A Hochhaus

Summary

Affiliation: University of Heidelberg
Country: Germany

Publications

  1. doi request reprint Suitability of the PAXgene system to stabilize bone marrow RNA in imatinib-resistant patients with chronic myeloid leukemia
    Thomas Ernst
    III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Clin Chem Lab Med 46:318-22. 2008
  2. ncbi request reprint [Selective tyrosine kinase inhibitor imatinib (STI571) in haematological and oncological disease]
    A Hochhaus
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Germany
    Dtsch Med Wochenschr 127:451-6. 2002
  3. ncbi request reprint [Therapy of chronic myelogenous leukemia in 2004]
    A Hochhaus
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg
    Dtsch Med Wochenschr 129:2122-7. 2004
  4. ncbi request reprint Clinical resistance to imatinib: mechanisms and implications
    Andreas Hochhaus
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim, Universitat Heidelberg, Wiesbadener Strasse 7 11, 68305 Mannheim, Germany
    Hematol Oncol Clin North Am 18:641-56, ix. 2004
  5. doi request reprint Cause and management of therapy resistance
    Andreas Hochhaus
    III Medizinische Klinik, Universitatsmedizin Mannheim, Universitat Heidelberg, 68167 Mannheim, Germany
    Best Pract Res Clin Haematol 22:367-79. 2009
  6. doi request reprint Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia
    A Hochhaus
    Universitatsmedizin Mannheim, Heidelberg University, Mannheim, Germany
    Leukemia 23:1054-61. 2009
  7. ncbi request reprint Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance
    A Hochhaus
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 18:1321-31. 2004
  8. ncbi request reprint First-Line management of CML: a state of the art review
    Andreas Hochhaus
    Medizinische Fakultaet Mannheim, University of Heidelberg, Heidelberg, Germany
    J Natl Compr Canc Netw 6:S1-S10. 2008
  9. ncbi request reprint [Current therapy concepts in chronic myeloid leukemia. Study IV of the German CML Study Group]
    A Hochhaus
    III Medizinische Universitätsklinik, Klinikum Mannheim, Universitat Heidelberg, Wiesbadener Strasse 7 11, 68305 Mannheim
    Internist (Berl) 43:1228, 1231-8, 1241-4. 2002
  10. ncbi request reprint Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib
    A Hochhaus
    III Medizinische Klinik, Medizinische Fakultat Mannheim, Universitat Heidelberg, Mannheim, Germany
    Leukemia 22:1200-6. 2008

Collaborators

Detail Information

Publications142 found, 100 shown here

  1. doi request reprint Suitability of the PAXgene system to stabilize bone marrow RNA in imatinib-resistant patients with chronic myeloid leukemia
    Thomas Ernst
    III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Clin Chem Lab Med 46:318-22. 2008
    ..In CML, blood but not bone marrow samples have been examined using RNA stabilization in previous studies. Therefore, we sought to investigate the applicability of the PAXgene system for bone marrow samples in CML...
  2. ncbi request reprint [Selective tyrosine kinase inhibitor imatinib (STI571) in haematological and oncological disease]
    A Hochhaus
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Germany
    Dtsch Med Wochenschr 127:451-6. 2002
  3. ncbi request reprint [Therapy of chronic myelogenous leukemia in 2004]
    A Hochhaus
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg
    Dtsch Med Wochenschr 129:2122-7. 2004
    ..The impact of the various treatment modalities (imatinib, interferon alpha, ara-C, allogeneic stem cell transplantation) will be elucidated. The recruitment of newly diagnosed CML patients into CML-study IV is recommended...
  4. ncbi request reprint Clinical resistance to imatinib: mechanisms and implications
    Andreas Hochhaus
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim, Universitat Heidelberg, Wiesbadener Strasse 7 11, 68305 Mannheim, Germany
    Hematol Oncol Clin North Am 18:641-56, ix. 2004
    ..Cytogenetic and molecular analyses at the time of resistance are suggested to guide therapy...
  5. doi request reprint Cause and management of therapy resistance
    Andreas Hochhaus
    III Medizinische Klinik, Universitatsmedizin Mannheim, Universitat Heidelberg, 68167 Mannheim, Germany
    Best Pract Res Clin Haematol 22:367-79. 2009
    ....
  6. doi request reprint Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia
    A Hochhaus
    Universitatsmedizin Mannheim, Heidelberg University, Mannheim, Germany
    Leukemia 23:1054-61. 2009
    ..The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML...
  7. ncbi request reprint Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance
    A Hochhaus
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 18:1321-31. 2004
    ..Management of resistance may include therapeutic strategies such as dose escalation to achieve individual optimal levels, combination therapy, as well as treatment interruption...
