80 results on '"Philipp Hemmati"'
Search Results
2. Effect of Combination Antibiotic Empirical Therapy on Mortality in Neutropenic Cancer Patients with Pseudomonas aeruginosa Pneumonia
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Adaia Albasanz-Puig, Xavier Durà-Miralles, Júlia Laporte-Amargós, Alberto Mussetti, Isabel Ruiz-Camps, Pedro Puerta-Alcalde, Edson Abdala, Chiara Oltolini, Murat Akova, José Miguel Montejo, Malgorzata Mikulska, Pilar Martín-Dávila, Fabián Herrera, Oriol Gasch, Lubos Drgona, Hugo Manuel Paz Morales, Anne-Sophie Brunel, Estefanía García, Burcu Isler, Winfried V. Kern, Pilar Retamar-Gentil, José María Aguado, Milagros Montero, Souha S. Kanj, Oguz R. Sipahi, Sebnem Calik, Ignacio Márquez-Gómez, Jorge I. Marin, Marisa Z. R. Gomes, Philipp Hemmati, Rafael Araos, Maddalena Peghin, José Luis del Pozo, Lucrecia Yáñez, Robert Tilley, Adriana Manzur, Andres Novo, Natàlia Pallarès, Alba Bergas, Jordi Carratalà, Carlota Gudiol, and on behalf of the IRONIC Study Group
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Pseudomonas aeruginosa ,bloodstream infection ,pneumonia ,septic shock ,neutropenia ,Biology (General) ,QH301-705.5 - Abstract
To assess the effect of combination antibiotic empirical therapy on 30-day case-fatality rate in neutropenic cancer patients with Pseudomonas aeruginosa (PA) bacteremic pneumonia. This was a multinational, retrospective cohort study of neutropenic onco-hematological patients with PA bloodstream infection (BSI) (2006–2018). The effect of appropriate empirical combination therapy, appropriate monotherapy and inappropriate empirical antibiotic therapy [IEAT] on 30-day case-fatality was assessed only in patients with PA bacteremic pneumonia. Among 1017 PA BSI episodes, pneumonia was the source of BSI in 294 (28.9%). Among those, 52 (17.7%) were caused by a multidrug-resistant (MDR) strain and 68 (23.1%) received IEAT, mainly when the infection was caused by an MDR strain [38/52 (73.1%) vs. 30/242 (12.4%); p < 0.001]. The 30-day case-fatality rate was higher in patients with PA bacteremic pneumonia than in those with PA BSI from other sources (55.1% vs. 31.4%; p < 0.001). IEAT was associated with increased 30-day case-fatality (aHR 1.44 [95%CI 1.01–2.03]; p = 0.042), whereas the use of appropriate combination empirical treatment was independently associated with improved survival (aHR 0.46 [95%CI 0.27–0.78]; p = 0.004). Appropriate empirical monotherapy was not associated with improved overall survival (aHR 1.25 [95%CI 0.76–2.05]; p = 0.39). Combination antibiotic empirical therapy should be administered promptly in febrile neutropenic patients with suspected pneumonia as the source of infection.
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- 2022
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3. BCR-ABL+ acute myeloid leukemia: are we always dealing with a high-risk disease?
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Nina Rosa Neuendorff, Philipp Hemmati, Renate Arnold, Jana Ihlow, Bernd Dörken, Carsten Müller-Tidow, and Jörg Westermann
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Specialties of internal medicine ,RC581-951 - Published
- 2018
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4. Physical and psychosocial aspects of adolescent and young adults after allogeneic hematopoietic stem-cell transplantation: results from a prospective multicenter trial
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Inken Hilgendorf, Andreas Hochhaus, Kathrin Rieger, Daniel Wolff, Philipp Yorck Herzberg, Stephanie von Harsdorf, Hildegard Greinix, Kristin Pulewka, Pia Heussner, Friederike Mumm, and Philipp Hemmati
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Adult ,Male ,Cancer Research ,Pediatrics ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Graft vs Host Disease ,Disease ,Hematopoietic stem cell transplantation ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Surveys and Questionnaires ,Multicenter trial ,medicine ,Humans ,Young adult ,Aged ,business.industry ,Age Factors ,Hematopoietic Stem Cell Transplantation ,General Medicine ,Middle Aged ,humanities ,Transplantation ,Distress ,Oncology ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,Quality of Life ,Female ,business ,Psychosocial ,030215 immunology - Abstract
Purpose Allogeneic hematopoietic stem-cell transplantation (alloHSCT) is physically and psychosocially demanding. Among transplant recipients, adolescent and young adults (AYA) represent a special group, as disease occurs early in life, resulting in the prospect of long survival time and high burden of alloHSCT sequelae. However, data focusing on AYA undergoing alloHSCT are rare. Methods Data resulting from a prospective multicenter trial initially focusing on graft-versus-host disease (GvHD) after alloHSCT were reused to analyse the differences between AYA and elderly patients. In total, data of 205 alloHSCT recipients were evaluated. Patients completed the FACTBMT, HAP, SF-36, 24-AM, LOT-R, BSSS, HADS, and GvHD questionnaires. Results Median age of AYA and non-AYA patients was 29 and 52 years. Using 24-AM-Test, evaluating personality traits, non-AYA reported to be more conscientious (p = 0.033). However, AYA described higher quality of life regarding physical role functioning (p = 0.001), physical functioning (p = 0.002), bodily pain (p = 0.023), and emotional role function (p = 0.027) in the SF-36. General health perception, vitality, social role functioning, and mental health were comparable among both groups. On HAP scale, AYA reported higher maximum (p = 0.003) and adjusted activity scores (p = 0.002), but showed similar restrictions regarding activity, self-supply, and self-determination. Conclusion AYA represent a particular group characterized by higher physical well-being and activity scores, and significantly vary from non-AYA patients in psychosocial aspects. Studies covering distinctive features of AYA undergoing alloHSCT are warranted to improve awareness of the special needs of this group.
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- 2017
5. Predictive significance of the European LeukemiaNet classification of genetic aberrations in patients with acute myeloid leukaemia undergoing allogeneic stem cell transplantation
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Olaf Penack, Il-Kang Na, Christian Jehn, Philipp Hemmati, Bernd Dörken, Lam G. Vuong, Theis H. Terwey, Renate Arnold, and Philipp le Coutre
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,Kaplan-Meier Estimate ,Young Adult ,03 medical and health sciences ,European LeukemiaNet ,0302 clinical medicine ,Recurrence ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,In patient ,Treatment Failure ,Proportional Hazards Models ,Retrospective Studies ,Proportional hazards model ,business.industry ,Incidence (epidemiology) ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Genetic Variation ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,Combined Modality Therapy ,Surgery ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Stem cell ,Myeloid leukaemia ,business ,030215 immunology - Abstract
Objectives The purpose of this study was to evaluate the predictive capacity of the European LeukemiaNet (ELN) classification of genetic risk in patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (alloSCT). Methods We retrospectively analysed 274 patients transplanted at our centre between 2004 and 2014. Results The ELN grouping is comparable to the Southwest Oncology Group/Eastern Cooperative Oncology Group (SWOG/ECOG) stratification in predicting the outcome after alloSCT [overall P = 0.0064 for disease-free survival (DFS), overall P = 0.003 for relapse]. Patients with an intermediate-1 profile have a significantly elevated 5-yr relapse incidence as compared to favourable risk patients, that is 40% vs. 15%, [hazard ratio (HR) 2.58, P = 0.048]. An intermediate-1 risk profile is an independent predictor for relapse as determined by multivariate Cox regression analysis (HR 3.05, P = 0.023). In intermediate-1 patients, the presence of an FLT3 internal tandem duplication (FLT3-ITD) is associated with a significantly increased relapse incidence (P = 0.0323), and a lower DFS (P = 0.0465). FLT3-ITD is an independent predictor for overall survival, DFS and relapse incidence in the intermediate-1 subgroup. Conclusions The ELN stratification of genetic risk predicts the outcome of patients with AML undergoing alloSCT. Patients with an intermediate-1 profile have a high risk for treatment failure due to relapse, which prompts the development of alternative treatment strategies.
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- 2016
6. BCR-ABL + acute myeloid leukemia: are we always dealing with a high-risk disease?
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Philipp Hemmati, Nina Rosa Neuendorff, Jörg Westermann, Jana Ihlow, Renate Arnold, Bernd Dörken, and Carsten Müller-Tidow
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Oncology ,medicine.medical_specialty ,Myeloid ,business.industry ,Myeloid leukemia ,Hematology ,Disease ,medicine.disease ,World health ,03 medical and health sciences ,Leukemia ,0302 clinical medicine ,medicine.anatomical_structure ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,Commentary ,medicine ,In patient ,Differential diagnosis ,business ,neoplasms ,030215 immunology - Abstract
TO THE EDITOR: BCR-ABL + acute myeloid leukemia (AML) has recently been listed in the 2016 revised World Health Organization (WHO) classification of myeloid malignancies as a provisional entity.[1][1] BCR-ABL + AML comprises a group of de novo AML in patients without evidence of an underlying
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- 2018
7. Impact of antibiotic resistance on outcomes of neutropenic cancer patients with
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Adaia, Albasanz-Puig, Carlota, Gudiol, Rocío, Parody, Cristian, Tebe, Murat, Akova, Rafael, Araos, Anna, Bote, Anne-Sophie, Brunel, Sebnem, Calik, Lubos, Drgona, Estefanía, García, Philipp, Hemmati, Fabián, Herrera, Karim Yaqub, Ibrahim, Burcu, Isler, Souha, Kanj, Winfried, Kern, Guillermo, Maestro de la Calle, Adriana, Manzur, Jorge Iván, Marin, Ignacio, Márquez-Gómez, Pilar, Martín-Dávila, Malgorzata, Mikulska, José Miguel, Montejo, Milagros, Montero, Hugo Manuel Paz, Morales, Isabel, Morales, Andrés, Novo, Chiara, Oltolini, Maddalena, Peghin, Jose Luis, Del Pozo, Pedro, Puerta-Alcalde, Isabel, Ruiz-Camps, Oguz Resat, Sipahi, Robert, Tilley, Lucrecia, Yáñez, Marisa Zenaide Ribeiro, Gomes, Jordi, Carratalà, and Amanda Aparecida, da Silva Machado
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Tazobactam ,bacteraemia ,Neutropenia ,Time Factors ,International Cooperation ,multidrug-resistant ,onco-haematological patients ,Bacteremia ,bloodstream infection ,pseudomonas aeruginosa ,Anti-Bacterial Agents ,Cephalosporins ,Observational Studies as Topic ,Logistic Models ,Infectious Diseases ,Research Design ,Drug Resistance, Multiple, Bacterial ,Neoplasms ,Protocol ,Humans ,Multicenter Studies as Topic ,Pseudomonas Infections ,Retrospective Studies - Abstract
Introduction Pseudomonas aeruginosa (PA) has historically been one of the major causes of severe sepsis and death among neutropenic cancer patients. There has been a recent increase of multidrug-resistant PA (MDRPA) isolates that may determine a worse prognosis, particularly in immunosuppressed patients. The aim of this study is to establish the impact of antibiotic resistance on the outcome of neutropenic onco-haematological patients with PA bacteraemia, and to identify the risk factors for MDRPA bacteraemia and mortality. Methods and analysis This is a retrospective, observational, multicentre, international study. All episodes of PA bacteraemia occurring in neutropenic onco-haematological patients followed up at the participating centres from 1 January 2006 to 31 May 2018 will be retrospectively reviewed. The primary end point will be overall case-fatality rate within 30 days of onset of PA bacteraemia. The secondary end points will be to describe the following: the incidence and risk factors for multidrug-resistant and extremely drug-resistant PA bacteraemia (by comparing the episodes due to susceptible PA with those produced by MDRPA), the efficacy of ceftolozane/tazobactam, the rates of persistent bacteraemia and bacteraemia relapse and the risk factors for very early (48 hours), early (7 days) and overall (30 days) case-fatality rates. Ethics and dissemination The Clinical Research Ethics Committee of Bellvitge University Hospital approved the protocol of the study at the primary site. To protect personal privacy, identifying information of each patient in the electronic database will be encrypted. The processing of the patients’ personal data collected in the study will comply with the Spanish Data Protection Act of 1998 and with the European Directive on the privacy of data. All data collected, stored and processed will be anonymised. Results will be reported at conferences and in peer-reviewed publications.
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- 2019
8. Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X-linked adrenoleukodystrophy
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Jörn-Sven Kühl, Giang Lam Vuong, Rudolf Peceny, Philipp Hemmati, Christian Jehn, Wolfgang Köhler, Nils Waldhüter, and Renate Arnold
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Internal capsule ,Transplantation Conditioning ,Cyclophosphamide ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Humans ,Adrenoleukodystrophy ,Genetics (clinical) ,business.industry ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,medicine.disease ,Transplantation ,Survival Rate ,Haematopoiesis ,030104 developmental biology ,Disease Progression ,Female ,Stem cell ,business ,030217 neurology & neurosurgery ,Busulfan ,medicine.drug - Abstract
The adult cerebral form of X-linked adrenoleukodystrophy (ACALD), an acute inflammatory demyelinating disease, results in a rapidly progressive neurodegeneration, typically leading to severe disability or death within a few years after onset. We have treated 15 men who had developed ACALD with allogeneic haematopoietic stem cell transplantation (HSCT) from matched donors after myeloablative conditioning with busulfan and cyclophosphamide. All patients engrafted and 11 survived (estimated survival 73 ± 11%), eight with stable cognition and seven of them with stable motor function (estimated event-free survival 36 ± 17%). Death after transplantation occurred within the first year after HSCT and was caused either primarily by infection (n = 3) or due to disease progression triggered by infection (n = 1). Patients with minor myelopathic symptoms (n = 4) or with no or mild cerebral symptoms pre-transplant (n = 7) had an excellent outcome. In contrast, no patient with major neurological symptoms associated with an extensive involvement of pyramidal tract fibres in the internal capsule (n = 5) survived without cognitive deterioration. Notably, early leukocyte recovery was associated with dismal outcome for yet unknown reasons. All ten tested survivors showed a reduction of plasma hexacosanoic acid (C26:0) in the absence of Lorenzo’s oil. Over time, the event-free survival could be improved from 2 out of 8 patients (25%) before 2013 to 5 out of 7 patients (71%) thereafter. Therefore, allogeneic HSCT appears to be a suitable treatment option for carefully selected ACALD patients when transplanted from matched donors after myeloablative, busulfan-based conditioning.
