179 results on '"J, Braess"'
Search Results
2. P416: CLONAL HEMATOPOIESIS IS COMMON IN AML LONG-TERM SURVIVORS AND MAY ASSOCIATE WITH DIABETES AND SECONDARY NEOPLASIAS, BUT NOT OTHER HEALTH OUTCOMES
- Author
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S. M. Krauß, E. Telzerow, A. S. Moret, D. Richter, M. Rothenberg-Thurley, D. Görlich, M. C. Sauerland, W. E. Berdel, B. Wörmann, U. Krug, J. Braess, P. Heussner, W. Enard, W. Hiddemann, K. Spiekermann, U. Platzbecker, and K. H. Metzeler
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
- Full Text
- View/download PDF
3. P558: GERMAN AMLCG-SURVIVORSHIP STUDY – SOMATIC LONG-TERM CONSEQUENCE OF AML AND ITS THERAPY: FROM HEART TO KIDNEY.
- Author
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A. S. Moret, E. Telzerow, C. Sauerland, M. Rothenberg-Thurley, F. H. A. Mumm, J. Braess, B. Wörmann, U. Krug, W. E. Berdel, W. Hiddemann, K. Spiekermann, P. Heußner, K. Kraywinkel, D. Görlich, and K. H. Metzeler
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
- Full Text
- View/download PDF
4. P479: DNA METHYLATION PROFILING REFINES THE PROGNOSTIC CLASSIFICATION OF ACUTE MYELOID LEUKEMIA PATIENTS TREATED WITH INTENSIVE CHEMOTHERAPY
- Author
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S. Vosberg, A. Ohnmacht, C. Moser, A. Arneth, V. Jurinovic, K. H. Metzeler, M. C. Sauerland, D. Görlich, W. E. Berdel, J. Braess, S. Amler, U. Krug, W. Hiddemann, K. Spiekermann, C. C. Oakes, M. P. Menden, T. Herold, and P. A. Greif
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
- Full Text
- View/download PDF
5. Unklare Leberraumforderungen bei einer 19-jährigen Patientin mit akuter myeloischer Leukämie
- Author
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J. Braess, C. Dierkes, M. Schenk, A. P. Karl, and B. Braun
- Subjects
0301 basic medicine ,Hepatitis ,medicine.medical_specialty ,biology ,business.industry ,030106 microbiology ,Myeloid leukemia ,Hepatology ,Mycobacterium abscessus ,Neutropenia ,medicine.disease ,biology.organism_classification ,Gastroenterology ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,Cholestasis ,Internal medicine ,Internal Medicine ,medicine ,Differential diagnosis ,business - Abstract
A 19-year old woman with acute myeloid leukemia presented with newly observed liver lesions during ongoing consolidation therapy. Due to unexplained cholestasis during induction, biliary duct drainage was performed. Microbiologic and histologic examinations revealed the presence of atypical mycobacteria, namely Mycobacterium abscessus. With an appropriate antiinfective regime which was continuously administered using a portable pump in the outpatient setting, further mycobacterial spread during simultaneous chemotherapy-associated neutropenia was prevented. Despite multiple bacterial resistance mechanisms, proper treatment of leukemia with curative intention could be ensured.
- Published
- 2016
6. Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer
- Author
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Stefan Krüger, Juergen Wolf, Thomas Zander, Carina Heydt, Florian Kron, D. Koschel, Anne M. Schultheis, Anna Kron, R. Riedel, Monika Serke, Roman K. Thomas, Britta Kaminsky, Kato Kambartel, Danila Seidel, J. Benedikter, Matthias Scheffler, Jana Fassunke, Michaela Angelika Ihle, C. Alidousty, Christian Grohé, J. Braess, Sabine Merkelbach-Bruse, Sebastian Michels, Reinhard Büttner, Bernhard Schaaf, Lucia Nogova, Frank Ueckeroth, and Martin Sebastian
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Adenocarcinoma ,Cohort Studies ,Carcinoma, Adenosquamous ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Carcinoma ,Humans ,Anaplastic Lymphoma Kinase ,ddc:610 ,Lung cancer ,neoplasms ,Survival rate ,Aged ,Aged, 80 and over ,Gene Rearrangement ,Crizotinib ,Proportional hazards model ,business.industry ,Editorials ,Hematology ,Gene rearrangement ,Middle Aged ,Prognosis ,medicine.disease ,Chemotherapy regimen ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Cohort ,Female ,Tumor Suppressor Protein p53 ,business ,Follow-Up Studies ,medicine.drug - Abstract
Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
- Published
- 2018
7. Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia
- Author
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M Rothenberg-Thurley, S Amler, D Goerlich, T Köhnke, N P Konstandin, S Schneider, M C Sauerland, T Herold, M Hubmann, B Ksienzyk, E Zellmeier, S K Bohlander, M Subklewe, A Faldum, W Hiddemann, J Braess, K Spiekermann, and K H Metzeler
- Subjects
Cancer Research ,Oncology ,Hematology - Abstract
Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ⩾1 mutation during remission at a variant allele frequency of ⩾2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (P0.0001) and, in multivariate analyses adjusting for age, genetic risk, and allogeneic transplantation, with inferior relapse-free survival (hazard ratio, 2.34; P=0039) and overall survival (hazard ratio, 2.14; P=036). Patients with persisting mutations had a higher cumulative incidence of relapse before, but not after allogeneic stem cell transplantation. Our work underlines the relevance of mutation persistence during first remission as a novel risk factor in AML. Persistence of pre-leukemic clones may contribute to the inferior outcome of elderly AML patients. Allogeneic transplantation abrogated the increased relapse risk associated with persisting pre-leukemic clones, suggesting that mutation persistence may guide postremission treatment.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.350.
- Published
- 2017
8. [Unclear liver lesions in a 19-year-old woman with acute myeloid leukemia]
- Author
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B, Braun, A P, Karl, C, Dierkes, M, Schenk, and J, Braess
- Subjects
Diagnosis, Differential ,Leukemia, Myeloid, Acute ,Mycobacterium Infections ,Young Adult ,Treatment Outcome ,Humans ,Antineoplastic Agents ,Female ,Chemical and Drug Induced Liver Injury ,Anti-Bacterial Agents ,Hepatitis - Abstract
A 19-year old woman with acute myeloid leukemia presented with newly observed liver lesions during ongoing consolidation therapy. Due to unexplained cholestasis during induction, biliary duct drainage was performed. Microbiologic and histologic examinations revealed the presence of atypical mycobacteria, namely Mycobacterium abscessus. With an appropriate antiinfective regime which was continuously administered using a portable pump in the outpatient setting, further mycobacterial spread during simultaneous chemotherapy-associated neutropenia was prevented. Despite multiple bacterial resistance mechanisms, proper treatment of leukemia with curative intention could be ensured.
- Published
- 2016
9. Die multimodale Therapie des Bronchialkarzinoms im Stadium IIIA – unter der besonderen Berücksichtigung der chirurgischen Resektion
- Author
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M Allgäuer, J Braess, H-S Hofmann, Michael Ried, S Krause, and Tamas Szöke
- Subjects
Pulmonary and Respiratory Medicine - Published
- 2016
10. 78-jähriger Patient mit Hyperferritinämie bei vermuteter Hämochromatose und milder Anämie
- Author
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N. Moosmann and J. Braess
- Subjects
Nephrology ,medicine.medical_specialty ,business.industry ,General surgery ,Internal medicine ,Internal Medicine ,medicine ,Hepatology ,business - Published
- 2012
11. Impact of co-occurring genomic alterations on overall survival of BRAF V600E and non-V600E mutated NSCLC patients: Results of the Network Genomic Medicine
- Author
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A. Kron, R. Riedel, Sabine Merkelbach-Bruse, Sebastian Michels, Juergen Wolf, Jana Fassunke, Diana S.Y. Abdulla, Rieke Fischer, J. Braess, U. Graeven, S. Krueger, Florian Kron, Ch. Grohé, Frank Ueckeroth, B. Pauli, Matthias Scheffler, Lucia Nogova, Reinhard Büttner, and Britta Kaminsky
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Hematology ,BRAF V600E ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Co occurring ,030220 oncology & carcinogenesis ,Internal medicine ,Mutation (genetic algorithm) ,Overall survival ,Medicine ,Genomic medicine ,business ,V600E - Published
- 2017
12. Hämatologie 2010
- Author
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M Dreyling, M Subklewe, J Braess, and K Spiekermann
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General Medicine - Published
- 2010
13. Moderne Leukämiediagnostik beim Erwachsenen
- Author
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S Bohlander, Christian Buske, Karsten Spiekermann, Michaela Feuring-Buske, Bernhard Heilmeier, Stephanie Schneider, J Braess, and Wolfgang Hiddemann
- Subjects
medicine.medical_specialty ,Fluoreszenz in situ hybridisierung ,medicine.diagnostic_test ,Chemistry ,Cytogenetics ,General Medicine ,medicine.disease ,Molecular biology ,law.invention ,Leukemia ,Immunophenotyping ,law ,medicine ,Polymerase chain reaction ,Fluorescence in situ hybridization - Published
- 2009
14. Risikoadaptierte Therapie der akuten myeloischen Leukämie
- Author
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W. Hiddemann, K. Spiekermann, J. Braess, M. Feuring-Buske, C. Buske, and T. Büchner
- Subjects
Internal Medicine - Published
- 2006
15. Graft-versus-host disease-like immunophenotype and apoptotic keratinocyte death in paraneoplastic pemphigus
- Author
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K Dames, B Wörmann, Christine Neumann, U Brinck, J. Braess, V Blaschke, Kristian Reich, Thomas M. Rünger, and M Letschert
- Subjects
integumentary system ,business.industry ,Acantholysis ,Dermatology ,medicine.disease ,Fas ligand ,3. Good health ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Pemphigus ,0302 clinical medicine ,Paraneoplastic pemphigus ,medicine.anatomical_structure ,Apoptosis ,030220 oncology & carcinogenesis ,Immunology ,medicine ,Cytotoxic T cell ,business ,Keratinocyte ,CD8 - Abstract
Paraneoplastic pemphigus (PP) is an autoimmune disease, which is frequently associated with non-Hodgkin's lymphoma. Autoantibodies against components of the cytoplasmic plaque of epithelial desmosomes are usually present in the sera and are believed to play a major pathogenic part in acantholysis and suprabasal epidermal blistering. However, another typical histological feature of PP, interface dermatitis with keratinocyte dyskeratosis, is shared with skin diseases that involve epithelial damage mediated by T cells. Here, we present the detailed characterization of the cutaneous T-cell response in a patient with PP and demonstrate a selective epidermal accumulation of activated CD8+ T cells together with an increased local production of interferon-gamma and tumour necrosis factor-alpha, and a strong expression of HLA-DR and ICAM-1 on keratinocytes. Apoptosis was identified as a key mechanism of keratinocyte death, and appeared independent of the FAS/FAS ligand (FAS-L) pathway, as epidermal expression of FAS was not increased compared with normal skin, and FAS-L was undetectable on the protein and mRNA level. Triple therapy with high-dose corticosteroids, cyclophosphamide and intravenous immunoglobulins reduced levels of pemphigus-like autoantibodies and reversed the cutaneous inflammatory reaction leading to long-standing clinical remission. Our findings support the concept of a major contribution of cytotoxic T lymphocytes to the immunopathology of paraneoplastic pemphigus.