  8. ncbi request reprint First-Line management of CML: a state of the art review
    Andreas Hochhaus
    Medizinische Fakultaet Mannheim, University of Heidelberg, Heidelberg, Germany
    J Natl Compr Canc Netw 6:S1-S10. 2008
    ..This article reviews the current role of allo-SCT, imatinib, and IFN-alpha in treating newly diagnosed chronic-phase CML, highlighting the benefits and challenges of long-term patient management, and discusses emerging trends...
  9. ncbi request reprint [Current therapy concepts in chronic myeloid leukemia. Study IV of the German CML Study Group]
    A Hochhaus
    III Medizinische Universitätsklinik, Klinikum Mannheim, Universitat Heidelberg, Wiesbadener Strasse 7 11, 68305 Mannheim
    Internist (Berl) 43:1228, 1231-8, 1241-4. 2002
  10. ncbi request reprint Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib
    A Hochhaus
    III Medizinische Klinik, Medizinische Fakultat Mannheim, Universitat Heidelberg, Mannheim, Germany
    Leukemia 22:1200-6. 2008
    ..Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML...
  11. ncbi request reprint Dasatinib for the treatment of Philadelphia chromosome-positive chronic myelogenous leukaemia after imatinib failure
    Andreas Hochhaus
    III Medizinische Klinik, Abt Leukaemieforschung, Medizinische Fakultaet Mannheim, University of Heidelberg, 68167 Mannheim, Germany
    Expert Opin Pharmacother 8:3257-64. 2007
    ..Side effects of dasatinib, including pleural effusions, are manageable with modification of dose or schedule. Phase III dose optimisation studies and future indications are also discussed...
  12. ncbi request reprint Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy
    Andreas Hochhaus
    III Medizinische Klinik, Medizinische Fakultat Mannheim, Universitat Heidelberg, Theodor Kutzer Ufer 1 3, 68167 Mannheim, Germany
    Blood 109:2303-9. 2007
    ..This trial was registered at www.clinicaltrials.gov as CA180013...
  13. ncbi request reprint Resistance to targeted therapy in chronic myelogenous leukemia
    Andreas Hochhaus
    III Medizinische Klinik, Medizinische Fakultat Mannheim, University of Heidelberg, Mannheim, Germany
    Semin Hematol 44:S15-24. 2007
    ..Additional strategies include imatinib dose escalation, combination therapy, and treatment interruption to stop clonal selection of resistant cells...
  14. ncbi request reprint Management of Bcr-Abl-positive leukemias with dasatinib
    Andreas Hochhaus
    III Medizinische Klinik, Abteilung Leukaemieforschung, Medizinische Fakultaet Mannheim, University of Heidelberg, 68167 Mannheim, Germany
    Expert Rev Anticancer Ther 7:1529-36. 2007
    ..Adverse events experienced with dasatinib include myelosuppression and fluid retention (e.g., pleural effusions), which were manageable with dose adjustment or treatment...
  15. ncbi request reprint [Drug therapy of chronic myeloid leukemia]
    Andreas Hochhaus
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim
    Med Klin (Munich) 97:7-15. 2002
    ..91% of all CML patients in chronic phase achieve a hematologic remission within 11 months and 55% cytogenetic remission. In blast crisis, 29% achieve hematologic remission which may be durable...
  16. ncbi request reprint [Selective inhibition of tyrosine kinases - a new therapeutic principle in oncology]
    A Hochhaus
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Onkologie 24:65-71. 2001
    ..Clinical responses to STI571 in various malignancies may stimulate greater interest in the clinical use of tyrosine kinase inhibitors...
  17. ncbi request reprint Molecular monitoring of response to imatinib (Glivec) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission
    P Paschka
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 17:1687-94. 2003
    ..1% are associated with continuous remission...
  18. ncbi request reprint Expression of the p210BCR-ABL oncoprotein drives centrosomal hypertrophy and clonal evolution in human U937 cells
    M Giehl
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 21:1971-6. 2007
    ....
  19. ncbi request reprint Gene expression signature of primary imatinib-resistant chronic myeloid leukemia patients
    O Frank
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Universitätsklinikum Mannheim der Ruprecht Karls Universität Heidelberg, Mannheim, Germany
    Leukemia 20:1400-7. 2006
    ..The resulting expression signature point to involvement of BCR-ABL-independent mechanisms of resistance...
  20. ncbi request reprint Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML)
    B Hanfstein
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 26:2096-102. 2012
    ..001) and correspondingly >0% Ph+ (34% of pts; 5-year OS: 91%) compared with 0% Ph+ (66% of pts; 5-year OS: 97%; P=0.015). Treatment optimization is recommended for pts missing these landmarks...
  21. ncbi request reprint Gender aspects in chronic myeloid leukemia: long-term results from randomized studies
    U Berger
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim, Universitat Heidelberg, 68305 Mannheim, Germany
    Leukemia 19:984-9. 2005
    ..0006). This is the first analysis of gender aspects in CML using randomized trials. It demonstrates the relevance of analyses of gender differences in CML and in malignant disease at large...