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- 2019
9. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells
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Donald Bunjes, Sebastian Halbach, Dietmar Pfeifer, Philipp Hemmati, Robert S. Negrin, Fabio Ciceri, Jean-Yves Cahn, Markus Ditschkowski, Pavan Reddy, Kathrin Hanke, Daniela Dörfel, Susan Klaeger, Jürgen Finke, Zehan Hu, Gabriele Ihorst, Gérard Socié, Sanaz Taromi, Andreas Hochhaus, Glen A Kennedy, Omid Shah, Andreas Neubauer, Robert Thimme, Michael Schultheiss, Sabine Spath, Dietrich W. Beelen, Sandra Duquesne, Arnim Weber, Geoffrey R. Hill, Ronjon Chakraverty, Jürgen Kuball, Guido Kobbe, Nikolas von Bubnoff, Andrea S. Henden, Betul Oran, Burkhard Becher, Bernhard Kuster, Christoph Rummelt, Lena Osswald, Hartmut Bertz, Wolfgang Bethge, Eva-Maria Wagner, Arnon Nagler, Eliana Ruggiero, Saar Gill, Miguel Waterhouse, Andreas Mackensen, Dominik Bettinger, Francis Baumgartner, Florian Kuchenbauer, Anita Sarma, Takanori Teshima, Erika L. Pearce, Antonia M.S. Müller, Kathleen Stabla, John M. Magenau, Evelyn Ullrich, Nicolaus Kröger, Georg Häcker, Simone Thomas, Myriam Labopin, Ghulam J. Mufti, Jan E. Ehlert, Lutz P. Müller, Marie Follo, Dominik Wolf, Tony Andreas Müller, Michael Lübbert, Jacqueline Schnell, Christof Scheid, Takeshi Kondo, Donal P. McLornan, Thomas Pabst, Konrad Wilhelm, Chiara Bonini, Wolf Rösler, Simon Richardson, Cordula A. Jilg, Andrea Schmidts, Luca Vago, Joseph H. Antin, Annette Schmitt-Graeff, Yakup Tanriver, Michael A. Caligiuri, Wolfgang Herr, Kai-Li Yan, Lukas Braun, Daniel J. Weisdorf, Katayoun Rezvani, Giang Lam Vuong, Tilman Brummer, Stephan Meckel, Ralph Wäsch, Geoffroy Andrieux, Soroush Doostkam, Hauke Busch, Dennis Dong Hwan Kim, Sabine Gerull, Bruce R. Blazar, Robert Zeiser, Merav Bar, Flore Sicre-de-Fontbrune, Daniel Feger, Melanie Börries, Wolfgang Melchinger, Petya Apostolova, C. Leiber, Udo Holtick, Walter J.F.M. van der Velden, Renate Arnold, Rainer Claus, Justus Duyster, Nimitha R. Mathew, David O’Sullivan, Alexandros Spyridonidis, S K Metzelder, Thomas Schroeder, Jörg Halter, Johanna Haag, Friedrich Stölzel, Christoph Schmid, Anna Lena Illert, Claudia Lengerke, Björn Hackanson, Joern Dengjel, Francis Ayuk, Rainer Ordemann, Sonia Tugues, Marco Prinz, Inken Hilgendorf, Andreas Burchert, Mathew, Nimitha R, Baumgartner, Franci, Braun, Luka, O'Sullivan, David, Thomas, Simone, Waterhouse, Miguel, Müller, Tony A, Hanke, Kathrin, Taromi, Sanaz, Apostolova, Petya, Illert, Anna L, Melchinger, Wolfgang, Duquesne, Sandra, Schmitt-Graeff, Annette, Osswald, Lena, Yan, Kai-Li, Weber, Arnim, Tugues, Sonia, Spath, Sabine, Pfeifer, Dietmar, Follo, Marie, Claus, Rainer, Lübbert, Michael, Rummelt, Christoph, Bertz, Hartmut, Wäsch, Ralph, Haag, Johanna, Schmidts, Andrea, Schultheiss, Michael, Bettinger, Dominik, Thimme, Robert, Ullrich, Evelyn, Tanriver, Yakup, Vuong, Giang Lam, Arnold, Renate, Hemmati, Philipp, Wolf, Dominik, Ditschkowski, Marku, Jilg, Cordula, Wilhelm, Konrad, Leiber, Christian, Gerull, Sabine, Halter, Jörg, Lengerke, Claudia, Pabst, Thoma, Schroeder, Thoma, Kobbe, Guido, Rösler, Wolf, Doostkam, Soroush, Meckel, Stephan, Stabla, Kathleen, Metzelder, Stephan K, Halbach, Sebastian, Brummer, Tilman, Hu, Zehan, Dengjel, Joern, Hackanson, Björn, Schmid, Christoph, Holtick, Udo, Scheid, Christof, Spyridonidis, Alexandro, Stölzel, Friedrich, Ordemann, Rainer, Müller, Lutz P, Sicre-de-Fontbrune, Flore, Ihorst, Gabriele, Kuball, Jürgen, Ehlert, Jan E, Feger, Daniel, Wagner, Eva-Maria, Cahn, Jean-Yve, Schnell, Jacqueline, Kuchenbauer, Florian, Bunjes, Donald, Chakraverty, Ronjon, Richardson, Simon, Gill, Saar, Kröger, Nicolau, Ayuk, Franci, Vago, Luca, Ciceri, Fabio, Müller, Antonia M, Kondo, Takeshi, Teshima, Takanori, Klaeger, Susan, Kuster, Bernhard, Kim, Dennis Dong Hwan, Weisdorf, Daniel, van der Velden, Walter, Dörfel, Daniela, Bethge, Wolfgang, Hilgendorf, Inken, Hochhaus, Andrea, Andrieux, Geoffroy, Börries, Melanie, Busch, Hauke, Magenau, John, Reddy, Pavan, Labopin, Myriam, Antin, Joseph H, Henden, Andrea S, Hill, Geoffrey R, Kennedy, Glen A, Bar, Merav, Sarma, Anita, Mclornan, Donal, Mufti, Ghulam, Oran, Betul, Rezvani, Katayoun, Sha, Omid, Negrin, Robert S, Nagler, Arnon, Prinz, Marco, Burchert, Andrea, Neubauer, Andrea, Beelen, Dietrich, Mackensen, Andrea, von Bubnoff, Nikola, Herr, Wolfgang, Becher, Burkhard, Socié, Gerard, Caligiuri, Michael A, Ruggiero, Eliana, Bonini, Chiara, Häcker, Georg, Duyster, Justu, Finke, Jürgen, Pearce, Erika, Blazar, Bruce R, and Zeiser, Robert
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0301 basic medicine ,Sorafenib ,medicine.drug_class ,Interferon Regulatory Factor-7 ,Medizin ,Graft vs Host Disease ,CD8-Positive T-Lymphocytes ,Article ,General Biochemistry, Genetics and Molecular Biology ,Tyrosine-kinase inhibitor ,Mice ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Animals ,Humans ,Transplantation, Homologous ,Medicine ,ddc:610 ,neoplasms ,Interleukin-15 ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,General Medicine ,Cellular Reprogramming ,medicine.disease ,Activating Transcription Factor 4 ,3. Good health ,Gene Expression Regulation, Neoplastic ,Transplantation ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,Tandem Repeat Sequences ,Interleukin 15 ,030220 oncology & carcinogenesis ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,Cancer research ,IRF7 ,business ,CD8 ,medicine.drug - Abstract
Contains fulltext : 190745.pdf (Publisher’s version ) (Closed access) Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD(+) leukemia cells. This synergized with the allogeneic CD8(+) T cell response, leading to long-term survival in six mouse models of FLT3-ITD(+) AML. Sorafenib-related IL-15 production caused an increase in CD8(+)CD107a(+)IFN-gamma(+) T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD(+) AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8(+) T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.
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- 2018
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10. BCR-ABL1+ Acute Myeloid Leukemia: Clonal Selection of a BCR-ABL1- Subclone as a Cause of Refractory Disease with Nilotinib Treatment
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Jörg Westermann, Seval Türkmen, Renate Arnold, Michaela Schwarz, Bernd Dörken, Philipp Hemmati, Philipp le Coutre, Thomas Burmeister, Christiane Bommer, and Nina Rosa Neuendorff
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Myeloid ,business.industry ,Clone (cell biology) ,Myeloid leukemia ,Hematology ,General Medicine ,Disease ,medicine.disease ,Philadelphia chromosome ,humanities ,Leukemia ,medicine.anatomical_structure ,Nilotinib ,hemic and lymphatic diseases ,Immunology ,Cancer research ,Medicine ,business ,medicine.drug ,Clonal selection - Abstract
The presence of a Philadelphia chromosome with a corresponding BCR-ABL1 rearrangement is the hallmark of chronic myeloid leukemia, but is considered a very rare event in de novo acute myeloid leukemia (AML). Here, we report the first case in which a dominant Philadelphia chromosome-positive subclone was detected upon relapse in a formerly Philadelphia chromosome-negative MLL-AF6+ AML. Due to refractory disease under salvage chemotherapy, the patient was started on nilotinib treatment. As a result, the Philadelphia chromosome-positive subclone was eradicated within 1 month; however, disease progressed and was again dominated by the Philadelphia chromosome-negative founding clone, demonstrating rapid clonal expansion under nilotinib-induced selection pressure. © 2014 S. Karger AG, Basel
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- 2014
11. Pseudomonas aeruginosa Bloodstream Infections Presenting with Septic Shock in Neutropenic Cancer Patients: Impact of Empirical Antibiotic Therapy
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Cristina Royo-Cebrecos, Júlia Laporte-Amargós, Marta Peña, Isabel Ruiz-Camps, Carolina Garcia-Vidal, Edson Abdala, Chiara Oltolini, Murat Akova, Miguel Montejo, Malgorzata Mikulska, Pilar Martín-Dávila, Fabián Herrera, Oriol Gasch, Lubos Drgona, Hugo Manuel Paz Morales, Anne-Sophie Brunel, Estefanía García, Burcu Isler, Winfried V. Kern, Zaira R. Palacios-Baena, Guillermo Maestr de la Calle, Maria Milagro Montero, Souha S. Kanj, Oguz R. Sipahi, Sebnem Calik, Ignacio Márquez-Gómez, Jorge I. Marin, Marisa Z. R. Gomes, Philipp Hemmatii, Rafael Araos, Maddalena Peghin, Jose L. Del Pozo, Lucrecia Yáñez, Robert Tilley, Adriana Manzur, Andrés Novo, Jordi Carratalà, and Carlota Gudiol
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Pseudomonas aeruginosa ,bacteremia ,septic shock ,bloodstream infection ,neutropenia ,cancer ,Biology (General) ,QH301-705.5 - Abstract
This large, multicenter, retrospective cohort study including onco-hematological neutropenic patients with Pseudomonas aeruginosa bloodstream infection (PABSI) found that among 1213 episodes, 411 (33%) presented with septic shock. The presence of solid tumors (33.3% vs. 20.2%, p < 0.001), a high-risk Multinational Association for Supportive Care in Cancer (MASCC) index score (92.6% vs. 57.4%; p < 0.001), pneumonia (38% vs. 19.2% p < 0.001), and infection due to multidrug-resistant P. aeruginosa (MDRPA) (33.8% vs. 21.1%, p < 0.001) were statistically significantly higher in patients with septic shock compared to those without. Patients with septic shock were more likely to receive inadequate empirical antibiotic therapy (IEAT) (21.7% vs. 16.2%, p = 0.020) and to present poorer outcomes, including a need for ICU admission (74% vs. 10.5%; p < 0.001), mechanical ventilation (49.1% vs. 5.6%; p < 0.001), and higher 7-day and 30-day case fatality rates (58.2% vs. 12%, p < 0.001, and 74% vs. 23.1%, p < 0.001, respectively). Risk factors for 30-day case fatality rate in patients with septic shock were orotracheal intubation, IEAT, infection due to MDRPA, and persistent PABSI. Therapy with granulocyte colony-stimulating factor and BSI from the urinary tract were associated with improved survival. Carbapenems were the most frequent IEAT in patients with septic shock, and the use of empirical combination therapy showed a tendency towards improved survival. Our findings emphasize the need for tailored management strategies in this high-risk population.
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- 2024
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12. Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy
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Giang Lam Vuong, John A. Snowden, Wolfgang Köhler, Renate Arnold, Godfrey T. Gillett, Philipp Hemmati, Michael Stadler, Jörn-Sven Kühl, Felipe Suarez, and Patrick Aubourg
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Internal capsule ,Aftercare ,Disease ,Gastroenterology ,Severity of Illness Index ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Postoperative Complications ,Internal medicine ,Outcome Assessment, Health Care ,Medicine ,Humans ,Adrenoleukodystrophy ,Expanded Disability Status Scale ,business.industry ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Spinal cord ,medicine.disease ,Surgery ,Transplantation ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Disease Progression ,Feasibility Studies ,Neurology (clinical) ,Stem cell ,business ,030217 neurology & neurosurgery - Abstract
The adult cerebral inflammatory form of X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disease, as devastating as childhood cerebral adrenoleukodystrophy. Allogeneic haematopoietic stem cell transplantation has been demonstrated to provide long-term neurological benefits for boys with the childhood cerebral form, but results in adults are sparse and inconclusive. We analysed data from 14 adult males with adult cerebral adrenoleukodystrophy treated with allogeneic haematopoietic stem cell transplantation on a compassionate basis in four European centres. All presented with cerebral demyelinating lesions and gadolinium enhancement. Median age at diagnosis of adult cerebral adrenoleukodystrophy was 33 years (range 21-48 years). In addition to cerebral inflammation, five patients had established severe motor disability from adrenomyeloneuropathy affecting only the spinal cord and peripheral nerves (Expanded Disability Status Scale score ≥ 6). Eight patients survived (estimated survival 57 ± 13%) with a median follow-up of 65 months (minimum 38 months). Death was directly transplant-/infection-related (n = 3), due to primary disease progression in advanced adult cerebral adrenoleukodystrophy (n = 1), or secondary disease progression (n = 2) after transient multi-organ failure or non-engraftment. Specific complications during stem cell transplantation included deterioration of motor and bladder functions (n = 12) as well as behavioural changes (n = 8). Arrest of progressive cerebral demyelination and prevention of severe loss of neurocognition was achieved in all eight survivors, but deterioration of motor function occurred in the majority (n = 5). Limited motor dysfunction (Expanded Disability Status Scale score < 6) prior to transplantation was associated with significantly improved survival [78 ± 14% (n = 9) versus 20 ± 18%(n = 5); P < 0.05] and maintenance of ambulation (Expanded Disability Status Scale score < 7) post-transplant (78% versus 0%; P = 0.021). In contrast, bilateral involvement of the internal capsule on brain MRI was associated with poorer survival [20 ± 18% (n = 5) versus 78 ± 14% (n = 9); P < 0.05]. This study is the first to support the feasibility, complications and potential long-term neurological benefit of allogeneic haematopoietic stem cell transplantation in adult cerebral adrenoleukodystrophy. Further studies are warranted to attempt to improve outcomes through patient selection and optimization of transplantation protocols.
