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  • 1
    In: Leukemia, Springer Science and Business Media LLC, Vol. 33, No. 12 ( 2019-12), p. 2830-2841
    Type of Medium: Online Resource
    ISSN: 0887-6924 , 1476-5551
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
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  • 2
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3169-3169
    Abstract: Abstract 3169 Background: Adapted from the adult definition, pediatric antiphospholipid syndrome [APS] has been defined as one or more arterial or venous thrombosis associated with persistent antiphospholipid antibodies, i.e. IgM or IgG anticardiolipin antibodies [ACL: cut-off 〉 99th age-dependent percentile] or the presence of lupus anticoagulants confirmed in at least one follow-up visit more than 8 to 12 weeks apart. Antiphospholipid antibodies play an important role in the development of pediatric thromboembolism [TE] with arterial TE or stroke being more often associated with primary APS compared to deep venous thrombosis [DVT], which is observed predominantly in children with secondary APS. However, results of single studies on the risk thromboembolism onset associated with APS have been contradictory or inconclusive, mainly due to lack of statistical power. The aim of this study was to estimate the impact of APS on risk of childhood arterial and venous TE via meta-analysis of published observational studies. Methods: A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2010 was conducted using key words in combination both as MeSH terms and text words. Citations were independently screened by two authors and those meeting the a priori defined inclusion criteria were retained. Data on year of publication, study design, laboratory methodologies, country of origin, number of patients/controls, ethnicity, type and location of TE were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed-effects and random-effects models. Results: Eight of 319 (DVT) and seven out of 185 (arterial TE) references found met inclusion criteria: In total 1403 patients and 1904 population-based controls aged neonate to 18 years were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. In addition, regression analysis did not reveal statistical significant differences between locations of TE, age at first disease onset, study country, or publication year. Thus, data from arterial and venous TE were analyzed together. A statistically significant association with a first TE onset was demonstrated with a cumulative summary ORs/CIs (fixed-effects model) of 5.9/3.6-9.7. Conclusions: The present meta-analysis indicates that APS serves as a clinical meaningful risk factor for a first symptomatic TE in children. However, the impact of APS upon outcome and recurrence risk needs to be further investigated. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2009
    In:  Annals of Hematology Vol. 88, No. 10 ( 2009-10), p. 1037-1038
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 88, No. 10 ( 2009-10), p. 1037-1038
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2009
    detail.hit.zdb_id: 1458429-3
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 20, No. 22 ( 2002-11-15), p. 4413-4419
    Abstract: PURPOSE: This trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group compares the use of high-dose therapy (HDT) as part of primary treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide followed by involved-field (IF) radiotherapy in a randomized, multicenter, phase III study. PATIENTS AND METHODS: Three hundred twelve patients with “aggressive” non-Hodgkin’s lymphoma aged ≤ 60 years with elevated serum lactate dehydrogenase levels were included from 1990 to 1997. Patients with at least a minor response after two cycles of CHOEP (CHOP + etoposide 3 × 100 mg/m 2 ) were to receive three further cycles of CHOEP followed by IF radiotherapy (arm A) or one further cycle of CHOEP followed by autologous stem-cell transplantation and IF radiotherapy (arm B). RESULTS: Among 158 patients randomized to arm B, 103 (65%) received HDT. The complete remission rate at the end of treatment was 62.9% in arm A and 69.9% in arm B. With a median observation time of 45.5 months, overall survival for all 312 patients was 63% after 3 years (63% for arm A, 62% for arm B; P = .68). Event-free survival was 49% for arm A versus 59% for arm B (P = .22). Relapse in arm B was associated with a significantly worse survival rate than relapse in arm A (P 〈 .05). Relapse after HDT occurred early (median interval, 3 months). Six patients developed secondary neoplasia, three in arm A and three in arm B. CONCLUSION: Results of the randomized trial comparing CHOP-like chemotherapy with early HDT do not support the use of HDT with carmustine, etoposide, cytarabine, and melphalan following shortened standard chemotherapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2002
