Aberrant glioblastoma neovascularization patterns and their correlation with DCE-MRI-derived parameters following temozolomide and bevacizumab treatment.
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ABSTRACT:
SUBMITTER: Xue W
PROVIDER: S-EPMC5654943 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The compartment model analysis using medical imaging data is the well-established but extremely time consuming technique for quantifying the changes in microvascular physiology of targeted organs in clinical patients after antivascular therapies. In this paper, we present a first graphics processing unit-accelerated method for compartmental modeling of medical imaging data. Using this approach, we performed the analysis of dynamic contrast-enhanced magnetic resonance imaging data from bevacizumab-treated glioblastoma patients in less than one minute per slice without losing accuracy. This approach reduced the computation time by more than 120-fold comparing to a central processing unit-based method that performed the analogous analysis steps in serial and more than 17-fold comparing to the algorithm that optimized for central processing unit computation. The method developed in this study could be of significant utility in reducing the computational times required to assess tumor physiology from dynamic contrast-enhanced magnetic resonance imaging data in preclinical and clinical development of antivascular therapies and related fields.
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Project description:There is limited evidence that imaging biomarkers can predict subsequent response to therapy. Such prognostic and/or predictive biomarkers would facilitate development of personalised medicine. We hypothesised that pre-treatment measurement of the heterogeneity of tumour vascular enhancement could predict clinical outcome following combination anti-angiogenic and cytotoxic chemotherapy in colorectal cancer (CRC) liver metastases.Ten patients with 26 CRC liver metastases had two dynamic contrast-enhanced MRI (DCE-MRI) examinations before starting first-line bevacizumab and FOLFOX-6. Pre-treatment biomarkers of tumour microvasculature were computed and a regression analysis was performed against the post-treatment change in tumour volume after five cycles of therapy. The ability of the resulting linear model to predict tumour shrinkage was evaluated using leave-one-out validation. Robustness to inter-visit variation was investigated using data from a second baseline scan.In all, 86% of the variance in post-treatment tumour shrinkage was explained by the median extravascular extracellular volume (v(e)), tumour enhancing fraction (E(F)), and microvascular uniformity (assessed with the fractal measure box dimension, d(0)) (R(2)=0.86, P<0.00005). Other variables, including baseline volume were not statistically significant. Median prediction error was 12%. Equivalent results were obtained from the second scan.Traditional image analyses may over-simplify tumour biology. Measuring microvascular heterogeneity may yield important prognostic and/or predictive biomarkers.
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Project description:In previous trials, bevacizumab failed to prolong the overall survival time in newly diagnosed glioblastoma and at the first recurrence. Randomized clinical trials at the second or further recurrence following the failure of radiotherapy, temozolomide and lomustine, and retrospective analyses focusing on this specific cohort, are not yet available. A total of 62 patients with glioblastoma who received bevacizumab after the failure of standard care, including radiotherapy, temozolomide and lomustine, were retrospectively identified. Patient characteristics, previous treatment details, concomitant therapy, response based on the Response Assessment in Neuro-Oncology criteria, and progression-free survival (PFS) and overall survival (OS) times and rates were evaluated. Furthermore, the PFS and OS times and rates were analyzed for responders and non-responders. Of the patients, 54.8% (n=34) responded to treatment [complete response (CR) 3.2%, n=2; partial response (PR) 51.6%, n=32]. The median PFS time was 3.5 months and the median OS time was 7.5 months. The PFS rate at 6 months was 21.5% and the OS rate at 12 months was 11.5%. Responders (CR or PR) experienced a superior median PFS time compared with non-responders (i.e. stable or progressive disease; 5.4 vs. 1.9 months; P<0.0001) and a superior PFS rate at 6 months (34.9 vs. 7.1%; P<0.0001). The median OS time (8.6 vs. 6.4 months; P<0.0001) and OS rate at 12 months (21.3 vs. 0%; P<0.0001) were also superior in patients who exhibited a response to bevacizumab treatment. In conclusion, the objective response rate and the PFS and OS times and rates indicate that bevacizumab has activity in patients with glioblastoma following the failure of radiotherapy, temozolomide, and lomustine. A randomized trial comparing bevacizumab with best supportive care in these patients is advised.