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- 2017
13. Cytogenetic risk grouping by the monosomal karyotype classification is superior in predicting the outcome of acute myeloid leukemia undergoing allogeneic stem cell transplantation in complete remission
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Philipp Hemmati, Renate Arnold, Bernd Dörken, Lam G. Vuong, Theis H. Terwey, Philipp le Coutre, and Anthea Schulze-Luckow
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Multivariate analysis ,Adolescent ,Karyotype ,Graft vs Host Disease ,Subgroup analysis ,Young Adult ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Prospective Studies ,Aged ,business.industry ,Incidence (epidemiology) ,Remission Induction ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,Surgery ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Female ,Stem cell ,business ,Follow-Up Studies ,Monosomal karyotype - Abstract
We retrospectively analyzed the impact of cytogenetic abnormalities grouped according to the monosomal karyotype (MK) classification or the Southwest Oncology/Eastern Cooperative Oncology Group (SWOG/ECOG) definition in 263 patients with acute myeloid leukemia (AML) who underwent allogeneic stem cell transplantation (alloSCT) in complete remission (CR) at our center. Risk grouping using the MK criteria shows a highly significant difference in 5-yr overall survival (OS) ranging between 67%, for the most favorable, and 32%, for the poorest risk group (P = 0.001). Although similarly precise in predicting OS, the MK scheme better separates patients with respect to relapse incidence as compared to the SWOG/ECOG grouping (P = 0.0001 vs. P = 0.01). Notably, patients displaying non-MK abnormalities (MK-) had a 5-yr relapse incidence identical to those cytogenetically normal (CN), that is 24%. Multivariate analysis revealed that the MK classification is an independent prognosticator and superior in predicting OS (hazard ratios, HR 3.74, P = 0.01) and relapse incidence (HR 3.74, P = 0.005) as compared to the SWOG/ECOG criteria. Finally, subgroup analysis revealed that the prognostic capacity of the MK classification is highly significant in patients treated with standard myeloablative conditioning prior to alloSCT (P = 0.0011 for OS, P = 0.0007 for relapse). In contrast, the MK grouping failed to predict OS or relapse incidence in patients treated with reduced intensity conditioning. Taken together, these results indicate that the MK classification is superior in predicting the overall outcome of patients with AML undergoing alloSCT in CR. Furthermore, our data suggest that the genetic risk profile of MK- and CN patients is mostly overlapping in this setting.
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- 2013
14. A Rare Case of Acute Myeloid Leukemia with a t(2;3) Chromosomal Translocation Characterized by Thrombophilia and Chemoresistance
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Gürkan Bal, Ulrich Richter, Philipp le Coutre, Hanno Riess, Philipp Hemmati, Carsten-Oliver Schulz, Cecilia Bozzetti, Lars Fransecky, Renate Arnold, and Seval Türkmen
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0301 basic medicine ,Blood Platelets ,Male ,Chromosomal translocation ,Thrombophilia ,Translocation, Genetic ,03 medical and health sciences ,Proto-Oncogenes ,Medicine ,Humans ,Platelet ,Genetics ,Thrombocytosis ,Case Study ,business.industry ,Platelet Count ,Myeloid leukemia ,General Medicine ,Anagrelide ,Middle Aged ,medicine.disease ,MDS1 and EVI1 Complex Locus Protein ,Transplantation ,DNA-Binding Proteins ,Leukemia, Myeloid, Acute ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,Cancer research ,Quinazolines ,Stem cell ,business ,Platelet Aggregation Inhibitors ,medicine.drug ,Stem Cell Transplantation ,Transcription Factors - Abstract
We hereby report a case of acute myeloid leukemia with translocation t(2;3) and involvement of the ectopic virus integration site-1 (EVI1) gene. Like most other 3q26-related disorders reported thus far, we describe a phenotype with elevated platelet counts and dysmegakaryopoesis. The clinical course of our patient was complicated by symptomatic thrombophilia and chemoresistance. In addition, our case exhibited FLT3 (Fms-related tyrosine kinase 3) internal tandem duplication. Although anagrelide was successful in controlling elevated platelet counts, allogeneic stem cell transplantation failed to overcome chemoresistance due to simultaneous graft-versus-host-disease and relapse of acute myeloid leukemia. Given the dismal outcome of our case and previously reported cases, we propagate the implementation of targeted therapies to newly diagnosed patients with acute myeloid leukemia t(2;3). Preclinical models indicate drugs that plausibly target the EVI1-related molecular vulnerability as candidates for basket trials. Anagrelide exhibited a hopeful signal of activity in 3q26-related thrombocytosis and should be evaluated for implementation as supportive care.
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- 2016
15. Biweekly Pegylated Liposomal Doxorubicin (Caelyx) in Heavily Pretreated Metastatic Breast Cancer: A Phase 2 Study
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Philipp Hemmati, Silvia Lehenbauer-Dehm, Bernd Flath, Peter Schmid, Christian Jehn, and Sherko Kümmel
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0301 basic medicine ,Adult ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Anthracycline ,medicine.medical_treatment ,Phases of clinical research ,Breast Neoplasms ,Vinorelbine ,Vinblastine ,Gastroenterology ,Disease-Free Survival ,Drug Administration Schedule ,Polyethylene Glycols ,Capecitabine ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Doxorubicin ,Anthracyclines ,Aged ,Chemotherapy ,Antibiotics, Antineoplastic ,business.industry ,Middle Aged ,medicine.disease ,Metastatic breast cancer ,Thrombocytopenia ,Cardiotoxicity ,Surgery ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Hand-Foot Syndrome ,Taxoids ,business ,medicine.drug - Abstract
Background Pegylated liposomal doxorubicin (PLD) has shown to be as effective as conventional doxorubicin in the treatment of metastatic breast cancer but provides a lower risk of cardiotoxicity. This phase 2 study in heavily pretreated patients with metastatic breast cancer was initiated to evaluate a biweekly instead of a 4-week schedule of PLD in order to obtain a more flexible and tolerable regimen. Patients and Methods A total of 25 patients with 2 or more prior lines of chemotherapy for metastatic disease were treated with PLD (25 mg/m 2 ) at 2-week intervals for a maximum of 12 courses. Pretreatment with anthracyclines was allowed as long as the cumulative doxorubicin dose at study entry was below 400 mg/m 2 . Most patients were pretreated with anthracyclines, taxanes, vinorelbine, alkylating agents, and capecitabine. Results The clinical benefit rate, ie, objective response or stable disease, for at least 6 months was 22.7% for all patients and 22.2% in anthracycline- and taxane-pretreated patients, respectively. Median duration of clinical benefit and median time to progression were 12.5 months (95% confidence interval [CI], 10.1-32.3) and 7 weeks (95% CI, 5.4-8.6), respectively. Median overall survival was 9.6 months (95% CI, 5.4-13.9). One- and 2-year survival rates were 38% and 4%, respectively. Myelosuppression was low, with no grade 3 or 4 neutropenia or thrombocytopenia. Most common nonhematologic toxicities were nausea, alopecia, asthenia, and hand–foot syndrome. The low rate of hematologic toxicity and hand–foot syndrome is clinically noteworthy. Conclusion Biweekly PLD is an easily manageable schedule with a favorable toxicity profile. Efficacy was moderate in heavily pretreated patients.
- Published
- 2015
16. A modified EBMT risk score predicts the outcome of patients with acute myeloid leukemia receiving allogeneic stem cell transplants
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Bernd Dörken, Gero Massenkeil, Theis H. Terwey, Lam G. Vuong, Philipp Hemmati, Renate Arnold, and Philipp le Coutre
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medicine.medical_specialty ,Univariate analysis ,Framingham Risk Score ,business.industry ,Incidence (epidemiology) ,Hazard ratio ,Hematology ,General Medicine ,Surgery ,Transplantation ,Internal medicine ,Cohort ,medicine ,Cumulative incidence ,Risk assessment ,business - Abstract
The systematic and standardized pretransplant risk assessment represents an important tool to predict the outcome of patients undergoing allogeneic stem cell transplantation (alloSCT). To investigate the capacity of a modified European group for blood and marrow transplantation (mEBMT) risk score to predict the outcome of patients with acute myeloid leukemia (AML) receiving allogeneic stem cell transplants, we retrospectively analyzed 214 patients transplanted at our center between 1995 and 2008. Overall survival (OS) of the whole cohort at 1, 3, and 5 yr was 62%, 48%, and 45%, whereas the cumulative incidence of relapse or non-relapse mortality (NRM) was 26%, 33%, and 33% or 19%, 21%, and 22%. In univariate analysis, a higher mEBMT risk score was associated with an inferior OS ranging from 69% for patients with a score of 0/1 to 26% for patients with a score of 5/6 at 5 yr (P
- Published
- 2011
17. Validation of the Human Activity Profile Questionnaire in Patients after Allogeneic Hematopoietic Stem Cell Transplantation
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Pia Heussner, Inken Hilgendorf, Philipp Hemmati, Mathias Freund, Stephanie von Harsdorf, Ernst Holler, Stephanie J. Lee, Philipp Yorck Herzberg, Hildegard T. Greinix, Kathrin Rieger, Daniel Wolff, Melanie Horak, and Friederike Mumm
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Psychometrics ,medicine.medical_treatment ,GVHD ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Hospital Anxiety and Depression Scale ,Human Activity Profile ,Young Adult ,Quality of life ,immune system diseases ,Surveys and Questionnaires ,hemic and lymphatic diseases ,Internal medicine ,Activities of Daily Living ,medicine ,Humans ,Prospective Studies ,Young adult ,Prospective cohort study ,Aged ,Language ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Clinical trial ,Treatment Outcome ,Allogeneic hematopoietic stem cell transplantation ,Quality of Life ,Physical therapy ,Female ,business - Abstract
Chronic graft-versus-host disease (cGVHD) associated morbidity and mortality remain major barriers for successful allogeneic hematopoietic stem cell transplantation (alloHSCT). Currently, no reliable measures are established to monitor cGVHD activity changes for use in clinical trials. The Human Activity Profile (HAP) patient self-report was proposed by the National Institutes of Health (NIH) cGVHD consensus project as an independent measure of patients' functional status that could also indirectly reflect improvement of cGVHD, but that has not been validated in an alloHSCT patient population. One hundred seventy-six patients (median age 44 years [range: 18-72 years] after alloHSCT were evaluated with a German translation of the HAP, the NIH criteria-based cGVHD activity assessment, the Lee cGVHD Symptom-Scale, FACT-BMT, SF36, Berlin Social Support Scale, 24-Item Adjective Measure (24-AM), Hospital Anxiety and Depression Scale, and the NCCN-Distress-Thermometer. Enrollment occurred a median of 286 (range: 85-4003) days after alloHSCT. Follow-up surveys were conducted at 1, 2, 3, 5, 8, and 12 months after the baseline survey. Although 117 patient had cGVHD at time of enrollment (mild n = 33, moderate n = 50, or severe n = 34), 59 patients were included into the study in the absence of cGVHD between days 85 and 395 after transplantation. The maximum activity score (MAS) and adjusted activity score (AAS) of the HAP correlated inversely with grading of cGVHD severity (mild, moderate, or severe) (r = −0.25 for MAS and −0.24 for AAS). Lung manifestations of cGVHD correlated with AAS (r = 0.17), but not with MAS. HAP scores correlated with subscales from other instruments measuring physical domains, especially the physical functioning scale of the SF36. Performance was improved by use of an HSCT-modified HAP scoring system that excluded activities prohibited within the first year after alloHSCT. No significant correlation of the HAP was found with personality, age, sex, symptom burden, or social functioning or social well-being. Moreover, the HAP displayed a higher sensitivity to change of cGVHD activity compared to the SF36 and the FACT-BMT. In addition, steroid myopathy correlated with both HAP scores, but not the SF36. The HAP is a simple and valid questionnaire for the evaluation of the physical activity in patients after alloHSCT, with the advantage of detecting changes in cGVHD status independently of other quality-of-life measures and with a superior sensitivity compared to the SF36.