- Published
- 1999
16. Mucocutaneous autoimmune syndrome following fludarabine therapy for low-grade non-Hodgkin's lymphoma of B-cell type (B-NHL)
- Author
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K. Reich, J. Braess, Frank Strutz, Bernhard Wörmann, Wolfgang Hiddemann, Christine Neumann, and S. Willert
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Lymphoma, B-Cell ,Cyclophosphamide ,Mucocutaneous zone ,Antineoplastic Agents ,Autoimmunity ,Skin Diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,B cell ,030304 developmental biology ,Autoimmune disease ,0303 health sciences ,integumentary system ,business.industry ,Syndrome ,Hematology ,General Medicine ,medicine.disease ,3. Good health ,Non-Hodgkin's lymphoma ,Lymphoma ,Fludarabine ,Pemphigus ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,business ,Immunosuppressive Agents ,Vidarabine ,medicine.drug - Abstract
A 40-year-old patient with low-grade B-NHL developed a generalized macular-papular rash following the first cycle of fludarabine treatment which progressed to a complete epidermal necrolysis following the second cycle. Clinical symptoms and the results of the direct and indirect immunofluorescence were consistent with a mucocutaneous autoimmune syndrome (pemphigus). Immunohistochemical analysis demonstrated a dense epidermal infiltration of CD8+ lymphocytes associated with the histological features of single-cell necrosis of keratinocytes. Early and aggressive immunosuppressive treatment with steroids, cyclophosphamide, and high-dose immunoglobulins resulted in regression of symptoms and complete reconstitution of epidermal integrity. The malignant lymphoma has completely regressed. The findings suggest a fludarabine-induced defect in immunosurveillance – resulting in the uncontrolled activation of autoaggressive T-cell clones – as a pathogenetic mechanism of this life-threatening dermatological complication.
- Published
- 1997
17. Detection and determination of the major metabolites of [3H]cytosine arabinoside by high-performance liquid chromatography
- Author
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C. C. Kaufmann, M. Unterhalt, J. Braess, E. Schleyer, B. Ramsauer, Wolfgang Hiddemann, and J. Pförtner
- Subjects
Metabolite ,HL-60 Cells ,01 natural sciences ,High-performance liquid chromatography ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Spectrophotometry ,medicine ,Humans ,Chromatography, High Pressure Liquid ,Detection limit ,Chromatography ,medicine.diagnostic_test ,010401 analytical chemistry ,Cytarabine ,General Chemistry ,3. Good health ,0104 chemical sciences ,chemistry ,030220 oncology & carcinogenesis ,In vitro system ,Calibration ,Spectrophotometry, Ultraviolet ,Quantitative analysis (chemistry) ,Cytosine ,medicine.drug - Abstract
An ion-pair high-performance liquid chromatographic assay involving solid-phase scintillation detection was established for the rapid identification and determination of all major metabolites of tritium-labelled cytosine arabinoside (Ara-C) in an in vitro system. In a single run of 50 min, Ara-C, Ara-CMP, Ara-CDP-choline, Ara-CDP, Ara-U, Ara-UMP, Ara-CTP, Ara-UDP and Ara-UTP can be measured. The method is fast, sensitive, with limits of detection ranging from 40 to 200 pg (absolute), and highly reproducible.
- Published
- 1996
18. Highly sensitive high-performance liquid chromatographic assay for 1-β-d-arabinofuranosylcytosine-5′-stearyl phosphate (cytarabine-ocfosfate)
- Author
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C. C. Kaufmann, M. Unterhalt, B. Ramsauer, J. Braess, Wolfgang Hiddemann, and E. Schleyer
- Subjects
Detection limit ,Chromatography ,Arabinonucleotides ,Coefficient of variation ,Extraction (chemistry) ,Reproducibility of Results ,Antineoplastic Agents ,General Chemistry ,Phosphate ,High-performance liquid chromatography ,Highly sensitive ,chemistry.chemical_compound ,Drug Stability ,Pharmacokinetics ,chemistry ,Cytidine Monophosphate ,Humans ,Quantitative analysis (chemistry) ,Chromatography, High Pressure Liquid - Abstract
An ion-pair HPLC method for the determination of 1-beta-D-arabinofuranosylcytosine-5'-stearyl phosphate (cytarabine-ocfosfate I) was developed, using a phenyl-bonded column under reversed-phase conditions with a mobile phase of acetonitrile-buffered water (pH 6.8) (50:50) for isocratic elution. A reproducible sample clean-up was achieved by solid-phase extraction. In order to reach the low limit of detection of 2 ng/ml, an enrichment switching system was used. The present validation leads to a limit of quantification of 5 ng/ml with a coefficient of variation (C.V.) of 10%. The total time of measurement was shortened by a back-flush procedure to restore the conditions after each run. UV detection at 275 nm was applied. The recoveries for plasma samples ranged from 56.4 to 64.1%, regardless of drug concentrations. The intra-assay C.V. was about 4% (40 measurements at four different concentrations). The inter-assay recovery (ten measurements over ten days) at a plasma concentration of 50 ng/ml was 57% with a C.V. of 8.25%. Based on this HPLC method, the pharmacokinetics of I were measured during a clinical phase I/II study.
- Published
- 1995
19. High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG
- Author
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E, Lengfelder, C, Haferlach, S, Saussele, T, Haferlach, B, Schultheis, S, Schnittger, W-D, Ludwig, P, Staib, C, Aul, A, Grüneisen, W, Kern, A, Reichle, H, Serve, W E, Berdel, J, Braess, K, Spiekermann, B, Wörmann, M-C, Sauerland, A, Heinecke, W, Hiddemann, R, Hehlmann, T, Büchner, and W, Zschille
- Subjects
Acute promyelocytic leukemia ,Adult ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Tretinoin ,Gastroenterology ,Young Adult ,Maintenance therapy ,Leukemia, Promyelocytic, Acute ,Internal medicine ,Germany ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Cumulative incidence ,Longitudinal Studies ,Lymphocyte Count ,Survival analysis ,Chemotherapy ,business.industry ,Remission Induction ,Cytarabine ,Induction chemotherapy ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Surgery ,Leukemia ,Treatment Outcome ,Oncology ,business ,medicine.drug - Abstract
The objective of this study for newly diagnosed acute promyelocytic leukemia (APL) was to evaluate the efficacy of an intensified double induction chemotherapy including high dose ara-C (HD) and all-trans retinoic acid (ATRA) followed by consolidation and 3 years maintenance therapy. In contrast to APL studies stratifying therapy according to pretreatment white blood cell (WBC) count or =10 x 10(9)/l (low/intermediate and high risk according to the Sanz score), our patients received uniform therapy. From 1994 to 2005, 142 patients (age, 16-60 years) were enrolled. In the low/intermediate (n=105) vs high (n=37) WBC group, the rates of complete remission were 95.2 vs 83.8%, of induction death were 4.8 vs 16.2% (P=0.05) and of molecular remission were 87.5 vs 91.3% (P=1). Long-term overall survival was 84.4 vs 73.0% (P=0.12), event free survival was 78.3 vs 67.3% (P=0.11), relapse free survival was 82.1 vs 80.0% (P=0.83) and the cumulative incidence of relapse was 7.4 vs 11.4% (P=0.46). No relapse or death occurred after 4.7 years. ATRA and intensified chemotherapy including HD ara-C followed by prolonged maintenance therapy reduced the relapse risk in high risk patients. Pretreatment WBC count > or =10 x 10(9)/l count was no relevant prognostic factor for relapse.
- Published
- 2009
20. [Severe microcytic anemia with megaloblastic changes in the bone marrow. A hematological paradoxon?]
- Author
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R, Reibke, A, Hausmann, J, Cnossen, W, Hiddemann, K, Spiekermann, and J, Braess
- Subjects
Adult ,Diagnosis, Differential ,Male ,Anemia, Pernicious ,beta-Thalassemia ,Humans ,Vitamin B 12 Deficiency - Abstract
We discuss the case of a 32 year-old male with severe microcytic anemia (hemoglobin 2,9 g/dl) and megaloblastic changes in the bone marrow. The patient reported of substantial dietary weight loss. The family history was positive for beta-thalassemia. Previous blood work showed iron deficiency with mild anemia. Further work-up verified beta-thalassemia minor and revealed severely decreased vitamin B12 levels with positive anti intrinsic-factor antibodies, pathognomonic for autoimmune pernicious anemia. The paradoxon therefore dissolved as a pernicious anemia with megaloblastic changes with microcytic erythrocytes due to beta-thalassemia.
