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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Jahrestagung der Gesellschaft für Medizinische Ausbildung (GMA); 20140925-20140927; Hamburg; DOCP136 /20140911/
    Publication Date: 2014-09-12
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
    Keywords: CANCER ; radiotherapy ; RISK ; TISSUE ; RADIATION-THERAPY ; METASTASIS ; CLINICAL-TRIALS ; PROGNOSTIC-FACTORS ; LOCALIZATION ; POSITRON-EMISSION-TOMOGRAPHY ; ADULT PATIENTS ; EUROPEAN-ORGANIZATION ; ADJUVANT CHEMOTHERAPY ; HIGH-GRADE ; NEOADJUVANT CHEMOTHERAPY ; REGIONAL HYPERTHERMIA
    Abstract: Background: The role of chemotherapy in high-risk soft tissue sarcoma is controversial. Though many patients undergo initial curative resection, distant metastasis is a frequent event, resulting in 5-year overall survival rates of only 50-60%. Neo-adjuvant and adjuvant chemotherapy (CTX) has been applied to achieve pre-operative cytoreduction, assess chemosensitivity, and to eliminate occult metastasis. Here we report on the results of our non-randomized phase II study on neo-adjuvant treatment for high-risk STS. Method: Patients with potentially curative high-risk STS (size 〉= 5 cm, deep/extracompartimental localization, tumor grades II-III [FNCLCC]) were included. The protocol comprised 4 cycles of neo-adjuvant chemotherapy (EIA, etoposide 125 mg/m(2) iv days 1 and 4, ifosfamide 1500 mg/m(2) iv days 1 - 4, doxorubicin 50 mg/m(2) day 1, pegfilgrastim 6 mg sc day 5), definitive surgery with intra-operative radiotherapy, adjuvant radiotherapy and 4 adjuvant cycles of EIA. Result: Between 06/2005 and 03/2010 a total of 50 subjects (male = 33, female = 17, median age 50.1 years) were enrolled. Median follow-up was 30.5 months. The majority of primary tumors were located in the extremities or trunk (92%), 6% originated in the abdomen/retroperitoneum. Response by RECIST criteria to neo-adjuvant CTX was 6% CR (n = 3), 24% PR (n = 12), 62% SD (n = 31) and 8% PD (n = 4). Local recurrence occurred in 3 subjects (6%). Distant metastasis was observed in 12 patients (24%). Overall survival (OS) and disease-free survival (DFS) at 2 years was 83% and 68%, respectively. Multivariate analysis failed to prove influence of resection status or grade of histological necrosis on OS or DFS. Severe toxicities included neutropenic fever (4/50), cardiac toxicity (2/50), and CNS toxicity (4/50) leading to CTX dose reductions in 4 subjects. No cases of secondary leukemias were observed so far. Conclusion: The current protocol is feasible for achieving local control rates, as well as OS and DFS comparable to previously published data on neo-/adjuvant chemotherapy in this setting. However, the definitive role of chemotherapy remains unclear in the absence of large, randomized trials. Therefore, the current regimen can only be recommended within a clinical study, and a possibly increased risk of secondary leukemias has to be taken into account
    Type of Publication: Journal article published
    PubMed ID: 22152120
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  • 3
    Keywords: IN-VITRO ; TYROSINE KINASE ; DISEASE ; DOWN-REGULATION ; BONE-MARROW ; cytogenetics ; LYMPHOCYTES ; MUTATIONS ; drug resistance ; microenvironment ; TOLL-LIKE RECEPTORS ; chronic lymphocytic leukemia ; DISEASE PROGRESSION ; molecular genetics ; MARROW STROMAL CELLS ; NORMAL B-CELLS ; PEST DOMAIN MUTATION ; PROMISING THERAPEUTIC TARGET
    Abstract: There is remarkable heterogeneity in the clinical course and biological characteristics of patient subgroups with chronic lymphocytic leukemia (CLL). Mutations of key tumor suppressors (ATM, miR-15a/16-1 and TP53) have been identified in CLL, and these aberrations are important "drivers" of the disease and some of its clinical characteristics. While some mutations are associated with poor outcome [particularly del(17p) and TP53 mutation], others are linked to a favorable clinical course [e.g. del(13q) as sole aberration]. In addition to genetic aberrations, antigen drive and microenvironmental interactions contribute to the pathogenesis of CLL. How the genetic aberrations impact on the process of antigen drive or microenvironmental interactions is currently unclear. Our improved understanding of the biology and clinical course of specific genetic subgroups is beginning to be translated into more specific and targeted treatment approaches. As a result, genetic subgroups are treated in distinct protocols. This review summarizes the contribution of the microenvironment and the most important genetic aberrations in CLL and how our improved knowledge of the biology of CLL may translate into improved treatment results.