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- 2010
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18. Erratum: Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells
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Nimitha R Mathew, Francis Baumgartner, Lukas Braun, David O'Sullivan, Simone Thomas, Miguel Waterhouse, Tony A Müller, Kathrin Hanke, Sanaz Taromi, Petya Apostolova, Anna L Illert, Wolfgang Melchinger, Sandra Duquesne, Annette Schmitt-Graeff, Lena Osswald, Kai-Li Yan, Arnim Weber, Sonia Tugues, Sabine Spath, Dietmar Pfeifer, Marie Follo, Rainer Claus, Michael Lübbert, Christoph Rummelt, Hartmut Bertz, Ralph Wäsch, Johanna Haag, Andrea Schmidts, Michael Schultheiss, Dominik Bettinger, Robert Thimme, Evelyn Ullrich, Yakup Tanriver, Giang Lam Vuong, Renate Arnold, Philipp Hemmati, Dominik Wolf, Markus Ditschkowski, Cordula Jilg, Konrad Wilhelm, Christian Leiber, Sabine Gerull, Jörg Halter, Claudia Lengerke, Thomas Pabst, Thomas Schroeder, Guido Kobbe, Wolf Rösler, Soroush Doostkam, Stephan Meckel, Kathleen Stabla, Stephan K Metzelder, Sebastian Halbach, Tilman Brummer, Zehan Hu, Joern Dengjel, Björn Hackanson, Christoph Schmid, Udo Holtick, Christof Scheid, Alexandros Spyridonidis, Friedrich Stölzel, Rainer Ordemann, Lutz P Müller, Flore Sicre-de-Fontbrune, Gabriele Ihorst, Jürgen Kuball, Jan E Ehlert, Daniel Feger, Eva-Maria Wagner, Jean-Yves Cahn, Jacqueline Schnell, Florian Kuchenbauer, Donald Bunjes, Ronjon Chakraverty, Simon Richardson, Saar Gill, Nicolaus Kröger, Francis Ayuk, Luca Vago, Fabio Ciceri, Antonia M Müller, Takeshi Kondo, Takanori Teshima, Susan Klaeger, Bernhard Kuster, Dennis Kim, Daniel Weisdorf, Walter van der Velden, Daniela Dörfel, Wolfgang Bethge, Inken Hilgendorf, Andreas Hochhaus, Geoffroy Andrieux, Melanie Börries, Hauke Busch, John Magenau, Pavan Reddy, Myriam Labopin, Joseph H Antin, Andrea S Henden, Geoffrey R Hill, Glen A Kennedy, Merav Bar, Anita Sarma, Donal McLornan, Ghulam Mufti, Betul Oran, Katayoun Rezvani, Omid Shah, Robert S Negrin, Arnon Nagler, Marco Prinz, Andreas Burchert, Andreas Neubauer, Dietrich Beelen, Andreas Mackensen, Nikolas von Bubnoff, Wolfgang Herr, Burkhard Becher, Gerard Socié, Michael A Caligiuri, Eliana Ruggiero, Chiara Bonini, Georg Häcker, Justus Duyster, Jürgen Finke, Erika Pearce, Bruce R Blazar, and Robert Zeiser
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General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 2018
19. BCR-ABL positive cells and chronic myeloid leukemia in immune suppressed organ transplant recipients
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Philipp le Coutre, Petra Reinke, Ralf Trappe, Ruth Neuhaus, Philipp Hemmati, Marc Lalancette, Frauke Ringel, Bernd Dörken, and Peter T. Daniel
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medicine.medical_specialty ,education.field_of_study ,Population ,Clone (cell biology) ,Myeloid leukemia ,Chromosomal translocation ,Hematology ,General Medicine ,Biology ,Fusion protein ,Organ transplantation ,Immune system ,hemic and lymphatic diseases ,Immunology ,medicine ,education ,Tyrosine kinase - Abstract
The constitutively activated tyrosine kinase activity of the p210bcr-abl fusion protein, generated by a t(9;22)(q34;q11) chromosomal translocation, is pathogenetically associated with chronic myeloid leukemia (CML). However, mechanisms contributing to the expansion of a BCR-ABL positive clone are largely obscure. In the presence of an impaired immune surveillance, cells carrying any of these alterations may become phenotypically relevant. Therefore, immunosuppressed solid organ recipients represent an optimal population to investigate the frequency of mRNA products of this translocation. Blood leukocytes were studied in 201 individuals (100 organ recipients and 101 control individuals) for the presence of BCR-ABL transcripts by a nested-reverse transcriptase-polymerase chain reaction assay, routinely used in our institution. In 5/100 immunosuppressed patients, at least one out of two RT-PCR products was bcr-abl positive while all controls were negative. These findings were extended by four CML cases of organ transplant recipients (three renal and one liver transplants). Three of these cases developed CML in a total of 2088 transplantations in 9 yr, suggesting a higher incidence of CML in these patients.
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- 2010
20. A modified EBMT risk score and the hematopoietic cell transplantation-specific comorbidity index for pre-transplant risk assessment in adult acute lymphoblastic leukemia
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Bernd Dörken, Ekkehart Dietz, Renate Arnold, Gero Massenkeil, Peter Martus, Philipp Hemmati, Theis H. Terwey, and Lam G. Vuong
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,Comorbidity ,Hematopoietic stem cell transplantation ,Risk Assessment ,Cohort Studies ,Young Adult ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,Preoperative Care ,Humans ,Medicine ,Karnofsky Performance Status ,Aged ,Retrospective Studies ,Framingham Risk Score ,Performance status ,business.industry ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Histocompatibility ,Surgery ,Transplantation ,Research Design ,Adult Acute Lymphoblastic Leukemia ,Original Article ,Female ,business ,Follow-Up Studies - Abstract
Disease stage is the most important prognostic parameter in allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia, but other factors such as donor/host histocompatibility and gender combination, recipient age, performance status and comorbidities need to be considered. Several scoring systems are available to predict outcome in HCT recipients; however, their prognostic relevance in acute lymphoblastic leukemia is not well defined.In the present study we evaluated a modified EBMT risk score (mEBMT) and the HCT-specific comorbidity index (HCT-CI) in 151 adult acute lymphoblastic leukemia patients who received allogeneic HCT from 1995 until 2007 at our center.Disease status was first complete remission (CR1) (47%), CR1 (21%) or no CR (32%). Overall survival (OS) at one, two and five years was 62%, 51% and 40% and non-relapse mortality (NRM) was 21%, 24% and 32%. Median mEBMT was 3 (0-6). Higher mEBMT was associated with inferior OS (hazard ratio per score unit (HR): 1.50, P0.001), higher NRM (HR: 1.36, P=0.042) and higher relapse mortality (HR: 1.68, P0.001). Disease stage was the predominant prognostic factor in this score. Comorbidities were present in 71% of patients with mild hepatic disease (29%), moderate pulmonary disease (28%) and infections (23%) being the most common. Median HCT-CI was 1 (0-9). In univariate analysis a trend for inferior OS (HR: 1.08, P=0.20) and higher NRM (HR: 1.14, P=0.11) with increasing HCT-CI was observed but the level of significance was not reached. In additional analyses we found that reduced Karnofsky Performance Status (KPS) was associated with inferior OS (HR: 1.34, P=0.023) and higher relapse mortality (HR: 1.71, P=0.001) when analyzed univariately. However, KPS was associated with disease stage and significance was lost in multivariate analysis.The mEBMT was prognostic in our patient cohort with predominant influence of disease stage, whereas a trend but no significant prognostic value was observed for the HCT-CI.
- Published
- 2009
21. Cooperative effect of p21Cip1/WAF−1 and 14-3-3σ on cell cycle arrest and apoptosis induction by p14ARF
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Bernhard Gillissen, Philipp Hemmati, Peter T. Daniel, Bernd Dörken, Jana Wendt, and Guillaume Normand
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Cyclin-Dependent Kinase Inhibitor p21 ,Exonucleases ,G2 Phase ,Cancer Research ,Cell cycle checkpoint ,Apoptosis ,DNA Fragmentation ,Cyclin B ,Biology ,Mice ,p14arf ,Cell Line, Tumor ,CDC2 Protein Kinase ,Tumor Suppressor Protein p14ARF ,Biomarkers, Tumor ,Genetics ,Animals ,Humans ,CHEK1 ,Molecular Biology ,Mitotic catastrophe ,Mitosis ,Cyclin-dependent kinase 1 ,G1 Phase ,Cytochromes c ,Cell cycle ,Cyclin-Dependent Kinases ,Mitochondria ,Neoplasm Proteins ,Cell biology ,14-3-3 Proteins ,Caspases ,Exoribonucleases ,Cancer research ,Tumor Suppressor Protein p53 ,DNA Damage - Abstract
P14(ARF) (p19(ARF) in the mouse) plays a central role in the regulation of cellular proliferation. Although the capacity of p14(ARF) to induce a cell cycle arrest in G1 phase depends on a functional p53/p21-signaling axis, the G2 arrest triggered by p14(ARF) is p53/p21-independent. Using isogeneic HCT116 cells either wild-type or homozygously deleted for p21, 14-3-3sigma or both, we further investigated the cooperative effect of p21 and 14-3-3sigma on cell cycle regulation and apoptosis induction by p14(ARF). In contrast to DNA damage, which induces mitotic catastrophe in 14-3-3sigma-deficient cells, we show here that the expression of p14(ARF) triggers apoptotic cell death, as evidenced by nuclear DNA fragmentation and induction of pan-caspase activities, irrespective of the presence or absence of 14-3-3sigma. The activation of the intrinsic mitochondrial apoptosis pathway by p14(ARF) was confirmed by cytochrome c release from mitochondria and induction of caspase-9- (LEHDase) and caspase-3/7-like (DEVDase) activities. Moreover, 14-3-3sigma/p21 double-deficient cells were exceedingly sensitive to apoptosis induction by p14(ARF) as compared to wild-type cells or cells lacking either gene alone. Notably, p14(ARF)-induced apoptosis was preceded by an arrest in the G2 phase of cell cycle, which coincided with downregulation of cdc2 (cdk1) protein expression and lack of its nuclear localization. This indicates that p14(ARF) impairs mitotic entry by targeting the distal DNA damage-signaling pathway and induces apoptotic cell death, rather than mitotic catastrophe, out of a transient G2 arrest. Furthermore, our data delineate that the disruption of G2/M cell cycle checkpoint control critically determines the sensitivity of the cell toward p14(ARF)-induced mitochondrial apoptosis.
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- 2008
22. Apoptosis Susceptibility Prolongs the Lack of Memory B Cells in Acute Leukemic Patients After Allogeneic Hematopoietic Stem Cell Transplantation
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Carmen Scheibenbogen, Henning Göldner, Bernd Dörken, Youngseong Oh, Christian Jehn, Martin Szyska, Angela Mensen, Jörg Westermann, Renate Arnold, Philipp Hemmati, Sonya C. Becker, and Il-Kang Na
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Adult ,Male ,Receptors, CXCR5 ,Transplantation Conditioning ,medicine.medical_treatment ,Primary Cell Culture ,B-Lymphocyte Subsets ,Gene Expression ,Receptors, Antigen, B-Cell ,Apoptosis ,Hematopoietic stem cell transplantation ,T-Lymphocyte Subsets ,medicine ,Humans ,Transplantation, Homologous ,Lymphocyte Count ,CD40 Antigens ,Transplantation ,CD40 ,biology ,business.industry ,Histocompatibility Testing ,breakpoint cluster region ,Hematopoietic Stem Cell Transplantation ,Germinal center ,Immunosuppression ,Hematology ,HLA-DR Antigens ,Immunoglobulin D ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,B cell intrinsic and germinal center defects ,Tumor Necrosis Factor Receptor Superfamily, Member 7 ,Long-term memory B cell paucity ,Immunosurveillance ,Leukemia, Myeloid, Acute ,Case-Control Studies ,Toll-Like Receptor 9 ,Allogeneic hematopoietic stem cell transplantation ,Immunology ,biology.protein ,Female ,business ,Unrelated Donors ,Immunologic Memory ,Biomarkers - Abstract
Long-term survival after allogeneic hematopoietic stem cell transplantation requires intact immunosurveillance, which is hampered by lymphoid organ damage associated with conditioning therapy, graft-versus-host disease, and immunosuppression. Our study aimed to identify the mechanisms contributing to sustained low memory B cell numbers after transplantation. Peripheral B and T cell subset recovery and functional marker expression were investigated in 35 acute leukemic patients up to 1 year after transplantation. Apoptosis of B cells after CD40/TLR-9, CD40/BCR, and CD40/BCR/TLR-9-dependent stimulation and drug efflux capacity were analyzed. One half of the patients suffered from infections after day 180. All patients had strongly diminished CD27+ memory B cells despite already normalized total B cell numbers and fully recovered CD27−IgD− memory B cells, putatively of extra-follicular origin. Circulating memory follicular helper T cells were reduced in the majority of patients as well. Naive B cells exhibited a decreased expression of CXCR5, which mediates follicular B cell entry. Additionally, a lower HLA-DR expression was found on naive B cells, impairing antigen presentation. Upon CD40/TLR-9–dependent activation, B cells underwent significantly increased apoptosis paralleled by an aberrant up-regulation of Fas-L on activated T cells and Fas on resting B cells. Significantly increased B cell apoptosis was also observed after CD40/BCR and CD40/BCR/TLR-9–dependent activation. Drug efflux capacity of naive B cells was diminished in cyclosporin A–treated patients, additionally contributing to an apoptosis-prone phenotype. We conclude that B cell survival and migration and T cell communication defects are contributing candidates for an impaired germinal center formation of memory B cells after allogeneic hematopoietic stem cell transplantation. Follow-up studies should evaluate effectiveness of revaccinations on the cellular level and should address the long-term sequelae of B cell defects after transplantation.
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- 2015
23. Prolonged Stimulation-Induced Pro-Apoptotic B Cells and Deficits in the Germinal Center Formation of Memory B Cells within One Year after Allogeneic HSCT
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Philipp Hemmati, Jörg Westermann, Renate Arnold, Il-Kang Na, Bernd Dörken, Angela Mensen, Youngseong Oh, Carmen Scheibenbogen, Lam G. Vuong, and Christian Jehn
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medicine.medical_specialty ,Transplantation ,business.industry ,Germinal center ,Hematology ,Gastroenterology ,Bone transplantation ,Apoptosis ,Internal medicine ,Allogeneic hsct ,Viral studies ,Cohort ,Overall survival ,Medicine ,Prolonged stimulation ,business - Abstract
s / Biol Blood Marrow Transplant 21 (2015) S147eS170 S167 overall survival (OS) was 54% (95% CI, 41e66%) for the entire cohort with an OS for NNGF of 73% (95% CI, 55 e 85%) and for NGF OS was 30% (95% CI, 14e47%) (p
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- 2015
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24. Up-regulated MSI2 is associated with more aggressive chronic myeloid leukemia
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Jaspal Kaeda, Robert Slany, Rolf Schwarzer, Martin Gresse, Philipp le Coutre, Anne Carson, Elisabetta Vagge, Frauke Ringel, Fabrizio Pane, Franziska Jundt, Thomas Burmeister, Michaela Schwarz, Ken I. Mills, Jörg Westermann, Giuseppe Saglio, Concetta Quintarelli, Anna Serra, Bernd Dörken, Leila Amini, Philipp Hemmati, Christian Oberender, Antje van Lessen, Steffen Koschmieder, Kaeda, J, Ringel, F, Oberender, C, Mills, K, Quintarelli, Concetta, Pane, Fabrizio, Koschmieder, S, Slany, R, Schwarzer, R, Saglio, G, Hemmati, P, van Lessen, A, Amini, L, Greese, M, Vagge, E, Burmeister, T, Serra, A, Carson, A, Schwarz, M, Westermann, J, Jundt, F, D?rken, B, and le Coutre, P.