- Published
- 2009
21. [Modern leukemia diagnosis in adults]
- Author
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B, Heilmeier, K, Spiekermann, S, Bohlander, C, Buske, M, Feuring-Buske, S, Schneider, W, Hiddemann, and J, Braess
- Subjects
Adult ,Leukemia ,Neoplasm, Residual ,Histocytochemistry ,Cytogenetic Analysis ,Cytological Techniques ,Humans ,Prognosis ,Polymerase Chain Reaction ,In Situ Hybridization, Fluorescence ,Immunophenotyping ,Oligonucleotide Array Sequence Analysis - Abstract
Identification of numerous criteria important in the pathogenesis, biology, prognosis and treatment of the different types of leukemia necessitates a broad spectrum of diagnostic methods for the initial diagnosis and in the further course of the disease. In addition to cytomorphology with cytochemistry, which is been path-breaking for the application of further diagnostic methods, cytogenetics has become an obligatory diagnostic tool. Immunophenotyping and, even more relevant, molecular genetics plays an important role. Other diagnostic techniques are widely developed. The diagnostic procedures are described, with a focus on their mode of operation as well as their clinical significance. Because of their high clinical relevance and growing complexity, the diagnosis of leukemias should be performed in specialized laboratories.
- Published
- 2009
22. [Nonsymptomatic leukocytosis]
- Author
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D, Sauter, K, Spiekermann, M, Feuring-Buske, and J, Braess
- Subjects
Diagnosis, Differential ,Inflammation ,Leukocyte Count ,Leukocytosis ,Humans ,Family Practice ,Infections - Abstract
Leukocytosis is a condition often met with in the clinical and ambulatory setting. Although it is usually caused by an increase in the numbers of neutrophilic granulocytes, an increase in other leukocytes populations may also account for leukocytosis. Etiologically, both primary pathological conditions affecting the white blood cells, such as various forms of leukemia and lymphomas, and also rare genetic disorders must be considered. Decidedly more common, however, are reactive changes caused by infections, cigarette smoking, chronic inflammation, necrotic tissue or certain drugs. Although moderate leukocytosis in the absence of a clinical correlate and/or an apparent trigger, requires no diagnostic clarification, it should be kept under observation. If the etiology is uncertain, or a treatment-requiring disorder is suspected, the differential blood count is at the focus of the further diagnostic work-up. Depending upon the findings, this is supplemented by additional laboratory parameters, bone marrow examination, microbiological investigations and imaging procedures. Leukostasis resulting from vasoocclusion in the presence of very high numbers of leukocytes represents an emergency situation, and is an indication for leukapheresis.
- Published
- 2007
23. Chronic systemic aspergillosis in a patient with acute myeloid leukemia
- Author
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J. Braess, E. Schleyer, W. Kern, R. Rüchel, C. Pott, Hartmut Bertz, Jürgen Finke, and Wolfgang Hiddemann
- Subjects
Adult ,Neutropenia ,medicine.medical_treatment ,Aspergillosis ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,030212 general & internal medicine ,Mycosis ,Bone Marrow Transplantation ,0303 health sciences ,Chemotherapy ,Leukopenia ,030306 microbiology ,business.industry ,Myeloid leukemia ,Hematology ,General Medicine ,medicine.disease ,Combined Modality Therapy ,3. Good health ,medicine.anatomical_structure ,Leukemia, Myeloid ,Chronic Disease ,Immunology ,Female ,Bone marrow ,Systemic candidiasis ,medicine.symptom ,business - Abstract
Systemic aspergillosis is a well-recognized complication of chemotherapy-induced neutropenia. In this report a patient with acute myeloid leukemia is described in whom a chronic aspergillosis with systemic involvement developed after recovery from neutropenia following intensive chemotherapy and allogeneic bone marrow transplantation. The clinical features of a chronic course of systemic aspergillosis suggest a distinct clinical entity comparable to chronic systemic candidiasis.
- Published
- 1998
24. [Risk-adapted therapy of acute myeloid leukemia]
- Author
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W, Hiddemann, K, Spiekermann, J, Braess, M, Feuring-Buske, C, Buske, and T, Büchner
- Subjects
Leukemia, Myeloid, Acute ,Risk Factors ,Practice Guidelines as Topic ,Humans ,Antineoplastic Agents ,Practice Patterns, Physicians' ,Risk Assessment - Abstract
Genetic and molecular techniques have provided increasing insights into the biology of acute myeloid leukemia (AML). These investigations showed that AML is not a homogeneous disease but a heterogeneous group of biologically different subentities. These subentities are currently primarily defined by cytogenetics and molecular markers. They differ substantially in response to therapy and long-term outcome and hence allow different risk groups of patients to be defined. These will guide therapeutic decisions in future therapeutic strategies and may ultimately lead to an individualized treatment concept.
- Published
- 2006
25. Proliferative activity of leukaemic blasts and cytosine arabinoside pharmacodynamics are associated with cytogenetically defined prognostic subgroups in acute myeloid leukaemia
- Author
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J, Braess, G, Jahns-Streubel, C, Schoch, D, Haase, T, Haferlach, M, Fiegl, S, Voss, W, Kern, E, Schleyer, and W, Hiddemann
- Subjects
Adult ,Aged, 80 and over ,Antimetabolites, Antineoplastic ,Cytarabine ,Granulocyte-Macrophage Colony-Stimulating Factor ,HL-60 Cells ,Middle Aged ,Prognosis ,Translocation, Genetic ,Leukemia, Myeloid ,Karyotyping ,Chromosome Inversion ,Granulocyte Colony-Stimulating Factor ,Humans ,Cell Division ,Aged - Abstract
The biological mechanisms responsible for the association of specific karyotypes with prognosis in acute myeloid leukaemia (AML) remain largely unclear. A prospective study was performed to evaluate how far cytogenetically defined prognostic subgroups of AML differ in their proliferative activity as a potential mechanism for differential sensitivities to S-phase-specific induction chemotherapy comprising cytosine arabinoside (AraC). One hundred and eighty-seven patients with de novo AML were included in the study; 25 patients with a favourable [inv(16), t(8;21), t(15;17)] karyotype, 99 with a normal karyotype, 29 with an unfavourable karyotype (-5, 5q-, -7, 7q-, complex aberrations) and 34 with cytogenetic aberrations of unknown prognostic significance (all others). The favourable group demonstrated the highest ex vivo proliferative activity (PA) (3.41 pmol/105 cells), significantly (P = 0.02) exceeding the unfavourable group with the lowest PA (0.72) and the group with a normal karyotype (1.06) or with karyotype of unknown significance (1.05) that both demonstrated an intermediate PA. Samples with a high PA (median of the whole group) were more likely to produce interleukin 3, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF) (56%, 43% and 50%) than cells with a low PA (33%, 36% and 36%; n.s.). The effect of priming by exogenous GM-CSF or G-CSF was significantly more pronounced in samples with a low PA than in rapidly proliferating samples (P0.01). For the whole group, a high PA was closely associated with an increased incorporation of AraC triphosphate (AraCTP) into the DNA (P0.0001). Clinically, a high PA was associated with a better complete remission (CR) rate in the normal (95% versus 62%) and the unfavourable group (75% versus 33%). The significant differences in proliferative activity between cytogenetic subgroups of AML are associated with increased cytosine arabinoside pharmacodynamics and constitute one potential mechanism for the different response of cytogenetic subgroups to AraC-based induction therapy.
- Published
- 2001
26. Hepatic arterial infusion with oxaliplatin, folinic acid, and 5-fluorouracil in patients with hepatic metastases from colorectal cancer: role of carcino-embryonic antigen in assessment of response
- Author
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W, Kern, B, Beckert, N, Lang, T, Waggershauser, J, Braess, A, Schalhorn, and W, Hiddemann
- Subjects
Male ,Organoplatinum Compounds ,Liver Neoplasms ,Leucovorin ,Antineoplastic Agents ,Middle Aged ,Carcinoembryonic Antigen ,Oxaliplatin ,Hepatic Artery ,Outcome and Process Assessment, Health Care ,Treatment Outcome ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Infusions, Intra-Arterial ,Female ,Fluorouracil ,Neoplasm Metastasis ,Colorectal Neoplasms ,Aged - Abstract
Therapy for patients with hepatic metastases from colorectal cancer (CRC) remains controversial and may be improved by regional oxaliplatin which proved to be effective when administered systemically to patients with advanced CRC.During the current study, which aims to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetics of oxaliplatin applied as hepatic intra-arterial infusion combined with folinic acid and 5-fluorouracil in patients with hepatic metastases from CRC, serial levels of carcino-embryonic antigen were determined and their relationship to response to therapy was assessed.Toxicity mainly consisted of nausea, pain, mucositis, sensorial neuropathy, diarrhoea, and thrombocytopenia. The results of tumor marker analyses suggest that progressive disease may be detected early by increasing CEA levels and responsive disease may be characterized by low or decreasing values.Further analyses are warranted to determine the role of CEA in the assessment of response as compared to imaging techniques.
- Published
- 2001
27. Microalbuminuria during cisplatin therapy: relation with pharmacokinetics and implications for nephroprotection
- Author
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W, Kern, J, Braess, C C, Kaufmann, S, Wilde, E, Schleyer, and W, Hiddemann
- Subjects
Adult ,Male ,Osteosarcoma ,Metabolic Clearance Rate ,Antineoplastic Agents ,Bone Neoplasms ,Middle Aged ,Kidney ,Kidney Function Tests ,Testicular Neoplasms ,Area Under Curve ,Creatinine ,Albuminuria ,Humans ,Cisplatin ,Biomarkers ,Biotransformation ,Half-Life - Abstract
To assess the relation of cisplatin-induced nephrotoxicity to its pharmacology.In 22 chemonaive patients (median age, 32 years) receiving 100-150 mg/m2 cisplatin for a total of 54 courses of therapy pharmacokinetics of ultra-filtrable platin were analyzed. Nephrotoxicity was sensitively assessed by nephelometric analyses of urinary marker-proteins.The parameters calculated for ultrafiltrable platin were (two-compartment-model): terminal half-life, 36 hours (coefficient of variation [CV], 22%); AUC, 12852 ng h/ml (33%); volume of distribution, 3531 (44%); total clearance, 285 ml/min (30%); renal clearance, 149 ml/min (23%); maximum concentration, 1720 ng/ml (66%); renal elimination, 57% of applied dose (26%). A pathological urinary excretion of albumin20 mg/l and alpha-1-microglobulin10 mg/l was detected in 39 out of 54 and 42 out of 54 cycles, respectively. The degree of albuminuria was related with urinary monoaquoplatin concentrations (p = 0.003).Nephrotoxicity of cisplatin appears to depend on the urinary monoaquoplatin concentrations which may be modulated by application of saline.
