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Rades D.,University of Lübeck | Rades D.,University of Hamburg | Dziggel L.,University of Lübeck | Nagy V.,Oncology and Radiotherapy Institute | And 5 more authors.
Radiotherapy and Oncology | Year: 2013

Background and purpose Survival scores for patients with brain metastasis exist. However, the treatment regimens used to create these scores were heterogeneous. This study aimed to develop and validate a survival score in homogeneously treated patients. Materials and methods Eight-hundred-and-eighty- two patients receiving 10 × 3 Gy of WBRT alone were randomly assigned to a test group (N = 441) or a validation group (N = 441). In the multivariate analysis of the test group, age, performance status, extracranial metastasis, and systemic treatment prior to WBRT were independent predictors of survival. The score for each factor was determined by dividing the 6-month survival rate (in %) by 10. Scores were summed and total scores ranged from 6 to 19 points. Patients were divided into four prognostic groups. Results The 6-month survival rates were 4% for 6-9 points, 29% for 10-14 points, 62% for 15-17 points, and 93% for 17-18 points (p < 0.001) in the test group. The survival rates were 3%, 28%, 54% and 96%, respectively (p < 0.001) in the validation group. Conclusions Since the 6-month survival rates in the validation group were very similar to the test group, this new score (WBRT-30) appears valid and reproducible. It can help making treatment choices and stratifying patients in future trials. © 2013 Elsevier Ireland Ltd. All rights reserved.


Rades D.,University of Lübeck | Dziggel L.,University of Lübeck | Haatanen T.,University of Hamburg | Veninga T.,Dr Bernard Verbeeten Institute | And 2 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: To create and validate scoring systems for intracerebral control (IC) and overall survival (OS) of patients irradiated for brain metastases. Methods and Materials: In this study, 1,797 patients were randomly assigned to the test (n = 1,198) or the validation group (n = 599). Two scoring systems were developed, one for IC and another for OS. The scores included prognostic factors found significant on multivariate analyses. Age, performance status, extracerebral metastases, interval tumor diagnosis to RT, and number of brain metastases were associated with OS. Tumor type, performance status, interval, and number of brain metastases were associated with IC. The score for each factor was determined by dividing the 6-month IC or OS rate (given in percent) by 10. The total score represented the sum of the scores for each factor. The score groups of the test group were compared with the corresponding score groups of the validation group. Results: In the test group, 6-month IC rates were 17% for 14-18 points, 49% for 19-23 points, and 77% for 24-27 points (p < 0.0001). IC rates in the validation group were 19%, 52%, and 77%, respectively (p < 0.0001). In the test group, 6-month OS rates were 9% for 15-19 points, 41% for 20-25 points, and 78% for 26-30 points (p < 0.0001). OS rates in the validation group were 7%, 39%, and 79%, respectively (p < 0.0001). Conclusions: Patients irradiated for brain metastases can be given scores to estimate OS and IC. IC and OS rates of the validation group were similar to the test group demonstrating the validity and reproducibility of both scores. © 2011 Elsevier Inc.


Gontero P.,San Giovanni Battista Hospital | Sylvester R.,EORTC Headquarters | Pisano F.,San Giovanni Battista Hospital | Joniau S.,University Hospitals Leuven | And 31 more authors.
European Urology | Year: 2015

Background The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. Objective To assess prognostic factors in patients who received bacillus Calmette-Guérin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment. Design, setting, and participants Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011. Outcome measurements and statistical analysis Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS). Results and limitations With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age ≥70 yr, size ≥3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients ≥70 yr with tumor size ≥3 cm and 13% otherwise. Conclusions T1G3 patients ≥70 yr with tumors ≥3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression. Patient summary Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guérin, there is a subgroup of T1G3 patients with age ≥70 yr, tumor size ≥3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment. © 2014 European Association of Urology.


PubMed | University of Zagreb, University of Prague, University of Bologna, University of Ljubljana and Chiesi Farmaceutici SpA
Type: Journal Article | Journal: Current therapeutic research, clinical and experimental | Year: 2014

