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Freiburg, Germany

Goebell P.J.,Friedrich - Alexander - University, Erlangen - Nuremberg | Munch A.,Center for Urology | Muller L.,Oncology Outpatient Center | Hurtz H.J.,Joint practice for Oncology | And 3 more authors.
Urologic Oncology: Seminars and Original Investigations | Year: 2014

Objective: With an increasing choice of new treatment options, the management of side effects to maintain a chosen treatment if likely to be effective on the tumor remains important. The perception of side effects however varies between the physician and the patient, leading to possible wrong assumptions on tolerability that result in dose modifications, which may ultimately affect effectiveness. The aim was to assess fatigue in patients with advanced or metastatic renal cell carcinoma (RCC) by comparing the evaluation of the physician to the one provided by their respective patient. In addition, we aimed to assess possible influences of fatigue on parameters of quality of life. Methods: Patients receiving systemic treatment for advanced RCC and their physicians were questioned independently regarding incidence and severity of fatigue and its effect on quality of life. Results: Both physicians and patients completed 98 matching questionnaires. Patients were treated with sunitinib, sorafenib, bevacizumab combined with interferon alpha, temsirolimus, everolimus, or interferon alpha alone. Incidence and severity of fatigue was differently assessed by patients and physicians, with fatigue being more severe when reported by the patient. The severity of fatigue increased with progressing treatment lines. Quality of life was significantly lower in patients experiencing fatigue compared with patients without fatigue. Emotional, functional, and physical well-being were all affected by fatigue, the latter being the most affected subscale. Social well-being was least affected. Conclusion: Fatigue is a complex and cumulative condition of patients treated for advanced RCC, and it considerably affects patient's quality of life. As many of its underlying causes may be treated, the divergent perception of occurrence and severity of fatigue should be integrated in treatment concepts. The active role of the patient in helping to manage ailments through assessment should be implemented when optimizing treatment of RCC. © 2014 Elsevier Inc.

Steinmetz T.,Outpatient Clinic for Oncology and Haematology | Tschechne B.,Klinikum Neustadt am Rubenberge | Harlin O.,Vifor Pharma | Klement B.,Vifor Pharma | And 5 more authors.
Annals of Oncology | Year: 2013

Background: Intravenous (i.v.) iron can improve anaemia of chronic disease and response to erythropoiesis-stimulating agents (ESAs), but data on its use in practice and without ESAs are limited. This study evaluated effectiveness and tolerability of ferric carboxymaltose (FCM) in routine treatment of anaemic cancer patients. Patients and methods: Of 639 patients enrolled in 68 haematology/oncology practices in Germany, 619 received FCM at the oncologist's discretion, 420 had eligible baseline haemoglobin (Hb) measurements, and 364 at least one follow-up Hb measurement. Data of transfused patients were censored from analysis before transfusion. Results: The median total iron dose was 1000 mg per patient (interquartile range 600-1500 mg). The median Hb increase was comparable in patients receiving FCM alone (1.4 g/dl [0.2-2.3 g/dl; N = 233]) or FCM + ESA (1.6 g/dl [0.7-2.4 g/dl; N = 46]). Patients with baseline Hb up to 11.0 g/dl and serum ferritin up to 500 ng/ml benefited from FCM treatment (stable Hb ≥11.0 g/dl). Also patients with ferritin >500 ng/ml but low transferrin saturation benefited from FCM treatment. FCM was well tolerated, 2.3% of patients reported putative drug-related adverse events. Conclusions: The substantial Hb increase and stabilisation at 11-12 g/dl in FCM-treated patients suggest a role for i.v. iron alone in anaemia correction in cancer patients. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Graeser R.,ProQinase GmbH | Graeser R.,Janssen Pharmaceutical | Vrignaud P.,Sanofi S.A. | Esser N.,ProQinase GmbH | And 5 more authors.
Journal of Biomolecular Screening | Year: 2012