  22. doi request reprint Harmonization of molecular monitoring of CML therapy in Europe
    M C Muller
    III Medizinische Klinik, Universitatsmedizin Mannheim, Heidelberg University, Mannheim, Germany
    Leukemia 23:1957-63. 2009
    ..We provide recommendations for the propagation of the IS by national or regional laboratory networks...
  23. ncbi request reprint Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy
    A Hochhaus
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Germany
    Leukemia 16:2190-6. 2002
    ..However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents...
  24. pmc Capecitabine in combination with docetaxel and mitomycin C in patients with pre-treated tumours: results of an extended phase-I trial
    T Ernst
    Onkologisches Zentrum, III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Theodor Kutzer Ufer 1 3, Mannheim 68167, Germany
    Br J Cancer 97:1475-9. 2007
    ..The established regimen was well tolerated and the preliminary efficacy data in this heavily pre-treated patients population appears to be promising...
  25. ncbi request reprint Chronic myeloid leukemia in the elderly: long-term results from randomized trials with interferon alpha
    U Berger
    Klinikum Mannheim, Universitat Heidelberg, Mannheim, Germany
    Leukemia 17:1820-6. 2003
    ..We conclude that the course of CML is not different in the elderly. They require lower IFN doses, achieve the same hematologic and cytogenetic response rates and the same survival advantage at comparable toxicity...
  26. pmc Capecitabine in combination with mitomycin C in patients with gastrointestinal cancer: results of an extended multicentre phase-I trial
    R D Hofheinz
    Onkologisches Zentrum, III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Theodor Kutzer Ufer, D 68167 Mannheim, Germany
    Br J Cancer 91:834-8. 2004
    ..The favourable safety profile and promising activity of the capecitabine/mitomycin C combination, even in heavily pretreated patients, warrant further evaluation in patients with advanced colorectal and gastric cancers...
  27. ncbi request reprint Induction of centrosome and chromosome aberrations by imatinib in vitro
    A Fabarius
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Ruprecht Karls Universität Heidelberg, Mannheim, Germany
    Leukemia 19:1573-8. 2005
    ....
  28. ncbi request reprint Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha
    K Merx
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 16:1579-83. 2002
    ....
  29. pmc Pegylated liposomal doxorubicin in combination with mitomycin C, infusional 5-fluorouracil and sodium folinic acid. A phase-I-study in patients with upper gastrointestinal cancer
    R D Hofheinz
    Onkologisches Zentrum, III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Theodor Kutzer Ufer, D 68167 Mannheim, Germany
    Br J Cancer 90:1893-7. 2004
    ..Preliminary antitumour activity has been observed in patients with pretreated pancreatic cancer and in untreated gastric cancer...
  30. ncbi request reprint [Resistance to tumor specific therapy with imatinib by clonal selection of mutated cells]
    M C Muller
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim
    Dtsch Med Wochenschr 127:2205-7. 2002
    ..Because of progressive disease treatment with the tyrosine kinase inhibitor imatinib (STI571, Glivec (R)) had been started 9 months before. She had achieved complete hematological remission within 8 weeks, but not a cytogenetic response...
  31. doi request reprint Dasatinib-associated major molecular responses in patients with chronic myeloid leukemia in chronic phase following imatinib failure: response dynamics and predictive value
    A Hochhaus
    III Medizinische Klinik, Universitatsmedizin Mannheim, Universitat Heidelberg, Mannheim, Germany
    Leukemia 23:1628-33. 2009
    ..MMR at 12 months was associated with a longer duration of CCyR. Overall, this analysis shows that dasatinib treatment results in high MMR rates in patients with CML-CP after imatinib failure...
  32. ncbi request reprint Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea
    R Hehlmann
    Klinikum Mannheim, Universitat Heidelberg, Mannheim, Germany
    Leukemia 17:1529-37. 2003
    ..In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies...
  33. ncbi request reprint Tumor response to neoadjuvant chemoradiation in rectal cancer: predictor for surgical morbidity?
    K Horisberger
    Department of Surgery, University Hospital Mannheim, Mannheim, Germany
    Int J Colorectal Dis 23:257-64. 2008
    ..This report evaluates the influence of preoperative intensified radiochemotherapy on the rate and outcome of surgical complications...
  34. doi request reprint The molecular anatomy of the FIP1L1-PDGFRA fusion gene
    C Walz
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 23:271-8. 2009
    ..The variability in the anatomy of the FIP1L1-PDGFRA fusion has important implications for strategies to detect the fusion at diagnosis or for monitoring response to treatment...