- Subjects
Myeloid ,Male ,Oncology ,Cancer Research ,bcr-abl ,Messenger ,Fusion Proteins, bcr-abl ,Regulator ,Disease ,MSI2 ,Immunoenzyme Techniques ,hemic and lymphatic diseases ,80 and over ,Medicine ,HES1 ,Child ,Leukemic ,Aged, 80 and over ,Leukemia ,Stem cell ,Gene Expression Regulation, Leukemic ,Reverse Transcriptase Polymerase Chain Reaction ,RNA-Binding Proteins ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,Up-Regulation ,Survival Rate ,Leukemia, Myeloid, Chronic-Phase ,Disease Progression ,Female ,Signal Transduction ,Adult ,medicine.medical_specialty ,Adolescent ,Real-Time Polymerase Chain Reaction ,Transformation ,Young Adult ,Downregulation and upregulation ,Internal medicine ,Humans ,RNA, Messenger ,Aged ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Significant difference ,Fusion Proteins ,Hematopoietic Stem Cells ,medicine.disease ,Gene Expression Regulation ,Immunology ,RNA ,Chronic-Phase ,Follow-Up Studies ,business - Abstract
A better understanding of events triggering chronic myeloid leukemia progression is critical for optimized clinical management of chronic myeloid leukemia (CML). We sought to validate that increased expression of Musashi 2 (MSI2), a post-transcription regulator, is associated with progression and prognosis. Screening of 152 patients with CML showed that MSI2 was significantly decreased among patients with CML in chronic phase (CP) at diagnosis (p < 0.0001), but found no significant difference between the normal control group and treated patients with CML in CP. Moreover MSI2 was significantly increased (p < 0.0001) in patients with advance disease (AD) CML. Furthermore, our human hematopoietic cell line data imply that MSI2 and BCR-ABL1 mRNA expression are correlated. However, these data cast a doubt on earlier reports that MSI2 effects HES1 expression via NUMB-NOTCH signaling.
- Published
- 2015
25. Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells
- Author
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Jana Wendt, C von Haefen, Bernd Dörken, Peter T. Daniel, Bernhard Gillissen, Philipp Hemmati, Dilek Güner, and G. Chinnadurai
- Subjects
Cancer Research ,Programmed cell death ,Cell Survival ,Apoptosis ,Models, Biological ,Mitochondrial apoptosis-induced channel ,DU145 ,p14arf ,Tumor Suppressor Protein p14ARF ,Tumor Cells, Cultured ,Genetics ,Humans ,Clonogenic assay ,Molecular Biology ,bcl-2-Associated X Protein ,Caspase 7 ,Gene knockdown ,biology ,Caspase 3 ,Cytochrome c ,Apoptosis Inducing Factor ,Genes, p53 ,HCT116 Cells ,Caspase 9 ,Mitochondria ,Cell biology ,bcl-2 Homologous Antagonist-Killer Protein ,Caspases ,Cancer research ,biology.protein ,biological phenomena, cell phenomena, and immunity - Abstract
In contrast to the initial notion that the biological activity of p14(ARF) strictly depends on a functional mdm-2/p53 signaling axis, we recently demonstrated that p14(ARF) mediates apoptosis in a p53/Bax-independent manner. Here, we show that p14(ARF) induces breakdown of the mitochondrial membrane potential and cytochrome c release before triggering caspase-9- and caspase-3/7-like activities in p53/Bax-deficient DU145 prostate cancer cells expressing wild-type Bak. Re-expression of Bax in these cells failed to further enhance p14(ARF)-induced apoptosis, suggesting that p14(ARF)-induced apoptosis primarily depends on Bak but not Bax in these cells. To further define the role of Bak and Bax in p14(ARF)-induced mitochondrial apoptosis, we employed short interference RNA for the knockdown of bak in isogeneic, p53 wild-type HCT116 colon cancer cells either proficient or deficient for Bax. There, combined loss of Bax and Bak attenuated p14(ARF)-induced apoptosis whereas single loss of Bax or Bak was only marginally effective, as in the case of DU145. Notably, HCT116 cells deficient for Bax and Bak failed to release cytochrome c and showed attenuated activation of caspase-9 (LEHDase) and caspase-3/caspase-7 (DEVDase) upon p14(ARF) expression. These data indicate that p14(ARF) triggers apoptosis via a Bax/Bak-dependent pathway in p53-proficient HCT116, whereas Bax is dispensable in p53-deficient DU145 cells. Nevertheless, a substantial proportion of p14(ARF)-induced cell death proceeds in a Bax/Bak-independent manner. This is also the case for inhibition of clonogenic growth that occurs, at least in part, through an entirely Bax/Bak-independent mechanism.
- Published
- 2006
26. Allogeneic stem cell transplantation for refractory acute myeloid leukemia: a single center analysis of long-term outcome
- Author
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Bernd Dörken, Christian Jehn, Theis H. Terwey, Philipp le Coutre, Lam G. Vuong, Philipp Hemmati, Renate Arnold, and Il-Kang Na
- Subjects
Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Graft vs Host Disease ,Disease ,Kaplan-Meier Estimate ,Single Center ,Blast Count ,Gastroenterology ,Young Adult ,Refractory ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Transplantation, Homologous ,Aged ,Retrospective Studies ,Salvage Therapy ,business.industry ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,General Medicine ,Middle Aged ,Tissue Donors ,Surgery ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Drug Resistance, Neoplasm ,Female ,Stem cell ,business ,Follow-Up Studies - Abstract
For patients with refractory acute myeloid leukemia (AML) allogeneic stem cell transplantation (alloSCT) represents the only curative approach. We here analyzed the long-term outcome of 131 consecutive patients with active AML, which was either primary refractory or unresponsive to salvage chemotherapy, transplanted at our center between 1997 and 2013. After a median follow-up of 48 months for the surviving patients, disease-free survival (DFS) at 5 years post alloSCT was 26% (94% CI: 17-35%). Relapses, most of which occurred within the first 2 years from transplant, were the predominant cause of treatment failure affecting 48% (95% CI: 40-58%) of patients, whereas non-relapse mortality was 26% (95% CI: 20-36%) at 5 years and thereafter. A marrow blast count ≥20% before alloSCT was an independent prognosticator associated with an inferior DFS (HR: 1.58, p=0.027), whereas the development of chronic graft-versus-host disease (cGvHD) predicted an improved DFS (HR 0.21, p
- Published
- 2014
27. TRAIL sensitizes for ionizing irradiation-induced apoptosis through an entirely Bax-dependent mitochondrial cell death pathway
- Author
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Clarissa von Haefen, Peter T. Daniel, Jana Wendt, Philipp Hemmati, Claus Belka, and Bernd Dörken
- Subjects
Male ,Cancer Research ,Programmed cell death ,Cell Membrane Permeability ,DNA damage ,Apoptosis ,Mitochondrion ,Biology ,medicine.disease_cause ,TNF-Related Apoptosis-Inducing Ligand ,DU145 ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Receptor ,Molecular Biology ,bcl-2-Associated X Protein ,Membrane Glycoproteins ,Cell Death ,Tumor Necrosis Factor-alpha ,Prostatic Neoplasms ,Intracellular Membranes ,Mitochondria ,Cell biology ,Proto-Oncogene Proteins c-bcl-2 ,Gamma Rays ,Cancer cell ,Apoptosis Regulatory Proteins ,Carcinogenesis ,Signal Transduction - Abstract
The death ligand TRAIL has been suggested as a suitable biological agent for the selective induction of cell death in cancer cells. Moreover, TRAIL synergizes with DNA-damaging therapies such as chemotherapeutic drugs or ionizing irradiation (IR). Here, we show that synergy of TRAIL and IR, that is, crosssensitization between TRAIL and IR for induction of apoptosis, entirely depends on Bax proficiency in human DU145 and HCT116 carcinoma cells. DU145 prostate carcinoma cells that have lost Bax protein expression due to mutation fail to activate caspase-3 and -9 when exposed to TRAIL and IR. In contrast, TRAIL sensitized for IR-induced apoptosis and vice versa upon reconstitution of Bax expression. Notably, both DU145 and HCT116 still express significant levels of the multidomain proapoptotic Bcl-2 homolog Bak. This indicates that Bak is not sufficient to mediate crosssensitization and synergism between IR and TRAIL. These data clearly establish distinct roles for Bax and Bak in linking the TRAIL death receptor pathway to the mitochondrial apoptosis signaling cascade upon DNA damage by IR.
- Published
- 2005
28. Loss of p21 disrupts p14ARF-induced G1 cell cycle arrest but augments p14ARF-induced apoptosis in human carcinoma cells
- Author
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Jana Wendt, Peter T. Daniel, Guillaume Normand, Clarissa von Haefen, Dilek Güner, Bernd Dörken, Berlinda Verdoodt, Philipp Hemmati, and Anne Hasenjäger
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,Cancer Research ,Cell cycle checkpoint ,Tumor suppressor gene ,Genetic Vectors ,Apoptosis ,Cell Cycle Proteins ,Biology ,Kidney ,Adenoviridae ,Cell Line ,p14arf ,Cell Line, Tumor ,Tumor Suppressor Protein p14ARF ,Genetics ,Humans ,Molecular Biology ,Carcinoma ,Cell Cycle ,G1 Phase ,Cell cycle ,Bromodeoxyuridine ,Caspases ,Cancer research ,Colorectal Neoplasms ,A431 cells ,G1 phase ,Restriction point ,Gene Deletion - Abstract
The human INK4a locus encodes two structurally unrelated tumor suppressor proteins, p16 INK4a and p14 ARF (p19 ARF in the mouse), which are frequently inactivated in human cancer. Both the proapoptotic and cell cycle-regulatory functions of p14 ARF were initially proposed to be strictly dependent on a functional p53/mdm-2 tumor suppressor pathway. However, a number of recent reports have implicated p53-independent mechanisms in the regulation of cell cycle arrest and apoptosis induction by p14 ARF. Here, we show that the G1 cell cycle arrest induced by p14 ARF entirely depends on both p53 and p21 in human HCT116 and DU145 carcinoma cells. In contrast, neither loss of p53 nor p21 impaired apoptosis induction by p14 ARF as evidenced by nuclear DNA fragmentation, phosphatidyl serine exposure, and caspase activation, which included caspase-3/7- and caspase-9-like activities. However, lack of functional p21 resulted in the accumulation of cells in G2/M phase of the cell cycle and markedly enhanced p14 ARF-induced apoptosis that was, nevertheless, efficiently inhibited by the cell permeable broad-spectrum caspase inhibitor zVAD-fmk (valyl-alanyl-aspartyl-(O)-methyl)-fluoromethylketone). Thus, loss of cell cycle restriction point control in the absence of p21 may interfere with p14 ARF-induced apoptosis. Finally, these data indicate that the signaling events required for G1 cell cycle arrest and apoptosis induction by p14 ARF dissociate upstream of p53.
- Published
- 2005
29. p14ARF Induces G2 Cell Cycle Arrest in p53- and p21-deficient Cells by Down-regulating p34cdc2 Kinase Activity
- Author
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Bernd Dörken, Guillaume Normand, Jana Wendt, Berlinda Verdoodt, Philipp Hemmati, Peter T. Daniel, Clarissa von Haefen, Dilek Güner, and Evelyne May
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,G2 Phase ,Down-Regulation ,Cell Cycle Proteins ,Biology ,Biochemistry ,p14arf ,Cell Line, Tumor ,CDC2 Protein Kinase ,Tumor Suppressor Protein p14ARF ,Humans ,cdc25 Phosphatases ,Phosphorylation ,Kinase activity ,Molecular Biology ,Mitosis ,Cell Proliferation ,Regulation of gene expression ,Cyclin-dependent kinase 1 ,Cell growth ,Kinase ,Cell Cycle ,Cell Biology ,Cell cycle ,Cell biology ,Gene Expression Regulation, Neoplastic ,Tumor Suppressor Protein p53 - Abstract
The human INK4a gene locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p14(ARF). Although primarily proposed to require a functional p53.Mdm-2 signaling axis, recently p14(ARF) has been implicated in p53-independent cell cycle regulation. Here we show that p14(ARF) preferentially induces a G(2) arrest in tumor cells lacking functional p53 and/or p21. Expression of p14(ARF) impaired mitotic entry and enforced a primarily cytoplasmic localization of p34(cdc2) that was associated with a decrease in p34(cdc2) kinase activity and reduced p34(cdc2) protein expression. A direct physical interaction between p14(ARF) and p34(cdc2) was, nevertheless, ruled out by lack of co-immunoprecipitation. The p14(ARF)-induced depletion of p34(cdc2) was associated with impaired cdc25C phosphatase expression and a prominent shift to inhibitory Tyr-15-phosphorylation in G(2)-arrested cells lacking either p53, p21, or both. Finally, reconstitution of p34(cdc2) using a constitutively active, phosphorylation-deficient p34(cdc2AF) mutant alleviated this p14(ARF)-induced G(2) arrest, thereby allowing cell cycle progression. Taken together, these data indicate that p14(ARF) arrests cells lacking functional p53/p21 in the G(2) phase of the cell cycle by targeting p34(cdc2) kinase. This may represent an important fail-safe mechanism by which p14(ARF) protects p53/p21-deficient cells from unrestrained proliferation.