    Type of Publication: Journal article published
    PubMed ID: 22023519
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  • 4
    Keywords: GENE ; p53 ; STEM-CELL TRANSPLANTATION ; TP53 ; MINIMAL RESIDUAL DISEASE ; chronic lymphocytic leukemia ; CLL ; TERM-FOLLOW-UP ; allogeneic stem cell transplantation ; PHASE-III TRIAL ; TARGETED THERAPY ; TP53 mutation ; 17p deletion ; BTK ; INITIAL THERAPY ; 1ST-LINE THERAPY ; STUDY-GROUP GCLLSG ; MRD ; PREVIOUSLY UNTREATED PATIENTS ; SUBCUTANEOUS ALEMTUZUMAB
    Abstract: Chronic lymphocytic leukemia (CLL) with 17p deletion or mutations of the TP53 gene has a very poor outcome. Optimal treatment of these patients remains a major clinical challenge, and disagreement on the optimal treatment approach exists. Conventional chemo-immunotherapy with rituximab in combination with purine analogues yields lower response-rates and less satisfactory results than for CLL patients with intact p53. Allogeneic stem cell transplantation may allow long-term remissions in this challenging group of patients. In this review, we will discuss current treatment options as well as experimental approaches in clinical trials for CLL patients with deleted or mutated TP53. Particular emphasis will be placed on novel agents with the potential to change clinical practice and future perspectives for the management of these "highest risk" patients.
    Type of Publication: Journal article published
    PubMed ID: 23188619
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  • 5
    Keywords: THERAPY ; TRIAL ; GUIDELINES ; fludarabine ; rituximab ; TERM-FOLLOW-UP ; REGIMEN ; ALEMTUZUMAB ; 1ST COMPLETE REMISSION ; REFRACTORY CLL
    Abstract: BACKGROUND: In a single-center retrospective donor versus no-donor comparison, we investigated if allogeneic stem cell transplantation (alloSCT) can improve the dismal course of poor-risk chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: All patients with CLL who were referred for evaluation of alloSCT within a 7-year time frame and had a donor search indication according to the EBMT criteria or because of Richter's transformation were included. Patients for whom a matched donor could be found within 3 months (matches) were compared with patients without such a donor (controls). Primary end point was overall survival measured from the 3-month landmark after search initiation. RESULTS: Of 105 patients with donor search, 97 (matches 83; controls 14) were assessable at the 3-month landmark. Matches and controls were comparable for age, gender, time from diagnosis, number of previous regimens, and remission status. Disregarding if alloSCT was actually carried out or not, survival from the 3-month landmark was significantly better in matches versus controls [hazard ratio 0.38, 95% confidence interval (CI) 0.17-0.85; P = 0.014]. The survival benefit of matches remained significant on multivariate analysis. CONCLUSION: This study provides first comparative evidence that alloSCT may have the potential to improve the natural course of poor-risk CLL as defined by the EBMT criteria.