  35. ncbi request reprint Imatinib restores expression of CD62L in BCR-ABL-positive cells
    S Fruehauf
    Department of Internal Medicine V, University of Heidelberg, Germany
    J Leukoc Biol 73:600-3. 2003
    ..Restoration of defective cell adhesion mediated via the CD62L pathway may be one mechanism of action of imatinib in BCR-ABL-positive leukemias...
  36. ncbi request reprint Impact of chemoradiotherapy-induced anemia on survival in uniformly staged patients with locally advanced squamous cell carcinoma of the esophagus
    R D Hofheinz
    Okologisches Zentrum, III, Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Germany
    Onkologie 27:462-6. 2004
    ....
  37. ncbi request reprint Dynamics of BCR-ABL mRNA expression in first-line therapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C
    M C Muller
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 17:2392-400. 2003
    ....
  38. ncbi request reprint Imatinib and beyond--the new CML study IV. A randomized controlled comparison of imatinib vs imatinib/interferon-alpha vs imatinib/low-dose AraC vs imatinib after interferon-alpha failure in newly diagnosed chronic phase chronic myeloid leukemia
    U Berger
    III Medizinische Universitätsklinik, Klinikum Mannheim, Universitat Heidelberg, Wiesbadener Strasse 7 11, 68305 Mannheim, Germany
    Ann Hematol 83:258-64. 2004
  39. ncbi request reprint Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML Study Gr
    A Hochhaus
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin, Mannheim der Universität Heidelberg, Mannheim, Germany
    Blood 95:62-6. 2000
    ..We suggest that for patients who reach CR, IFN should be continued at least until relatively low levels of residual leukemia are achieved. (Blood. 2000;95:62-66)..
  40. doi request reprint Patients with malignant hematological disorders treated on a palliative care unit: prognostic impact of clinical factors
    M Kripp
    III Medizinische Klinik, Universitatsmedizin Mannheim, Universitat Heidelberg, Theodor Kutzer Ufer 1 3, 68167, Mannheim, Germany
    Ann Hematol 93:317-25. 2014
    ..These parameters might help clinicians to estimate prognosis of remaining life span and individualize treatment and/or end-of-life care options for patients. ..
  41. ncbi request reprint Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma
    G Metzgeroth
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 21:1183-8. 2007
    ....
  42. ncbi request reprint Cytogenetic response to prior treatment with interferon-alpha is predictive for survival after allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia
    O Maywald
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität, Heidelberg, Mannheim, Germany
    Leukemia 20:477-84. 2006
    ..We therefore conclude that allogeneic HSCT in CyR should be investigated prospectively as an alternative treatment option in defined patient groups...
  43. ncbi request reprint AraC-based pharmacotherapy of chronic myeloid leukaemia
    A Reiter
    III Medizinische Universitätsklinik, Klinikum Mannheim, Fakultät für Klinische Medizin der Universtät Heidelberg, Germany
    Expert Opin Pharmacother 2:1129-35. 2001
    ..The clinical benefits may therefore be outweighed by the dose-limiting toxicity for both application forms. Combinations with other drugs, e.g., STI571 or homoharringtonine, have shown promising early results in vitro and in vivo...
  44. ncbi request reprint Improvement of molecular monitoring of residual disease in leukemias by bedside RNA stabilization
    M C Muller
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 16:2395-9. 2002
    ..Comparable results were achieved using G6PD transcripts as standard. We conclude that the new PAXgene stabilization method could improve RNA quality and the comparability of molecular monitoring within and between multicenter trials...
  45. ncbi request reprint Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure
    R Hehlmann
    III Medizinische Universitätsklinik, Klinikum Mannheim, Universitat Heidelberg, Heidelberg, Germany
    Blood 94:3668-77. 1999
    ..We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN...
  46. pmc A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer
    F Willeke
    Chirurgische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Br J Cancer 96:912-7. 2007
    ..The local recurrence and distant failure rates observed after a median 28 months are low compared with standard 5-fluorouracil based therapy...
  47. doi request reprint Adjuvant IMRT/XELOX radiochemotherapy improves long-term overall- and disease-free survival in advanced gastric cancer
    J Boda-Heggemann
    Department of Radiation Oncology, Universitatsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Theodor Kutzer Ufer 1 3, 68167, Mannheim, Germany
    Strahlenther Onkol 189:417-23. 2013
    ..We report on the long-term outcomes of two consecutive patient cohorts that were treated with either IMRT and intensive chemotherapy, or 3D-CRT and conventional chemotherapy...
  48. pmc Adhesion to fibronectin stimulates proliferation of wild-type and bcr/abl-transfected murine hematopoietic cells
    A Kramer
    III Medizinische Klinik, Klinikum Mannheim, Universitat Heidelberg, Wiesbadener Str 7 11, 68305 Mannheim, Germany
    Proc Natl Acad Sci U S A 96:2087-92. 1999
    ....
