Oncology and Tumor Immunology

Buch, Germany

Oncology and Tumor Immunology

Buch, Germany
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Maschmeyer G.,Oncology and Palliative Care | Carratala J.,University of Barcelona | Buchheidt D.,University of Mannheim | Hamprecht A.,University of Cologne | And 8 more authors.
Annals of Oncology | Year: 2015

Up to 25% of patients with profound neutropenia lasting for > 10 days develop lung infiltrates, which frequently do not respond to broad-spectrum antibacterial therapy. While a causative pathogen remains undetected in the majority of cases, Aspergillus spp., Pneumocystis jirovecii, multi-resistant Gram-negative pathogens, mycobacteria or respiratory viruses may be involved. In at-risk patients who have received trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis, filamentous fungal pathogens appear to be predominant, yet commonly not proven at the time of treatment initiation. Pathogens isolated from blood cultures, bronchoalveolar lavage (BAL) or respiratory secretions are not always relevant for the etiology of pulmonary infiltrates and should therefore be interpreted critically. Laboratory tests for detecting Aspergillus galactomannan, β-D-glucan or DNA from blood, BAL or tissue samples may facilitate the diagnosis; however, most polymerase chain reaction assays are not yet standardized and validated. Apart from infectious agents, pulmonary side-effects from cytotoxic drugs, radiotherapy or pulmonary involvement by the underlying malignancy should be included into differential diagnosis and eventually be clarified by invasive diagnostic procedures. Pre-emptive treatment with mold-active systemic antifungal agents improves clinical outcome, while other microorganisms are preferably treated only when microbiologically documented. High-dose TMP/SMX is first choice for treatment of Pneumocystis pneumonia, while cytomegalovirus pneumonia is treated primarily with ganciclovir or foscarnet in most patients. In a considerable number of patients, clinical outcome may be favorable despite respiratory failure, so that intensive care should be unrestrictedly provided in patients whose prognosis is not desperate due to other reasons. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Simon S.T.,Institute of Palliative Care | Simon S.T.,University of Cologne | Bausewein C.,Institute of Palliative Care | Bausewein C.,King's College London | And 7 more authors.
Journal of Pain and Symptom Management | Year: 2013

Context: Although episodic breathlessness (EB) is reported to be highly prevalent in advanced disease, our understanding about it is limited. Objectives: The aim of this study was to systematically review and synthesize the evidence on EB regarding definition, characteristics, and patients' experiences. Methods: Systematic review using searches in six databases, hand search, and personal contacts with authors in the field. Search terms included the combination of "episodic" and "breathlessness" (and synonyms) with five different diseases. Selection criteria included patients with advanced disease and information about EB based on original research. All retrieved studies were reviewed by two independent investigators. Results: Twenty-seven studies (of 7584) were included in this review. Only eight studies explored EB as a primary outcome. EB is poorly defined. It is characterized by high prevalence (81%-85%), high frequency (daily), short duration (often less than 10 minutes), and severe peak intensity. EB either develops without any known trigger or is triggered by physical exertion, emotions, or environmental influences. Conclusion: EB is a common symptom in patients with advanced disease, but information about characteristics and experiences is limited. As there is no common terminology, an agreed definition is needed to foster research to develop effective treatments for EB. © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Matutes E.,Royal Marsden Hospital | Pickl W.F.,Medical University of Vienna | Veer M.V.,Erasmus University Rotterdam | Morilla R.,Royal Marsden Hospital | And 11 more authors.
Blood | Year: 2011

The features of 100 mixed-phenotype acute leukemias (MPALs), fulfilling WHO 2008 criteria, are documented. Myeloid and T-lineage features were demonstrated by cytoplasmic myeloperoxidase and CD3; B-lineage features were demonstrated by at least 2 B-lymphoid markers. There were 62 men and 38 women; 68% were adults. Morphology was consistent with acute lymphoblastic leukemia (ALL; 43%), acute myeloid leukemia (AML; 42%), or inconclusive (15%). Immunophenotyping disclosed B + myeloid (59%), T + myeloid (35%), B + T (4%), or trilineage (2%) combinations. Cytogenetics evidenced t(9;22)/(Ph+) (20%), 11q23/ MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes. There was no correlation between age, morphology, immunophenotype, or cytogenetics. Response to treatment and outcome were available for 67 and 70 patients, respectively; 27 received ALL, 34 AML, 5 a combination of ALL + AML therapy, and 1 imatinib. ALL treatment induced a response in 85%, AML therapy in 41%; 3 of 5 patients responded to the combination therapy. Forty (58%) patients died, 33 of resistant disease. Overall median survival was 18 months and 37% of patients are alive at 5 years. Age, Ph+, and AML therapy were predictors for poor outcome (P < .001; P = .002; P = .003). MPAL is confirmed to be a poor-risk disease. Adults and Ph+ patients should be considered for transplantation in first remission. © 2011 by The American Society of Hematology.

Dorge P.,University of Kiel | Meissner B.,University of Kiel | Zimmermann M.,Hannover Medical School | Moricke A.,University of Kiel | And 12 more authors.
Haematologica | Year: 2013

IKZF1 gene deletions have been associated with a poor outcome in pediatric precursor B-cell acute lymphoblastic leukemia. To assess the prognostic relevance of IKZF1 deletions for patients treated on Berlin-Frankfurt-Münster Study Group trial ALL-BFM 2000, we screened 694 diagnostic acute lymphoblastic leukemia samples by Multiplex Ligation-dependent Probe Amplification. Patients whose leukemic cells bore IKZF1 deletions had a lower 5-year event-free survival (0.69±0.05 vs. 0.85±0.01; P<0.0001) compared to those without, mainly due to a higher cumulative incidence of relapses (0.21±0.04 vs. 0.10±0.01; P=0.001). Although IKZF1 deletions were significantly associated with the P2RY8-CRLF2 rearrangement, their prognostic value was found to be independent from this association. Thus, IKZF1 deletion is an independent predictor of treatment outcome and a strong candidate marker for integration in future treatment stratification strategies on ALL-BFM protocols. Clinicaltrials.gov identifier: NCT00430118. © 2013 Ferrata Storti Foundation.