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Project description:PurposeIn dynamic contrast enhanced (DCE) MRI, separation of signal contributions from perfusion and leakage requires robust estimation of parameters in a pharmacokinetic model. We present and quantify the performance of a method to compute tissue hemodynamic parameters from DCE data using established pharmacokinetic models.MethodsWe propose a Bayesian scheme to obtain perfusion metrics from DCE MRI data. Initial performance is assessed through digital phantoms of the extended Tofts model (ETM) and the two-compartment exchange model (2CXM), comparing the Bayesian scheme to the standard Levenberg-Marquardt (LM) algorithm. Digital phantoms are also invoked to identify limitations in the pharmacokinetic models related to measurement conditions. Using computed maps of the extra vascular volume (ve) from 19 glioma patients, we analyze differences in the number of un-physiological high-intensity ve values for both ETM and 2CXM, using a one-tailed paired t-test assuming un-equal variance.ResultsThe Bayesian parameter estimation scheme demonstrated superior performance over the LM technique in the digital phantom simulations. In addition, we identified limitations in parameter reliability in relation to scan duration for the 2CXM. DCE data for glioma and cervical cancer patients was analyzed with both algorithms and demonstrated improvement in image readability for the Bayesian method. The Bayesian method demonstrated significantly fewer non-physiological high-intensity ve values for the ETM (p<0.0001) and the 2CXM (p<0.0001).ConclusionWe have demonstrated substantial improvement of the perceptive quality of pharmacokinetic parameters from advanced compartment models using the Bayesian parameter estimation scheme as compared to the LM technique.
| S-EPMC6317807 | biostudies-literature
Project description:The purpose of this study was to assess the impact of bevacizumab alone and in combination with cytotoxic therapy on tumour vasculature in osteosarcoma (OS) using DCE-MRI.Six DCE-MRI and three (18)F-FDG PET examinations were scheduled in 42 subjects with newly diagnosed OS to monitor the response to antiangiogenic therapy alone and in combination with cytotoxic therapy before definitive surgery (week 10). Serial DCE-MRI parameters (K(trans), v(p), and v(e)) were examined for correlation with FDG-PET (SUV(max)) and association with drug exposure, and evaluated with clinical outcome.K(trans) (P=0.041) and v(p) (P=0.001) significantly dropped from baseline at 24 h after the first dose of bevacizumab alone, but returned to baseline by 72?h. Greater exposure to bevacizumab was correlated with larger decreases in v(p) at day 5 (P=0.04) and week 10 (P=0.02). A lower K(trans) at week 10 was associated with greater percent necrosis (P=0.024) and longer event-free survival (P=0.034).This is the first study to demonstrate significant changes of the plasma volume fraction and vascular leakage in OS with bevacizumab alone. The combination of demonstrated associations between drug exposure and imaging metrics, and imaging metrics and patient survival during neoadjuvant therapy, provides a compelling rationale for larger studies using DCE-MRI to assess vascular effects of therapy in OS.
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Project description:Lessons learnedTrials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy.Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted.BackgroundExtent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM.MethodsPatients received up to 4 cycles of TMZ at 200 mg/m(2) per day on days 1-5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m(2) or 340 mg/m(2) depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater.ResultsForty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial response, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2-13.5 months).ConclusionUpfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM.
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Project description:Although there have been a plethora of radiogenomics studies related to glioblastoma (GBM), most of them only used genomic information from tumor cells. In this study, we used radiogenomics profiling to identify MRI-associated immune cell markers in GBM, which was also correlated with prognosis. Expression levels of immune cell markers were correlated with quantitative MRI parameters in a total of 60 GBM patients. Fourteen immune cell markers (i.e., CD11b, CD68, CSF1R, CD163, CD33, CD123, CD83, CD63, CD49d and CD117 for myeloid cells, and CD4, CD3e, CD25 and CD8 for lymphoid cells) were selected for RNA-level analysis using quantitative RT-PCR. For MRI analysis, quantitative MRI parameters from FLAIR, contrast-enhanced (CE) T1WI, dynamic susceptibility contrast perfusion MRI and diffusion-weighted images were used. In addition, PFS associated with interesting mRNA data was performed by Kaplan-Meier survival analysis. CD163, which marks tumor associated microglia/macrophages (TAMs), showed the highest expression level in GBM patients. CD68 (TAMs), CSF1R (TAMs), CD33 (myeloid-derived suppressor cell) and CD4 (helper T cell, regulatory T cell) levels were highly positively correlated with nCBV values, while CD3e (helper T cell, cytotoxic T cell) and CD49d showed a significantly negative correlation with apparent diffusion coefficient (ADC) values. Moreover, regardless of any other molecular characteristics, CD49d was revealed as one independent factor for PFS of GBM patients by Cox proportional-hazards regression analysis (P = 0.0002). CD49d expression level CD49d correlated with ADC can be considered as a candidate biomarker to predict progression of GBM patients.