- Published
- 2005
30. Multidomain Bcl-2 homolog Bax but not Bak mediates synergistic induction of apoptosis by TRAIL and 5-FU through the mitochondrial apoptosis pathway
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Claus Belka, Alicja Mrozek, Jana Wendt, Bernd Dörken, Peter T. Daniel, Clarissa von Haefen, Dilek Güner, Bernhard Gillissen, and Philipp Hemmati
- Subjects
Male ,Cancer Research ,Programmed cell death ,Blotting, Western ,Apoptosis ,Mitochondrion ,medicine.disease_cause ,TNF-Related Apoptosis-Inducing Ligand ,DU145 ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Receptor ,Molecular Biology ,bcl-2-Associated X Protein ,Mutation ,Membrane Glycoproteins ,biology ,Tumor Necrosis Factor-alpha ,Cytochrome c ,Cytochromes c ,Membrane Proteins ,Cell biology ,Enzyme Activation ,bcl-2 Homologous Antagonist-Killer Protein ,Proto-Oncogene Proteins c-bcl-2 ,Caspases ,biology.protein ,Fluorouracil ,biological phenomena, cell phenomena, and immunity ,Apoptosis Regulatory Proteins ,Carcinogenesis - Abstract
The death ligand TRAIL synergizes with DNA-damaging therapies such as chemotherapeutic drugs or ionizing irradiation. Here, we show that the synergism of TRAIL and 5-fluorouracil (5-FU) and cross-sensitization between TRAIL and 5-FU for induction of apoptosis, entirely depend on Bax proficiency in human DU145 and HCT116 carcinoma cells. DU145 prostate carcinoma cells that have lost Bax protein expression due to mutation fail to release cytochrome c and to activate caspase-3 and -9 when exposed to TRAIL and 5-FU. In contrast, TRAIL sensitized for 5-FU-induced apoptosis and vice versa upon reconstitution of Bax expression. Isobolographic analyses of ED50 doses for 5-FU at increasing TRAIL concentrations showed a clear synergism of TRAIL and 5-FU in Bax-expressing cells. In contrast, the effect was merely additive in DU145 cells lacking Bax. Notably, both DU145 and HCT116 Bax-deficient cells still express Bak. This indicates that Bak is not sufficient to mediate cross-sensitization and synergism between 5-FU and TRAIL. Stable overexpression of Bak in DU145 sensitized for epirubicin-induced apoptosis but failed to confer synergy between TRAIL and 5-FU. Moreover, we show by the use of EGFP-tagged Bax and Bak that TRAIL and 5-FU synergistically trigger oligomerization and clustering of Bax but not Bak. These data clearly establish distinct roles for Bax and Bak in linking the TRAIL death receptor pathway to the mitochondrial apoptosis signaling cascade and delineate a higher degree of specificity in signaling for cell death by multidomain Bcl-2 homologs.
- Published
- 2004
31. Smac induces cytochrome c release and apoptosis independently from Bax/Bcl-xL in a strictly caspase-3-dependent manner in human carcinoma cells
- Author
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Peter T. Daniel, Guillaume Normand, Anne Hasenjäger, Bernd Dörken, Antje Müller, Martin Schuler, Bernhard Gillissen, and Philipp Hemmati
- Subjects
Cancer Research ,Programmed cell death ,bcl-X Protein ,Apoptosis ,Breast Neoplasms ,Bcl-xL ,Caspase 3 ,Cysteine Proteinase Inhibitors ,Adenoviridae ,Mitochondrial Proteins ,Bcl-2-associated X protein ,Proto-Oncogene Proteins ,Tumor Cells, Cultured ,Genetics ,Humans ,Molecular Biology ,Caspase ,bcl-2-Associated X Protein ,Caspase-9 ,biology ,Cytochrome c ,Carcinoma ,Intracellular Signaling Peptides and Proteins ,Cytochromes c ,Caspase Inhibitors ,Caspase 9 ,Cell biology ,Enzyme Activation ,Proto-Oncogene Proteins c-bcl-2 ,Caspases ,Mutation ,biology.protein ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Oligopeptides ,Protein Processing, Post-Translational - Abstract
The mitochondrial apoptosis pathway mediates cell death through the release of various pro-apoptotic factors including cytochrome c and Smac, the second mitochondrial activator of caspases, into the cytosol. Smac was shown previously to inhibit IAP proteins and to facilitate initiation of the caspase cascade upon cytochrome c release. To investigate Smac function during apoptosis and to explore Smac as an experimental cancer therapeutic, we constructed an expression system based on a single adenoviral vector containing Smac under control of the Tet-off system supplied in cis. Conditional expression of Smac induced apoptosis in human HCT116 and DU145 carcinoma cells regardless of the loss of Bax or overexpression of Bcl-x(L). Nevertheless, apoptosis induced by Smac was associated with cytochrome c release and breakdown of the mitochondrial membrane potential. This indicates that Smac acts independently of Bax and Bcl-x(L) during initiation of apoptosis and triggers a positive feedback loop that results in Bax/Bcl-x(L)-independent activation of mitochondria. In caspase-proficient cells, Smac-induced apoptosis could be inhibited partially by cell-permeable LEHD (caspase-9 inhibitor) and DEVD (caspase-3 inhibitor) peptides. Furthermore, loss of caspase-3 expression in MCF-7 cells carrying a caspase-3 null mutation completely abrogated the sensitivity for Smac-induced apoptotic or nonapoptotic, necrosis-like cell death, while re-expression of caspase-3 conferred sensitivity. Altogether, caspase-3 but not caspase-9 activation was necessary for execution of Smac-induced cell death. Notably, Smac did not induce caspase-9 processing in the absence of caspase-3. Thus, caspase-9 processing occurs secondary to caspase-3 activation during Smac-induced apoptosis. Altogether, Smac is capable of circumventing defects in mitochondrial apoptosis signaling such as loss of Bax or overexpression of Bcl-x(L) that are frequently observed in tumor cells resistant to anticancer therapy. Consequently, Smac appears to be a promising therapeutic target in anticancer treatment.
- Published
- 2004
32. Pharmakogenomik maligner Tumoren
- Author
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Isrid Sturm, Philipp Hemmati, Peter T. Daniel, and Dilek Güner
- Subjects
Gynecology ,medicine.medical_specialty ,Oncology ,business.industry ,Medicine ,Hematology ,business - Abstract
Nahezu alle nichtchirurgischen Tumortherapien basieren auf dem Prinzip, Zellzyklusarrest oder Zelltod in Tumorzellen auszulosen. Therapieresistenz maligner Tumoren resultiert somit in direkter Konsequenz aus Storungen zentraler Schlusselgene der Zellzyklus- und Apoptoseregulation. Die Analyse solcher genetischen Veranderungen ermoglicht die Identifikation von Risikopatienten mit ungenugendem Ansprechen auf Chemotherapeutika oder Bestrahlung sowie schlechter Prognose der Tumorerkrankung. Dies ist die Basis fur ein molekulares Verstandnis der pharmakogenetischen Grundlagen des Ansprechens auf Tumortherapien und auch fur den gezielteren klinischen Einsatz von Tumortherapeutika. Insbesondere zeigen aktuelle Daten zur Pharmakogenomik maligner Tumoren, dass Defekte zentraler regulatorischer Gene, z. B. von Komponenten des p53-Signalwegs, nicht immer in globaler Therapieresistenz resultieren, sondern durch Einsatz adaquater Therapiemodalitaten uberwunden werden konnen.
- Published
- 2004
33. Multigene analysis of Rb pathway and apoptosis control in esophageal squamous cell carcinoma identifies patients with good prognosis
- Author
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Peter T. Daniel, Matthias W. Lorenz, Sandra Hermann, Bernd Dörken, Isrid Sturm, Steffen Hauptmann, Volker Budach, Reinhard Wurm, Dilek Güner, and Philipp Hemmati
- Subjects
Cancer Research ,biology ,Tumor suppressor gene ,Kinase ,Retinoblastoma protein ,Cancer ,medicine.disease ,Cyclin D1 ,Bcl-2-associated X protein ,Oncology ,Epidermoid carcinoma ,Cancer research ,biology.protein ,medicine ,Cyclin - Abstract
Deregulation of cell-cycle G(1)-restriction point control by disruption of Rb-pathway components is a frequent event in cancer. In concert with the inactivation of cell death pathways, such events not only contribute to tumor development but also determine the intrinsic and acquired resistance to cancer therapy and, ultimately, disease prognosis. We previously observed that the cyclin-dependent kinase inhibitor p16(INK4a) and the proapoptotic Bcl-2 homolog Bax are positive prognostic factors and identify patients with good prognosis in esophageal squamous cell carcinoma (SCC). In the present study, we therefore extend our analysis to additional genes controlling the G(1) restriction point and apoptosis, respectively. This retrospective analysis was performed in a cohort of 53 patients undergoing surgery for esophageal SCC with curative intent, i.e., R0 resection. Protein expression profiles of cyclin D1, p16(INK4a), Rb, p21(CIP/WAF-1), p53, Bax and Bcl-2 were analyzed by immunohistochemistry and compared to p53 mutational status, as determined by SSCP-PCR of exons 5-8. Loss of p16(INK4a), Rb, p21(CIP/WAF-1) or Bax and overexpression of cyclin D1 were associated individually with shorter overall survival, while Bcl-2 expression and p53 mutation were not of prognostic relevance. The longest survival was observed in a subgroup of patients whose tumors bore a combination of favorite genotypes, i.e., low cyclin D1 and high Rb, p21(CIP/WAF-1), p16(INK4a) and Bax protein expression. These results show that multigene analyses based on limited sets of functionally linked genes reliably identify patients with good vs. poor prognosis.
- Published
- 2002
34. Impact of early remission by induction therapy on allogeneic stem cell transplantation for acute myeloid leukemia with an intermediate-risk karyotype in first complete remission
- Author
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Christian Jehn, Theis H. Terwey, Philipp Hemmati, Lam G. Vuong, Bernd Dörken, Renate Arnold, Il-Kang Na, and Philipp le Coutre
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Multivariate analysis ,Time Factors ,Adolescent ,Antineoplastic Agents ,Recurrence ,Internal medicine ,Medicine ,Humans ,Transplantation, Homologous ,Cumulative incidence ,Adverse effect ,Aged ,Retrospective Studies ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Karyotype ,Hematology ,General Medicine ,Induction Chemotherapy ,Middle Aged ,Survival Analysis ,Surgery ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Cohort ,Multivariate Analysis ,Female ,Stem cell ,business - Abstract
For patients with acute myeloid leukemia (AML) early achievement of remission during induction treatment is an important predictor for long-term outcome irrespective of the type of consolidation therapy employed. Here, we retrospectively examined the prognostic impact of early remission (ER) versus delayed remission (DR) in a cohort of 132 AML patients with an intermediate risk karyotype undergoing allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1). In contrast to patients showing DR, patients achieving ER had a significantly higher 3-year overall survival (OS) and disease-free survival (DFS) of 76% versus 54% (p=0.03) and 76% versus 53% (p=0.03). Likewise, three years after alloSCT the cumulative incidence of relapse (CI-R) was significantly lower in the ER subgroup as compared to patients achieving DR, i.e. 10% versus 35% (p=0.004), whereas non-relapse mortality (NRM) did not differ significantly. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, p=0.002) and a higher CI-R (HR 3.55, p=0.002). Taken together, these data may indicate that the rapid achievement of remission predicts a favorable outcome in patients with intermediate risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be fully overcome by alloSCT.
- Published
- 2014
35. Severe radiotoxicity in an allogeneic transplant recipient with a heterozygous ATM mutation
- Author
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Theis H. Terwey, Philipp Hemmati, Benjamin N. Ostendorf, Uwe Pleyer, Dirk Böhmer, and Renate Arnold
- Subjects
Adult ,Heterozygote ,Transplantation Conditioning ,medicine.medical_treatment ,Transplant recipient ,Hematopoietic stem cell transplantation ,Ataxia Telangiectasia Mutated Proteins ,Biology ,medicine.disease_cause ,Erythema Nodosum ,medicine ,Ataxia telangiectasia mutated ,Humans ,Transplantation, Homologous ,Risk factor ,Heterozygous mutation ,Mutation ,B-Lymphocytes ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Radiation therapy ,Toxicity ,Cancer research ,Female ,Whole-Body Irradiation - Abstract
Patients receiving radiotherapy often experience toxicity of the skin and mucous membranes. While radiotherapy is a mainstay of myeloablative conditioning for allogeneic hematopoietic stem cell transplantation (ASCT), no risk factors for radiotoxicity have been identified in this setting. Here, we report on a patient with excessive radiation-induced toxicity after ASCT who carried a heterozygous mutation in the Ataxia telangiectasia mutated (ATM) gene. This is the first case to suggest a genetic basis for increased radiotoxicity after myeloablative ASCT.
- Published
- 2014
36. Synchronous tuberculosis, Epstein-Barr virus-associated lymphoproliferative disorder and cytomegalovirus infection in an allogeneic transplant recipient: a case report
- Author
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Olaf Penack, Igor Wolfgang Blau, Bernhard Gebauer, Hendrik Nogai, Lam G. Vuong, Philipp Hemmati, Benjamin N. Ostendorf, Christian Jehn, Renate Arnold, and Ioannis Anagnostopoulos
- Subjects
Multidisciplinary ,Tuberculosis ,Case Study ,Post-transplant lymphoproliferative disorder ,business.industry ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Myeloid leukemia ,medicine.disease ,medicine.disease_cause ,Epstein–Barr virus ,Virus ,Allogeneic stem cell transplantation ,Transplantation ,Immunology ,medicine ,Epstein-Barr virus ,Stem cell ,business - Abstract
Background Allogeneic stem cell transplant recipients are prone to infections by various organisms. Tuberculosis (TB) represents a rare infectious complication, especially in countries non-endemic for TB. Case report Here, we report the case of a German patient with exposure to TB decades before he was diagnosed with disseminated TB as well as synchronous Epstein-Barr virus associated lymphoproliferative disorder and cytomegalovirus infection after allogeneic stem cell transplantation for refractory acute myeloid leukemia. Tuberculostatic and virostatic therapy was administered and the patient could be discharged with no apparent signs of infection two weeks after initiation of therapy. Conclusion This case illustrates the need for awareness of mycobacterial infections in patients from non-endemic regions undergoing stem cell transplantation even if other reasons for fever are present.
- Published
- 2014
37. BCR-ABL1(+) acute myeloid leukemia: clonal selection of a BCR-ABL1(-) subclone as a cause of refractory disease with nilotinib treatment
- Author
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Nina Rosa, Neuendorff, Michaela, Schwarz, Philipp, Hemmati, Seval, Türkmen, Christiane, Bommer, Thomas, Burmeister, Bernd, Dörken, Philipp, le Coutre, Renate, Arnold, and Jörg, Westermann
- Subjects
Male ,Salvage Therapy ,Leukemia, Myeloid, Acute ,Pyrimidines ,Recurrence ,Fusion Proteins, bcr-abl ,Humans ,Philadelphia Chromosome ,Aged - Abstract
The presence of a Philadelphia chromosome with a corresponding BCR-ABL1 rearrangement is the hallmark of chronic myeloid leukemia, but is considered a very rare event in de novo acute myeloid leukemia (AML). Here, we report the first case in which a dominant Philadelphia chromosome-positive subclone was detected upon relapse in a formerly Philadelphia chromosome-negative MLL-AF6(+) AML. Due to refractory disease under salvage chemotherapy, the patient was started on nilotinib treatment. As a result, the Philadelphia chromosome-positive subclone was eradicated within 1 month; however, disease progressed and was again dominated by the Philadelphia chromosome-negative founding clone, demonstrating rapid clonal expansion under nilotinib-induced selection pressure.
