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Knebel S.,Albert Ludwigs University of Freiburg | Pasantes J.J.,Albert Ludwigs University of Freiburg | Pasantes J.J.,University of Vigo | Thi D.A.D.,Albert Ludwigs University of Freiburg | And 3 more authors.
Cytogenetic and Genome Research | Year: 2011

Pericentric inversions of the human Y chromosome (inv(Y)) are the result of breakpoints in Yp and Yq. Whether these breakpoints occur recurrently on specific hotspots or appear at different locations along the repeat structure of the human Y chromosome is an open question. Employing FISH for a better definition and refinement of the inversion breakpoints in 9 cases of inv(Y) chromosomes, with seemingly unvarying metacentric appearance after banding analysis, unequivocally resulted in heterogeneity of the pericentric inversions of the human Y chromosome. While in all 9 inv(Y) cases the inversion breakpoints in the short arm fall in a gene-poor region of X-transposed sequences proximal to PAR1 and SRY in Yp11.2, there are clearly 3 different inversion breakpoints in the long arm. Inv(Y)-types I and II are familial cases showing inversion breakpoints that map in Yq11.23 or in Yq11.223, outside the ampliconic fertility gene cluster of DAZ and CDY in AZFc. Inv(Y)-type III shows an inversion breakpoint in Yq11.223 that splits the DAZ and CDY fertility gene-cluster in AZFc. This inversion type is representative of both familial cases and cases with spermatogenetic impairment. In a further familial case of inv(Y), with almost acrocentric morphology, the breakpoints are within the TSPY and RBMY repeat in Yp and within the heterochromatin in Yq. Therefore, the presence of specific inversion breakpoints leading to impaired fertility in certain inv(Y) cases remains an open question. Copyright © 2011 S. Karger AG, Basel.


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.


Eichelberg C.,University of Regensburg | Vervenne W.L.,Deventer Ziekenhuis | De Santis M.,Ludwig Boltzmann Research Institute | Fischer Von Weikersthal L.,Gesundheitszentrum Klinikum Amberg | And 16 more authors.
European Urology | Year: 2015

Background Understanding how to sequence targeted therapies for metastatic renal cell carcinoma (mRCC) is important for maximisation of clinical benefit. Objectives To prospectively evaluate sequential use of the multikinase inhibitors sorafenib followed by sunitinib (So-Su) versus sunitinib followed by sorafenib (Su-So) in patients with mRCC. Design, setting, and participants The multicentre, randomised, open-label, phase 3 SWITCH study assessed So-Su versus Su-So in patients with mRCC without prior systemic therapy, and stratified by Memorial Sloan Kettering Cancer Center risk score (favourable or intermediate). Intervention Patients were randomised to sorafenib 400 mg twice daily followed, on progression or intolerable toxicity, by sunitinib 50 mg once daily (4 wk on, 2 wk off) (So-Su), or vice versa (Su-So). Outcome measurements and statistical analysis The primary endpoint was improvement in progression-free survival (PFS) with So-Su versus Su-So, assessed from randomisation to progression or death during second-line therapy. Secondary endpoints included overall survival (OS) and safety. Results and limitations In total, 365 patients were randomised (So-Su, n = 182; Su-So, n = 183). There was no significant difference in total PFS between So-Su and Su-So (median 12.5 vs 14.9 mo; hazard ratio [HR] 1.01; 90% confidence interval [CI] 0.81-1.27; p = 0.5 for superiority). OS was similar for So-Su and Su-So (median 31.5 and 30.2 mo; HR 1.00, 90% CI 0.77-1.30; p = 0.5 for superiority). More So-Su patients than Su-So patients reached protocol-defined second-line therapy (57% vs 42%). Overall, adverse event rates were generally similar between the treatment arms. The most frequent any-grade treatment-emergent first-line adverse events were diarrhoea (54%) and hand-foot skin reaction (39%) for sorafenib; and diarrhoea (40%) and fatigue (40%) for sunitinib. Conclusions Total PFS was not superior with So-Su versus Su-So. These results demonstrate that sorafenib followed by sunitinib and vice versa provide similar clinical benefit in mRCC. Patient summary We investigated if total progression-free survival (PFS) is improved in patients with advanced/metastatic kidney cancer who are treated with sorafenib and then with sunitinib (So-Su), compared with sunitinib and then sorafenib (Su-So). We found that total PFS was not improved with So-Su compared with Su-So, but both treatment options were similarly effective in patients with advanced/metastatic kidney cancer. Trial registration ClinicalTrials.gov identifier NCT00732914, www.clinicaltrials.gov © 2015 European Association of Urology.


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.


PubMed | HOPE Practice for Oncology, Martin Luther University of Halle Wittenberg, Lahn Dill Kliniken, Klinik fur Tumorbiologie and 11 more.
Type: Clinical Trial, Phase III | Journal: The Lancet. Oncology | Year: 2015

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.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 988% CI 143. 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.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 170 months (IQR 95-254). Median time to failure of strategy was 69 months (95% CI 61-85) for the fluoropyrimidine plus bevacizumab group, 61 months (53-74) for the bevacizumab alone group, and 64 months (48-76) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio [HR] 108 [95% CI 085-137]; p=053; upper limit of the one-sided 998% CI 142), whereas no treatment was not (HR 126 [099-160]; p=0056; upper limit of the one-sided 998% CI 165). 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).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.