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 21, No. 24 ( 2003-12-15), p. 4496-4504
    Abstract: Purpose: To examine the efficacy of prolonged maintenance chemotherapy versus intensified consolidation therapy for patients with acute myeloid leukemia (AML). Materials and Methods: Eight hundred thirty-two patients (median age, 54 years; range, 16 to 82 years) with de novo AML were randomly assigned to receive 6-thioguanine, cytarabine, and daunorubicin (TAD) plus cytarabine and mitoxantrone (HAM; cytarabine 3 g/m 2 [age 〈 60 years] or 1 g/m 2 [age ≥ 60 years] × 6) induction, TAD consolidation, and monthly modified TAD maintenance for 3 years, or TAD-HAM-TAD and one course of intensive consolidation with sequential HAM (S-HAM) with cytarabine 1 g/m 2 (age 〈 60 years) or 0.5 g/m 2 (age ≥ 60 years) × 8 instead of maintenance. Results: A total of 69.2% patients went into complete remission (CR). Median relapse-free survival (RFS) was 19 months for patients on the maintenance arm, with 31.4% of patients relapse-free at 5 years, versus 12 months for patients on the S-HAM arm, with 24.7% of patients relapse-free at 5 years (P = .0118). RFS from maintenance was superior in patients with poor risk by unfavorable karyotype, age ≥ 60 years, lactate dehydrogenase level greater than 700 U/L, or day 16 bone marrow blasts greater than 40% (P = .0061) but not in patients with good risk by complete absence of any poor risk factors. Although a survival benefit in the CR patients is not significant (P = .085), more surviving patients in the maintenance than in the S-HAM arm remain in first CR (P = .026). Conclusion: We conclude that TAD-HAM-TAD-maintenance first-line treatment has a higher curative potential than TAD-HAM-TAD-S-HAM and improves prognosis even among patients with poor prognosis.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2003
    detail.hit.zdb_id: 2005181-5
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  • 6
    In: Journal of Cell Science, The Company of Biologists, Vol. 115, No. 9 ( 2002-05-01), p. 1961-1971
    Abstract: Emerging data suggest that urokinase-type plasminogen activator (UPA),beyond its role in pericellular proteolysis, may also act as a mitogen. We investigated the function of endogenous UPA in mediating the mitogenic effects of platelet-derived growth factor (PDGF) and basic fibroblast growth factor(bFGF) on human vascular smooth muscle cells (SMC). Growth-arrested SMC constitutively expressed UPA, but UPA expression and secretion increased several times upon stimulation with either PDGF or bFGF. Inhibition of endogenous UPA with a polyclonal antibody significantly reduced DNA synthesis and proliferation of PDGF or bFGF stimulated SMC, this effect already being evident when the cells entered S-phase. The proliferative activity of endogenous UPA was dependent on a functional catalytic domain as demonstrated by inhibition experiments with a specific monoclonal antibody (394OA) and p-aminobenzamidine, respectively. In contrast, neither plasmin generation nor binding of UPA to its receptor (CD87) were required for UPA-mediated mitogenic effects. The results demonstrate that endogenous UPA is not only overexpressed in SMC upon stimulation with PDGF/bFGF, but also mediates the mitogenic activity of the growth factors in a catalytic-domain-dependent manner. Specific inhibition of this UPA domain may represent an attractive target for pharmacological interventions in atherogenesis and restenosis after angioplasty.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2002
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    SSG: 12
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  • 7
    In: Critical Care Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 7 ( 2000-07), p. 2209-2216
    Type of Medium: Online Resource
    ISSN: 0090-3493
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 2034247-0
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  • 8
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1447-1447
