemia and lymphoma, it is unclear these polymorphisms alter the susceptibility and clinical outcome of multiple myeloma (MM) patients. The aim of this study was to evaluate the impact of polymorphisms in genes encoding four main proteins of BER system: OGG1 Ser326Cys, XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYH Gln324His on the risk and survival of MM. Methods: We examined 93 patients [age range, 35–83 years; male/female44/49; Durie and Salmon stage I (n=8), stage II (n=22), stage III (n=61), unknown (n=2); Intenational staging system (ISS) 1 (n=21), 2 (n=21), 3 (n=29), unknown (n=22); IgG (n=55), IgA (n=15), IgD (n=2), non-secretory (n=3), Bence Jones (n=18)] with MM and 192 healthy controls. Genomic DNA was isolated from peripheral blood using the DNA extraction kit. Genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Allele and genotype frequencies were calculated by direct counting. Genotype and allele frequencies were compared between patients group and control group by using Χ2-test. The characteristics and laboratory features of MM patients with each polymorphisms were compared using Χ2-tests and student t-tests. The Kaplan-Meier method was used in the calculation of overall survival (OS). Difference between the survival curves by genotypes was compared using the generalized Wilcoxon test. For the multivariate survival analyses, cox proportional hazard models were used to define the prognostic factors for OS. Probability values 〈 0.05 were considered statistically significant. All patients and healthy controls received written information about the study. This study was approved by the Institutional Research Board of Gunma University Hospital. Results: The frequencies of genotypes of BER gene polymorphism in patients with MM were as follows: Ser/Ser 35.9%, Ser/Cys 34.8%, and Cys/Cys 29.3% for OGG1; Gln/Gln 22.6%, Gln/His 49.5%, and His/His 28% for MUTYH; Arg/Arg 57%, Arg/Gln 38.7% and Gln/Gln 4.3% for XRCC1; Asp/Asp 35.5%, Asp/Glu 41.9%, and Glu/Glu 22.6% for APE1. These results showed the OGG1 Cys/Cys genotype (low DNA repair type) compared with OGG1 non-Cys/Cys genotype increases the risk of MM (OR 1.86, 95% CI 1.04–3.31, p 〈 0.05). Furthermore, the Ser/Cys genotype compared with OGG1 non-Ser/Cys genotype strongly reduces the risk of MM (OR 0.39; 95% CI 0.24–0.06, p 〈 0.0005). In contrast, there was no statistically significant difference about the risk of MM in the allele and genotype frequencies of the XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYH Gln324His polymorphisms between the control group and the patients with MM. When comparing OS according to APE1 Asp148Glu polymorphism, the group with APE1 Glu/Glu (low DNA repair type) showed inferior OS (median OS 3.07 years vs.5.63 years, p=0.02). In a multivariate analysis using stepwise selection, APE Glu/Glu (low DNA repair type) (p=0.02), MUTYH His/His (low DNA repair type) (p=0.0001), ISS 3 (p=0.003), and Hb 〈 10 g/dl (p=0.03) were independent prognostic factors significantly associated with shorter survival. Conclusions: According to our data, BER gene polymorphisms may affect the carcinogenesis and prognosis of MM. It is suspected that low BER activity gave rise to high DNA damage, and induced malignant transformation of plasma cell and progression to aggressive myeloma. The BER gene polymorphisms may be one of useful prognostic markers of MM and require further verification as predictive biomarkers in a larger study population. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3981.3981
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 5
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    Polymorphisms of IL-10, IL-17A, IL-17F and IL-18 Affect the Clinical Features of Multiple Myeloma in Japanese Patients
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 4972-4972
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    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4972-4972
