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Bois A.D.,Kliniken Essen Mitte | Bois A.D.,University of Oslo | Kristensen G.,University of Lyon | Ray-Coquard I.,Italian National Cancer Institute | And 26 more authors.
The Lancet Oncology | Year: 2016

Background: Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. Methods: In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m2) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. Findings: Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). Interpretation: Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. Funding: Boehringer Ingelheim. © 2016 Elsevier Ltd.


PubMed | University Utrecht, UMC St. Radboud Nijmegen, University of Toronto, Leiden University and 7 more.
Type: Journal Article | Journal: PloS one | Year: 2014

High bilirubin/albumin (B/A) ratios increase the risk of bilirubin neurotoxicity. The B/A ratio may be a valuable measure, in addition to the total serum bilirubin (TSB), in the management of hyperbilirubinemia. We aimed to assess whether the additional use of B/A ratios in the management of hyperbilirubinemia in preterm infants improved neurodevelopmental outcome.In a prospective, randomized controlled trial, 615 preterm infants of 32 weeks gestation or less were randomly assigned to treatment based on either B/A ratio and TSB thresholds (consensus-based), whichever threshold was crossed first, or on the TSB thresholds only. The primary outcome was neurodevelopment at 18 to 24 months corrected age as assessed with the Bayley Scales of Infant Development III by investigators unaware of treatment allocation. Secondary outcomes included complications of preterm birth and death.Composite motor (100 13 vs. 101 12) and cognitive (101 12 vs. 101 11) scores did not differ between the B/A ratio and TSB groups. Demographic characteristics, maximal TSB levels, B/A ratios, and other secondary outcomes were similar. The rates of death and/or severe neurodevelopmental impairment for the B/A ratio versus TSB groups were 15.4% versus 15.5% (P = 1.0) and 2.8% versus 1.4% (P = 0.62) for birth weights 1000 g and 1.8% versus 5.8% (P = 0.03) and 4.1% versus 2.0% (P = 0.26) for birth weights of >1000 g.The additional use of B/A ratio in the management of hyperbilirubinemia in preterm infants did not improve their neurodevelopmental outcome.Controlled-Trials.com ISRCTN74465643.


PubMed | Gynecologic Oncology Center, Coordinating Center for Clinical Trials, Jan Kochanowski University, University of Duisburg - Essen and 21 more.
Type: Clinical Trial, Phase III | Journal: The Lancet. Oncology | Year: 2016

Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer.In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118.Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (172 months [95% CI 166-199] vs 166 months [139-191]; hazard ratio 084 [95% CI 072-098]; p=0024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown).Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability.Boehringer Ingelheim.


Joniau S.,Catholic University of Leuven | Abrahamsson P.-A.,Lund University | Bellmunt J.,Hospital Del Mar | Figdor C.,UMC St. Radboud Nijmegen | And 6 more authors.
European Urology | Year: 2012