  49. ncbi request reprint Panniculitis in a patient with chronic myelogenous leukaemia treated with imatinib
    S Ugurel
    Institute of Pathology and Department of Dermatology, Medical Centre Mannheim, University of Heidelberg, Theodor Kutzer Ufer 1, 68167 Mannheim, Germany
    Br J Dermatol 149:678-9. 2003
  50. doi request reprint Expression of transketolase-like gene 1 (TKTL1) depends on disease phase in patients with chronic myeloid leukaemia (CML)
    M Philipp
    III Medizinische Universitätsklinik, Wissenschaftliches Labor, Universitatsmedizin Mannheim, Pettenkoferstraße 22, 68169, Mannheim, Germany
    J Cancer Res Clin Oncol 140:411-7. 2014
    ..Chronic myeloid leukaemia (CML) cells show metabolic characteristics resembling deviations observed in TKTL1 overexpressing solid tumour cells. We therefore sought to evaluate TKTL1 gene expression in different phases of CML...
  51. ncbi request reprint BBR 3438, a novel 9-aza-anthrapyrazole, in patients with advanced gastric cancer: a phase II study group trial of the Central European Society of Anticancer-Drug Research (CESAR)
    R D Hofheinz
    Onkologisches Zentrum, III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim, Universitat Heidelberg, Germany
    Invest New Drugs 23:363-8. 2005
    ..In terms of antitumor activity, BBR 3438 was found to be ineffective in the treatment of gastric cancer...
  52. ncbi request reprint Harmonization of BCR-ABL mRNA quantification using a uniform multifunctional control plasmid in 37 international laboratories
    M C Muller
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 22:96-102. 2008
    ..We conclude that the use of a common control plasmid does indeed improve comparability of BCR-ABL mRNA quantification results. However, further standardizing efforts like introducing a calibrator and regular control rounds are needed...
  53. ncbi request reprint MDR1 expression predicts outcome of Ph+ chronic phase CML patients on second-line nilotinib therapy after imatinib failure
    M Agrawal
    III Medizinische Universitätsklinik, Medizinische Fakultat Mannheim, Universitat Heidelberg, Mannheim, Germany
    Leukemia 28:1478-85. 2014
    ..High MDR1 gene expression might identify patients whose mode of imatinib resistance is essentially determined by increased efflux activity of MDR1 and therefore can be overcome by second-line nilotinib treatment. ..
  54. ncbi request reprint Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis
    C Zheng
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Ruprecht Karls Universität Heidelberg, Mannheim, Germany
    Leukemia 20:1028-34. 2006
    ..Our data suggest the existence of a common gene expression profile of CML-BP and provide new insight into the molecular phenotype of blasts associated with disease progression and high malignancy...
  55. ncbi request reprint [Current pharmacotherapy of chronic myeloid leukemia]
    A Hochhaus
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Wiesbadener Strasse 7 11, 68305 Mannheim
    Internist (Berl) 43:270-83. 2002
  56. ncbi request reprint Treatment of a patient with advanced esophageal cancer with a combination of mitomycin C and capecitabine: activation of the thymidine phosphorylase as active principle?
    R D Hofheinz
    Onkologisches Zentrum, III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Germany
    Onkologie 26:161-4. 2003
    ..Capecitabine and MMC act synergistically due to an upregulation of the thymidine phosphorylase activity by MMC in a human xenograft model...
  57. ncbi request reprint Imatinib mesylate (Glivec, Gleevec) in the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST)
    A Hochhaus
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Ann Hematol 83:S65-6. 2004
  58. doi request reprint Dynamics of BCR-ABL mutated clones prior to hematologic or cytogenetic resistance to imatinib
    Thomas Ernst
    III Medizinische Klinik, Medizinische, Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Haematologica 93:186-92. 2008
    ..We sought to improve the diagnostic armamentarium by screening and to analyze the dynamics of mutated clones in chronic myeloid leukemia patients who experienced hematologic or cytogenetic relapse...
  59. ncbi request reprint Cytogenetic and molecular mechanisms of resistance to imatinib
    Andreas Hochhaus
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Semin Hematol 40:69-79. 2003
    ..Combination therapy from the start of treatment to reduce the frequency of resistance is currently being evaluated with several drugs...
  60. doi request reprint Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome: a phase-II study
    Georgia Metzgeroth
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Br J Haematol 143:707-15. 2008
    ..These data confirmed the long-term efficacy of imatinib for PDGFR-rearranged CEL patients, and also showed that a minority of HES cases without known molecular aberrations may benefit from imatinib...
  61. ncbi request reprint Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up
    Tanja Lahaye
    III Medizinische Klinik Mannheim der Universität Heidelberg, Mannheim, Germany
    Cancer 103:1659-69. 2005
    ..The advent of imatinib has considerably changed the treatment of chronic myeloid leukemia (CML). Early studies demonstrated high rates of hematologic and cytogenetic responses in all phases of the disease after limited observation periods...