    Abstract: Data on benefit and toxicity by treatment intensification for AML are now available and allow rediscussing current dosing. Methods In a multicenter trial involving patients between 16 and 86 years of age, patients below 60 years received uniform double induction by the 1st course with standard dose araC/ daunorubicin (60mg/m²x3)/ thioguanine followed by the 2nd course with high-dose araC (3g/m²x6)/ mitoxantrone (10mg/m²x3), or randomly two high-dose courses. As age adaption patients of 60y or older received the 2nd course only in case of persistent blasts, and high-dose araC at 1 instead of 3g/m². Post remission treatment was consolidation and maintenance or randomly autologous stem cell transplantation in younger patients. Results 3369 patients entered the trial with 1843 patients 60y or older. A multivariate analysis identified age as continuous variable, favorable cytogenetics/ molecular genetics, unfavorable cytogenetics, white blood cell count and lactate dehydrogenase as categorical variables to be risk factors predicting complete remission, overall survival as well as relapse free survival. To separate the age effect from the treatment effect, two subgroups of similar age and baseline characteristics but different treatment were compared. Thus, the 239 patients aged 57-59 and the 336 patients aged 60-62 years shared not only similar age but also similar baseline characteristics, while their treatment by protocol and age adaption differed substantially. The difference as expressed by the cumulative araC dosis amounted to a factor of 3.6, which however did not translate into a different overall survival (equally 28%) or relapse rate (equally 70%) at 5 years. In contrast to different treatment, different age had a strong effect on outcome. Thus, the survival in patients aged 16-46y was 65% at 5 years versus 40% in those of 47-59y receiving the same treatment (p 〈 0.001). A corresponding age related difference was also found between the patients of 60-66y and those of 67-86y (p 〈 0.001) receiving the same age adapted treatment. As shown by others in patients of 18-60y doubling an intermediate cumulative dose of araC produced excessive toxicity without therapeutic benefit (Löwenberg B et al. NEJM 2011; 364: 1027-36), while high dose daunorubicin (90mg/m²) instead of standard dose (45mg/m²) improved the remission rate and survival in younger patients (Fernandez H et al. NEJM 2009; 361: 1249-59) and older patients of 60-65y (Löwenberg B et al. NEJM 2009; 361: 1235-48). No comparable data are available about daunorubicin 60mg/m² the standard in present study. Conclusion Age and disease biology rather than chemotherapy intensity are the main determinants of outcome in AML. Once a certain intensity and antileukemic effect has been achieved, a further escalation does not seem to overcome the age factor in AML. Present data require rediscussing current chemotherapy dosing and treatment alternatives. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 9
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4445-4445
    Abstract: Oral mucositis is a frequent problem in high-dose methotrexate (HD-MTX) based chemotherapy, impairing the patient’s quality of life, leading to higher rates of infections and delaying subsequent chemotherapy. Numerous substances have been used to prevent or treat oral mucositis, but none of them has proven clinical benefit. Palifermin, a recombinant human keratinocyte growth factor, can lead to a prevention of oral mucositis by different effects. Clinical activity of palifermin has been proven in a controlled randomized study with patients undergoing high-dose therapy with autologous stem cell rescue. The purpose of this report is to describe the effect of palifermin in patients treated within the GMALL-B-ALL 2002 protocol containing HD-MTX who developed a severe mucositis in cycles A1 or B1. Ten patients who were treated within this protocol developed a severe WHO grade III–IV oral mucositis in cycles A1 or B1. Before and after the subsequent similar or identical cycles A2 or B2 palifermin was given to reduce the risk of mucositis. Thus, patients serve as their own control for efficacy of palifermin. All ten patients developed a grade III–IV mucositis in cycles A1 or B1 without palifermin, whereas only 2/10 developed a grade III–IV mucositis in corresponding cycles A2 or B2 with palifermin (Mann-Whitney-Wilcoxon-test p 〈 0.05). Five patients were treated with a lower palifermin dose than recommended. Also these patients did not develop a higher grade mucositis. Only 4/10 patients showed infections in the cycles with palifermin compared to 10/10 patients without palifermin. The duration of mucositits in patients who aquired a higher-grade (III, IV) mucositis despite treatment with palifermin could be reduced from 12.9 days (median) without to 10.4 days with palifermin. In conclusion, palifermin can significantly reduce the incidence and severeness of oral mucositis and may influence clinical sequelae such as infection and quality of life.