Showing papers by "W. Peter Vandertop published in 2015"

Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria

Abstract: Methods. A multicenter retrospective cohort study was performed in the Netherlands, the UK, and Germany with central review of clinical data and MRI scans of children with DIPG. Cox proportional hazards with backward regression was used to select prognostic variables (P , .05) to predict the accumulated 12-month risk of death. These predictors were transformed into a practical risk score. The model’s performance was validated by bootstrapping techniques. Results. A total of 316 patients were included. The median overall survival was 10 months. Multivariate Cox analysis yielded 5 prognostic variables of which the coefficients were included in the risk score. Age ≤3 years, longer symptom duration at diagnosis, and use of oral and intravenous chemotherapy were favorable predictors, while ring enhancement on MRI at diagnosis was an unfavorable predictor. With increasing risk score categories, overall survival decreased significantly. The model can distinguish between patients with very short, average, and increased overall survival (medians of 7.0, 9.7, and 13.7 mo, respectively). The area under the receiver operating characteristic curve was 0.68. Conclusions. We developed a DIPG survival prediction tool that can be used to predict the outcome of patients and for stratification in trials. Validation of the model is needed in a prospective cohort.

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

Abstract: Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1(R132H), a structural alteration that leads to catalysis of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1(R132H) that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1(R132H) mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1(R132H) inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1(R132H) inhibitors in these patients may limit irradiation efficacy in this setting.

A twenty-year review of diagnosing and treating children with diffuse intrinsic pontine glioma in The Netherlands.

Abstract: Introduction: Children with diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis, with a median overall survival of 9 months. Our aims are to determine the incidence of DIPG in the Netherlands and to identify points for improvement in clinical research, a prerequisite for increasing the chance to find a cure. Methods: We performed a population-based retrospective cohort study by evaluating all children diagnosed with DIPG in the Netherlands between 1990 and 2010. Results: The incidence of DIPG in the Netherlands corresponds with international literature. Between 1990 and 2010, a large heterogeneity of treatment schedules was applied and only a minority of patients was included in clinical trials. Discussion: Given the rarity of DIPG, we emphasize the need for (inter-)national trials to facilitate the identification of potentially effective therapeutics in the future. This can be supported by the recent development of a European DIPG registry enabling international study collaborations.

Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis.

Abstract: Drug resistance is a major issue in the treatment of glioblastoma Almost all glioblastomas are intrinsically resistant to chemotherapeutic temozolomide (TMZ) or develop resistance during treatment The interaction networks of microRNAs (miRNAs) and mRNAs likely regulate most biological processes and can be employed to better understand complex processes including drug resistance in cancer In this study, we examined if integrative miRNA/mRNA network analysis using the web-service tool mirConnX could be used to identify drug resistance factors in glioblastoma We used TMZ-resistant glioblastoma cells and their integrated miRNA/mRNA networks to identify TMZ-sensitizing factors TMZ resistance was previously induced in glioblastoma cell lines U87, Hs683, and LNZ308 miRNA/mRNA expression profiling of these cells and integration of the profiles using mirConnX resulted in the identification of plant homeodomain (PHD)-like finger 6 (PHF6) as a potential TMZ-sensitizing factor in resistant glioblastoma cells Analysis of PHF6 expression showed significant upregulation in glioblastoma as compared to normal tissue Interference with PHF6 expression in three TMZ-resistant subclones significantly enhanced TMZ-induced cell kill in two of these cell lines Altogether, these results demonstrate that mirConnX is a feasible and useful tool to investigate miRNA/mRNA interactions in TMZ-resistant cells and has potential to identify drug resistance factors in glioblastoma

Yield of spinal imaging in nonaneurysmal, nonperimesencephalic subarachnoid hemorrhage