  62. pmc Dose-dependent severe cutaneous reactions to imatinib
    S Ugurel
    Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany
    Br J Cancer 88:1157-9. 2003
    ..We here report on two out of four melanoma patients treated with high-dose imatinib presenting with severe and strongly dose-dependent skin eruptions, suggesting a cutaneous reactivity pattern different from allergic hypersensitivity...
  63. ncbi request reprint The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1
    C Walz
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, 68305 Mannheim, Germany
    Leukemia 19:1005-9. 2005
    ..MYO18A-FGFR1 is structurally similar to other fusion tyrosine kinases and is likely to be the causative transforming lesion in this unusual MDS/MPD...
  64. pmc Capecitabine-associated hand-foot-skin reaction is an independent clinical predictor of improved survival in patients with colorectal cancer
    R D Hofheinz
    TagesTherapieZentrum TTZ, Interdisciplinary Tumour Centre, University Hospital Mannheim, University of Heidelberg, Theodor Kutzer Ufer 1 3, Haus 9, Mannheim 68167, Germany
    Br J Cancer 107:1678-83. 2012
    ..In the present analysis, we sought to evaluate the potential association of HFSR and survival in German patients with metastatic colorectal cancer and locally advanced rectal cancer treated with cape in clinical trials...
  65. ncbi request reprint Early results from a phase I study on orally administered tris(8-quinolinolato)gallium(III) (FFC11, KP46) in patients with solid tumors--a CESAR study (Central European Society for Anticancer Drug Research--EWIV)
    R D Hofheinz
    Onkologisches Zentrum, III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Germany
    Int J Clin Pharmacol Ther 43:590-1. 2005
  66. ncbi request reprint Centrosome aberrations in chronic myeloid leukemia correlate with stage of disease and chromosomal instability
    M Giehl
    Medical Clinic III, Faculty for Clinical Medicine Mannheim of University Heidelberg, Mannheim, Germany
    Leukemia 19:1192-7. 2005
    ..They may be considered as the driving force of disease progression and could serve as future prognostic markers...
  67. ncbi request reprint A further milestone towards comprehensive standardization of quantitative RT-PCR protocols for leukemic fusion gene transcripts has been reached
    A Hochhaus
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Leukemia 17:2383-4. 2003
  68. doi request reprint Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV
    Susanne Saussele
    III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Blood 115:1880-5. 2010
    ..We conclude that allo SCT could become the preferred second-line option after imatinib failure for suitable patients with a donor. The study is registered at the National Institutes of Health, http://clinicaltrials.gov: NCT00055874...
  69. ncbi request reprint An international study to standardize the detection and quantitation of BCR-ABL transcripts from stabilized peripheral blood preparations by quantitative RT-PCR
    Martin C Muller
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Haematologica 92:970-3. 2007
    ..5 mL samples tested positive. For higher dilutions, a PB volume of 5 or 10 ml was required to improve sensitivity. The study showed the feasibility of RQ-PCR standardization independent of the PCR machine used...
  70. ncbi request reprint Standardization of preanalytical factors for minimal residual disease analysis in chronic myelogenous leukemia
    Martin C Muller
    III Medizinische Universitätsklinik Mannheim der Universität Heidelberg, Mannheim, Deutschland
    Acta Haematol 112:30-3. 2004
    ..The definition of 'undetectable BCR-ABL' in an individual patient should take these preanalytical parameters into consideration...
  71. ncbi request reprint Chronic myeloid leukaemia
    Rudiger Hehlmann
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Lancet 370:342-50. 2007
    ..Up to 87% of patients achieve complete cytogenetic remission, therefore we provide guidance for monitoring disease status. Many trials of new drugs and combination therapies that include imatinib are underway...
  72. ncbi request reprint [Clinical research at the European LeukemiaNet]
    S Saussele
    III Medizinische Universitätsklinik, Klinikum Mannheim der Universität Heidelberg, 68305 Mannheim
    Dtsch Med Wochenschr 131:2423-6. 2006
  73. ncbi request reprint Chronic myelogenous leukemia (CML): resistance to tyrosine kinase inhibitors
    A Hochhaus
    III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Ann Oncol 17:x274-9. 2006
  74. ncbi request reprint Advances in the treatment of haematological malignancies: optimal sequence of CML treatment
    A Hochhaus
    III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Ann Oncol 18:ix58-63. 2007
  75. ncbi request reprint Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment
    Andreas Hochhaus
    Medizinische Fakultaet Mannheim, University of Heidelberg, Mannheim, Germany
    Blood 111:1039-43. 2008
    ..5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN...
  76. doi request reprint Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib
    Paul La Rosée
    III Medizinische Klinik, Medizinische Fakultat Mannheim, Universitat Heidelberg, Theodor Kutzer Ufer 1 3 68167 Mannheim, Germany
    Haematologica 93:765-9. 2008
    ..Monitoring the actual BCR-ABL inhibition in nilotinib treated patients using pCRKL as a surrogate is a means to establish effective dosing and to characterize resistance mechanisms against nilotinib...