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Project description:PurposeTumor hypoxia is a major cause of radiation resistance, often present in various solid tumors. Dynamic [18 F]-fluoromisonidazole (FMISO) PET imaging is able to reliably assess tumor hypoxia. Comprehensive characterization of tumor microenvironment through FMISO-PET and dynamic contrast enhanced (DCE) MR multimodality imaging might be a valuable alternative to the dynamic FMISO-PET acquisition. The aim of this work was to explore the correlation between the FMISO-PET and DCE-MRI kinetic parameters.MethodsThis study was done on head and neck cancer patients (N = 6), who were imaged dynamically with FMISO-PET and DCE-MRI on the same day. Images were registered and analyzed for kinetics on a voxel basis. FMISO-PET images were analyzed with the two-tissue compartment three rate-constant model. Additionally, tumor-to-muscle ratio (TMR) maps were evaluated. DCE-MRI was analyzed with the extended Tofts model. Voxel-wise Pearson's coefficients were calculated for each patient to assess pairwise parameter correlations.ResultsMedian correlations between FMISO uptake parameters and DCE-MRI kinetic parameters varied across the parameter pairs in the range from -0.05 to 0.71. The highest median correlation of r = 0.71 was observed for the pair Vb -vp , while the K1 -Ktrans median correlation was r = 0.45. Median correlation coefficients for the K1 -vp and the Ki -Ktrans pairs were r = 0.42 and r = 0.32, respectively. Correlations between FMISO uptake rate parameter Ki and DCE-MRI kinetic parameters varied substantially across the patients, whereas correlations between the FMISO and DCE-MRI vascular parameters were consistently high. Median TMR-K1 and TMR-Ktrans correlations were r = 0.52 and r = 0.46, respectively, but varied substantially across the patients.ConclusionsBased on this clinical evidence, we can conclude that the vascular fraction parameters obtained through DCE-MRI kinetic analysis or FMISO kinetic analysis measure the same biological property, while other kinetic parameters are unrelated. These results might be useful in the design of future clinical trials involving FMISO-PET/DCE-MR multimodality imaging for the assessment of tumor microenvironment.
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Project description:Patients with unresectable glioblastomas have a poor prognosis, with median survival of 6-10 months. We conducted a phase II trial of upfront 5-day temozolomide (TMZ) and bevacizumab (BV) in patients with newly diagnosed unresectable or multifocal glioblastoma. Patients received up to four cycles of TMZ at 200 mg/m(2) on days 1-5, and BV at 10 mg/kg on days 1 and 15 of a 28-day cycle. Brain magnetic resonance imaging (MRI) was performed monthly. Therapy was continued as long as there was no tumor progression, grade 4 nonhematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary end point was best tumor response as measured on MRI. Forty-one patients were accrued over 12 months; 39 had a full set of MRI scans available for evaluation. Assessment for best radiographic responses was as follows: partial responses in 24.4%, stable disease in 68.3%, and progressive disease in 2.4%. Treatment-related toxicities included seven grade 4 toxicities and one grade 5 toxicity (myocardial infarction). From this study, it was concluded that an upfront regimen of TMZ and BV for unresectable glioblastoma was well tolerated and provided a significant level of disease stabilization. Therapeutic toxicities were consistent with those seen in the adjuvant setting using these agents. The upfront approach to treatment of glioblastoma in the unresectable population warrants further investigation in randomized controlled phase III trials.
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