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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    detail.hit.zdb_id: 80069-7
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  • 10
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 805-805
    Abstract: Abstract 805 Background: The interaction of von Willebrand factor [VWF] and its cleaving protease ADAMTS13 for preventing thrombosis in the microvasculature has been well described in patients with thrombotic thrombocytopenic purpura [TTP] . Recently it has been hypothesized that ADAMTS13 may protect the brain from ischemia by regulating VWF-platelet interaction after reperfusion, and that lower levels are associated with cardiovascular disease in young adults. Pediatric stroke is known as a multifactorial disease: Apart from various underlying mechanisms inherited genetic traits and intra-arterial thrombus formation constitute as major risk factors. The aim of the present nested case-control study was to determine the role of reduced ADAMTS13 levels in pediatric stroke. Methods: 208 pediatric patients with confirmed stroke (6 months to 18 years) and 128 population-based control children were investigated. Patients with liver disease, sepsis or antiphospholipid antibodies were excluded. ADAMTS13 activity [AC] and antigen [Ag] levels [kit: Technoclone, Vienna, Austria] have been evaluated 6 to 12 months after first stroke onset. Non-parametric statistics was performed for descriptive analysis [median (min-max) values] and inter-group comparisons [Mann-Whitney U test]. Correlation analysis was performed using Spearman rank correlation analysis. A p-value 〈 0.05 was considered as statistically significant. First: Age-dependent percentiles were calculated from the control cohort and the number of patients and controls 〈 10th percentiles were compared to those 〉 10th percentiles. Second: ADAMTS13 levels were distributed into quartiles. The number of patients versus controls in the lowest quartile [1st: 16–86%] was compared to the 2nd [87-101%] , 3rd [102-112%] and 4th [113-156%] quartile using a multivariate statistical model [logistic regression] adjusted for VWF, factor VIIIC, blood group [BG] and age. Results are shown as odds ratios/95% confidence intervals [OR/CI]. Results: ADAMTS13 AC levels beyond the acute stroke onset were significantly lower in patients compared to controls [98% (16-143) vs. 103% (60-156), p=0.03], and 46 of 208 patients [22%] showed values 〈 10th percentiles compared with 5 of 123 controls [4%: p 〈 0.001]. The corresponding adjusted OR/CI was 7.13/2.7-19.0. In the quartile comparison adjusted for VWF, FVIIIC, BG and age the following OR/CIs were calculated: 1st vs. 2nd [2.17/1.04-4.53] , 1st vs. 3rd [2.35/1.11-4.94] and 1st vs. 4th [2.45/1.15-5.22] . In addition, moderate positive correlations were found between ADAMTS13 AC and i) ADAMTS13 Ag [rho=0.30; p 〈 0.001], ii), BG [rho=0.18; p=0.002] and iii) age [rho=0.16; p=0.004], but not between ADAMTS13 and VWF, or FVIIIC. VWF AG levels were higher in patients compared to controls [112 (34-453) vs.104% (50-451)] without reaching statistical significance [p=0.65]. Platelet count in patients and controls was within the normal age-dependent reference range. Conclusions: Compared to healthy control children pediatric stroke survivors showed significantly reduced ADAMTS13 activities with a corresponding OR of 7.13 [percentile comparison] and 2.3 [quartile comparison] . Our findings support the concept that ADAMTS13 deficiency is associated in the pathogenesis of non TTP-dependent microangiopathy in cerebro- and cardiovascular diseases. To elucidate if this deficiency state in children with stroke beyond the acute disease onset is congenital or acquired further investigations are ongoing. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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