The insulin-like growth factor I receptor (IGF1-R) system has long been implicated in cancer and is a promising target for tumor therapy. Besides in vitro screening assays, the discovery of specific inhibitors against IGF-1R requires relevant cellular models, ideally applicable to both in vitro and in vivo studies. With this aim in mind, the authors generated an inducible cell line using the tetracycline-responsive gene expression system to mimic the effects of therapeutic inhibition of the IGF-1R both in vitro and on established tumors in vivo. Inducible overexpression of IGF-1R in murine embryonic fibroblasts was achieved and resulted in the transformation of the cells as verified by their ability to grow in soft agar and in nude mice. Continuous repression of exogenous IGF-1R expression completely prevented outgrowth of the tumors. Furthermore, induced repression of IGF-1R expression in established tumors resulted in regression of the tumors. Interestingly, however, IGF-1R-independent relapse of tumor growth was observed upon prolonged IGF-1R repression. The IGF-1R cell line generated using this approach was successfully employed to test reference small-molecule inhibitors in vitro and an IGF-1R-specific inhibitory antibody, EM164, in vivo. Besides efficacy as a read-out, phospho-AKT could be identified as a pharmacodynamic biomarker, establishing this cell line as a valuable tool for the preclinical development of IGF-1R inhibitors. © 2012 Society for Laboratory Automation and Screening.

Belanger R.R.,Laval University | Labbe C.,Laval University | Lefebvre F.,Laval University | Teichmann B.,Laval University | Teichmann B.,IOMEDICO AG
Canadian Journal of Plant Pathology | Year: 2012

Pseudozyma flocculosa (syn: Sporothrix flocculosa) was first discovered and described in 1987 as an epiphytic yeast on powdery mildew-infected clover leaves. It was subsequently found to be a powerful antagonist of powdery mildews which prompted its study and development as a biocontrol agent (BCA). Most BCAs exert their activity through the manifestation of one or more of the following modes of action: competition, parasitism, antibiosis and induced resistance. In the case of P. flocculosa, in vitro bioassays, electron microscopy studies, and chemical analyses all pointed to a single mode of action: antibiosis. This conclusion was reinforced by the characterization and purification of an active molecule, flocculosin, and by the demonstration of its powerful antimicrobial activity. This was further supported by the discovery of a complex gene cluster regulating the synthesis of flocculosin, a molecule nearly identical to ustilagic acid - a compound produced by U. maydis under the control of a similar gene cluster. Despite this strong evidence, there is new evidence to indicate that flocculosin plays a secondary, if any, role in the antagonistic activity of P. flocculosa. The biocontrol process instead appears to be mediated by an intricate interaction involving nutrients produced by the plant, harvested by the phytopathogen and exploited by P. flocculosa. With the imminent completion of sequencing of the P. flocculosa genome, the recent publication of the barley powdery mildew genome (Blumeria graminis f. sp. hordei), and the availability of many plant genomes, the latest developments in DNA sequencing and transcriptomic analyses will allow unparalleled insight into the complex and delicate balance defining this unique tripartite interaction. © 2012 Copyright 2012 The Canadian Phytopathological Society.

Hegewisch-Becker S.,HOPE Practice for Oncology | Graeven U.,Kliniken Maria Hilf GmbH | Lerchenmuller C.A.,Practice for Oncology | Killing B.,Lahn Dill Kliniken | And 13 more authors.
The Lancet Oncology | Year: 2015

Background: The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab. Methods: In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00973609. Findings: Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5-25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1-8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3-7·4) for the bevacizumab alone group, and 6·4 months (4·8-7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio [HR] 1·08 [95% CI 0·85-1·37]; p=0·53; upper limit of the one-sided 98·8% CI 1·42), whereas no treatment was not (HR 1·26 [0·99-1·60]; p=0·056; upper limit of the one-sided 98·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 [19%] patients in the fluoropyrimidine plus bevacizumab group, 67 [43%] in the bevacizumab monotherapy group, and 73 [46%] in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 [13%] of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 [14%] of 156 patients in the bevacizumab alone group, and 12 [8%] of 158 patients in the no treatment group). Interpretation: Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies. Funding: RochePharma AG and AIO Studien gGmbH. © 2015 Elsevier Ltd.

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