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  • 1
    Keywords: CYCLOPHOSPHAMIDE ; CD38 EXPRESSION ; fludarabine ; GENOMIC ABERRATIONS ; rituximab ; POOR SURVIVAL ; INDEPENDENT PREDICTOR ; INITIAL THERAPY ; PROGRESSION-FREE ; SF3B1 MUTATIONS
    Abstract: Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) 〉/=10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age 〉/=65 years, Eastern Cooperative Oncology Group performance status 〉/=1, beta2-microglobulin 〉/=3.5 mg/L, TK 〉/=10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.
    Type of Publication: Journal article published
    PubMed ID: 24652989
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  • 2
    Abstract: Background In chronic lymphocytic leukemia (CLL), a variety of surrogate markers for genetic features and outcome have been described based on gene expression analyses. Previous studies mostly focused on individual markers and selected disease characteristics, which makes it difficult to estimate the relative value of the novel markers. Therefore, in the present study a comprehensive approach was chosen investigating eighteen promising, partly novel expression markers in a well characterized patient cohort with long clinical follow-up and full genetic information (IGHV status, genomic abnormalities). DESIGN AND METHODS: Expression markers were evaluated using real-time quantitative RT-PCR in CD19+ purified samples of 151 patients. Multivariate analyses were performed to test the markers; capability to identify patients at genetic risk and as prognostic markers in the context with established prognosis factors. RESULTS: Regarding individual markers, ZAP70 achieved the highest assignment rate (81%) for patients at genetic risk (IGHV unmutated, V3-21 usage, 11q- or 17p-), followed by LPL and TCF7 (76% both). This rate was improved to 88% by a 4-gene combination (ZAP70, TCF7, DMD, ATM). In multivariate analysis of treatment-free survival, IGHV mutation status and expression of ADAM29 were of independent prognostic value besides disease stage. Regarding overall survival, expression of ATM, ADAM29, TCL1, and SEPT10 provided prognostic information in addition to clinical and genetic factors. Conclusions Gene expression markers are suitable for screening but not as surrogate for genetic risk factors. While many individual markers may be associated with outcome, only few are of independent prognostic significance. Genetic prognostic factors cannot be substituted by the expression markers.
    Type of Publication: Journal article published
    PubMed ID: 19951976
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  • 3
    Keywords: IN-VIVO ; TRANSGENIC MICE ; CELL-DEATH ; INDUCED APOPTOSIS ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; p53 ; C-MYC ; Bcl-2 ; NKG2D RECEPTOR ; MEDIATED TUMOR SURVEILLANCE
    Abstract: In E mu-myc transgenic animals lymphoma formation requires additional genetic alterations, which frequently comprise loss of p53 or overexpression of BCL-2. We describe that the nature of the "second hit" affects the ability of the immune system to contain lymphoma development. Tumors with disrupted p53 signaling killed the host more rapidly than BCL-2 overexpressing ones. Relaxing immunologic control, using Tyk2(-/-) mice or by Ab-mediated depletion of CD8(+) T or natural killer (NK) cells accelerated formation of BCL-2-overexpressing lymphomas but not of those lacking p53. Most strikingly, enforced expression of BCL-2 prolonged disease latency in the absence of p53, whereas blocking p53 function in BCL-2-overexpressing tumors failed to accelerate disease. This shows that blocking apoptosis in p53-deficient cells by enforcing BCL-2 expression can mitigate disease progression increasing the "immunologic visibility." In vitro cytotoxicity assays confirmed that high expression of BCL-2 protein facilitates NK and T cell-mediated killing. Moreover, we found that high BCL-2 expression is accompanied by significantly increased levels of the NKG2D ligand MULT1, which may account for the enhanced killing. Our findings provide first evidence that the nature of the second hit affects tumor immunosurveillance in c-MYC-driven lymphomas and define a potential shortcoming of antitumor therapies targeting BCL-2.
    Type of Publication: Journal article published
    PubMed ID: 21878673
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  • 4
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    German Medical Science; Düsseldorf, Köln
    In:  68. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 90. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie und 45. Tagung des Berufsverbandes der Fachärzte für Orthopädie; 20041019-20041023; Berlin; DOC04dguE10-1740 /20041019/
    Publication Date: 2004-10-20
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 5
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    German Medical Science; Düsseldorf, Köln
    In:  67. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 89. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie und 44. Tagung des Berufsverbandes der Fachärzte für Orthopädie; 20031111-20031116; Berlin; DOC03dguO16-4 /20031111/
    Publication Date: 2003-11-11
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 6
    ISSN: 1433-0474
    Keywords: Schlüsselwörter Body-mass-Index ; Übergewicht ; Adipositas ; Key words Body Mass Index ; Overweight ; Obesity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Objective: To examine changes in Body Mass Index (BMI) in children in the last twenty years and to determine the prevalence of overweight and obesity. Design and Subjects: Body height and body weight were measured in Jena school children 7 to 14 years of age in cross-sectional anthropological investigations in 1975, 1985 and 1995 and from these measurements the Body Mass Index (BMI) was calculated. The investigated children were classified as overweight or obese by the age- and sex-specific 90th or 97th percentile values of BMI from Rolland-Cachera et al. [31] recommended by the European Childhood Obesity Group. Results: Between 1975 and 1995 the BMI of Jena children increased. The prevalence of overweight and obesity among the children increased also. These changes were striking between 1985 and 1995. Conclusions: Changing living conditions, e. g. changes in the leisure-time lifestyle, in dietary practices and in the families, related to the unification of Germany in 1989, may be caused this trend.