Potthoff K.,University of Heidelberg | Habl G.,University of Heidelberg | Bruckner T.,University of Heidelberg | Suppan C.,University of Heidelberg | And 4 more authors.
BMC Cancer | Year: 2014

Background: Cetuximab is a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR). Skin reactions are the most common side effects of cetuximab. Rhagades of the tips of the fingers and toes, the heels and especially the interphalangeal joints are one of the most frightening and painful dermatological side effects that may develop from EGFR-inhibitor therapy. Rhagades are characterized by pain, severe tenderness and poor healing response. They are challenging to treat. Thus, rhagades often poses the most significant threat to the quality of life (QoL) for these patients. Ethyl-2-cyanoacrylate (ECA), an ethyl ester of the 2-cyano-2-propenoic acid, is often used as adhesive in a variety of different work settings in industry, i.e. as a component in nail-care products such as nail glue. In addition, ECA is used for various medical indications, such as for liquid bandages and for suture-less surgery. Wound healing can be accelerated with ECA. The purpose of the SUPPORT trial is to investigate the efficacy of ECA for the treatment of cetuximab-induced rhagades and to assess the clinical usefulness of the SUPO score, a new classification system for rhagades induced by EGFR-inhibitor therapy.Methods/Design: The SUPPORT trial is an open-label, prospective, randomized, national multicenter intervention study to evaluate the effectiveness of ECA versus the standard treatment of each institution on the pain intensity and QoL in patients with locally advanced head and neck cancer suffering from painful cetuximab-induced rhagades during radioimmunotherapy. Primary endpoint is the assessment of the pain intensity 24 hours after application of ECA or the standard treatment quantified by the visual analogue scale (VAS). Secondary endpoints are the evaluation of QoL assessed by the EORTC-QoL-C30 questionnaire and the Dermatological Life Quality Index (DLQI).Discussion: During treatment with EGFR inhibitors it is necessary to recognize and manage side effects promptly to assure better patient QoL. The SUPPORT trial is the first randomized clinical trial evaluating a new treatment option for painful cetuximab-induced rhagades. Furthermore, the new SUPO score will be prospectively assessed in terms of clinical usefulness for classification of EGFR inhibitor-induced rhagades.Trial registration: Current Controlled Trials NCT01693159. © 2014 Potthoff et al.; licensee BioMed Central Ltd.


Habl G.,University of Heidelberg | Potthoff K.,University of Heidelberg | Haefner M.F.,University of Heidelberg | Abdollahi A.,German Cancer Research Center | And 4 more authors.
BMC Cancer | Year: 2013

Background: In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before.Methods/design: The HICARE study is a national, multicenter, prospective phase IV study exploring the different types of skin reactions that occur in patients with LASCCHN undergoing radioimmun(chemo)therapy with the EGFR inhibitor cetuximab. 500 patients with LASCCHN will be enrolled in 40 participating sites in Germany. Primary endpoint is the rate of radiation dermatitis NCI CTCAE grade 3 and 4 (v. 4.02). Radioimmunotherapy will be applied according to SmPC, i.e. cetuximab will be administered as loading dose and then weekly during the radiotherapy. Irradiation will be applied as intensity-modulated radiation therapy (IMRT) or 3D-dimensional radiation therapy.Discussion: The HICARE trial is expected to be one of the largest trials ever conducted in head and neck cancer patients. The goal of the HICARE trial is to differentiate skin reactions caused by radiation from those caused by the monoclonal antibody cetuximab, to evaluate the incidence and severity of these skin reactions and to correlate them with outcome parameters. Besides, the translational research program will help to identify and confirm novel peripheral blood based molecular predictors and surrogates for treatment response and resistance. © 2013 Habl et al.; licensee BioMed Central Ltd.


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.


Becker M.,Onkologische Praxis Minden Porta | Tschechne B.,Praxis fur Hamatologie und internistische Onkologie | Reeb M.,Onkologische Schwerpunktpraxis | Schwinger U.,MVZ Leuschnerstr. 1 | And 3 more authors.
Annals of Hematology | Year: 2015

Bendamustine has demonstrated clinical activity and a favorable safety profile as monotherapy or in combination with rituximab in lymphoid malignancies. As interventional trials do not always reflect clinical reality, we were interested in the treatment modalities and the outcome of bendamustine-based first-line therapy in patients with advanced indolent non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL) in routine practice. Between April 2010 and October 2011, 324 patients were enrolled in a prospective non-interventional multicenter study. Choice of the bendamustine regimen was at the treating physician’s discretion. Effectiveness was assessed by best response. Mean age at onset of therapy was 69 years. The majority (94 %) of the patients was treated with bendamustine in combination with rituximab at a median bendamustine dose of 177 mg/m2 per cycle. Most often, bendamustine was administered on days 1 and 2 (87 %) at 4-week intervals over a median of 6 cycles. Two hundred eighty-one patients qualified for evaluation of response. The overall response rate was 86 % (complete response 43 %, partial response 43 %, stable disease 10 %, progressive disease 4 %). Side effects of all grades were documented for 161 of the 323 patients (50 %), most frequently affecting blood/bone marrow (35 %). Fifty-four (17 %) patients experienced side effects of grade 3 (15 %) or grade 4 (2 %), and two patients grade 5 toxicities. Bendamustine-based first-line treatment of patients with advanced indolent NHL and MCL in clinical routine practice was assessed as effective and well tolerated in our study. Response was comparable to results from interventional clinical trials. © 2015, The Author(s).


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.

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