Context: The first therapeutic cancer vaccine demonstrating effectiveness in a phase 3 study was approved by the US Food and Drug Administration on 29 April 2010. The pivotal trial demonstrated overall survival (OS) benefit in patients treated with antigen-loaded leukapheresis cells compared with a control infusion. Results of other prostate cancer (PCa) vaccination strategies are awaited, as this approach may herald a new era in the care for patients with advanced PCa. Objective: Consider effectiveness and safety of vaccination strategies in the treatment of PCa. Evidence acquisition: We searched three bibliographic databases (January 1995 through October 2010) for randomised phase 2 and 3 studies of vaccination strategies for PCa based on predetermined relevant Medical Subject Heading terms and free text terms. Evidence synthesis: Data from 3 randomised phase 3 and 10 randomised phase 2 vaccination trials are discussed with respect to clinical outcome in terms of progression-free survival and OS, toxicity, prostate-specific antigen (PSA) response, and immunologic response. Three phase 3 trials (D9901, D9902A, and D9902B) that enrolled a total of 737 patients, all controlled and double-blinded, tested the efficacy of sipuleucel-T. The largest of these three trials, called Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT), has demonstrated safety and effectiveness of sipuleucel-T (now marketed as Provenge) as measured by prolonged survival of 512 asymptomatic patients with metastatic castration-resistant PCa (mCRPC). The study showed a 4.1-mo median survival benefit in the sipuleucel-T vaccine-treated group compared with the control group (25.8 vs 21.7 mo; hazard ratio [HR]: 0.78; 95% confidence interval [CI], 0.62-0.98; p = 0.032) and extended 3-yr survival (31.7% vs 23.0%). In contrast, two phase 3 vaccination trials with a whole-tumour-cell mixture of two PCa cell lines (GVAX) and testing GVAX either alone or in combination with chemotherapy versus chemotherapy alone (VITAL1 and 2) were terminated prematurely based on futility and increased deaths. Other phase 2 vaccination trials testing different types of vaccines in castration-resistant PCa patients have been reported with variable outcomes. Notably, a controlled, double-blind, randomised phase 2 vaccine trial of PROSTVAC-VF, a recombinant viral vector containing complementary DNA encoding PSA, in 125 patients with chemotherapy-naïve, minimally symptomatic mCRPC also demonstrated safety but no significant effect on the time to disease progression. In comparison with controls (n = 40), PROSTVAC-VF-treated patients (n = 82) experienced longer median survival of 8.5 mo (25.1 vs 16.6 mo; HR: 0.56; 95% CI, 0.37-0.85; p = 0.0061) and extended 3-yr survival (30% vs 17%). In general, PCa vaccines are perceived to have less toxicity compared with current cytotoxic or targeted therapies. Evaluation of clinical efficacy of different vaccination strategies (eg, protein-, peptide- and DNA-based vaccines) in the context of properly designed and controlled phase 3 studies is warranted. Conclusions: Cancer vaccines represent a new paradigm in the treatment of PCa. The IMPACT trial showed improved survival but no difference in time to disease progression in mCRPC patients with minimal tumour burden. Observations in phase 2 and 3 trials pave the way for other vaccination approaches for this disease, raise questions regarding the most appropriate clinical trial designs, and underscore the importance of identifying biomarkers for antitumour effect to better implement such therapies. © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.


Van Der Geer S.,Catharina Hospital | Frunt M.,UMC St Radboud Nijmegen | Romero H.L.,TU Eindhoven | Dellaert N.P.,TU Eindhoven | And 4 more authors.
Journal of the European Academy of Dermatology and Venereology | Year: 2012

Background The number of skin cancer patients, especially patients with basal cell carcinoma (BCC), is rapidly increasing. Resources available at dermato-oncology units have not increased proportionally, which affects the throughput time of patients. Objective To assess the feasibility and safety of implementation of the one-stop-shop concept for the treatment of patients with BCC at a dermato-oncology unit. Methods A pilot study on a one-stop-shop concept for BCC was performed to investigate procedure safety and patient satisfaction. Fresh frozen sections were used to diagnose the tumours, and subsequently treatment with photodynamic therapy or excision was performed on the same day. Time spent in the hospital was measured and questionnaires were used to evaluate patient satisfaction. Results Sixteen patients, who together had 19 tumours, were included. Diagnoses were made within a mean time of 100 min (range 27-160 min). The mean throughput time was 4 hours and 7 min (range 60-420 min). No complications were observed, and patient satisfaction was high. Conclusion The one-stop-shop concept for the treatment of skin cancer patients is feasible and efficient for both patients and dermato-oncology units. Further research is necessary to investigate cost-effectiveness when larger patient groups are involved. © 2011 European Academy of Dermatology and Venereology.


Romero H.L.,TU Eindhoven | Dellaert N.P.,TU Eindhoven | van der Geer S.,Catharina Hospital | Frunt M.,UMC St Radboud Nijmegen | And 2 more authors.
Health Care Management Science | Year: 2013

Hospitals and health care institutions are facing the challenge of improving the quality of their services while reducing their costs. The current study presents the application of operations management practices in a dermatology oncology outpatient clinic specialized in skin cancer treatment. An interesting alternative considered by the clinic is the implementation of a one-stop-shop concept for the treatment of new patients diagnosed with basal cell carcinoma. This alternative proposes a significant improvement in the average waiting time that a patient spends between the diagnosis and treatment. This study is focused on the identification of factors that influence the average throughput time of patients treated in the clinic from the logistic perspective. A two-phase approach was followed to achieve the goals stated in this study. The first phase included an integrated approach for the deterministic analysis of the capacity using a demand-supply model for the hospital processes, while the second phase involved the development of a simulation model to include variability to the activities involved in the process and to evaluate different scenarios. Results showed that by managing three factors: the admission rule, resources allocation and capacity planning in the dermato-oncology unit throughput times for treatments of new patients can be decreased with more than 90 %, even with the same resource level. Finally, a pilot study with 16 patients was also conducted to evaluate the impact of implementing the one stop shop concept from a clinical perspective. Patients turned out to be satisfied with the fast diagnosis and treatment. © 2012 Springer Science+Business Media, LLC.


