Van Meirhaeghe J.,Dienst Orthopedie en Traumatologie |
Bastian L.,Klinikum Leverkusen |
Ranstam J.,Lund University |
Tillman J.B.,Medtronic Inc. |
Wardlaw D.,Woodend Hospital
Spine | Year: 2013
Objective. To compare the efficacy and safety of balloon kyphoplasty (BKP) with nonsurgical management (NSM) during 24 months in patients with painful vertebral compression fractures (VCFs). Summary of Background Data. Recently, several large randomized controlled trials have been conducted and reported how vertebral augmentation compares with NSM for patients with acute VCFs. Few of these trials report on the surgical aspects and radiographical vertebral deformity results. Methods. Adults with 1 to 3 VCFs were randomized within 3 months of pain to undergo bilateral BKP (n = 149) or NSM (n = 151). Surgical parameters, subjective quality of life assessments and objective functional (timed up and go) and radiographical assessments were collected. Results. Compared with NSM, the BKP group had greater improvements in SF-36 physical component summary (PCS) scores at 1 month (5.35 points; 95% CI, 3.41 - 7.30; P < 0.0001) and when averaged across the 24 months (overall treatment effect 2.71 points; 95% CI, 1.34-4.09; P = 0.0001). The kyphoplasty group also had greater functionality by assessing timed up and go (overall treatment effect - 2.49 s; 95% CI, - 0.82 to - 4.15; P = 0.0036). At 24 months, the change in index fracture kyphotic angulation was statistically significantly improved in the kyphoplasty group (average 3.13° of correction for kyphoplasty compared with 0.82° in the control, P = 0.003). Number of baseline prevalent fractures (P = 0.0003) and treatment assignment (P = 0.004) are the most predictive variables for PCS improvement; however, in patients who underwent BKP, there may also be a link with kyphotic angulation. In BKP, the highest quart for kyphotic angulation correction had higher PCS improvement (13.4 points) than the quart having lowest correction of angulation (7.40 points, P = 0.0146 for difference). The most common adverse events temporally related to surgery (i.e., within 30 d) were back pain (20 BKP, 11 NSM) new VCF (11 BKP, 7 NSM), nausea/vomiting (12 BKP, 4 NSM), and urinary tract infection (10 BKP, 3 NSM). Several other adverse events were possibly related to patient positioning in the operating room. Conclusion. Compared with NSM, BKP improves patient quality of life and pain averaged during 24 months and results in better improvement of index vertebral body kyphotic angulation. Perioperative complications may be reduced with more care in patient positioning. Copyright © 2013 Lippincott Williams & Wilkins.
Gluer C.-C.,Universitatsklinikum Schleswig Holstein |
Marin F.,Lilly Research Center |
Ringe J.D.,Klinikum Leverkusen |
Hawkins F.,Hospital 12 Of Octubre |
And 17 more authors.
Journal of Bone and Mineral Research | Year: 2013
Data on treatment of glucocorticoid-induced osteoporosis (GIO) in men are scarce. We performed a randomized, open-label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T-score ≤ -1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1-L3) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high-resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X-ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18-month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE-derived strength than risedronate. Copyright © 2013 American Society for Bone and Mineral Research.
Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: An open-label, multicentre, randomised, phase 3 non-inferiority trial
Rummel M.J.,Justus Liebig University |
Niederle N.,Klinikum Leverkusen |
Maschmeyer G.,Ernst von Bergmann Klinikum |
Banat G.A.,Justus Liebig University |
And 16 more authors.
The Lancet | Year: 2013
Background: Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas. Methods: We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m2 on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m2 on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335. Findings: 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69·5 months [26·1 to not yet reached] vs 31·2 months [15·2-65·7]; hazard ratio 0·58, 95% CI 0·44-0·74; p<0·0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p<0·0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0·0001), infections (96 [37%] vs 127 [50%]); p=0·0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0·0001), and stomatitis (16 [6%] vs 47 [19%]; p<0·0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0·024). Interpretation: In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects. Funding: Roche Pharma AG, Ribosepharm/Mundipharma GmbH.