  77. doi request reprint Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations
    Martin C Muller
    III Medizinische Klinik, Universitatsmedizin Mannheim, Universitat Heidelberg, Mannheim, Germany
    Blood 114:4944-53. 2009
    ..Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844...
  78. ncbi request reprint Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide (Trisenox) through glutathione-depletion in imatinib-resistant cells
    Heiko Konig
    III Medizinische Klinik, Medizinische Fakultat Mannheim, Universitat Heidelberg, Mannheim, Germany
    Haematologica 92:838-41. 2007
    ..These data provide a rationale for the clinical development of optimized ATO-based regimens through incorporation of GSH-modulators in CML treatment...
  79. ncbi request reprint Dynamics of cytogenetic aberrations in Philadelphia chromosome positive and negative hematopoiesis during dasatinib therapy of chronic myeloid leukemia patients after imatinib failure
    Alice Fabarius
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Ruprecht Karls Universität Heidelberg, Mannheim, Germany
    Haematologica 92:834-7. 2007
    ..Seventy-one patients treated with dasatinib after imatinib failure for a median of nine months were evaluated. Novel aberrations within Ph positive and negative clones appeared in six and three patients, respectively...
  80. ncbi request reprint Molecular surveillance of chronic myeloid leukemia patients in the imatinib era - evaluation of response and resistance
    Peter Paschka
    III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Acta Haematol 112:85-92. 2004
    ..The definition of molecular surrogate endpoints beyond CCR for studies which are currently planned demands standardization of the nomenclature and of technologies to measure these targets...
  81. ncbi request reprint Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2-PDGFRA fusion gene
    Christoph Walz
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Genes Chromosomes Cancer 45:950-6. 2006
    ....
  82. ncbi request reprint Minimal residual disease in chronic myeloid leukaemia patients
    Andreas Hochhaus
    Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, III Medizinische Universitätsklinik, Wiesbadener Strasse 7 11, 68305 Mannheim, Germany
    Best Pract Res Clin Haematol 15:159-78. 2002
    ....
  83. doi request reprint Chronic myelogenous leukemia: ESMO clinical recommendations for the diagnosis, treatment and follow-up
    A Hochhaus
    III Medizinische Klinik, Medizinische Fakultaet Mannheim, Universitaet Heidelberg, Mannheim, Germany
    Ann Oncol 19:ii63-4. 2008
  84. ncbi request reprint Proliferating status of peripheral blood progenitor cells from patients with BCR/ABL-positive chronic myelogenous leukemia
    A Kramer
    III Medizinische Klinik, Klinikum Mannheim, Universitat Heidelberg, Mannheim, Germany
    Leukemia 15:62-8. 2001
    ..These data suggest that BCR/ABL leads to an enhanced cell cycle activation of CD34+ cells, which seems to be, at least in part, independent of additional factors provided by the bone marrow microenvironment...
  85. ncbi request reprint Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor beta gene
    Christoph Walz
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str 7 11 68305 Mannheim, Germany
    Haematologica 92:163-9. 2007
    ....
  86. doi request reprint Identification of a MYO18A-PDGFRB fusion gene in an eosinophilia-associated atypical myeloproliferative neoplasm with a t(5;17)(q33-34;q11.2)
    Christoph Walz
    III Medizinische Klinik, Universitatsmedizin Mannheim, Germany
    Genes Chromosomes Cancer 48:179-83. 2009
    ..Patients with PDGFRB fusions genes are excellent candidates for treatment with imatinib; complete cytogenetic and even molecular remissions are common while primary or secondary resistance seems to be very rare...
  87. ncbi request reprint Efficacy of different regimens of adjuvant radiochemotherapy for treatment of glioblastoma
    Antonella Scheda
    Klinik fur Strahlentherapie und Radioonkologie, Medizinische Fakultat Mannheim, Universitat Heidelberg, Germany
    Tumori 93:31-6. 2007
    ..We retrospectively analyzed the impact of different adjuvant chemotherapy regimens in a group of patients treated for glioblastoma compared to patients receiving only postoperative radiotherapy...
  88. ncbi request reprint Detection of centrosome aberrations in disease-unrelated cells from patients with tumor treated with tyrosine kinase inhibitors
    Michelle Giehl
    III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Eur J Haematol 85:139-48. 2010
    ..Despite good response and acceptable tolerability, little is known concerning long-term toxicity. Furthermore, the influence of these inhibitors on disease-unrelated cells is not investigated yet...