    Abstract: Abstract 4972 Background: The growth of plasma cells in multiple myeloma (MM) is dependent on a complex interplay among various cytokines, adhesion molecules and other factors in the tumor microenvironment. Several cytokines, including Interleukin (IL)-6, IL-10 and IL-17 have been shown to promote myeloma cell growth in vitro. Furthermore, several investigators have shown the increase in levels of serum IL-6, IL-10, IL-17, and IL-18 in MM patients compared with healthy donors. Although many studies have shown that the dysregulation of these cytokines can be associated with MM development, there are a few reports showing the influence of polymorphisms in cytokine genes on the risk of MM. We examined the single nucleotide polymorphisms (SNPs) of these cytokines: IL-10 (rs1800870 − 1082 A/G, rs1800871 − 819 T/C, and rs1800872 − 592 A/C), IL-17A (rs2275913, −197G/A), IL-17F (rs763780, 7488 T/C), and IL-18(rs187238 −137G/C and rs1946518 −607 A/C) in MM patients, and analyzed the relationship between these SNPs and the susceptibility and clinical features. Patients and Methods: Ninety three patients [age range, 35–83 years; male/female 44/49; Durie and Salmon stage I (n=8), stage II (n=22), stage III (n=61), unknown (n=2); International staging system (ISS) 1 (n=21), 2 (n=21), 3 (n=29), unknown (n=22); IgG (n=55), IgA (n=15), IgD (n=2), non-secretory(n=3), Bence Jones(n=18)] with MM and 192 healthy race- and sex-matched healthy controls were examined. Genomic DNA was isolated from peripheral blood using the DNA extraction Kit. Genotyping of IL-10, IL-17A, and IL-17F polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the genotyping of the IL-18 polymorphism was determined by the allelic specific polymerase chain reaction technique. Genotype and allele frequencies were compared between the study groups using Χ2-test. The characteristics and laboratory features of MM patients with each polymorphisms were compared using Χ2-tests and student t-tests. The Kaplan-Meier method was used in the calculation of overall survival (OS). OS were compared with the log-rank test. Probability values 〈 0. 05 were considered statistically significant. Results: Genotype and allele frequencies of cytokines in MM patients and the control: The frequencies of genotypes of cytokines in patients with MM were as follows: AA 92. 5% and AG 7. 5% for IL-10–1082; TT 43%, TC 48. 4% and CC 8. 6% for IL-10–819; AA 43%, AC 48. 4% and CC 8. 6% for IL-10–592; AA 19. 4%, AG 40. 9% and GG 39. 8% for IL-17A-197; TT 82. 8% and TC 17. 2% for IL-17F; GG 65. 6%, GC 26. 9% and CC 7. 5% for IL-18–137; AA 35. 5%, AC 47. 3% and CC 17. 2% for IL-18–607 loci. No significant differences were observed in the allele or genotype frequencies of IL-10 and IL-17F polymorphisms between MM patients and the control group. However, patients with MM had a significantly higher frequency of the IL-18–137 CC genotype compared to the control group (7. 5% vs. 2. 2%, P 〈 0. 05). The number of IL-18–137 C alleles among the patients with MM was also higher than in the control group (21% vs. 13. 3%, p 〈 0. 05). Furthermore, MM patients had a significantly lower frequency of the IL-17A A/G genotype compared to the control group (40. 9% vs. 58. 7%, P 〈 0. 01). Patients' characteristics according to cytokine polymorphisms: IL-10 592 CC genotype (high producer type) was significantly associated with advanced ISS (P=0. 03) and higher β2 microglobulin level (CC vs non CC; 9. 81±4. 78 g/dL vs. 5. 27±3. 27g/dL, p 〈 0. 05). IL-17A-197 AA genotype (high producer type) was also significantly associated with higher bone scale (66. 6% vs 44%, p=0. 05). IL-18–137 CC or GC genotype was significantly associated with advanced ISS (P 〈 0. 05) and lower hemoglobin level (8. 8±2. 6 mg/dL vs. 9. 9±2. 4 mg/dL, p=0. 04). Although there was no significant difference in overall survival of IL17 A, IL-17F and IL-18 polymorphisms, patients with IL-10–592 CC or IL-18–607 AA genotype showedtendency to more unfavorable survival (p=0. 07). A multivariate analysis using cox proportional hazard model demonstrated that Bence Jones protein (p=0. 001), ISS stage III (p 〈 0. 05), the use of new drugs (p=0. 001), IL-10–592CC genotype (P=0. 005) and IL-17 AA (P=0. 00001) were independent adverse prognostic factors. Conclusion: These results indicate that cytokine polymorphisms, including IL-10, IL-17 and IL-18, are associated with prevalence and clinical feature of MM in Japanese patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.4972.4972
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
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  • 6
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    Common Fragile Site Gene FRA16D WWOX (WW domain containing oxidoreductase) Is Frequently Altered in Plasma Cells of Multiple Myeloma and MGUS, Possibly Related to Disease Development
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 4646-4646
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4646-4646