- Published
- 2001
28. Multivariate Analysis of Prognostic Factors in Patients with Refractory and Relapsed Acute Myeloid Leukemia Undergoing Sequential High-Dose Cytosine Arabinoside and Mitoxantrone (S-HAM) Salvage Therapy: Significance of Cytogenetic Abnormalities
- Author
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W. Kern, C. Schoch, T. Haferlach, J. Braess, M. Unterhalt, B. Wörmann, T. Büchner, and W. Hiddemann
- Published
- 2001
29. The pharmacodynamic basis for the increased antileukaemic efficacy of cytosine arabinoside-based treatment regimens in acute myeloid leukaemia with a high proliferative activity
- Author
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J, Braess, S, Voss, G, Jahns-Streubel, C, Schoch, T, Haferlach, W, Kern, S, Keye, E, Schleyer, and W, Hiddemann
- Subjects
Adult ,Male ,Time Factors ,Cytarabine ,DNA ,Middle Aged ,Statistics, Nonparametric ,Leukemia, Myeloid ,Cytidine Deaminase ,Acute Disease ,Deoxycytidine Kinase ,Linear Models ,Humans ,Female ,Lymphocytes ,Cell Division ,Immunosuppressive Agents ,Aged ,Half-Life - Abstract
The current study was initiated to explore the mechanisms underlying the previously demonstrated association between the proliferative activity of leukaemic blasts and the response to cytosine arabinoside (AraC)-based therapy in de novo acute myeloid leukaemia (AML). The activity of key enzymes of AraC metabolism-deoxycytidine kinase (DCK), cytidine deaminase (DCD) and polymerase alpha (PolyA) were determined in blast cells from 33 patients. In addition, formation and retention of intracellular levels of AraC triphosphate (AraCTP) and DNA incorporation of AraC were measured, as was the proliferative activity of leukaemic blasts by [3H]-TdR incorporation before and after stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte CSF (G-CSF) for 48 h. AraC incorporation into the DNA (median 0.60 pmol/105 cells) was significantly related to the proliferative activity of AML blasts (r = 0.74, P0.001). Similarly, priming with GM-CSF or G-CSF increased both the proliferative activity of AML blasts by a median of 1.84- and 1.64-fold, respectively, and the incorporation of AraC into the DNA (1.29- and 1.40-fold respectively). In contrast, no relationship was found between the endogenous proliferative activity (EPA) and enzyme activities regulating AraC activation (DCK; median 4.70 pmol/min/mg protein), inactivation (DCD; median 2.92 pmol/min/mg protein) or inhibitory effects (PolyA; median 1.50 pmol/min/mg protein), nor the formation or retention of AraCTP (median 306.1 ng/107 cell and 1.6 h respectively). When samples were grouped according to EPA (more than or less than the median), slowly proliferating specimens had a higher response to cytokine priming for proliferative activity and incorporation of AraC into DNA. Clinical data of 15 patients were available. Although all eight patients with a high endogenous proliferative activity reached complete remission, only four out of seven patients with a low proliferative activity responded, whereas the other three patients were non-responders (P = 0.077).
- Published
- 2000
30. Successful modulation of high-dose cytosine arabinoside metabolism in acute myeloid leukaemia by haematopoietic growth factors: no effect of ribonucleotide reductase inhibitors fludarabine and gemcitabine
- Author
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J, Braess, C, Wegendt, G, Jahns-Streubel, W, Kern, S, Keye, M, Unterhalt, E, Schleyer, and W, Hiddemann
- Subjects
Cytarabine ,Granulocyte-Macrophage Colony-Stimulating Factor ,Hematopoietic Cell Growth Factors ,Deoxycytidine ,Gemcitabine ,Drug Administration Schedule ,Leukemia, Myeloid ,Deoxycytidine Kinase ,Granulocyte Colony-Stimulating Factor ,Ribonucleotide Reductases ,Arabinofuranosylcytosine Triphosphate ,Humans ,Enzyme Inhibitors ,Immunosuppressive Agents ,Vidarabine - Abstract
High-dose cytosine arabinoside (AraC)-containing regimens have shown the highest antileukaemic efficacy of all currently used regimens in the treatment of acute myeloid leukaemia (AML). This study aimed at increasing the antileukaemic potential of high-dose AraC by raising intracellular levels of AraC triphosphate (AraCTP), which is the mediator of cytotoxicity, via biochemical modulation by inhibitors of ribonucleotide reductase (RR) or haematopoietic growth factors (HGFs). Blasts from patients with de novo AML were analysed for their formation of AraCTP under high-dose AraC conditions (20 microM over 3 h) without prior modulation (n = 47) after a 2-h pre-exposure with fludarabine (50 microg/ml) (n = 40) or gemcitabine (30 ng/ml) (n = 40) and after a 48-h pre-exposure to granulocyte colony-stimulating-factor (G-CSF; 100 ng/ml) (n = 27) or granulocyte-macrophage colony-stimulating-factor (GM-CSF; 100 U/ml) (n = 28). Unmodulated formation of AraCTP (median 239.8 ng/107 cells) could not be increased via modulation by gemcitabine (232.4 ng/107 cells) or fludarabine (247.8 ng/107 cells). The lack of effect of RR inhibitors was also observed for all other known metabolites of AraC [Ara-cytosine monophosphate (CMP), Ara-cytosine diphosphate (CDP), AraCDP-choline, Ara-uridine monophosphate (UMP), Ara-uridine diphosphate (UDP) and Ara-uridine triphosphate (UTP)]. In contrast, pre-exposure to HGFs led to significant increases in AraCTP formation (G-CSF 556.0 ng/107 cells, 2.31-fold increase, P0.001; GM-CSF 447.9 ng/107 cells, 1.87-fold increase, P0.0001). To establish the mechanism responsible for these effects, the activity of the rate-limiting enzyme of AraC metabolism, deoxycytidine kinase (dCK), was investigated (n = 33). In vivo exposure to GM-CSF led to increases in dCK activity from unmodulated values at 0 h (29.8 pmol/min/mg protein) to 34.3 pmol/min/mg protein at 24 h (1.15-fold increase) and 54.5 pmol/min/mg protein at 48 h (1. 83-fold increase). The raise in dCK activity over 48 h was significant (P0.013).
- Published
- 2000
31. Oxaliplatin pharmacokinetics during a four-hour infusion
- Author
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W, Kern, J, Braess, B, Böttger, C C, Kaufmann, W, Hiddemann, and E, Schleyer
- Subjects
Adult ,Oxaliplatin ,Organoplatinum Compounds ,Area Under Curve ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,Humans ,Computer Simulation ,Fluorouracil ,Middle Aged ,Colorectal Neoplasms ,Infusions, Intravenous ,Models, Biological - Abstract
A new platin compound, oxaliplatin, has significant activity in advanced colorectal carcinomas. However, its pharmacokinetics have not been characterized adequately yet. This study extensively analyzes the pharmacokinetics of both ultrafiltrable (free) and protein-bound platin in 13 patients receiving 130 mg/m2 oxaliplatin as a 4-h infusion in combination with 375 mg/m2 5-fluorouracil as a 24-h infusion for advanced colorectal carcinomas. The interpatient variability was very low for all parameters analyzed. The levels of free platin decreased triphasically, with a mean terminal half-life of 27.3+/-10.6 h. The area under the time-concentration curve was 20.17+/-6.97 microg.h/ml and the total and renal clearances amounted to 222+/-65 and 121+/-56 ml/min, respectively. The values for the volume of distribution and for the maximum concentration at the end of infusion were 349+/-132 liters and 1612+/-553 ng/ml, respectively. On the basis of the simulation of the plasma levels and the urinary excretion of platin following the long-term administration of oxaliplatin as a constant-rate and a chronomodulated infusion, additional analyses are warranted to fully characterize the pharmacokinetics of the drug in these settings.
- Published
- 1999
32. Combination of aclarubicin and etoposide for the treatment of advanced acute myeloid leukemia: results of a prospective multicenter phase II trial. German AML Cooperative Group
- Author
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W, Kern, J, Braess, A, Grote-Metke, H, Kuse, R, Fuchs, D K, Hossfeld, A, Reichle, B, Wörmann, T, Büchner, and W, Hiddemann
- Subjects
Adult ,Aged, 80 and over ,Male ,Stomatitis ,Neutropenia ,Adolescent ,Middle Aged ,Disease-Free Survival ,Survival Rate ,Leukemia, Myeloid, Acute ,Leukocyte Count ,Recurrence ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Female ,Prospective Studies ,Aclarubicin ,Aged ,Etoposide - Abstract
In order to develop new strategies for the treatment of relapsed or refractory acute myeloid leukemia, the German AML Cooperative Group performed a prospective multicenter phase II study to evaluate the antileukemic efficacy of aclarubicin 60 mg/m2/day and etoposide 100 mg/m2/day each given for 5 days. Of 37 heavily pretreated evaluable patients (median age 42 years, range 18-81) 15 (40%) achieved a remission after one or two courses of treatment consisting of nine complete (24%) and six partial remissions (16%). Fourteen (38%) cases were non-responders and eight (22%) patients suffered from early deaths. Disease-free survival for patients in remission and overall survival were 3.2 months each. The median duration of critical neutropenia500/microl was 27 days. The most frequent non-hematologic side-effects were stomatitis (WHO III/IV, 48%), infections (40%), nausea/vomiting (26%) and diarrhea (24%). Cardiac toxicity was mild. This study suggests a substantial antileukemic efficacy and an acceptable toxicity of aclarubicin in combination with etoposide in heavily pretreated patients with advanced acute myeloid leukemia, and warrants further evaluations in a more favorable stage of the disease.