    Type of Publication: Journal article published
    PubMed ID: 24356631
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  • 6
    Keywords: IN-SITU HYBRIDIZATION ; STEM-CELL TRANSPLANTATION ; MULTIPLE-MYELOMA ; STAGING SYSTEM ; AL amyloidosis ; UNDETERMINED SIGNIFICANCE ; PRIMARY SYSTEMIC AMYLOIDOSIS ; GENETIC ABNORMALITIES ; BRAIN NATRIURETIC PEPTIDE ; SERUM CARDIAC TROPONINS
    Abstract: Chromosomal aberrations of plasma cells are well established pathogenetic and prognostic factors in multiple myeloma, but their prognostic implication in systemic light chain (AL) amyloidosis is unclear. Therefore, the aim of this study was to identify prognostic cytogenetic risk factors by interphase FISH in a series of 103 consecutive AL amyloidosis patients treated uniformly with melphalan/dexamethasone as first-line therapy. Detection of gain of 1q21 was predictive for a poor overall survival (OS) (median 12.5 versus 38.2 months, p=0.002). Hematologic event free survival (hem EFS) for gain of 1q21 was 5.0 versus 8.5 months in median (p=0.08) and haematologic remission rates (〉= VGPR) after three cycles were 5% versus 25% (p=0.06). Most important, in multivariate concordance analyses the adverse prognosis carried by gain of 1q21 was retained as an independent prognostic factor (OS: p=0.003, average hazard ratio (AHR) 3.64, hemEFS: p=0.008, AHR=2.35), along with the well established Mayo cardiac staging. Patients with t(11; 14) had a longer median OS with 38.2 months versus 17.5 months, though no statistical significance was reached. Deletion 13q14 and hyperdiploidy turned out to be prognostically neutral. In conclusion, we have identified gain of 1q21 as an independent adverse prognostic factor in AL amyloidosis patients treated with standard chemotherapy.
    Type of Publication: Journal article published
    PubMed ID: 24455967
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  • 7
    Keywords: AGE ; INTENSIVE CHEMOTHERAPY ; OLDER PATIENTS ; PHASE-III ; ARA-C ; RISK MYELODYSPLASTIC SYNDROMES ; RESPONSE CRITERIA ; CONVENTIONAL CARE REGIMENS ; INTERNATIONAL WORKING GROUP ; AML PATIENTS
    Abstract: We retrospectively analyzed and compared the efficacy and toxicity of azacitidine (AZA) and low-dose cytarabine (LD-Ara-C) in 65 palliative patients with acute myeloid leukemia (AML) showing high bone marrow blast counts (〉/=30%) before start of treatment. Twenty-seven and 38 patients received AZA and LD-Ara-C, respectively. The median patient age was 71 yr. Patient and disease characteristics did not differ between the treatment groups, except for BM blast counts, and peripheral leukocyte and blast counts which were significantly higher in the LD-Ara-C group. AZA and LD-Ara-C were first-line treatment in 12 (44%) and 17 patients (45%), respectively. Response and hematologic improvement rates were low and similar in both treatment groups. In both treatment groups, most common non-hematologic toxicities included febrile neutropenia, pneumonia, and bleedings without significant differences regarding frequencies. Estimated 1-yr survival rates were 15% (95% CI 8-22) and 13% (95% CI 7-19) in the AZA and LD-Ara-C groups, respectively, without statistically significant difference. In multivariate analysis (n = 65), previous treatment (HR 2.27, 95% CI 1.00-5.22, P = 0.05) and adverse cytogenetics (HR 2.50, 95% CI 1.20-5.22, P = 0.02) were independent predictors of poor survival. In our center and within the limitations of a retrospective study, both treatment regimens showed similar but limited efficacy in palliative patients with AML and high BM blast counts.
    Type of Publication: Journal article published
    PubMed ID: 24628527
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  • 8
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    Internist 56 (4), 381-390 
    Keywords: COMBINATION ; INHIBITION ; rituximab ; TERM-FOLLOW-UP ; PHASE-I TRIAL ; PENTOSTATIN ; BRAF V600E MUTATION ; CLADRIBINE TREATMENT ; LOW-DOSE VEMURAFENIB ; RAPID RESPONSE
    Abstract: Hairy cell leukemia was initially described as a distinct entity in 1958. It is rare B-cell malignancy characterized by an indolent course. Advances in the treatment and understanding of the biology of hairy cell leukemia have made the disease exquisitely amenable to treatment. This review summarizes the present understanding of hairy cell leukemia with a particular focus on the development of novel and targeted approaches to treatment.