    Abstract: Abstract 4646 The common fragile sites (CFSs) are regions of profound genomic instability, and hot-spots for deletions and other alterations in cancer cells. We have previously shown that promoter of FHIT is frequently methylated in multiple myeloma (MM) and correlated with worse prognosis. WWOX is located at a CFS region on chromosome 16q23.3, this gene is also a target of alterations in multiple cancers. The objective of current study is to find if this tumor suppressor gene is altered in MM and MGUS. Six myeloma cell lines, bone marrow mononuclear cells (BMMNC) of 165 MM and 25 MGUS patients were subjected to this study after obtaining informed consent. Isolated CD138 positive plasma cells (PC) of 24 MM were examined to see if the alteration occurred really in myeloma cells. Using methylation specific PCR, WWOX promoter methylation was detected in 2 of 6 cell lines, 35% of MM patients and 8% of MGUS patients (p=0.01). The overall survival of the MM patients with methylated WWOX tended to be worse than with unmethylated WWOX (p=0.2). Using nested RT-PCR, aberrant short transcripts of WWOX lacking exons coding SDR domain were detected in 4 cell lines, 68% of MM and 60% of MGUS (p=0.51) In isolated PC, aberrant transcripts of WWOX were detected in 58% of MM and 25% of MGUS (p=0.02). Real time PCR demonstrated higher WWOX expression in isolated PC of MM and MGUS than of BMMNC other than plasma cells (p=0.0001), and those higher WWOX were aberrant type (p=0.001). As aberrant WWOX is known to function as dominant negative for wild type, our results imply that this aberrant WWOX is an oncogene as well as losing tumor suppressor function. Since WWOX is demonstrated to regulate beta-catenin and NF-kB pathway, high frequency of aberrant WWOX expression indicates an important role in myeloma development. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.4646.4646
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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    detail.hit.zdb_id: 80069-7
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  • 7
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    Thalidomide-Induced Leukopenia in Japanese Patients with Refractory Multiple Myeloma.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 5089-5089
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 5089-5089
    Abstract: Background: Thalidomide is effective for treating refractory multiple myeloma; however, it induces many adverse events, including peripheral neuropathy, deep vein thrombosis, constipation, and neuropsychological symptoms. Hematological adverse events have rarely been reported in the United States and Europe. Some Japanese cases have been reported to reveal leucopenia during thalidomide therapy. We report here severe leucopenia, which has been observed in the JMSG phase II study “Low-dose thalidomide plus low-dose dexamethasone therapy for refractory myeloma”, and analyze the factors related to leucopenia. Patients and Methods: Patients with refractory myeloma were eligible. Thalidomide at 100 mg/day was administered on Days 1–7 and increased to 200 mg/day without severe adverse events, and continued until disease progression. Dexamethasone at 4 mg/day was administered on Days 1–28, decreased to 1 mg/day, and maintained at 1 mg/day. The response was assessed by the finding of a decline in paraprotein in serum or urine on two occasions at least 4 weeks apart. Results: Sixty-six patients (male/female ratio: 0.7; median age, 64.5 years; range, 40–74 years) were enrolled in the study. The myeloma subtypes were 48 IgG, 6 IgA, 1 IgD, and 11 light chain only. Forty-nine patients were refractory for conventional chemotherapy and 17 patients had relapsed disease after autologous stem cell transplantation. Responses were observed in 30 patients (4 near complete response, 9 partial response, and 17 minimal response) (45.5%). Median progression-free and overall survivals were 6.2 months and 23.3 months. The incidence rates of grade 2 or higher events were: peripheral neuropathy, 7.5%; hyperglycemia, 1.5%; skin rash, 4.5%; constipation, 4.5%; and deep vein thrombosis, 4.8%. Grade 1–2 incidence of leukopenia was 41% and of thrombocytopenia was 27%; Grade 3 or higher leucopenia was observed in 12%. One patient died from sepsis caused by severe leucopenia. Thalidomide-induced leucopenia was closely related to pre-treatment white blood cell count (p & lt;0.02) and platelet count (p & lt;0.001). Thrombocytopenia was related to pre-treatment platelet count (p & lt;0.01). In addition, the