Several studies have shown that antihypertensive monotherapy is commonly insufficient to control blood pressure (BP) in hypertensive patients and that concomitant use of 2 drugs is necessary in 50% of these patients. The combination of an angiotensin-converting enzyme (ACE) inhibitor and a diuretic, delapril plus indapamide (D+I), has been shown to be effective and tolerable, with no interaction between the 2 components. Another widely used combination of ACE inhibitor and diuretic is lisinopril plus hydrochlorothiazide (L+H).The aims of this study were to confirm the antihypertensive efficacy and tolerability of the fixed combination of D+I in mild to moderate hypertension, and to compare its therapeutic efficacy and tolerability with that of L+H.The antihypertensive efficacy and tolerability of a fixed combination of D+I (30-mg+2.5-mg tablets once daily) or L+H (20-mg+12.5-mg tablets once daily) in patients with mild to moderate hypertension were compared in a multinational, multicenter, randomized, 2-armed, parallel-group study. Eligible patients were aged 18 to 75 years and had a diastolic blood pressure (DBP) 95 to 115 mm Hg and a systolic blood pressure (SBP) 180 mm Hg, both measured in the sitting position. After a single-blind, placebo run-in period of 2 weeks, patients were randomized to receive 1 of the 2 treatments for a 12-week period. The primary efficacy end point was the BP normalization rate (ie, the percentage of patients with a sitting DBP 90 mm Hg) after 12 weeks of treatment. Secondary end points were as follows: (1) the responder rate (ie, the percentage of patients whose sitting DBP was reduced by 10 mm Hg from baseline or had a DBP 90 mm Hg after 12 weeks of treatment), (2) the percentage of patients with a DBP 85 mm Hg, and (3) changes in sitting SBP and DBP after 4, 8, and 12 weeks of treatment.A total of 159 hypertensive patients (88 women, 71 men) were randomized to receive D+I (44 women, 36 men; mean [SD] age, 53 [(11)] years) or L+H (44 women, 35 men; mean [SD] age, 55 [(10)] years). No significant between-group differences were found in any of the primary or secondary end points of the study. Both combinations induced a significant reduction in sitting DBP and SBP from baseline (P<0.001 for both groups at week 12), without significant differences between the groups. Five mild to moderate adverse drug reactions (ADRs) occurred in each treatment group. No patient dropped out of the study because of an ADR.This study showed no difference between D+I and L+H interms of antihypertensive efficacy or tolerability in patients with mild to moderate hypertension.


PubMed | EORTC Headquarters, Genetic and Molecular Epidemiology Group, Rabin Medical Center, University of Turin and 18 more.
Type: Journal Article | Journal: BJU international | Year: 2016

To determine if a re-transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1-high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS).In a large retrospective multicentre cohort of 2451 patients with T1-HG/G3 initially treated with bacille Calmette-Gurin, 935 (38%) had a re-TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in four groups: group 1 (no muscle, no re-TUR), group 2 (no muscle, re-TUR), group 3 (muscle, no re-TUR) and group 4 (muscle, re-TUR). Clinical outcomes were compared across the four groups.Re-TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary TUR specimen. Adjusting for the most important prognostic factors, re-TUR in the absence of muscle had a borderline significant effect on time to recurrence [hazard ratio (HR) 0.67, P = 0.08], progression (HR 0.46, P = 0.06), CSS (HR 0.31, P = 0.07) and OS (HR 0.48, P = 0.05). Re-TUR in the presence of muscle in the primary TUR specimen did not improve the outcome for any of the endpoints.Our retrospective analysis suggests that re-TUR may not be necessary in patients with T1-HG/G3, if muscle is present in the specimen of the primary TUR.


PubMed | University of Prague, a Osler Medical Center and Dong - A University
Type: Journal Article | Journal: Expert review of cardiovascular therapy | Year: 2015

The optimal utilization of antiplatelet therapy in patients with renal impairment (RI) following acute coronary syndromes (ACS) represents an urgent, unmet and yet unsolved need with regards to the choice of agents, duration of treatment and potential dose/regimen adjustment. The lack of any large randomized trials designed and powered specifically in such high-risk patients, absence of the uniformed efficacy and safety data reporting policy to the FDA and endless overoptimistic publications based on post hoc analyses of primary trials sometimes exaggerating benefits and hiding risks, clouds reality. In addition, triaging RI patients is problematic due to ongoing kidney deterioration and the fact that such patients are prone to both vascular occlusions and bleeding. The authors summarize available FDA-confirmed evidence from the latest trials with approved antiplatelet agents, namely clopidogrel (CAPRIE, CURE, CREDO, CLARITY, CHARISMA); prasugrel (TRITON, TRILOGY); ticagrelor (PLATO, and PEGASUS); and vorapaxar (TRACER and TRA2P) in RI patient cohorts on top of aspirin as part of dual antiplatelet therapy (DAPT). We deliberately avoided any results unless they were verified by the FDA, with the exception of the recent PEGASUS, since Agency reviews are not yet available. Despite differences among the trials and DAPT choices, RI patients universally experience much higher (HR = 1.3-3.1) rates of primary endpoint events, and bleeding risks (HR = 1.7-3.6). However, only ticagrelor increases creatinine and uric acid levels above that of clopidogrel; has the worst incidence of serious adverse events, more adverse events, and inferior outcomes in patients with severe (eGFR <30 ml/min), especially in the lowest (eGFR <15 ml/min) RI subsets. Clopidogrel, prasugrel and vorapaxar appear safer. Moreover, less aggressive half dose (5 mg/daily) prasugrel and strict DAPT, are well justified in RI, but not predominantly triple strategies with vorapaxar as tested in TRA2P and especially in TRACER. In conclusion, data from clinical trials, their sub-studies and affiliated FDA reviews indicate that RI cause more vascular occlusions and bleeding in ACS patients treated with DAPT. Among the novel antiplatelet agents, prasugrel and vorapaxar, but probably not ticagrelor, offer advantage in RI patients.