PubMed | Martin Luther University of Halle Wittenberg, Oncology and Tumor Immunology, Albert Ludwigs University of Freiburg, Johannes Gutenberg University Mainz and 5 more.
Type: Journal Article | Journal: The EMBO journal | Year: 2016

Unfavorable patient survival coincides with lineage plasticity observed in human acute leukemias. These cases are assumed to arise from hematopoietic stem cells, which have stable multipotent differentiation potential. However, here we report that plasticity in leukemia can result from instable lineage identity states inherited from differentiating progenitor cells. Using mice with enhanced c-Myc expression, we show, at the single-cell level, that T-lymphoid progenitors retain broad malignant lineage potential with a high capacity to differentiate into myeloid leukemia. These T-cell-derived myeloid blasts retain expression of a defined set of T-cell transcription factors, creating a lymphoid epigenetic memory that confers growth and propagates myeloid/T-lymphoid plasticity. Based on these characteristics, we identified a correlating human leukemia cohort and revealed targeting of Jak2/Stat3 signaling as a therapeutic possibility. Collectively, our study suggests the thymus as a source for myeloid leukemia and proposes leukemic plasticity as a driving mechanism. Moreover, our results reveal a pathway-directed therapy option against thymus-derived myeloid leukemogenesis and propose a model in which dynamic progenitor differentiation states shape unique neoplastic identities and therapy responses.

Gokbuget N.,Goethe University Frankfurt | Kneba M.,University of Kiel | Raff T.,University of Kiel | Trautmann H.,University of Kiel | And 13 more authors.
Blood | Year: 2012

Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P < .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials. gov as NCT00199056 and NCT00198991. © 2012 by The American Society of Hematology.

Anders K.,Max Delbrück Center for Molecular Medicine | Buschow C.,Institute of Immunology | Herrmann A.,Beckman Research Institute | Milojkovic A.,Oncology and Tumor Immunology | And 7 more authors.
Cancer Cell | Year: 2011

The genetic instability of cancer cells frequently causes drug resistance. We established mouse cancer models, which allowed targeting of an oncogene by drug-mediated inactivation or monospecific CD8 + effector T (T E) cells. Drug treatment of genetically unstable large tumors was effective but selected resistant clones in the long term. In contrast, T E cells completely rejected large tumors (≥500 mm 3), if the target antigen was cancer-driving and expressed in sufficient amounts. Although drug-mediated oncogene inactivation selectively killed the cancer cells and left the tumor vasculature intact, which likely facilitated survival and growth of resistant clones, T E cell treatment led to blood vessel destruction and probably " bystander" elimination of escape variants, which did not require antigen cross-presentation by stromal cells. © 2011 Elsevier Inc.

Haugstetter A.M.,Oncology and Tumor Immunology | Loddenkemper C.,TU Munich | Loddenkemper C.,Charité - Medical University of Berlin | Lenze D.,TU Munich | And 7 more authors.
British Journal of Cancer | Year: 2010

Background: Cellular senescence is a terminal cell-cycle arrest that occurs in response to activated oncogenes and DNA-damaging chemotherapy. Whether cancer cell senescence at diagnosis might be predictive for treatment outcome is unknown. Methods: A senescence index (SI) was developed and used to retrospectively correlate the treatment outcome of 30 UICC stage IV colorectal cancer (CRC) patients with their SI at diagnosis. Results: 5-Fluorouracil/ leucovorin-treated CRC patients achieved a significantly longer progression-free survival when presenting with SI-positive tumours before therapy (median 12.0 vs 6.0 months; P=0.044).Conclusion:Cancer cell senescence predicts treatment outcome in metastasised CRC. Prospective analyses of larger patient cohorts are needed. © 2010 Cancer Research UK All rights reserved.

Schildmann E.K.,Oncology and Tumor Immunology | Davies A.N.,Foundation Medicine
Journal of Pain and Symptom Management | Year: 2010

Paraneoplastic Raynaud's phenomenon is a rare complication of a number of different malignancies (carcinomas, sarcomas, lymphomas, and leukemias). We present a case of paraneoplastic Raynaud's phenomenon in a patient with non-small-cell lung cancer that was associated with significant morbidity, involved a multidisciplinary approach, and eventually responded to a specialized intervention (i.e., iloprost trometamol). © 2010 U.S. Cancer Pain Relief Committee.

Binder D.,Oncology and Tumor Immunology | Hegenbarth K.,Oncology and Tumor Immunology
Clinical Medicine Insights: Oncology | Year: 2013

Lung cancer is one of the leading causes of death in industrialized and developing countries. Approximately 80% of patients are diagnosed with non-small cell histology. Although a multidisciplinary approach is necessary for the treatment of patients at early or locally-advanced stages of the disease, further successes in the treatment of patients with advanced disease will largely rely on improved systemic tumor control. Although therapies directed against the epidermal growth factor receptor (EGFR) have been incorporated into daily clinical practice, the value of other treatments remains to be elucidated. The current review highlights the most important driver mutations in non-small cell lung cancer (NSCLC) and describes recent study results and the status of EGFR-directed therapy, anaplastic lymphoma kinase (ALK)-directed agents, antiangiogenic therapy, and mesenchymal-epithelial transition factor (MET) inhibitors. However, many other agents with different modes of action are being examined in clinical research. © the author(s), publisher and licensee Libertas Academica Ltd.

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