- Published
- 2014
38. Bone marrow T-cell infiltration during acute GVHD is associated with delayed B-cell recovery and function after HSCT
- Author
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Bernd Dörken, Carmen Scheibenbogen, Andrea Stroux, Kamran Movassaghi, Maike Oey, Sonya Demski, Martin Szyska, Sybill Thomas, Angela Mensen, Korinna Jöhrens, Olga Blau, Friedrich Wittenbecher, Philipp Hemmati, Il-Kang Na, Jörg Westermann, Renate Arnold, and Ioannis Anagnostopoulos
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,T-Lymphocytes ,Immunology ,B-Lymphocyte Subsets ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Lymphocyte Activation ,Biochemistry ,Young Adult ,Bone Marrow ,Inside BLOOD Commentary ,medicine ,Gene Rearrangement, B-Lymphocyte, Light Chain ,Humans ,B cell ,Aged ,Leukemia ,Osteoblasts ,biology ,business.industry ,Hematopoietic Stem Cell Transplantation ,Osteoblast ,Cell Biology ,Hematology ,Gene rearrangement ,Middle Aged ,medicine.disease ,Allografts ,surgical procedures, operative ,medicine.anatomical_structure ,Acute Disease ,biology.protein ,Female ,Bone marrow ,Antibody ,business ,Infiltration (medical) ,Ex vivo - Abstract
B-cell immune dysfunction contributes to the risk of severe infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Delayed B-cell regeneration is found in patients with systemic graft-versus-host disease (GVHD) and is often accompanied by bone marrow (BM) suppression. Little is known about human BM GVHD. We analyzed the reconstitution kinetics of B-cell subsets in adult leukemic patients within 6 months after allo-HSCT. B-cell deficiency already existed before transplant and was aggravated after transplant. Onset of B-cell reconstitution characterized by transitional B-cell recovery occurred either early (months 2-3) or late (from month 6 on) and correlated highly positively with reverse transcription-polymerase chain reaction quantified numbers of κ-deleting recombination excision circles (KRECs). Delayed recovery was associated with systemic acute GVHD and full-intensity conditioning therapy. Histological analysis of BM trephines revealed increased T-cell infiltration in late recovering patients, which was associated with reduced numbers of osteoblasts. Functionally, late recovering patients displayed less pneumococcal polysaccharide-specific immunoglobin M-producing B cells on ex vivo B-cell activation than early recovering patients. Our results provide evidence for acute BM GVHD in allo-HSCT patients with infiltrating donor T cells and osteoblast destruction. This is associated with delayed B-cell reconstitution and impaired antibody response. Herein, KREC appears suitable to monitor BM B-cell output after transplant.
- Published
- 2014
39. Long-Term Outcome of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia Beyond First Complete Remission – a Single Center Experience
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Lam G. Vuong, Philipp Hemmati, Renate Arnold, Il-Kang Na, Bernd Dörken, Philipp le Coutre, and Theis H. Terwey
- Subjects
Oncology ,medicine.medical_specialty ,Transplantation ,endocrine system diseases ,business.industry ,Complete remission ,Myeloid leukemia ,Hematology ,Single Center ,Outcome (game theory) ,Term (time) ,surgical procedures, operative ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Stem cell ,business ,neoplasms - Published
- 2014
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40. Efficacy of Adoptive Immunotherapy By Donor Lymphocyte Infusions after Allogeneic Stem Cell Transplantation from Related an Unrelated Donors: A Single Center Retrospective Analysis
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Igor Wolfgang Blau, Philipp Hemmati, Theis H. Terwey, Lam G. Vuong, Bernd Dörken, Christin Vogelsänger, Christian Jehn, Olaf Penack, and Renate Arnold
- Subjects
medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Immunology ,Myeloid leukemia ,Cancer ,Immunosuppression ,Cell Biology ,Hematology ,medicine.disease ,Single Center ,Biochemistry ,Gastroenterology ,Chemotherapy regimen ,Surgery ,Lymphoma ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,030215 immunology - Abstract
Introduction: Allogeneic stem cell transplantation (alloSCT) has become an integral part in the therapy of patients with malignancies of the lympho-hematopoietic system. One of the main reasons for treatment failure after alloSCT is relapse of the underlying disease, which, in the majority of cases, is associated with a poor prognosis. Adoptive immunotherapy by the use of donor lymphocyte infusions (DLI) was shown to be effective in this setting. However, the conditions and the optimal timing of DLI administration for prophylaxis or treatment of (impending) relapse remains controversial. Patients and Methods: We retrospectively analyzed 160 consecutive patients (median age: 48 (range: 17-69) years) who received DLI after previous alloSCT performed at our center between 1998 and 2014. Indications for alloSCT were: acute myeloid leukemia (AML) (N=68), acute lymphoblastic leukemia (ALL) (N=49), myelodysplastic syndrome/myeloproliferative neoplasia (MDS/MPN) (N=26), or myeloma/lymphoma (N=17). The disease risk index (DRI) was low (N=1), intermediate (N=101), high (N=43), or very high (N=6) (unknown: N=9). Comorbidities, as specified by the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), were low (N=38), intermediate (N=79), or high (N=38) (unknown: N=5). In N=71 patients a 10/10 human leukocyte antigen (HLA) matched-related donor was chosen, whereas N=89 patients were transplanted from an unrelated donor, either matched (N=73) or mismatched (N=16). Conditioning was either myeloablative (MAC) (N=71) or reduced-intensity (RIC) (N=89). The median interval from alloSCT to first DLI was 7.1 (range: 1.0-93.2) months. Indication for DLI was prophylactic (e.g. high-risk of relapse or active disease at the time of alloSCT) (N=28), pre-emptive (e.g. persistent or increasing mixed chimerism/molecular relapse) (N=86), or hematologic relapse (N=46). Pre-treatment before DLI was none/cessation of immunosuppression (N=129), lymphodepleting chemotherapy (N=16), or other (N=15). The median number of DLI units given was 2 (range: 1 - 6) and the median cumulative CD3+ cell dose/kg body weight given was 1.1 x 10E7 (range: 5.0 - 16.0 x 10E7). Results: The median follow-up of all patients from day of alloSCT was 37.3 (range: 3.0 - 202.6) months, whereas the median follow-up from day of first DLI administration was 21.2 (range: 0.3 - 200.5) months. Overall survival (OS) of the entire cohort at 1, 3, and 5 years after alloSCT was 80.5%, 63.8%, and 57.7%. Calculated from the day of first DLI OS at the same time points was 68.8%, 61.0%, and 55.8%. At five years after alloSCT OS in the group of patients with AML or ALL was significantly lower as compared to patients with MDS/MPN or myeloma/lymphoma, i.e. 52.0% versus 66.2% (p=0.043). Furthermore, OS in the group of patients receiving pre-emptive DLI was virtually identical to patients who received prophylactic DLI, i.e. 70.4% versus 69.8% at 5 years. In contrast, patients with hematologic relapse prior to DLI had an inferior outcome, i.e. an OS of 23.3% at 5 years. In addition to indication for DLI administration, i.e. prophylactic or pre-emptive versus therapeutic, the occurrence of chronic graft-versus-host disease (cGvHD) was the strongest predictor for outcome, i.e. long-term survival. Conclusions: Taken together, our data indicate that adoptive immunotherapy by the use of DLI is capable of inducing long-term remissions in patients after alloSCT. As pre-emptive and prophylactic treatment yielded virtually identical results, latter may be reserved for selected patients with (very) unfavorable disease characteristics, e.g. AML or ALL with active disease at the time of transplant. The optimal type of pre-treatment needs to be determined by investigating larger patient cohorts. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
41. Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas
- Author
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Michelle Mumy, Glenn Merlino, Kerri Bagnall, Erwin P. Bottinger, Lalage M. Wakefield, Philipp Hemmati, Ian Roberts, and John L. Jakubczak
- Subjects
Cellular differentiation ,Gene Expression ,Apoptosis ,Mice, Transgenic ,Protein Serine-Threonine Kinases ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Paracrine signalling ,Transforming Growth Factor beta ,Proliferating Cell Nuclear Antigen ,Acinar cell ,Animals ,Homeostasis ,Promoter Regions, Genetic ,Pancreas ,Molecular Biology ,R-SMAD ,General Immunology and Microbiology ,biology ,General Neuroscience ,Receptor, Transforming Growth Factor-beta Type II ,Cell Differentiation ,Transforming growth factor beta ,TGF beta receptor 2 ,Endoglin ,Immunohistochemistry ,Fibronectins ,Pancreatic Neoplasms ,Phenotype ,Liver ,Mutation ,Cancer research ,biology.protein ,Metallothionein ,Receptors, Transforming Growth Factor beta ,Cell Division ,Signal Transduction ,Research Article ,Transforming growth factor - Abstract
Using a dominant-negative mutant receptor (DNR) approach in transgenic mice, we have functionally inactivated transforming growth factor-beta (TGF-beta) signaling in select epithelial cells. The dominant-negative mutant type II TGF-beta receptor blocked signaling by all three TGF-beta isoforms in primary hepatocyte and pancreatic acinar cell cultures generated from transgenic mice, as demonstrated by the loss of growth inhibitory and gene induction responses. However, it had no effect on signaling by activin, the closest TGF-beta family member. DNR transgenic mice showed increased proliferation of pancreatic acinar cells and severely perturbed acinar differentiation. These results indicate that TGF-beta negatively controls growth of acinar cells and is essential for the maintenance of a differentiated acinar phenotype in the exocrine pancreas in vivo. In contrast, such abnormalities were not observed in the liver. Additional abnormalities in the pancreas included fibrosis, neoangiogenesis and mild macrophage infiltration, and these were associated with a marked up-regulation of TGF-beta expression in transgenic acinar cells. This transgenic model of targeted functional inactivation of TGF-beta signaling provides insights into mechanisms whereby loss of TGF-beta responsiveness might promote the carcinogenic process, both through direct effects on cell proliferation, and indirectly through up-regulation of TGF-betas with associated paracrine effects on stromal compartments.
- Published
- 1997
42. p14ARFinduces apoptosisviaan entirely caspase-3-dependent mitochondrial amplification loop
- Author
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Bernd Gillissen, Cindrilla Chumduri, Annika Müer, Tim Overkamp, Philipp Hemmati, Ana Milojkovic, Peter T. Daniel, and Reiner U. Jänicke
- Subjects
Cancer Research ,Programmed cell death ,Cell cycle checkpoint ,Oncology ,p14arf ,Tumor suppressor gene ,Apoptosis ,Cancer research ,Caspase 3 ,Mitochondrion ,Biology ,Mitosis ,Cell biology - Abstract
The p14(ARF) tumor suppressor triggers cell death or cell cycle arrest upon oncogenic stress. In MCF-7 breast carcinoma cells, expression of the tumor suppressor gene p14(ARF) fails to trigger apoptosis but induces an arrest in the G1 and, to a lesser extent, in the G2 phase in the cell division cycle. Here, inhibition of cell cycle arrest resulted in apoptosis induction in caspase-3 proficient MCF-7 cells upon expression of p14(ARF) . This occurred in the absence of S-phase progression or mitotic entry. In contrast, syngeneic, caspase-3-deficient MCF-7 cells remained entirely resistant to p14(ARF) -induced apoptosis. Thus, cell cycle checkpoint abrogation overcomes resistance to p14(ARF) -induced cell death and promotes cell death via a caspase-3-dependent pathway. Cell death coincided with dissipation of the mitochondrial membrane potential, release of cytochrome c, and was inhibitable by pan-caspase inhibitors and the caspase-3/7 inhibitor zDEVD-fmk. Of note, mitochondrial events of apoptosis execution depended entirely on caspase-3 proficiency indicating that caspase-3 either acts "up-stream" of the mitochondria in a "non-canonical" pathway or mediates a mitochondrial feedback loop to amplify the apoptotic caspase signal in p14(ARF) -induced stress signaling.
- Published
- 2013
43. Allogeneic Stem Cell Transplantation (SCT) in Elderly Patients with AML and ALL: Chance of Cure?
- Author
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Il-Kang Na, Theis H. Terwey, Philipp Hemmati, Wolfgang-Igor Blau, Lam G. Vuong, Christian Jehn, Olaf Penack, Livius Penter, Renate Arnold, Mohammad Ahmed A Shinawi, and Nils Waldhüter
- Subjects
Oncology ,Transplantation ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Hematology ,Stem cell ,business - Published
- 2016
44. p14ARF-induced Apoptosis in p53 Protein-deficient Cells Is Mediated by BH3-only Protein-independent Derepression of Bak Protein through Down-regulation of Mcl-1 and Bcl-xL Proteins
- Author
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Bernd Dörken, Thomas Pretzsch, Tim Overkamp, Annika Müer, Philipp Hemmati, Antje Richter, Ana Milojkovic, Peter T. Daniel, and Bernd Gillissen
- Subjects
bcl-X Protein ,Down-Regulation ,Bcl-xL ,Apoptosis ,Mitochondrion ,Biochemistry ,Mitochondrial apoptosis-induced channel ,p14arf ,Cell Line, Tumor ,Tumor Suppressor Protein p14ARF ,Humans ,Molecular Biology ,biology ,Cell Biology ,Fas receptor ,Molecular biology ,Cell biology ,Mitochondria ,bcl-2 Homologous Antagonist-Killer Protein ,Proto-Oncogene Proteins c-bcl-2 ,biology.protein ,Myeloid Cell Leukemia Sequence 1 Protein ,biological phenomena, cell phenomena, and immunity ,Signal transduction ,Tumor Suppressor Protein p53 ,Bcl-2 Homologous Antagonist-Killer Protein ,BH3 Interacting Domain Death Agonist Protein ,Signal Transduction - Abstract
The p14(ARF) tumor suppressor plays a central role in regulating cell cycle arrest and apoptosis. We reported previously that p14(ARF) is capable of triggering apoptosis in a p53-independent manner. However, the mechanism remained unclear. Here we demonstrate that the p53-independent activation of the mitochondrial apoptosis pathway by p14(ARF) is primarily mediated by the pro-apoptotic Bax-homolog Bak. Expression of p14(ARF) exclusively triggers a N-terminal conformational switch of Bak, but not Bax, which allows for mitochondrial permeability shift, release of cytochrome c, activation of caspases, and subsequent fragmentation of genomic DNA. Although forced expression of Bak markedly sensitizes toward p14(ARF)-induced apoptosis, re-expression of Bax has no effect. Vice versa, knockdown of Bak by RNA interference attenuates p14(ARF)-induced apoptosis, whereas down-regulation of Bax has no effect. Bak activation coincides with a prominent, caspase-independent deprivation of the endogenous Bak inhibitors Mcl-1 and Bcl-x(L). In turn, mitochondrial apoptosis is fully blocked by overexpression of either Mcl-1 or Bcl-x(L). Taken together, these data indicate that in the absence of functional p53 and Bax, p14(ARF) triggers mitochondrial apoptosis signaling by activating Bak, which is facilitated by down-regulating anti-apoptotic Mcl-1 and Bcl-x(L). Moreover, our data suggest that the simultaneous inhibition of two central endogenous Bak inhibitors, i.e. Mcl-1 and Bcl-x(L), may be sufficient to activate mitochondrial apoptosis in the absence of BH3-only protein regulation.