- Published
- 1998
33. Oral idarubicin pharmacokinetics--correlation of trough level with idarubicin area under curve
- Author
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E, Schleyer, S, Kühn, H, Rührs, M, Unterhalt, C C, Kaufmann, W, Kern, J, Braess, G, Sträubel, and W, Hiddemann
- Subjects
Adult ,Antibiotics, Antineoplastic ,Metabolic Clearance Rate ,Lymphoma, Non-Hodgkin ,Daunorubicin ,Cytarabine ,Administration, Oral ,Antineoplastic Agents ,Middle Aged ,Drug Administration Schedule ,Leukemia, Myeloid, Acute ,Leukemia, Myeloid ,Acute Disease ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Regression Analysis ,Idarubicin ,Chromatography, High Pressure Liquid ,Half-Life - Abstract
Idarubicin is the first anthracycline that can be successfully administered via the oral route and thus may facilitate antineoplastic chemotherapy in an improved quality of life. These perspectives are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under-the-curve values (AUC) for an appropriate adjustment of idarubicin dose. In this study we describe the pharmacokinetics of idarubicin and its main metabolite idarubicinol in 12 patients after oral application of 20 mg/m2 idarubicin on 3 consecutive days and demonstrate that the 24 h trough levels show a high correlation with AUC and may thus allow a rapid and easy determination of individual drug concentrations and an appropriate dose adjustment. The average terminal half-life was 30.5 h for idarubicin and 66.9 h for idarubicinol. The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4-445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the ratio of idarubicin/idarubicinol differed only two folds from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol concentrations were highly reproducible, however, upon measurements after repeated applications within individual patients. Moreover, idarubicinol and idarubicin AUCs showed a good correlation with r = 0.78, indicating that the interindividual variation of idarubicin AUC reflects differences in absorption rather than in metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by the respective AUC - measurement of a single data point with a high correlation with the AUC would be ideal. Our study demonstrates that the 24 h trough level shows such an excellent correlation (r = 0.96) with AUC, making it the perfect candidate for fast estimates of the individual bioavailability in a given patient. On this basis, the longitudinal measurement of the 24 h trough level may allow assessment of the impact of interindividual variations in AUC on clinical outcome and toxicity.
- Published
- 1998
34. AraC Metabolism in Fresh Leukemic Blasts/ Normal Bone Marrow/ Hematopoetic Stem Cells and its Impact on the Lipid Composition of Leukemic Cells (HL60)
- Author
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W. Kern, E. A. M. Fleer, E. Schleyer, J. Braess, Dinko Berkovic, S. Keye, Joachim Riggert, Michaela Feuring-Buske, Wolfgang Hiddemann, C. Wegendt, J. Pförtner, and M. Unterhalt
- Subjects
0303 health sciences ,Cell type ,Chemistry ,HL60 ,CD34 ,Metabolism ,Peripheral blood mononuclear cell ,Molecular biology ,carbohydrates (lipids) ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Immunology ,Stem cell ,Leukemic Blasts ,Intracellular ,030304 developmental biology - Abstract
Metabolites of tritium labeled AraC (AraCMP, -CDP, CTP, -CDP-choline) were determined by HPLC analysis. No significant differences in the formation of these metabolites could be found between fresh leukemic blasts, mononuclear cells from normal bone marrow and CD34/ 38 positive hematopoetic stem cells. AraCTP half-life, which has previously been shown to correlate with clinical parameters like CR duration, was longest in leukemic blasts. The intracellular pool of AraCTP precursors (AraCMP, -CDP) was similar and of low abundance (13–20% of AraCTP at all tested AraC concentrations) in all investigated cell types and therefore did not explain the differences in AraCTP half-life.
- Published
- 1998
35. Quantitative Cytosine Arabinoside Metabolism in HL60 and Raji Cells Using a Novel High Performance Liquid Chromatography Assay for Detection and Quantitation of 3H-Cytosine Arabinoside and Its Metabolites
- Author
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M. Unterhalt, C. C. Kaufmann, J. Pförtner, B. Ramsauer, Wolfgang Hiddemann, J. Braess, and E. Schleyer
- Subjects
Detection limit ,Chromatography ,HL60 ,Liquid scintillation counting ,food and beverages ,Metabolism ,biochemical phenomena, metabolism, and nutrition ,High-performance liquid chromatography ,Raji cell ,carbohydrates (lipids) ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,In vitro system ,heterocyclic compounds ,lipids (amino acids, peptides, and proteins) ,Cytosine ,030215 immunology - Abstract
An ion-pair high-performance liquid chromatography assay involving solid-phase scintillation detection was established for rapid identification and quantitation of all major metabolites of tritium-labeled cytosine arabinoside (ara-C) in an in vitro system. In a single run of 55 min ara-C, ara-CMP, ara-CDP-cholin, ara-CDP, ara-U, ara-UMP, ara-CTP, ara-UDP, and ara-UTP can be measured and quantitated. The presented method is fast, sensitive, with various limits of detection ranging from 40 to 200 pg (absolute), and highly reproducible. Metabolic profiles of HL60 and Raji cells following incubation with ara-C were established using this technique.
- Published
- 1997
36. Response to cytarabine ocfosfate (YNK01) in a patient with chronic lymphocytic leukemia refractory to treatment with chlorambucil/prednisone, fludarabine, and prednimustine/mitoxantrone
- Author
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C. C. Kaufmann, M. Unterhalt, M. Schüssler, W. Kern, J. Braess, E. Schleyer, A. Kaeser-Fröhlich, B. Ramsauer, and Wolfgang Hiddemann
- Subjects
Male ,Antimetabolites, Antineoplastic ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Administration, Oral ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Prednisone ,medicine ,Cytidine Monophosphate ,Humans ,Prodrugs ,030304 developmental biology ,0303 health sciences ,Mitoxantrone ,Chemotherapy ,Chlorambucil ,Arabinonucleotides ,business.industry ,Prednimustine ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,3. Good health ,Fludarabine ,chemistry ,030220 oncology & carcinogenesis ,Cytarabine ,business ,medicine.drug - Abstract
Cytarabine ocfosfate (YNK01) is a novel orally applicable prodrug of cytosine arabinoside. Recent pharmacokinetic studies have revealed a prolonged release of the cytotoxic agent cytosine arabinoside (araC) from hepatocytes into the systemic circulation, resulting in a half-life of approximately 24 h for araC. The specific pharmacokinetic characteristics of cytarabine ocfosfate lead to a prolonged exposure of leukemic cells to this antineoplasstic agent during the 14-day cycle. the oral applicability during outpatient treatment and the sustained antineoplastic activity of araC against slowly proliferating leukemic B-cells suggest that cytarabine ocfosfate might be a useful drug in the treatment of chronic lymphocytic leukemia. Four years after diagnosis of B-CLL, a 50-year-old patient was started on cytarabine ocfosfate. Sequentially, the patient's disease had proved refractory to treatment with chlorambucil/prednisone (31 months), fludarabine (5 months), and prednimustine/mitoxantrone (3 months). These established regimens were discontinued because of increasing lymphocytosis, significant thrombocytopenia, and progressive B-symptoms. Following three cycles of cytarabine ocfosfate B-symptoms resolved, lymphadenopathy disappeared, and thrombocytopenia was significantly reduced. The patient has been free of these symptoms on a dosage of 1500 mg cytarabine ocfosfate/day (cycle of 14 days with intervals of 14-21 days) for 24 months and remains in an ongoing partial remission.
- Published
- 1996
37. Pharmacokinetics of Ara-CMP-Stearate (YNK01) — Phase I Study of the Oral Ara-C Derivative
- Author
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C. C. Kaufmann, B. Ramsauer, Wolfgang Hiddemann, J. Braess, M. Unterhalt, Sabine Wilde, M. Schüssler, and E. Schleyer
- Subjects
Metabolite ,Urine ,Pharmacology ,Dosage form ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Oral administration ,Medicine ,heterocyclic compounds ,030304 developmental biology ,0303 health sciences ,business.industry ,food and beverages ,biochemical phenomena, metabolism, and nutrition ,Prodrug ,3. Good health ,Bioavailability ,carbohydrates (lipids) ,chemistry ,030220 oncology & carcinogenesis ,Cytarabine ,lipids (amino acids, peptides, and proteins) ,business ,medicine.drug - Abstract
Ara-CMP-Stearate (1-beta-D-Arabino-furanosylcytosine-5′-stearylphosphate, YNK 01, Fosteabine) is an the orally applicable prodrug of cytosine-arabinoside (Ara-C). During a recently started phase-I study in patients with advanced low-grade non-Hodgkin lymphomas or acute myeloid leukemia the pharmacokinetic parameters of Ara-CMP-Stearate (kindly provided by ASTA Medica, Frankfurt, FRG) were determined by HPLC analysis. 72 hours after a first starting dose which served for the determination of baseline pharmacokinetic parameters, Ara-CMP-Srearate was administered over 14 days by once daily oral application. Ara-CMP-Stearate was started at a dose of 100 mg/d and was escalated in subsequent patients to 200 mg/d, 300 mg/d and 600 mg/d. Plasma and urine concentratiions of Ara-CMP-Stearate, Ara-C and Ara-U were measured during the initial treatment phase and within 72 hours after the end of the 14 day treatment cycle. So far six patients have been treated with 100 mg/d, three with 200 mg/d and another six with 300 mg/d. One patient was treated consecutively with 100 mg, 300 mg and 600 mg. Fitting the results of the plasma concentration measurements of Ara-CMP-Stearate to a one compartment model, the following pharmacokinetic parameters were obtained (average and variation coefficient VC). Ara-CMP-Stearate dose independent parameters: Lag time = 1.04 h (0.57), tmax=5.72 h (0.30), t1/2 = 9.4 h (0.36). Dose dependent parameters: at 100 mg : AUC = 1099 ng·ml/h (0.31), concentrationmax=53.8 ng/ml (0.28), at 200 mg: AUC = 2753 ng·h/ml (0.32), concentrationmax = 154.8 ng/ml (0.46), at 300 mg: AUC = 2940 ng·h/ml (0.66), concentration max = 160.0 ng/ml (0.59). The long lag time and latemax can be explained by resorption in the distal part of the small intestine. No Ara-CMP-Stearate was detected in urine samples (limit of detection = 500pg/ml). Pharmacokinetcic parameters of ARA-C following Ara-CMP-Stearate application showed the following characteristics: t1/2 = 24.3 h (0.39), AUC (100mg) = 262 ng·h/ml (0.93), AUC (200mg) = 502 ng·h/ml (0.87), AUC (300mg) = 898 ng·h/ml (1.07). Since Ara-CMP-Stearate causes intravascular hemolysis after i.v. administration, it was not possible to determine its bioavailability by comparing the AUC after oral and i.v. application. Instead, the renal elimination of ARA-U, as the main metabolite of ARA-C was measured during the first 72 h period and after the last application. This approach allowed to estimate that an average of 15.8% of Ara-CMP-Stearate (VC 0.82) had undergone resorption and final metabolism to ARA-U. The observed half lifes for ARA-C(t1/2 = 24,4h, VC = 0,39) and Ara-U (t1/2 = 22,0 h, VC = 0,35) after Ara-CMP-Stearate administration were substantially longer than those after intravenous application of Ara-C suggesting a prolonged release of Ara-C from the prodrug due to a slow hepatic metabolism of Ara-CMP-Stearate. These data show that Ara-CMP-Stearate is able to maintain prolonged ARA-C plasma levels and suggest that ARA-C concentrations as in low dose and probably in standard dose ARA-C therapy can be achieved by oral application of Ara-CMP-Stearate.