incidence of leucopenia was significantly higher in patients with a pretreatment platelet count & lt;100×109/L (p & lt;0.001). There was no relationship between hematological adverse events and disease period. Conclusion: Low-dose thalidomide plus low-dose dexamethasone therapy was as effective as low-dose thalidomide plus high-dose dexamethasone therapy in patients with refractory multiple myeloma. The incidence of adverse events including deep vein thrombosis and hyperglycemia was lower than the data reported in the United States and Europe. However, leukopenia is one of the most serious adverse events in Japanese patients, especially in patients with low pretreatment white blood cell and platelet counts.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.5089.5089
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
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  • 8
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    IL-10-592 Polymorphism Predicts the Clinical Outcome of Japanese Patients with Multiple Myeloma and MGUS.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 4759-4759
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4759-4759
    Abstract: Introduction: Interleukin 10 (IL-10) has been reported as an anti-inflammatory cytokine and B-cell proliferation factor, and has been implicated in autoimmunity, tunorigenesis and stem cell transplantation tolerance. IL-10 is also reported to be involved in multiple myeloma (MM) cell proliferation and survival. The polymorphism of position-592, -819, and -1082 in the promoter of IL-10 gene is a strong determinant of IL-10 expression. However, it is unclear whether IL-10 polymorphisms alter the incidence and clinical outcome of MM. We examined the single nucleotide polymorphism (SNPs) located within the promoter region of IL-10 genes in patients with MM, monoclonal gammopathy of undetermined significance (MGUS) and healthy controls in Japan. Methods: Seventy nine patients with MM [age range, 40–83 years; stage I (n=9), stage II (n=20), stage III (n=50); IgG(n=47), IgA(n=12), IgD(n=1), non-secretory (n=3), Bence Jones(n=16)], 46 patients with MGUS (age range, 44–86 years), and 200 healthy controls were included. Fifteen patients with transformation of MGUS to MM were included in MM group. Genotyping in IL-10 -1082G/A, -819C/T, -592A/C was determined by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. Genotype and allele frequencies were compared between the study groups using χ2-test. The characteristics and laboratory features of MM patients with each IL-10 promoter polymorphism were compared using χ2-tests and student t-tests. Probability values 〈 0.05 were considered statistically significant. The Kaplan-Meier method was used in the calculation of overall survival. Overall survival curves were compared with the log-rank test. Results: IL-10-592 A/A, A/C and C/C genotype frequencies were not significantly different between MM patients (51%, 34%, and 15%) and controls (42%, 43%, and 15%). Higher frequency of −592A/A genotype was seen in our Asian control compared with Caucasian. The frequency of IL-10 -1082 and -819 were also not significantly different between MM patients and healthy controls. The IL-10-592A/C genotype was detected in 10 of 16 patients (63%) with transformation of MGUS to MM and 20 of 46 patients (43%) with MGUS who did not progress to MM (odds ratio [OR], 2.2; 95% confidence interval [95% CI] , 0.7–7.0; p=0.15). In MM patients who received autologous stem cell transplantation (ASCT), the overall survival was similar among 3 genotype groups. However, in patients who did not received ASCT, patients with IL-10-592A/C and C/C genotype had shorter overall survival compared with patients with IL-10-592A/A genotype (median survival, 32 months vs. not reached). Conclusion: It is reported that IL-10-592 A/C and C/C genotype are high producer of IL-10. Our results suggested that the IL-10-592 A/C and C/C genotype was not associated with the susceptibility to MM, however associated with poor prognosis in MM patients who did not receive ASCT. In addition, IL-10-592 A/C and C/C genotype may contribute to transformation of MGUS to MM. According these data, IL-10 may be implicated in the progression of MM and MGUS, and SNPs of IL-10 is one of prognostic factors in patients with MGUS and MM.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.4759.4759
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
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  • 9