Rades D.,University of Lübeck | Rades D.,University of Hamburg | Panzner A.,University of Lübeck | Dziggel L.,University of Lübeck | And 3 more authors.
Cancer | Year: 2012

BACKGROUND: Patients with brain metastases who have a favorable survival prognosis may benefit from intensive treatments, including neurosurgery and radiosurgery. However, many patients cannot receive such treatments, and whole-brain radiotherapy (WBRT) alone is their only option. The most common WBRT schedule is 30 grays (Gy) in 10 fractions. In this retrospective study, the authors investigated whether these patients benefit from a dose escalation beyond 30 Gy. METHODS: Data from 109 patients who received 30 Gy in 10 fractions were compared with 75 patients who received 40 Gy in 20 fractions. All patients had a favorable survival prognosis. Both groups were compared for local control (LC) and overall survival (OS). Subgroup analyses were performed for patients who had less radiosensitive tumors (N = 27) and for other patients (N = 157). RESULTS: The LC rate at 1 year was 28% after 30 Gy and 44% after 40 Gy (P =.064). On multivariate analysis, the 40 Gy dose was associated with improved LC (P =.047). The survival rate at 1 year was 50% after 30 Gy and 61% after 40 Gy (P =.007). On multivariate analysis, the 40 Gy dose was associated with improved OS (P =.008). On subgroup analysis of patients who had less radiosensitive tumors, the 1-year LC rate was 7% after 30 Gy and 38% after 40 Gy (P =.031); and the 1-year OS rate was 40% and 73%, respectively (P =.008). On subgroup analysis of patients who had other tumor types, the 1-year LC rate was 31% after 30 Gy and 45% after 40 Gy (P =.26); and the 1-year OS rate was 52% and 59%, respectively (P =.08). CONCLUSIONS: Escalation of the WBRT dose beyond 30 Gy resulted in better outcomes, particularly for patients who had less radiosensitive tumors. Copyright © 2011 American Cancer Society.


PubMed | Ludwig Maximilians University of Munich, University of Prague, University of Cincinnati and Otto Von Guericke University of Magdeburg
Type: Journal Article | Journal: Oncotarget | Year: 2016

DNA repair defects due to detrimental BRCA2-mutations confer increased susceptibility towards DNA interstrand-crosslinking (ICL) agents and define patient subpopulations for individualized genotype-based cancer therapy. However, due to the side effects of these drugs, there is a need to identify additional agents, which could be used alone or in combination with ICL-agents. Therefore, we investigated whether BRCA2-mutations might also increase the sensitivity towards TRAIL-receptors (TRAIL-R)-targeting compounds.Two independent model systems were applied: a BRCA2 gene knockout and a BRCA2 gene complementation model. The effects of TRAIL-R-targeting compounds and ICL-agents on cell viability, apoptosis and cell cycle distribution were compared in BRCA2-proficient versus-deficient cancer cells in vitro. In addition, the effects of the TRAIL-R2-targeting antibody LBY135 were assessed in vivo using a murine tumor xenograft model.BRCA2-deficient cancer cells displayed an increased sensitivity towards TRAIL-R-targeting agents. These effects exceeded and were mechanistically distinguishable from the well-established effects of ICL-agents. In vitro, ICL-agents expectedly induced an early cell cycle arrest followed by delayed apoptosis, whereas TRAIL-R-targeting compounds caused early apoptosis without prior cell cycle arrest. In vivo, treatment with LBY135 significantly reduced the tumor growth of BRCA2-deficient cancer cells in a xenograft model.BRCA2 mutations strongly increase the in vitro- and in vivo-sensitivity of cancer cells towards TRAIL-R-mediated apoptosis. This effect is mechanistically distinguishable from the well-established ICL-hypersensitivity of BRCA2-deficient cells. Our study thus defines a new genetic subpopulation of cancers susceptible towards TRAIL-R-targeting compounds, which could facilitate novel therapeutic approaches for patients with BRCA2-deficient tumors.