- Published
- 1996
38. Pharmacokinetics of Ara-CMP-Stearate (YNK01): phase I study of the oral Ara-C derivative
- Author
-
E, Schleyer, J, Braess, B, Ramsauer, M, Unterhalt, C, Kaufmann, S, Wilde, M, Schüssler, and W, Hiddemann
- Subjects
Leukemia, Myeloid, Acute ,Arabinonucleotides ,Dose-Response Relationship, Drug ,Lymphoma, Non-Hodgkin ,Arabinofuranosyluracil ,Cytarabine ,Cytidine Monophosphate ,Administration, Oral ,Humans ,Antineoplastic Agents ,Statistics, Nonparametric ,Half-Life - Abstract
Ara-CMP-Stearate (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate, YNK 01, Fosteabine) is the orally applicable prodrug of cytosine-arabinoside (Ara-C). During a phase I study in patients with advanced low-grade non-Hodgkin lymphomas or acute myeloid leukemia, the pharmacokinetic parameters of Ara-CMP-Stearate (kindly provided by ASTA Medica, Frankfurt, Germany) were determined by HPLC analysis. Seventy-two hours after a first starting dose which served for the determination of baseline pharmacokinetic parameters, Ara-CMP-Stearate was administered over 14 days by daily oral application. Ara-CMP-Stearate was started at a dose of 100 mg/day and was escalated in subsequent patients to 200 mg/day and 300 mg/day. Plasma and urine concentrations of Ara-CMP-Stearate, Ara-C and Ara-U were measured during the initial treatment phase and within 72 h after the end of the 14-day treatment cycle. So far six patients have been treated with 100 mg/day, three with 200 mg/day and another six with 300 mg/day. One patient was treated consecutively with 100 mg, 300 mg and 600 mg. Fitting the results of the plasma concentration measurements of Ara-CMP-Stearate to a one-compartment model, the following pharmacokinetic parameters were obtained (average and variation coefficient VC). Ara-CMP-Stearate dose-independent parameters: lag time = 1.04 h (0.57); tmax = 5.72 h (0.30); t1/2 = 9.4 h (0.36). Dose-dependent parameters: at 100 mg: AUC = 1099 ng/h/ml (0.31); concentration(max) = 53.8 ng/ml (0.28); at 200 mg: AUC = 2753 ng/h/ml (0.32); concentration(max) = 154.8 ng/ml (0.46); at 300 mg: AUC = 2940 ng/h/ml (0.66); concentration(max) = 160.0 ng/ml (0.59). The long lag time and late tmax can be explained by resorption in the distal part of the small intestine. No Ara-CMP-Stearate was detected in urine samples (limit of detection = 500 pg/ml). Pharmacokinetic parameters of Ara-C following Ara-CMP-Stearate application showed the following characteristics: t1/2 = 24.3 h (0.39); AUC (100 mg) = 262 ng/h/ml (0.93); AUC (200 mg) = 502 ng/h/ml (0.87); AUC (300 mg) = 898 ng/h/ml (1.07). Since Ara-CMP-Stearate causes intravascular hemolysis after intravenous administration, it was not possible to determine its bioavailability by comparing the AUC after oral and i.v. application. Instead, the renal elimination of Ara-U, as the main metabolite of Ara-C was measured during the first 72-h period and after the last application.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1995
39. Treatment of relapsing thrombotic thrombocytopenic purpura with cyclophosphamide pulse therapy
- Author
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J Braess, Clemens Grupp, U. Wieneke, U Kaboth, M Kneba, Gerhard A. Müller, Frank Strutz, and K W Rumpf
- Subjects
Transplantation ,medicine.medical_specialty ,Cyclophosphamide ,Pulse (signal processing) ,business.industry ,Pulse therapy ,Thrombotic thrombocytopenic purpura ,medicine.disease ,Gastroenterology ,Nephrology ,Internal medicine ,medicine ,business ,medicine.drug - Published
- 1998
40. How accurate is clinical prognostication by oncologists during routine practice in a general hospital and can it be improved by a specific prognosis training programme: a prospective interventional study.
- Author
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Kupf I, Thanner G, Gerken M, Crispin A, and Braess J
- Subjects
- Humans, Prospective Studies, Prognosis, Male, Female, Middle Aged, Germany, Aged, Hospitals, General, Adult, Oncologists education, Medical Oncology education, Clinical Competence, Neoplasms therapy
- Abstract
Objectives: Oncologists need competence in clinical prognostication to deliver appropriate care to patients with cancer. Most studies on prognostication have been restricted to patients in palliative care settings. This paper investigates (1) the prognostic accuracy of physicians regarding a broad cohort of patients with cancer with a median life expectancy of >2 years and (2) whether a prognosis training can improve prognostication., Design: Prospective single-centre study comprising 3 phases, each lasting 1 month., Setting: Large teaching hospital, department of oncology and haematology, Germany., Participants: 18 physicians with a professional experience from entry level to 34 years. 736 patients with oncological and malignant haematological diseases., Interventions: Baseline prognostication abilities were recorded during an 'untrained' phase 1. As an intervention, a specific prognosis-training programme was implemented prior to phases 2 and 3. In phase 3, physicians had to provide additional estimates with the inclusion of electronic prognostic tools., Outcome Measures: Prognostic estimates (PE) were collected using 'standard' surprise question (SQ), 'probabilistic' SQ (both for short-term prognostication up to 6 months) and clinician prediction of survival (CPS) (for long-term prognostication). Estimated prognoses were compared with observed survival. Phase 1 was compared with phases 2 and 3., Results: We included 2427 PE for SQ, 1506 for CPS and 800 for probabilistic SQ. Median OS was 2.5 years. SQ accuracy improved significantly (p<0.001) from 72.6% in phase 1 to 84.3% in phase 3. Probabilistic SQ in phase 3 showed 83.1% accuracy. CPS accuracy was 25.9% and could not be significantly improved. (Electronic) prognostic tools-used alone-performed significantly worse (p<0.0005) than physicians and-used by the clinicians-did not improve their performance., Conclusion: A specific prognosis-training programme could improve short-term and intermediate-term prognostication. Improvement of long-term prognostication was not possible. Inexperienced residents as well as experienced oncologists benefited from training., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2024
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41. Identifying long-term survivors and those at higher or lower risk of relapse among patients with cytogenetically normal acute myeloid leukemia using a high-dimensional mixture cure model.
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Archer KJ, Fu H, Mrózek K, Nicolet D, Mims AS, Uy GL, Stock W, Byrd JC, Hiddemann W, Braess J, Spiekermann K, Metzeler KH, Herold T, and Eisfeld AK
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- Humans, Middle Aged, Adult, Male, Female, Cancer Survivors, Recurrence, Young Adult, Prognosis, Survivors, Leukemia, Myeloid, Acute genetics
- Abstract
Patients with cytogenetically normal acute myeloid leukemia (CN-AML) may harbor prognostically relevant gene mutations and thus be categorized into one of the three 2022 European LeukemiaNet (ELN) genetic-risk groups. Nevertheless, there remains heterogeneity with respect to relapse-free survival (RFS) within these genetic-risk groups. Our training set included 306 adults on Alliance for Clinical Trials in Oncology studies with de novo CN-AML aged < 60 years who achieved a complete remission and for whom centrally reviewed cytogenetics, RNA-sequencing, and gene mutation data from diagnostic samples were available (Alliance trial A152010). To overcome deficiencies of the Cox proportional hazards model when long-term survivors are present, we developed a penalized semi-parametric mixture cure model (MCM) to predict RFS where RNA-sequencing data comprised the predictor space. To validate model performance, we employed an independent test set from the German Acute Myeloid Leukemia Cooperative Group (AMLCG) consisting of 40 de novo CN-AML patients aged < 60 years who achieved a complete remission and had RNA-sequencing of their pre-treatment sample. For the training set, there was a significant non-zero cure fraction (p = 0.019) with 28.5% of patients estimated to be cured. Our MCM included 112 genes associated with cure, or long-term RFS, and 87 genes associated with latency, or shorter-term time-to-relapse. The area under the curve and C-statistic were respectively, 0.947 and 0.783 for our training set and 0.837 and 0.718 for our test set. We identified a novel, prognostically relevant molecular signature in CN-AML, which allows identification of patient subgroups independent of 2022 ELN genetic-risk groups.Trial registration Data from companion studies CALGB 8461, 9665 and 20202 (trials registered at www.clinicaltrials.gov as, respectively, NCT00048958, NCT00899223, and NCT00900224) were obtained from Alliance for Clinical Trials in Oncology under data sharing study A152010. Data from the AMLCG 2008 trial was registered at www.clinicaltrials.gov as NCT01382147., (© 2024. The Author(s).)