Boonen S.,Catholic University of Leuven |
Boonen S.,Woodend Hospital |
Van Meirhaeghe J.,Dienst Orthopedie en Traumatologie |
Bastian L.,Klinikum Leverkusen |
And 6 more authors.
Journal of Bone and Mineral Research | Year: 2011
Vertebral fractures are often painful and lead to reduced quality of life and disability. We compared the efficacy and safety of balloon kyphoplasty to nonsurgical therapy over 24 months in patients with acute painful fractures. Adults with one to three vertebral fractures were randomized within 3 months from onset of pain to undergo kyphoplasty (n = 149) or nonsurgical therapy (n = 151). Quality of life, function, disability, and pain were assessed over 24 months. Kyphoplasty was associated with greater improvements in Short-Form 36 (SF-36) Physical Component Summary (PCS) scores when averaged across the 24-month follow-up period compared with nonsurgical therapy [overall treatment effect 3.24 points, 95% confidence interval (CI) 1.47-5.01, p = .0004]; the treatment difference remained statistically significant at 6 months (3.39 points, 95% CI 1.13-5.64, p = .003) but not at 12 months (1.70 points, 95% CI -0.59 to 3.98, p = .15) or 24 months (1.68 points, 95% CI -0.63 to 3.99, p = .15). Greater improvement in back pain was observed over 24 months for kyphoplasty (overall treatment effect -1.49 points, 95% CI -1.88 to -1.10, p < .0001); the difference between groups remained statistically significant at 24 months (-0.80 points, 95% CI -1.39 to -0.20, p = .009). There were two device-related serious adverse events in the second year that occurred at index vertebrae (a spondylitis and an anterior cement migration). There was no statistically significant difference between groups in the number of patients (47.5% for kyphoplasty, 44.1% for control) with new radiographic vertebral fractures; fewer fractures occurred (∼18%) within the second year. Compared with nonsurgical management, kyphoplasty rapidly reduces pain and improves function, disability, and quality of life without increasing the risk of additional vertebral fractures. The differences from nonsurgical management are statistically significant when averaged across 24 months. Most outcomes are not statistically different at 24 months, but the reduction in back pain remains statistically significant at all time points. Copyright © 2011 American Society for Bone and Mineral Research.
Berenson J.,Institute for Myeloma and Bone Cancer Research |
Pflugmacher R.,Universitatskinikum Bonn |
Jarzem P.,McGill University |
Zonder J.,Barbara Ann Karmanos Cancer Institute |
And 5 more authors.
The Lancet Oncology | Year: 2011
Background: Non-randomised trials have reported benefits of kyphoplasty in patients with cancer and vertebral compression fractures (VCFs). We aimed to assess the efficacy and safety of balloon kyphoplasty compared with non-surgical management for patients with cancer who have painful VCFs. Methods: The Cancer Patient Fracture Evaluation (CAFE) study was a randomised controlled trial at 22 sites in Europe, the USA, Canada, and Australia. We enrolled patients aged at least 21 years who had cancer and one to three painful VCFs. Patients were randomly assigned by a computer-generated minimisation randomisation algorithm to kyphoplasty or non-surgical management (control group). Investigators and patients were not masked to treatment allocation. The primary endpoint was back-specific functional status measured by the Roland-Morris disability questionnaire (RDQ) score at 1 month. Outcomes at 1 month were analysed by modified intention to treat, including all patients with data available at baseline and at 1 month follow-up. Patients in the control group were allowed to crossover to receive kyphoplasty after 1 month. This study is registered with ClinicalTrials.gov, NCT00211237. Findings: Between May 16, 2005, and March 11, 2008, 134 patients were enrolled and randomly assigned to kyphoplasty (n=70) or non-surgical management (n=64). 65 patients in the kyphoplasty group and 52 in the control group had data available at 1 month. The mean RDQ score in the kyphoplasty group changed from 17·6 at baseline to 9·1 at 1 month (mean change -8·3 points, 95% CI -6·4 to -10·2; p<0·0001). The mean score in the control group changed from 18·2 to 18·0 (mean change 0·1 points; 95% CI -0·8 to 1·0; p=0·83). At 1 month, the kyphoplasty treatment effect for RDQ was -8·4 points (95% CI -7·6 to -9·2; p<0·0001). The most common adverse events within the first month were back pain (four of 70 in the kyphoplasty group and five of 64 in the control group) and symptomatic vertebral fracture (two and three, respectively). One patient in the kyphoplasty group had an intraoperative non-Q-wave myocardial infarction, which resolved and was attributed to anaesthesia. Another patient in this group had a new VCF, which was thought to be device related. Interpretation: For painful VCFs in patients with cancer, kyphoplasty is an effective and safe treatment that rapidly reduces pain and improves function. Funding: Medtronic Spine LLC. © 2011 Elsevier Ltd.