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    Addition of Rituximab Improves Progression-Free and Overall Survival in Patients with B-Cell Lymphoma Receiving Doxorubicin-Containing Chemotherapy
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 1292-1292
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1292-1292
    Abstract: Background: Many clinical trials have documented the efficacy of rituximab in B-cell lymphomas. However, it remains unclear whether rituximab will improve long-term prognosis of the patients. This multicenter retrospective cohort study was conducted to evaluate the clinical impact of the drug in the treatment of B-cell lymphomas. Study design: We retrospectively analyzed clinical characteristics, 2-year progression-free survival(2y PFS) and 2-year overall survival(2y OS) of all B-cell lymphoma patients who were newly diagnosed and initially treated with either CHOP-like regimen alone (R(−) group) or in combination with rituximab (R(+) group) between 2000 and 2004 at our 20 hospitals belonging to the National Hospital Organization. Since rituximab was approved in 2002 for indolent B-cell lymphomas and in 2003 for aggressive B-cell lymphomas in Japan, the patients were almost automatically divided into the 2 groups dependent on the year they underwent treatment. Results: Of the 1,072 patients enrolled, 335 were given rituximab, while 737 did not receive it for the initial induction therapy. 2y PFS was 74.3% and 61.2% for R(+) group and R(−) group, respectively(P 〈 .0001). 2y OS also significantly improved with the addition of rituximab, 86.6% vs 65.3%(P 〈 .0001). In 746 patients with diffuse large B-cell lymphoma, R(+) group (183 patients) and R(−) group (563 patients) showed 2y PFS of 71.6% and 62.2% (P=.0017), 2y OS of 78.5% and 62.5% (P 〈 .0001) respectively. In 195 patients with follicular lymphoma, R(+) group (104 patients) and R(−) group (91 patients) exhibited 2y PFS of 80.1% and 64.5% (P 〈 .0001), 2y OS of 94.9% and 81.5% (P 〈 .0001), respectively. Conclusion: The addition of rituximab to the chemotherapy regimen significantly improves the clinical outcome in patients with previously untreated B-cell lymphoma regardless of the clinical aggressiveness.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.1292.1292
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Prevalence and clinical characteristics of myelodysplastic syndrome with bone marrow eosinophilia or basophilia
    American Society of Hematology ; 2003
    In:  Blood Vol. 101, No. 9 ( 2003-05-01), p. 3386-3390
    Details
    In: Blood, American Society of Hematology, Vol. 101, No. 9 ( 2003-05-01), p. 3386-3390
    Abstract: By retrospectively analyzing 288 patients with de novo myelodysplastic syndrome (MDS), we sought to determine the prevalence and clinical characteristics of bone marrow eosinophilia and basophilia that were detected at presentation. Bone marrow eosinophilia and basophilia were defined as a differential count of each cell type exceeding 5.0% and 1.0%, respectively. Of 288 patients with MDS, 36 (12.5%) fulfilled this criterion for bone marrow eosinophilia (MDS-Eos); 34 patients (11.8%) showed basophilia (MDS-Bas), and 11 (3.8%) satisfied both criteria (MDS-EosBas). The remaining 229 patients had neither eosinophilia nor basophilia in their bone marrow (MDS−/−) at presentation. Cytogenetic analysis was carried out on unstimulated bone marrow cells obtained from 264 patients. When the cytogenetic categorization of the IPSS (International Prognostic Scoring System) for MDS was applied, significantly higher numbers of MDS-Eos and MDS-Bas patients had chromosomal abnormalities carrying intermediate or poor prognosis, compared with the MDS−/− patients. Specific chromosomal abnormalities and complex karyotypes were associated with MDS-Eos and/or MDS-Bas. In accordance with these results, the overall survival rate was significantly lower, and the evolution to acute myelogenous leukemia (AML) occurred more frequently in the MDS-Eos and MDS-Bas than in the MDS−/− patients. Multivariate analysis demonstrated that bone marrow basophilia was an independent risk factor for evolution to AML. Our study indicates that bone marrow eosinophilia and basophilia in patients with MDS predict a poorer prognosis.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood-2002-03-0947
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2003
    detail.hit.zdb_id: 1468538-3
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