Bartelink L.R.,UMC St Radboud Nijmegen | Feitz W.F.,Radboud University Nijmegen | Kluivers K.B.,UMC St Radboud Nijmegen | Withagen M.I.J.,UMC St Radboud Nijmegen | Vierhout M.E.,UMC St Radboud Nijmegen
International Urogynecology Journal and Pelvic Floor Dysfunction | Year: 2011

The incidence of pelvic organ prolapse is 18% in women with bladder exstrophy. A vaginal t echnique to correct the prolapse may be preferable in these women with multiple abdominal operations in their histories. We have performed a modified Prolift™ procedure for the repair of severe uterine prolapse in two young women. A review of the literature is presented. © The Author(s) 2011.


PubMed | UMC St. Radboud Nijmegen, Radboud University Nijmegen and Netherlands Institute for Sea Research
Type: | Journal: Frontiers in microbiology | Year: 2014

Anaerobic ammonium oxidizing (anammox) bacteria are responsible for a significant portion of the loss of fixed nitrogen from the oceans, making them important players in the global nitrogen cycle. To date, marine anammox bacteria found in both water columns and sediments worldwide belong almost exclusively to Candidatus Scalindua species. Recently the genome assembly of a marine anammox enrichment culture dominated by Candidatus Scalindua profunda became available and can now be used as a template to study metagenome data obtained from various oxygen minimum zones (OMZs). Here, we sequenced genomic DNA from suspended particulate matter recovered at the upper (170 m deep) and center (600 m) area of the OMZ in the Arabian Sea by SOLiD and Ion Torrent technology. The genome of Candidatus Scalindua profunda served as a template to collect reads. Based on the mapped reads marine anammox Abundance was estimated to be at least 0.4% in the upper and 1.7% in the center area. Single nucleotide variation (SNV) analysis was performed to assess diversity of the Candidatus Scalindua populations. Most highly covered were the two diagnostic anammox genes hydrazine synthase (scal_01318c, hzsA) and hydrazine dehydrogenase (scal_03295, hdh), while other genes involved in anammox metabolism (narGH, nirS, amtB, focA, and ACS) had a lower coverage but could still be assembled and analyzed. The results show that Candidatus Scalindua is abundantly present in the Arabian Sea OMZ, but that the diversity within the ecosystem is relatively low.


Muradin M.S.M.,University Utrecht | Rosenberg A.J.W.P.,University Utrecht | Van Der Bilt A.,UMC Utrecht | Stoelinga P.J.W.,UMC St Radboud Nijmegen | Koole R.,University Utrecht
International Journal of Oral and Maxillofacial Surgery | Year: 2012

A previous report from the authors' department showed that a modified alar cinch suture combined with a muco-musculo-periosteal V-Y closure (mACVY) improves nasolabial mobility. To test if the improvements were equal to the range of nasolabial mobility in non-dysgnathic persons, a prospective study was carried out in 56 patients: 31 with mACVY, 25 with simple closing sutures (SCS) and 18 non-operated, angle class I volunteers. Standardized full facial frontal photographs, taken immediately preoperatively and 18 months postoperatively were used. The landmarks, alare, crista philtri and cheilion were analysed. The test has a standard deviation of 0.9 mm. Intra-group changes, paired t-test, and inter-group differences, unpaired t-test (p < 0.05) were statistically analysed. The results show significant preoperative differences in nasolabial mobility compared with the control group, for both groups. Postoperative mobility improved in both groups, but significantly with mACVY with horizontal movement of cheilion and alare, and the vertical movement of crista philtri and less so for the vertical movement of crista philtri with SCS. Postoperative inter-group differences in mobility were small and significant for SCS vs the control group. It can be concluded that using mACVY improves orofacial movement to the level of normal class I volunteers. © 2011 International Association of Oral and Maxillofacial Surgeonss. Published by Elsevier Ltd. All rights reserved.

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