  89. ncbi request reprint Detection and quantification of leukemia-specific rearrangements
    Andreas Hochhaus
    III Medizinische Universitätsklinik, Klinikum Mannheim, Universitat Heidelberg, Mannheim, Germany
    Methods Mol Med 68:67-96. 2002
  90. ncbi request reprint Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis
    Stefan Fruehauf
    Internal Medicine V, University of Heidelberg, Heidelberg, Germany
    Cancer 109:1543-9. 2007
    ..Imatinib has demonstrated synergistic effects in vitro with mitoxantrone, etoposide, and cytarabine...
  91. doi request reprint ABL single nucleotide polymorphisms may masquerade as BCR-ABL mutations associated with resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia
    Thomas Ernst
    III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str 7 11, 68305 Mannheim, Germany
    Haematologica 93:1389-93. 2008
    ..Novel point mutations should be confirmed by analyzing the normal ABL alleles to exclude polymorphisms...
  92. ncbi request reprint Centrosome aberrations after nilotinib and imatinib treatment in vitro are associated with mitotic spindle defects and genetic instability
    Alice Fabarius
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Br J Haematol 138:369-73. 2007
    ..Our data suggest that distinct tyrosine kinases likewise targeted by both drugs are essential actuators in maintenance of centrosome and karyotype integrity...
  93. doi request reprint Centrosome aberrations and G1 phase arrest after in vitro and in vivo treatment with the SRC/ABL inhibitor dasatinib
    Alice Fabarius
    III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Wiesbadener Strasse 7 11, 68305 Mannheim, Germany
    Haematologica 93:1145-54. 2008
    ..Dasatinib is a multitargeted inhibitor of ABL, the SRC family, and other tyrosine kinases. We sought to evaluate the effects of this drug on cell proliferation, centrosomes, mitotic spindles, and cell cycle progression in vitro and in vivo...
  94. ncbi request reprint Gefitinib in combination with 5-fluorouracil (5-FU)/folinic acid and irinotecan in patients with 5-FU/oxaliplatin- refractory colorectal cancer: a phase I/II study of the Arbeitsgemeinschaft für Internistische Onkologie (AIO)
    Ralf Dieter Hofheinz
    Onkologisches Zentrum, III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Germany
    Onkologie 29:563-7. 2006
    ..This phase I/II dose-finding study evaluated gefitinib in combination with a 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI-AIO) regimen in patients with metastatic colorectal cancer...
  95. doi request reprint mRNA expression of platelet-derived growth factor receptor-beta and C-KIT: correlation with pathologic response to cetuximab-based chemoradiotherapy in patients with rectal cancer
    Philipp Erben
    III Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Int J Radiat Oncol Biol Phys 72:1544-50. 2008
    ....
  96. ncbi request reprint Irinotecan and capecitabine as second-line treatment after failure for first-line infusional 24-h 5-fluorouracil/folinic acid in advanced colorectal cancer: a phase II study
    Ralf Dieter Hofheinz
    Onkologisches Zentrum, III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Anticancer Drugs 16:39-45. 2005
    ..Efficacy and toxicity data are comparable to 5-FU/irinotecan combinations, although the likelihood of severe diarrhea appears to be higher with capecitabine/irinotecan...
  97. ncbi request reprint Topoisomerase I expression correlates to response to neoadjuvant irinotecan-based chemoradiation in rectal cancer
    Karoline Horisberger
    Chirurgische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
    Anticancer Drugs 20:519-24. 2009
    ....
  98. ncbi request reprint Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia
    Rudiger Hehlmann
    III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Strasse 7 11, 63805 Mannheim, Germany
    Blood 109:4686-92. 2007
    ..032). The general recommendation of HSCT as first-line treatment option in chronic phase CML can no longer be maintained. It should be replaced by a trial with modern drug treatment first...
  99. ncbi request reprint Liposomal encapsulated anti-cancer drugs
    Ralf Dieter Hofheinz
    Onkologisches Zentrum, III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim, Universitat Heidelberg, Mannheim, Germany
    Anticancer Drugs 16:691-707. 2005
    ..Meanwhile, virtually all anti-cancer drugs have been encapsulated in liposomes using different technologies. This review will summarize preclinical and clinical data of approved and exemplary emerging liposomal anti-cancer agents...
  100. ncbi request reprint Pegylated liposomal doxorubicin and mitomycin C in combination with infusional 5-fluorouracil and sodium folinic acid in the treatment of advanced gastric cancer: results of a phase II trial
    Senta Ulrike Gnad-Vogt
    Onkologisches Zentrum, III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Anticancer Drugs 16:435-40. 2005
    ..Its safety and good tolerability as established in the phase I trial was confirmed...
  101. ncbi request reprint The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2
    Andreas Reiter
    III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany
    Cancer Res 65:2662-7. 2005
    ..We conclude that human autoantigen pericentriolar material (PCM1)-JAK2 is a novel, recurrent fusion gene in hematologic malignancies. Patients with PCM1-JAK2 disease are attractive candidates for targeted signal transduction therapy...