Abstract: Objective: We studied the yield of MRI of the spinal neuraxis in patients with nonperimesencephalic subarachnoid hemorrhage (NPSAH). Methods: In a prospective, multicenter study, we performed T1-weighted and T2-weighted MRI of the spinal axis in a consecutive series of patients with a spontaneous NPSAH without intracranial vascular pathology on intracranial vascular imaging. Results: A spinal origin of the hemorrhage was found in 3 of 75 patients (4%; 95% confidence interval 0–8.4). The lesions were 1 lumbar ependymoma and 2 cervical cavernous malformations. All 3 patients presented without focal neurologic deficits and 2 had a CT-negative subarachnoid hemorrhage but positive lumbar puncture. Patients with a spinal origin were younger than patients without a spinal origin (38 vs 56 years; p Conclusions: The yield and clinical relevance of MRI of the spinal axis in patients who present with NPSAH is low. We do not recommend routine MRI of the spinal axis in this patient population, but it might be justified in a subgroup of patients.

Time Course and Risk Factors for Myocardial Dysfunction After Aneurysmal Subarachnoid Hemorrhage

Abstract: Background: Myocardial wall motion abnormalities (WMAs) are independent risk factors for a poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE: To study the time course of WMAs during the initial phase after aSAH and to investigate which clinical, electrocardiographic, or myocardial serum markers are predictors of early or late development of WMAs. METHODS: In a prospective, multicenter cohort study in patients with aSAH, we performed serial electrocardiography and echocardiography and measured troponin T and N-terminal pro-B-type natriuretic peptide. WMAs present on admission were considered early WMAs; those that developed during the clinical course were considered late WMAs. Using multivariable regression analysis, we calculated odds ratios with corresponding 95% confidence intervals for clinical parameters, electrocardiography, and myocardial serum makers with early or late occurrence of WMAs. RESULTS: We included 301 patients (mean age ± SD, 57 ± 13) years. Multivariable odds ratios for early WMAs were poor clinical condition, 2.7 (95% confidence interval: 1.1-6.8); sinus tachycardia, 5.0 (1.3-19.9); ST-segment depression, 3.7 (1.02-13.1); ST-segment elevation, 16.6 (1.5-178.9); and increased troponin T, 2.8 (1.1-7.3). Multivariable odds ratios (95% confidence intervals) for late development of WMAs were 6.8 (1.6-30) for a myocardial infarct pattern on admission electrocardiography and 3.4 (1.4-8.5) for increased troponin T on admission. CONCLUSION: WMAs may be present on admission or develop during the course of aSAH. Poor neurological condition on admission, sinus tachycardia, ST-segment depression, and ST-segment elevation on admission electrocardiography and increased troponin T are independent predictors of early WMAs; a myocardial infarct pattern on admission ECG and increased troponin T independently predict late WMAs. CLINICAL TRIAL REGISTRATION: NCT00123695. ABBREVIATIONS: aSAH, aneurysmal subarachnoid hemorrhage CI, confidence interval ECG, electrocardiography OR, odds ratio WMA, wall motion abnormality.

Bioluminescence-mediated longitudinal monitoring of adipose-derived stem cells in a large mammal ex vivo organ culture

Abstract: Recently, ex vivo three-dimensional organ culture systems have emerged to study the physiology and pathophysiology of human organs. These systems also have potential as a translational tool in tissue engineering; however, this potential is limited by our ability to longitudinally monitor the fate and action of cells used in regenerative therapies. Therefore, we investigated luciferase-mediated bioluminescence imaging (BLI) as a non-invasive technique to continuously monitor cellular behavior in ex vivo whole organ culture. Goat adipose-derived stem cells (gADSCs) were transduced with either Firefly luciferase (Fluc) or Gaussia luciferase (Gluc) reporter genes and injected in isolated goat intervertebral discs (IVD). Luciferase activity was monitored by BLI for at least seven days of culture. Additionally, possible confounders specific to avascular organ culture were investigated. Gluc imaging proved to be more suitable compared to Fluc in monitoring gADSCs in goat IVDs. We conclude that BLI is a promising tool to monitor spatial and temporal cellular behavior in ex vivo organ culture. Hence, ex vivo organ culture systems allow pre-screening and pre-validation of novel therapeutic concepts prior to in vivo large animal experimentation. Thereby, organ culture systems can reduce animal use, and improve the speed of innovation by overcoming technological, ethical and financial challenges.