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- 2024
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42. Sotorasib in KRAS G12C-mutated non-small cell lung cancer: A multicenter real-world experience from the compassionate use program in Germany.
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Stratmann JA, Althoff FC, Doebel P, Rauh J, Trummer A, Hünerlitürkoglu AN, Frost N, Yildirim H, Christopoulos P, Burkhard O, Büschenfelde CMZ, Becker von Rose A, Alt J, Aries SP, Webendörfer M, Kaldune S, Uhlenbruch M, Tritchkova G, Waller CF, Rittmeyer A, Hoffknecht P, Braess J, Kopp HG, Grohé C, Schäfer M, Schumann C, Griesinger F, Kuon J, Sebastian M, and Reinmuth N
- Subjects
- Humans, Compassionate Use Trials, B7-H1 Antigen, Kelch-Like ECH-Associated Protein 1 genetics, Proto-Oncogene Proteins p21(ras) genetics, NF-E2-Related Factor 2, Germany, Mutation, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Brain Neoplasms, Piperazines, Pyridines, Pyrimidines
- Abstract
Background: Sotorasib is a first-in-class KRAS p.G12C-inhibitor that has entered clinical trials in pretreated patients with non-small cell lung cancer (NSCLC) in 2018. First response rates were promising in the CodeBreaK trials. It remains unclear whether response to sotorasib and outcomes differ in a real-world setting when including patients underrepresented in clinical trials., Methods: Patients with KRAS p.G12C-mutated advanced or metastatic NSCLC received sotorasib within the German multicenter sotorasib compassionate use program between 2020 to 2022. Data on efficacy, tolerability, and survival were analyzed in the full cohort and in subgroups of special interest such as co-occurring mutations and across PD-L1 expression levels., Results: We analyzed 163 patients who received sotorasib after a median of two treatment lines (range, 0 to 7). Every fourth patient had a poor performance status and 38% had brain metastases (BM). The objective response rate was 38.7%. The median overall survival was 9.8 months (95% CI, 6.5 to not reached). Median real-world (rw) progression-free survival was 4.8 months (9% CI, 3.9 to 5.9). Dose reductions and permanent discontinuation were necessary in 35 (21.5%) and 7 (4.3%) patients, respectively. Efficacy seems to be influenced by PD-L1 expression and a co-occurring KEAP1 mutation. KEAP1 was associated with an inferior survival. Other factors such as BM, STK11, and TP53 mutations had no impact on response and survival., Conclusion: First results from a real-world population confirm promising efficacy of sotorasib for the treatment of advanced KRAS p.G12C-mutated NSCLC. Patients with co-occurring KEAP1 mutations seem to derive less benefit., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JAS reports personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from Roche, personal fees from BMS, personal fees from Amgen, personal fees from LEO pharma, personal fees from Novartis, personal fees from Takeda, outside of the submitted work. FCA has received a research grant from Novartis, support for attending meetings and/or travel from Amgen, and consultant fees from IQVIA.PD has nothing to disclose. JR has nothing to disclose. AT has nothing to disclose. ANH has nothing to disclose. NF reports personal fees from AbbVie, Amgen, AstraZeneca, BeiGene, Berlinchemie, Boehringer Ingelheim, Bristol Myers&Squibb, Lilly, Merck Sharp&Dohme, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, outside of the submitted work. HY has nothing to disclose. PC has received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, Roche, and Takeda, speaker’s honoraria from AstraZeneca, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. OB has nothing to disclose. CMB has nothing to disclose. ABVD has nothing to disclose. JA has nothing to disclose. SPA as nothing to disclose. MW has nothing to disclose. SK has nothing to disclose. MU has nothing to disclose. GT has nothing to disclose. CFW has nothing to disclose. AR reports grants from AbbVie, grants from AstraZeneca, grants from BMS, grants from Boehringer Ingelheim, grants from Daichi Sankyo, grants from Eli Lilly, grants from GSK, grants from MSD, grants from Novartis, grants from Pfizer, grants from Roche, outside the submitted work. PH has nothing to disclose. JB has nothing to disclose. HGK has nothing to disclose. CG has nothing to disclose. MSch has nothing to disclose. CSch has nothing to disclose. FG reports personal fees from AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Siemens, Amgen, Ariad, Abbvie, Tesaro / GSK, Sanofi, Daiichi-Sankyo, Beigene, outside of the submitted work. MSch has nothing to disclose. MS reports personal fees from Lilly, Astra-Zeneca, Bristol-Myers & Squibb, Merck Sharp & Dohme, Pfizer, Takeda, Roche, AbbVie, Boehringer-Ingelheim, Celgene, Novartis, grants from Astra Zeneca outside the submitted work. NR reports personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from Boehringer-Ingelheim, personal fees from Daiichi Sankyo, personal fees from GSK, personal fees from Hoffmann-La Roche, personal fees from Janssen, personal fees from MSD, personal fees from Merck, personal fees from Lilly, personal fees from Pfizer, personal fees from Takeda, outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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43. Friday Leukemia-a Structural Phenomenon.
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Rausch C, Arnreich C, Rothenberg-Thurley M, Dufour A, Schneider S, Gittinger H, Bücklein V, Subklewe M, Sauerland C, Görlich D, Krug U, Berdel WE, Wörmann BJ, Hiddemann W, Braess J, von Bergwelt-Baildon M, Spiekermann K, Metzeler KH, and Herold T
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- Humans, Risk Factors, Leukemia
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- 2024
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44. Prognostic impact of CEBPA mutational subgroups in adult AML.
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Georgi JA, Stasik S, Kramer M, Meggendorfer M, Röllig C, Haferlach T, Valk P, Linch D, Herold T, Duployez N, Taube F, Middeke JM, Platzbecker U, Serve H, Baldus CD, Muller-Tidow C, Haferlach C, Koch S, Berdel WE, Woermann BJ, Krug U, Braess J, Hiddemann W, Spiekermann K, Boertjes EL, Hills RK, Burnett A, Ehninger G, Metzeler K, Rothenberg-Thurley M, Dufour A, Dombret H, Pautas C, Preudhomme C, Fenwarth L, Bornhäuser M, Gale R, and Thiede C
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- Adult, Humans, CCAAT-Enhancer-Binding Proteins genetics, Frameshift Mutation, Mutation, Prognosis, Leukemia, Myeloid, Acute
- Abstract
Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIP
InDel ), frameshift InDel or nonsense mutations inducing translational stop (bZIPSTOP ) or single base-pair missense alterations (bZIPms ), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIPInDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIPInDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIPms )., (© 2024. The Author(s).)- Published
- 2024
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45. A prospective observational study of real-world treatment and outcome in secondary CNS lymphoma.
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Habringer S, Demel UM, Fietz AK, Lammer F, Schroers R, Hofer S, Bairey O, Braess J, Meier-Stiegen AS, Stuhlmann R, Schmidt-Hieber M, Hoffmann J, Zinngrebe B, Kaiser U, Reimer P, Möhle R, Fix P, Höffkes HG, Langenkamp U, Büschenfelde CMZ, Hopfer O, Stoltefuß A, La Rosée P, Blasberg H, Jordan K, Kaun S, Meurer A, Unteroberdörster M, von Brünneck AC, Capper D, Heppner FL, Chapuy B, Janz M, Schwartz S, Konietschke F, Vajkoczy P, Korfel A, and Keller U
- Subjects
- Humans, Aged, Prospective Studies, Antineoplastic Combined Chemotherapy Protocols adverse effects, Rituximab therapeutic use, Treatment Outcome, Transplantation, Autologous, Retrospective Studies, Observational Studies as Topic, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse etiology, Hematopoietic Stem Cell Transplantation adverse effects, Central Nervous System Neoplasms drug therapy
- Abstract
Background: Secondary central nervous system lymphoma (SCNSL) confers a dismal prognosis and treatment advances are constrained by the lack of prospective studies and real-world treatment evidence., Methods: Patients with SCNSL of all entities were included at first diagnosis and patient characteristics, treatment data, and outcomes were prospectively collected in the Secondary CNS Lymphoma Registry (SCNSL-R) (NCT05114330)., Findings: 279 patients from 47 institutions were enrolled from 2011 to 2022 and 243 patients (median age: 66 years; range: 23-86) were available for analysis. Of those, 49 (20 %) patients presented with synchronous (cohort I) and 194 (80 %) with metachronous SCNSL (cohort II). The predominant histology was diffuse large B-cell lymphoma (DLBCL, 68 %). Median overall survival (OS) from diagnosis of CNS involvement was 17·2 months (95 % CI 12-27·5), with longer OS in cohort I (60·6 months, 95 % CI 45·5-not estimable (NE)) than cohort II (11·4 months, 95 % CI 7·8-17·7, log-rank test p < 0.0001). Predominant induction regimens included R-CHOP/high-dose MTX (cohort I) and high-dose MTX/cytarabine (cohort II). Rituximab was used in 166 (68 %) of B-cell lymphoma. Undergoing consolidating high-dose therapy and autologous hematopoietic stem cell transplantation (HDT-ASCT) in partial response (PR) or better was associated with longer OS (HR adjusted 0·47 (95 % CI 0·25-0·89), p = 0·0197)., Interpretation: This study is the largest prospective cohort of SCNSL patients providing a comprehensive overview of an international real-world treatment landscape and outcomes. Prognosis was better in patients with SCNSL involvement at initial diagnosis (cohort I) and consolidating HDT-ASCT was associated with favorable outcome in patients with PR or better., Competing Interests: Declaration of Competing Interest U.Ke. served in an advisory role for BMS/ Celgene, Takeda, Janssen, Gilead/ Kite, Roche, Abbvie, AstraZeneca, Novartis, Lilly, Pentixapharm and received travel support from BMS/ Celgene, Takeda, Janssen, Roche, Abbvie, Gilead/ Kite, AstraZeneca, Novartis, Lilly, Pentixapharm. S.H. served in an advisory role for Pentixapharm. Ro.S. served in an advisory role for BMS/ Celgene, Janssen, Gilead/ Kite, and Novartis. M.S-H. has an advisory role for Celgene GmbH, Amgen GmbH, Gilead/ Kite, Sanofi-Aventis, Glaxo Smith Kline, Bristol Myers Squibb, Shionogi and received financial support from Janssen-Cilag, Takeda, Novartis, Pfizer, Roche, Vifor Pharma, Celgene. P.L.R. received payment from Novartis, MSD, Abbvie, Roche, Incyte, Janssen-Cilag and travel support from Abbvie, Novartis, BMS, Janssen-Cilag and Roche. K.J. received royalties from Elsevier and Wolters Kluwer, obtained consulting fees and honoraria from Amgen, art tempi, Astra Zeneca, BD Solutions, Helsinn, Hexal, Karyopharm med update GmbH, MSD, Mundipharma, onkowissen, Riemser, Roche, Shire (Takeda), Vifor Pharma and Voluntis, B.C. received research grants from Gilead, received honoraria from BMS, Astra Zeneca, Gilead, Roche, Sandoz, Incyte, Abbvie and received travel support from Roche and Gilead. St. S. received research grants from Protherics Medicines Development Ltd., served in an advisory role for AMGEN, Gilead Sciences, Pfizer, SERB SAS, received honoraria from Akademie für Infektionsmedizin e.V., AMGEN, AVIR Pharma, CSi Hamburg GmbH, Gilead Sciences, Labor28, Novartis, Persberg Group GmbH/DGIM e.V., Pfizer, Vivantes GmbH and received travel support from Gilead Sciences and Novartis. A.K. Received financial support from Riemser. All remaining authors have declared no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2024
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46. Sex-associated differences in frequencies and prognostic impact of recurrent genetic alterations in adult acute myeloid leukemia (Alliance, AMLCG).