- Published
- 2012
45. Grouping of Genetic Risk By the European Leukemia Net Classification Predicts Overall Survival and Relapse Incidence in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation
- Author
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Bernd Dörken, Il-Kang Na, Philipp le Coutre, Lam G. Vuong, Renate Arnold, Theis H. Terwey, Christian Jehn, and Philipp Hemmati
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Disease ,Impedance threshold device ,medicine.disease ,Biochemistry ,Surgery ,Transplantation ,Leukemia ,Refractory ,Internal medicine ,medicine ,Cumulative incidence ,business - Abstract
Introduction: In acute myeloid leukemia (AML) genetic risk factors are among the strongest predictors for overall outcome. Recently, the European Leukemia Net (ELN) proposed a revised classification based on the presence or absence of specific cytogenetic and/or molecular aberrations. Here, we evaluated the prognostic significance of this system in patients with AML undergoing allogeneic stem cell transplantation (alloSCT). Patients and Methods: A total of 363 patients transplanted at our center between 2004 and 2014 was retrospectively evaluated. According to the ELN classification genetic risk was favorable (N=51), intermediate-1 (N=120), intermediate-2 (N=98), or adverse (N=94). Remission status at the time of alloSCT was first complete remission (CR1) (N=204), CR>1 (N=61), or refractory (N=98). In 107 patients standard myeloablative conditioning (MAC) was used, whereas reduced intensity conditioning (RIC) was applied in 256 patients. Grafts were from either related (N=103) or unrelated (matched: N=191, mismatched: N=69) donors. The median age was 52 (range: 18-75) years. Results: For the surviving patients the median follow-up was 30 (range: 3-129) months. Whereas in the subgroup of patients aged ≥60 years (N=98) no significant differences in disease-free survival (DFS) or cumulative incidence of relapse (CI-R) between the 4 ELN subgroups were found, the ELN classification was highly predictive for in the subgroups aged Conclusions: Taken together, our data suggest that the ELN classification of genetic risk is suitable for predicting relapse and overall survival of patients with AML aged Disclosures No relevant conflicts of interest to declare.
- Published
- 2015
46. Allogeneic Stem Cell Transplantation in High Risk ALL Patients: Influence of ALL Subtypes
- Author
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Philipp Hemmati, Gero Massenkeil, Theis H. Terwey, Lam G. Vuong, Olaf Penack, Renate Arnold, and Benjamin N. Ostendorf
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Oncology ,Transplantation ,medicine.medical_specialty ,business.industry ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Hematology ,Stem cell ,business - Published
- 2014
47. Reduced intensity conditioning prior to allogeneic stem cell transplantation in first complete remission is effective in patients with acute myeloid leukemia and an intermediate-risk karyotype
- Author
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Philipp le Coutre, Philipp Hemmati, Lam G. Vuong, Bernd Dörken, Stefan Neuburger, Renate Arnold, Theis H. Terwey, and Gero Massenkeil
- Subjects
Adult ,Male ,medicine.medical_specialty ,Myeloid ,Transplantation Conditioning ,Graft vs Host Disease ,Kaplan-Meier Estimate ,Gastroenterology ,Young Adult ,Recurrence ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Risk factor ,Aged ,Retrospective Studies ,Chromosome Aberrations ,Hematology ,business.industry ,Remission Induction ,Myeloid leukemia ,Cancer ,Retrospective cohort study ,Middle Aged ,Mycophenolic Acid ,medicine.disease ,Surgery ,Transplantation ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Cyclosporine ,Female ,business ,Immunosuppressive Agents ,Follow-Up Studies ,Stem Cell Transplantation - Abstract
To evaluate the efficacy of reduced intensity conditioning (RIC) prior to allogeneic stem cell transplantation (alloSCT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1), we retrospectively analyzed the outcome of 93 consecutive patients transplanted at our institution either following RIC (n = 37) or standard myeloablative conditioning (MAC) (n = 56) between 1999 and 2007. Projected overall survival (OS) or disease-free survival (DFS) for all patients at 1, 2, and 5 years was 78 or 70%, 65 or 57%, and 61 or 53% in the RIC group versus 73 or 70%, 68 or 62%, and 56 or 54% in the standard MAC group. In the subgroup of patients with an intermediate-risk karyotype projected OS at 1, 2, and 5 years was 86, 68, and 68% following RIC (n = 21) or 75, 69, and 66% following standard MAC (n = 36). Relapse or treatment-related mortality (TRM) was 15 or 17% (RIC group) and 26 or 14% (standard MAC group). Taken together, these data suggest that RIC-alloSCT may induce stable remissions in patients with AML transplanted in CR1. In particular, patients with an intermediate-risk karyotype ineligible to transplantation following standard MAC may benefit from RIC-alloSCT in CR1 at a low TRM.
- Published
- 2009
48. Systematic genetic dissection of p14ARF-mediated mitochondrial cell death signaling reveals a key role for p21CDKN1 and the BH3-only protein Puma/bbc3
- Author
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Bernd Gillissen, Bernd Dörken, Jana Wendt, Tim Overkamp, Annika Müer, Philipp Hemmati, Peter T. Daniel, and Ana Milojkovic
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,Programmed cell death ,Cell cycle checkpoint ,Biology ,Cell Line ,Mitochondrial Proteins ,p14arf ,Cyclin-dependent kinase ,hemic and lymphatic diseases ,Puma ,Proto-Oncogene Proteins ,Drug Discovery ,Tumor Suppressor Protein p14ARF ,Animals ,Humans ,RNA, Small Interfering ,Genetics (clinical) ,bcl-2-Associated X Protein ,Cell Death ,Cell cycle ,biology.organism_classification ,HCT116 Cells ,Cell biology ,Mitochondria ,Enzyme Activation ,Apoptosis ,Caspases ,biology.protein ,Molecular Medicine ,biological phenomena, cell phenomena, and immunity ,Tumor Suppressor Protein p53 ,Apoptosis Regulatory Proteins ,Restriction point ,Signal Transduction - Abstract
Induction of cell death by p14(ARF) is mediated through a Bax/Bak-dependent mitochondrial apoptosis pathway. To investigate the upstream signaling events required for the activation of Bax and/or Bak and to determine the functional impact of de-regulated cell cycle restriction point control in this context, we genetically dissected the impact of BH3-only proteins and the role of the cyclin-dependent kinase (cdk) inhibitor p21(CDKN1). Using isogenic HCT116 colorectal cancer cells, either wild-type or homozygously deleted for the BH3-only protein Puma/bbc3 and/or p21(CDKN1) or p53-reconstituted DU145 prostate cancer cells, we show that p14(ARF)-induced apoptosis is attenuated in the absence of Puma. Upon expression of p14(ARF) in HCT116 cells, Puma is rapidly induced at both the mRNA and protein level. Puma-proficient HCT116 cells undergo apoptotic (nuclear) DNA fragmentation, which is preceded by the N-terminal conformational change of Bax, the breakdown of the mitochondrial membrane potential, and induction of caspase-9 (LEHD)-like and caspase-3/7 (DEVD)-like activities. In contrast, p14(ARF)-induced apoptosis is markedly attenuated in isogenic HCT116 cells bi-allelically deleted for puma. The sensitivity of Puma-deficient cells to p14(ARF)-induced apoptosis is fully restored by functional reconstitution of Puma using a conditional adenoviral expression vector. Notably, the concomitant deletion of p21(CDKN1) strongly enhances p14(ARF)-induced apoptosis in Puma-proficient cells, but not in isogenic Puma-deficient cells. These results indicate that p14(ARF)-induced mitochondrial apoptosis critically depends on the BH3-only protein Puma. In the presence of a functional p53/Puma/Bax-signaling axis, p14(ARF)-triggered apoptosis is enhanced by loss of p21(CDKN1)-mediated cell cycle checkpoint control.
- Published
- 2009
49. Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis
- Author
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Ilker Oztop, Frank Essmann, Anja Richter, Bernd Dörken, Peter T. Daniel, Bernhard Gillissen, Philipp Hemmati, Antje Richter, and G. Chinnadurai
- Subjects
Male ,Programmed cell death ,Cancer Research ,Cell Membrane Permeability ,Cell ,Apoptosis ,Kidney ,Models, Biological ,Article ,Adenoviridae ,Cell Line ,Mitochondrial Proteins ,Bcl-2-associated X protein ,Cell Line, Tumor ,Puma ,hemic and lymphatic diseases ,medicine ,Humans ,Transgenes ,Research Articles ,Fluorescent Dyes ,bcl-2-Associated X Protein ,biology ,Cytochromes c ,Membrane Proteins ,Prostatic Neoplasms ,Cell Biology ,Carbocyanines ,HCT116 Cells ,biology.organism_classification ,Mitochondria ,Neoplasm Proteins ,Cell biology ,Myeloid Cell Leukemia Sequence 1 Protein ,bcl-2 Homologous Antagonist-Killer Protein ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Cell culture ,biology.protein ,Benzimidazoles ,biological phenomena, cell phenomena, and immunity ,Apoptosis Regulatory Proteins ,Bcl-2 Homologous Antagonist-Killer Protein - Abstract
B cell lymphoma 2 (Bcl-2) homology domain 3 (BH3)–only proteins of the Bcl-2 family are important functional adaptors that link cell death signals to the activation of Bax and/or Bak. The BH3-only protein Nbk/Bik induces cell death via an entirely Bax-dependent/Bak-independent mechanism. In contrast, cell death induced by the short splice variant of Bcl-x depends on Bak but not Bax. This indicates that Bak is functional but fails to become activated by Nbk. Here, we show that binding of myeloid cell leukemia 1 (Mcl-1) to Bak persists after Nbk expression and inhibits Nbk-induced apoptosis in Bax-deficient cells. In contrast, the BH3-only protein Puma disrupts Mcl-1–Bak interaction and triggers cell death via both Bax and Bak. Targeted knockdown of Mcl-1 overcomes inhibition of Bak and allows for Bak activation by Nbk. Thus, Nbk is held in check by Mcl-1 that interferes with activation of Bak. The finding that different BH3-only proteins rely specifically on Bax, Bak, or both has important implications for the design of anticancer drugs targeting Bcl-2.
- Published
- 2007
50. Achieving Early Remission By Induction Therapy Predicts a Favorable Outcome in Patients with Acute Myeloid Leukemia and an Intermediate Risk Karyotype Undergoing Allogeneic Stem Cell Transplantation in First Complete Remission
- Author
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Theis H. Terwey, Philipp le Coutre, Renate Arnold, Bernd Dörken, Philipp Hemmati, Il-Kang Na, Lam G. Vuong, and Christian Jehn
- Subjects
medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Immunosuppression ,Cell Biology ,Hematology ,Total body irradiation ,Biochemistry ,Gastroenterology ,Fludarabine ,Transplantation ,Internal medicine ,medicine ,Cytarabine ,Cumulative incidence ,business ,Busulfan ,medicine.drug - Abstract
Purpose: Acute myeloid leukemia (AML) is a highly heterogeneous disease. In addition to patient-related factors (co-morbidities, age, physical performance) and disease-specific variables (genetic risk profile) response to treatment is an important prognostic factor. In particular, the rapid achievement of hematologic remission by induction therapy was shown to predict overall outcome irrespective of the type of post-remission therapy employed. Here, we specifically investigated the impact of achieving early remission (ER), i.e. absence of leukemic blasts in the bone marrow at the end of the first course of induction therapy, as compared to delayed remission (DR) on the outcome of patients with AML who underwent allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1) at our center. Patients and Methods: We retrospectively analyzed 132 consecutive patients (ER: N=79, DR: N=53) with AML and an intermediate risk karyotype transplanted at our center between 1994 and 2013. Median age at alloSCT was 48 years. Before referral to transplantation, all patients were treated in a German multicenter AML trial. Patients aged Results: After a median follow-up of 56 (4-220) months for the surviving patients, 87 patients (66%) are alive and in CR. 26 patients (20%) relapsed after a median interval of 8 (1-133) months, whereas 19 patients (14%) died from NRM. Projected overall survival (OS) of the entire cohort after 1, 3, 5 and 10 years was 81%, 68%, 65%, and 61%. At the same time points the cumulative incidence of relapse (CI-R) or non-relapse mortality (CI-NRM) was 12%, 19%, 22%, and 22% or 13%, 13%, 13%, and 17%. In contrast to patients showing DR, patients achieving ER had a significantly higher 3-year OS and disease-free survival (DFS) of 76% versus 54% (p=0.03) and 76% versus 53% (p=0.03). Likewise, 3 years after alloSCT the CI-R was significantly lower in the ER subgroup as compared to patients achieving DR, i.e. 10% versus 35% (p=0.004). In contrast, NRM did not differ significantly between the ER and the DR subgroup. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, p=0.002) and a higher CI-R (HR 3.55, p=0.002). Notably, there was no significant difference in OS, DFS, or CI-R between patients treated with MAC versus RIC in the ER or the DR subgroup. Conclusions: Taken together, these data indicate that rapid achievement of remission may predict a favorable outcome in patients with intermediate risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be necessarily overcome by alloSCT. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
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