    Notes: Zusammenfassung Fragestellung/Hintergrund: Es wurden Veränderungen des Body-mass-Index (BMI) bei Kindern in den letzten 20 Jahren untersucht und die Prävalenz von Übergewicht und Adipositas bestimmt. Methode und Probanden: Körperhöhe und Körpergewicht wurden im Rahmen anthropologischer Querschnittsuntersuchungen in den Jahren 1975, 1985 und 1995 bei 7- bis 14jährigen Jenaer Kindern erfaßt und daraus der Body-mass-Index berechnet. Die Einstufung der untersuchten Kinder als übergewichtig und adipös erfolgte anhand der von der European Childhood Obesity Group empfohlenen alters- und geschlechtsspezifischen 90. oder 97. Perzentile für den BMI von Rolland-Cachera et al. [31]. Ergebnisse: Zwischen 1975 und 1995 stieg der BMI der Jenaer Kinder an. Der prozentuale Anteil von Kindern, die als übergewichtig oder adipös einzustufen sind, nahm ebenfalls zu. Diese Veränderungen fielen zwischen 1985 und 1995 besonders deutlich aus. Schlußfolgerungen: Veränderte Lebensbedingungen, wie z. B. Änderungen beim Freizeitverhalten, beim Ernährungsverhalten oder in der Familienstruktur, die im Zusammenhang mit der politischen Wende im Jahr 1989 auftraten, werden als Ursache für diesen Trend angesehen.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0584
    Keywords: Acute lymphoblastic leukemia ; Treatment ; Granulocyte colony stimulating factor ; Febrile neutropenia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Our purpose was to evaluate the ability of re-combinant human granulocyte colony-stimulating factor (r-metHuG-CSF) as an adjunct to induction chemo-therapy of acute lymphoblastic leukemia (ALL) to ameliorate chemotherapy-induced neutropenia and thus allow patients to receive full doses of chemotherapy on time. Sixteen consecutive patients with adult ALL (13 de novo, three relapsed) were treated with induction chemo-therapy according to the BMFT protocol and received in addition r-metHuG-CSF (200μg/m2/day). Patients who were treated with the same induction chemotherapy but without G-CSF between 1982 and 1990 served as controls. Fifteen of the 16 patients achieved complete hematological remission. One patient died because of fungal septicemia. Compared with historical controls, G-CSF-treated patients had a significantly faster neutrophil recovery in phase I, resulting in neutrophil counts 〉 1000/μl at day 17 vs day 26 (in median) in controls. In phase II, the onset of severe leukocytopenia (〈 1500/μl) was significantly (p = 0.01) delayed and the degree of leukocytopenia less pronounced (mean nadir 3300/μl) in G-CSF-treated patients compared with controls (1880/μl). The number of days of febrile neutropenia was not different in phase I. In phase II it was lower in study patients (0 vs 1.1 days), but the difference did not reach statistical significance (p = 0.09). Full doses of chemo-therapy could be given on time to 11/13 (85%) G-CSF pa-tients but to only 7/30 (23%) controls. These data indicate that (a) G-CSF can be given along with chemotherapy in induction treatment of ALL without compromising efficacy; (b) the duration of neutropenia in phase I is markedly shortened and the degree of leukocytopenia in phase II ameliorated; (c) these beneficial effects allow patients to receive full doses of chemotherapy on time.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0584
    Keywords: Transient lupus anticoagulant ; Adenovirus ; Factor II and XII deficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A potent lupus anticoagulant (LA) was detected in four children, 1 week after the clinical onset of an adenovirus infection. The adenovirus infection was documented by direct virus detection in the stool of one patient and serologically in the others. None of the children had elevated titers of IgM- and only one of IgG-anticardiolipin antibodies (ACA). All patients had a marked reduction of prothrombin activity as well as antigen. Prothrombin-antibody complexes were demonstrated in the patients' plasma or mixtures of patient and normal plasma. Factor XII activity was moderately reduced in three of the patients. All coagulation abnormalities returned to normal within 4–12 weeks. Localized bleeding was observed in two cases, but there was no generalized bleeding tendency or evidence of thrombosis.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-0584
    Keywords: Granulocytic sarcoma of the prostate Acute myelogenous leukemia ; AML1/ETO Rearrangement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We describe a 68-year-old patient who developed granulocytic sarcoma of the prostate 9 years after complete remission following successful treatment of acute myelogenous leukemia (FAB, M2). PCR analysis of bone marrow samples in first remission and at the time of relapse detected an AML1/ETO rearrangement typical for AMLs with t (8; 21). The CD 56 antigen was not expressed on the leukemic cells. Systemic chemotherapy led to a short-lasting regression of the tumor, but the patient subsequently developed overt bone marrow relapse and died during chemotherapy. While granulocytic sarcoma as a primary manifestation of AML is well known, as the first manifestation of relapse it appears to be very uncommon.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0584
    Keywords: Acute lymphoblastic leukemia Treatment ; Prognostic factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Sixty-one consecutive patients with acute lymphoblastic leukemia (ALL) (B-ALL excluded) were treated with the protocol described by Hoelzer et al. [15]. The complete remission (CR) rate was 85% (52/61 patients). Three patients died during induction therapy; six patients were refractory to treatment. The median duration of continuous complete remission (CCR), disease-free survival (DFS), and overall survival was 41.5, 41.4, and 40.8 months, respectively. At 5 years the probability of CCR was 49%, of DFS 43.5%, and of overall survival 41.6%. In the univariate analysis older age (〉35 years,p=0.01), bcr-abl positivity (p=0.007), and time to CR (〉4 weeks,p=0.05) were significantly unfavorable prognostic factors. In the multivariate analysis only age (p=0.006) and time to CR (p = 0.02) remained significant. Thus, our data confirm the high efficacy of this treatment regimen with regard to CR rate and remission duration.
    Type of Medium: Electronic Resource
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