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Ozga M, Nicolet D, Mrózek K, Yilmaz AS, Kohlschmidt J, Larkin KT, Blachly JS, Oakes CC, Buss J, Walker CJ, Orwick S, Jurinovic V, Rothenberg-Thurley M, Dufour A, Schneider S, Sauerland MC, Görlich D, Krug U, Berdel WE, Woermann BJ, Hiddemann W, Braess J, Subklewe M, Spiekermann K, Carroll AJ, Blum WG, Powell BL, Kolitz JE, Moore JO, Mayer RJ, Larson RA, Uy GL, Stock W, Metzeler KH, Grimes HL, Byrd JC, Salomonis N, Herold T, Mims AS, and Eisfeld AK
- Subjects
- Adult, Humans, Male, Female, Prognosis, Nucleophosmin, Mutation, fms-Like Tyrosine Kinase 3 genetics, Sex Characteristics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy
- Abstract
Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients' sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal karyotype, FLT3-ITD, DNMT3A, NPM1 and WT1 mutations and less often complex karyotype, ASXL1, SRSF2, U2AF1, RUNX1, or KIT mutations. More women were in the 2022 European LeukemiaNet intermediate-risk group and more men in adverse-risk group. We found sex differences in co-occurring mutation patterns and prognostic impact of select genetic alterations. The mutation-associated splicing events and gene-expression profiles also differed between sexes. In patients aged <60 years, SF3B1 mutations were male-specific adverse outcome prognosticators. We conclude that sex differences in AML-associated genetic alterations and mutation-specific differential splicing events highlight the importance of patients' sex in analyses of AML biology and prognostication., (© 2023. The Author(s).)
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- 2024
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47. Secondary-type mutations do not impact outcome in NPM1-mutated acute myeloid leukemia - implications for the European LeukemiaNet risk classification.
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Eckardt JN, Bill M, Rausch C, Metzeler K, Spiekermann K, Stasik S, Sauer T, Scholl S, Hochhaus A, Crysandt M, Brümmendorf TH, Krug U, Wörmann B, Hiddemann W, Görlich D, Sauerland C, Steffen B, Einsele H, Neubauer A, Burchert A, Schäfer-Eckart K, Berdel WE, Schliemann C, Krause SW, Hänel M, Hanoun M, Kaufmann M, Fransecky L, Braess J, Ruhnke L, Schetelig J, Middeke JM, Serve H, Baldus CD, Platzbecker U, Müller-Tidow C, Bornhäuser M, Herold T, Thiede C, and Röllig C
- Subjects
- Humans, Mutation, Nuclear Proteins genetics, Prognosis, Leukemia, Myeloid, Acute genetics
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- 2023
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48. Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.
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Pastore F, Gittinger H, Raab S, Tschuri S, Ksienzyk B, Konstandin NP, Schneider S, Rothenberg-Thurley M, Horny HP, Werner M, Sauerland MC, Amler S, Görlich D, Berdel WE, Wörmann B, Braess J, Hiddemann W, Tischer J, Herold T, Metzeler KH, and Spiekermann K
- Subjects
- Adult, Humans, Middle Aged, Retrospective Studies, Disease-Free Survival, Neoplasm Recurrence, Local genetics, Chromosome Aberrations, Prognosis, Chromosomes, Leukemia, Megakaryoblastic, Acute genetics, Leukemia, Megakaryoblastic, Acute therapy, Leukemia, Myeloid, Acute genetics, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Acute megakaryoblastic leukaemia (AMKL) is associated with poor prognosis. Limited information is available on its cytogenetics, molecular genetics and clinical outcome. We performed genetic analyses, evaluated prognostic factors and the value of allogeneic haematopoietic stem cell transplantation (allo-HSCT) in a homogenous adult AMKL patient cohort. We retrospectively analysed 38 adult patients with AMKL (median age: 58 years, range: 21-80). Most received intensive treatment in AML Cooperative Group (AMLCG) trials between 2001 and 2016. Cytogenetic data showed an accumulation of adverse risk markers according to ELN 2017 and an unexpected high frequency of structural aberrations on chromosome arm 1q (33%). Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%). Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks (95% CI: 21-45). Patients undergoing allo-HSCT (n = 14) had a superior median OS (68 weeks; 95% CI: 11-126) and relapse-free survival (RFS) of 27 weeks (95% CI: 4-50), although cumulative incidence of relapse after allo-HSCT was high (62%). The prognosis of AMKL is determined by adverse genetic risk factors and therapy resistance. So far allo-HSCT is the only potentially curative treatment option in this dismal AML subgroup., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2023
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49. Chronic Active Epstein-Barr Virus (EBV) Infection Controlled by Allogeneic Stem Cell Transplantation and EBV-Specific T Cells.
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Meedt E, Weber D, Bonifacius A, Eiz-Vesper B, Maecker-Kolhoff B, Delecluse S, Delecluse HJ, Lorenz M, Schwarz K, Meedt ST, Braess J, Herr W, Holler E, Edinger M, and Wolff D
- Subjects
- Female, Humans, Adult, Herpesvirus 4, Human, Transplantation, Homologous adverse effects, T-Lymphocytes, Epstein-Barr Virus Infections therapy, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease
- Abstract
We report sustained remission of chronic active Epstein-Barr virus (EBV) infection in a 27-year-old female patient treated with third-party EBV-specific T cells followed by allogeneic hematopoietic stem cell transplantation (HSCT). The viremia cleared after administration of anti-T-lymphocyte globulin for graft-versus-host disease (GvHD) prophylaxis. Subsequent expansion of EBV-infected host T cells was controlled by transfusion of donor-derived EBV-specific T cells., Competing Interests: Potential conflicts of interest. D. Wolff received honoraria from Novartis and Neovii. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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50. Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia.
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Rausch C, Rothenberg-Thurley M, Dufour A, Schneider S, Gittinger H, Sauerland C, Görlich D, Krug U, Berdel WE, Woermann BJ, Hiddemann W, Braess J, von Bergwelt-Baildon M, Spiekermann K, Herold T, and Metzeler KH
- Subjects
- Humans, Middle Aged, Risk Factors, Prognosis, Mutation, Risk Assessment, Leukemia, Myeloid, Acute drug therapy
- Abstract
The revised 2022 European LeukemiaNet (ELN) AML risk stratification system requires validation in large, homogeneously treated cohorts. We studied 1118 newly diagnosed AML patients (median age, 58 years; range, 18-86 years) who received cytarabine-based induction chemotherapy between 1999 and 2012 and compared ELN-2022 to the previous ELN-2017 risk classification. Key findings were validated in a cohort of 1160 mostly younger patients. ELN-2022 reclassified 15% of patients, 3% into more favorable, and 12% into more adverse risk groups. This was mainly driven by patients reclassified from intermediate- to adverse-risk based on additional myelodysplasia-related mutations being included as adverse-risk markers. These patients (n = 79) had significantly better outcomes than patients with other adverse-risk genotypes (5-year OS, 26% vs. 12%) and resembled the remaining intermediate-risk group. Overall, time-dependent ROC curves and Harrel's C-index controlling for age, sex, and AML type (de novo vs. sAML/tAML) show slightly worse prognostic discrimination of ELN-2022 compared to ELN-2017 for OS. Further refinement of ELN-2022 without including additional genetic markers is possible, in particular by recognizing TP53-mutated patients with complex karyotypes as "very adverse". In summary, the ELN-2022 risk classification identifies a larger group of adverse-risk patients at the cost of slightly reduced prognostic accuracy compared to ELN-2017., (© 2023. The Author(s).)
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- 2023
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