Serebruany V.L.,Osler Medical Center | Tomek A.,University of Prague | Pokov A.N.,Osler Medical Center | Kim M.H.,Dong - A University
Expert Review of Cardiovascular Therapy | Year: 2015

The optimal utilization of antiplatelet therapy in patients with renal impairment (RI) following acute coronary syndromes (ACS) represents an urgent, unmet and yet unsolved need with regards to the choice of agents, duration of treatment and potential dose/regimen adjustment. The lack of any large randomized trials designed and powered specifically in such high-risk patients, absence of the uniformed efficacy and safety data reporting policy to the FDA and endless overoptimistic publications based on post hoc analyses of primary trials sometimes exaggerating benefits and hiding risks, clouds reality. In addition, triaging RI patients is problematic due to ongoing kidney deterioration and the fact that such patients are prone to both vascular occlusions and bleeding. The authors summarize available FDA-confirmed evidence from the latest trials with approved antiplatelet agents, namely clopidogrel (CAPRIE, CURE, CREDO, CLARITY, CHARISMA); prasugrel (TRITON, TRILOGY); ticagrelor (PLATO, and PEGASUS); and vorapaxar (TRACER and TRA2P) in RI patient cohorts on top of aspirin as part of dual antiplatelet therapy (DAPT). We deliberately avoided any results unless they were verified by the FDA, with the exception of the recent PEGASUS, since Agency reviews are not yet available. Despite differences among the trials and DAPT choices, RI patients universally experience much higher (HR = 1.3-3.1) rates of primary endpoint events, and bleeding risks (HR = 1.7-3.6). However, only ticagrelor increases creatinine and uric acid levels above that of clopidogrel; has the worst incidence of serious adverse events, more adverse events, and inferior outcomes in patients with severe (eGFR <30 ml/min), especially in the lowest (eGFR <15 ml/min) RI subsets. Clopidogrel, prasugrel and vorapaxar appear safer. Moreover, less aggressive half dose (5 mg/daily) prasugrel and strict DAPT, are well justified in RI, but not predominantly triple strategies with vorapaxar as tested in TRA2P and especially in TRACER. In conclusion, data from clinical trials, their sub-studies and affiliated FDA reviews indicate that RI cause more vascular occlusions and bleeding in ACS patients treated with DAPT. Among the novel antiplatelet agents, prasugrel and vorapaxar, but probably not ticagrelor, offer advantage in RI patients. © 2015 Taylor & Francis.


News Article | December 23, 2015
Site: www.materialstoday.com

The stability, selectivity and activity of nanocatalysts depend on the electronic interactions between the metal particles and their oxide support. Understanding the nature of the electron transfer across the metal/surface interface is key to improving such catalysts. A European team has now used synchrotron radiation photoelectron spectroscopy, scanning tunneling microscopy and density functional theory to determine the charge transfer per platinum atom and how this is greatest for particles containing approximately fifty platinum atoms. Noble metal nanoparticle catalysts on oxides are a class of the most common catalytic materials used across the chemical industry, in fuel production, as environmental catalysts, photocatalysts and electrocatalysts. Efficient use of the expensive and rare metal elements they contain is a priority, so chemists and materials scientists are constantly on the lookout for new ways to improve efficacy and efficiency. The details are controversial and have been for thirty years. What is known with certainty is that electronic structure, nanoscopic structure, structural flexibility and interaction with the support are the major factors in determining how well such catalysts function. Writing in the journal Nature Materials, the team also showed that one electron is transferred for every ten platinum atoms from the nanoparticle to the support. By contrast, for larger particles, the charge transfer limit is established by the support whereas nucleation effects partially inhibit charge transfer in smaller particles. "These mechanistic and quantitative insights into charge transfer will help to make better use of particle size effects and electronic metal–support interactions in metal/oxide nanomaterials," the team reports. The team comprises scientists from SISSA and CNR-IOM of Trieste, the University of Barcelona, Spain, ELETTRA Sincrotrone Trieste, Italy, Friedrich Alexander Universität Erlangen-Nürnberg, Germany and Univerzita Karlova of Prague, Czech Republic. "By combining experimental measurements and theoretical numerical simulations, we established guidelines for controlling the charge of nanoparticles and obtaining catalysts having maximum efficiency," explains team member Stefano Fabris of the CNR-IOM/SISSA. "The experimental measurements were carried out by researchers from the University of Prague at ELETTRA Sincrotrone Trieste, whereas the simulations were the result of my collaboration with the University of Barcelona." If industrial production of methanol as feedstock for fuel cells can be scaled up sustainably, perhaps by using a light-driven system that in some ways mimics photosynthesis, then the catalysts studied by the European team could be critical in releasing the pent up energy from that methanol as electricity generated in a fuel cell. David Bradley blogs at Sciencebase Science Blog and tweets @sciencebase, he is author of the bestselling science book "Deceived Wisdom".

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