Alternative analyses for handling incomplete follow-up in the intention-to-treat analysis: The randomized controlled trial of balloon kyphoplasty versus non-surgical care for vertebral compression fracture (FREE)
Ranstam J.,Skåne University Hospital |
Turkiewicz A.,Skåne University Hospital |
Boonen S.,Leuven University Center for Metabolic Bone Diseases |
Van Meirhaeghe J.,Algemeen Ziekenhuis St Jan Bruges Oostende AV |
And 2 more authors.
BMC Medical Research Methodology | Year: 2012
Background: Clinical trial participants may be temporarily absent or withdraw from trials, leading to missing data. In intention-to-treat (ITT) analyses, several approaches are used for handling the missing information - complete case (CC) analysis, mixed-effects model (MM) analysis, last observation carried forward (LOCF) and multiple imputation (MI). This report discusses the consequences of applying the CC, LOCF and MI for the ITT analysis of published data (analysed using the MM method) from the Fracture Reduction Evaluation (FREE) trial. Methods. The FREE trial was a randomised, non-blinded study comparing balloon kyphoplasty with non-surgical care for the treatment of patients with acute painful vertebral fractures. Patients were randomised to treatment (1:1 ratio), and stratified for gender, fracture aetiology, use of bisphosphonates and use of systemic steroids at the time of enrolment. Six outcome measures - Short-form 36 physical component summary (SF-36 PCS) scale, EuroQol 5-Dimension Questionnaire (EQ-5D), Roland-Morris Disability (RMD) score, back pain, number of days with restricted activity in last 2 weeks, and number of days in bed in last 2 weeks - were analysed using four methods for dealing with missing data: CC, LOCF, MM and MI analyses. Results: There were no missing data in baseline covariates values, and only a few missing baseline values in outcome variables. The overall missing-response level increased during follow-up (1 month: 14.5%; 24 months: 28%), corresponding to a mean of 19% missing data during the entire period. Overall patterns of missing response across time were similar for each treatment group. Almost half of all randomised patients were not available for a CC analysis, a maximum of 4% were not included in the LOCF analysis, and all randomised patients were included in the MM and MI analyses. Improved estimates of treatment effect were observed with LOCF, MM and MI compared with CC; only MM provided improved estimates across all six outcomes considered. Conclusions: The FREE trial results are robust as the alternative methods used for substituting missing data produced similar results. The MM method showed the highest statistical precision suggesting it is the most appropriate method to use for analysing the FREE trial data. Trial Registration. This trial is registered with ClinicalTrials.gov (number NCT00211211). © 2012 Ranstam et al; licensee BioMed Central Ltd.