    Type of Publication: Journal article published
    PubMed ID: 25787322
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  • 9
    Keywords: PATHWAY ; GENE ; transcription ; T-CELLS ; ANTIGEN-PRESENTING CELLS ; KAPPA-B ; CD40 ; IMMUNE-SYSTEM ; MYELOFIBROSIS ; JAK2 INHIBITOR
    Abstract: Inhibition of Janus-activated kinase-1 (JAK1) is a promising clinical concept for post-transplant immunosuppression and autoimmunity. However, it also raises concerns regarding possible immunosuppressive side effects. Our study investigates JAK1 signalling in the context of CD40L and bacterially activated human MoDC using siRNA and biological inhibitors. We demonstrate that strong stimuli (e.g. intact Escherichia coli or LPS in addition to IL-1beta) induce IL-12p70 via a ROS/RELA/CDK9 pathway that is inhibited by simultaneous JAK1/STAT3 signalling. Transcription is effective if RELA recruits the positive transcription elongation factor b (P-TEFb) component CDK9 to a combined RELA/STAT3 binding site -50 to -20bp upstream of the start site of the IL-12p35 promoter. STAT3 simultaneously attaches to this site and inhibits CDK9 binding. In the presence of IFNgamma, JAK1/2 inhibitors block STAT1/IRF1/IRF8-dependent activation and simultaneously enhance CDK9-dependent activation signals. This inverse regulation of IFNgamma- vs. E. coli-induced cytokine production by JAK inhibitors including Ruxolitinib was similarly observed for IL-6 and TNF-alpha production, but not for IL-10 production. Thus, JAK1 inhibition enhances IL-12p70 production in this context by increased DNA binding of CDK9. In contrast, weak RELA-activation signals (CD40L, LPS) depended on IFN-gamma induced STAT1/IRF1/IRF8 co-signalling, which was completely blocked by JAK inhibitors as reported before. Our results suggest a novel molecular mechanism of how cytokine responses to invading pathogens are separable from IFNgamma-dependent autoimmunity by targeting JAK1/STAT3 activation.
    Type of Publication: Journal article published
    PubMed ID: 25931145
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  • 10
    Keywords: BREAST-CANCER ; chemotherapy ; NON-HODGKINS-LYMPHOMA ; HEMATOLOGICAL MALIGNANCIES ; YOUNG-PATIENTS ; CHILDHOOD-CANCER SURVIVORS ; PREMATURE MENOPAUSE ; ANTI-MULLERIAN HORMONE ; GONADAL-FUNCTION ; INHIBIN-B
    Abstract: BACKGROUND: Chemotherapy-associated ovarian damage comprises not only infertility, but also premature menopause. The latter has been reported as a consequence of alkylating chemotherapy for breast cancer or Hodgkin's lymphoma. In this study, we assessed the long-term impact of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimens on ovarian function in patients with aggressive non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: Long-term survivors after CHOP or CHOP plus etoposide (CHOEP) treatment within the Mabthera International Trial or the NHL-B1 trial of the German NHL Study Group were requested to respond to a questionnaire and to consent to blood sampling for hormone assessment. RESULTS: A total of 46 of 81 contacted patients with a median age of 32.5 years at the time of enrolment into the aforementioned clinical trials responded to the questionnaire. The median follow-up after completion of treatment was 14 years. Last menstrual bleeding occurred significantly earlier in patients compared with the general population (47 versus 51 years, P 〈 0.0001). In comparison to the distribution of menopausal symptoms in the general population, the percentage of women with moderate or severe menopausal symptoms was increased. In 23 patients who agreed to participate in laboratory analyses, anti-Muller hormone as a marker of ovarian reserve was decreased when compared with correspondent age groups of the general population. CONCLUSION: Although most female patients regain fertility after CHOP-like chemotherapy, late ovarian impairment occurs frequently. Therefore, awareness of such delayed side-effects at the time of counselling is of importance.
    Type of Publication: Journal article published
    PubMed ID: 25962442
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