Wardlaw D.,Woodend Hospital |
Van Meirhaeghe J.,Dienst Orthopedie en Traumatologie |
Ranstam J.,Skåne University Hospital |
Bastian L.,Klinikum Leverkusen |
Boonen S.,Catholic University of Leuven
Expert Review of Medical Devices | Year: 2012
Balloon kyphoplasty (BKP) is a minimally invasive surgical procedure indicated for treatment of painful vertebral compression fractures. During BKP, cannulae are placed percutaneously into the vertebral body, allowing insertion of inflatable balloons. Inflating the balloons partially restores vertebral body height, compacts the bone and creates a cavity for placement of bone cement after balloon removal. Placement of the cement reduces and stabilizes the fracture. BKP differs from vertebroplasty in that it aims to restore vertebral height and reduce kyphotic deformity. Case reports and observational studies have consistently shown that BKP significantly reduces pain, increases mobility and functional capacity and improves quality of life for up to 3 years. Clinically significant adverse events have been rarely reported. These findings were confirmed in randomized and nonrandomized prospective controlled studies. The objective of this review is to describe the surgical procedures involved in BKP and to review the evidence supporting its use. © 2012 Expert Reviews Ltd.
PubMed | University of Auckland, Charité - Medical University of Berlin, Ludwig Maximilians University of Munich, Klinikum Leverkusen and 3 more.
Type: Journal Article | Journal: Blood | Year: 2016
The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients.
van Ahlen H.,Klinikum Osnabruck |
Zumbe J.,Klinikum Leverkusen |
Stauch K.,Bayer Vital GmbH |
Hanisch J.U.,Bayer Vital GmbH
Journal of Sexual Medicine | Year: 2010
Introduction: The Real-Life Safety and Efficacy of vardenafil study is an international, open-label, prospective, noncomparative, noninterventional study in men with erectile dysfunction (ED). Aim: To determine the safety and efficacy of vardenafil in a large international pool of men with ED (aged ≥18 years) and associated underlying conditions (N = 73,946), in a real-life setting. Methods: Patients attended an initial physician visit and one to two follow-up visits. Data were acquired by physician interviews and patient diaries and recorded in case report forms (CRFs). Data were pooled from 47 countries in Europe, Asia-Pacific, Latin America, and the rest of the world (excluding the United States and Japan for methodological reasons). Results were stratified by baseline ED severity, body mass index (BMI), and the presence of hypertension, diabetes, lipid metabolism disorder, or cardiovascular disease (CVD). Main Outcome Measures: CRFs and patient questionnaires containing questions on overall improvement of erection, satisfaction with efficacy, and desire to continue vardenafil use. Results: Many participants had hypertension (32.0%), diabetes (22.1%), lipid metabolism disorder (14.6%), or CVD (42.2%). High percentages of patients reported improvements in erectile function, irrespective of baseline ED severity (mild, 97.0%; moderate, 96.2%; severe, 85.5%), BMI (<25, 94.1%; ≥25 and <30, 94.6%; ≥30, 92.9%), or the presence of hypertension (93.6%), diabetes (92.6%), lipid metabolism disorder (94.7%), or CVD (93.3%). Over 90% of patients, including those with underlying conditions, reported being " satisfied" or " very satisfied" with vardenafil efficacy, and stated their intention to continue vardenafil use after the end of the study period. The incidence of adverse events was low, and 97.0% of patients were either " satisfied" or " very satisfied" with vardenafil tolerability. Conclusions: These data from a worldwide population of men with ED and associated underlying conditions show that vardenafil is effective and well-tolerated for the treatment of ED in a real-life setting, supporting its use as a first-line ED therapy. © 2010 International Society for Sexual Medicine.
MacK-Detlefsen B.,Kliniken der Stadt Koeln GGmbH |
Boemers T.M.,Kliniken der Stadt Koeln GGmbH |
Groneck P.,Klinikum Leverkusen |
Bald R.,Klinikum Leverkusen
Journal of Pediatric Surgery | Year: 2011
Placental mesenchymal dysplasia (PMD) is an uncommon disorder that has to be differentiated histologically from a partial mole. In contrast to a hydatitiform mole, PMD can coexist with a viable fetus. Placental mesenchymal dysplasia is characterized by placentomegaly and dilatation of the chorionic vessels. In our case, multiple hepatic mesenchymal hamartomas in a preterm were associated with PMD. This association is an extremely rare anomaly. Mesenchymal hamartomas occur in 5% of all primary liver tumors in children and are generally benign lesions. © 2011 Elsevier Inc.