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Amide Proton Transfer-Weighted (APTw) MRI as a Marker for Risk Stratification of Overall Survival in Patients with Lower Grade Gliomas1Johns Hopkins University, Baltimore, MD, United States, 2Zhujiang Hospital,Southern Medical University, guangzhou, MD, United States, 3Whiting School of Engineering, Baltimore, MD, United States, 4Department of Epidemiology and Health Statistics, School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, China
Synopsis
We explored the possibility of using the APTw signal intensity as a noninvasive imaging marker for stratifying the risk of overall survival (OS) in patients with lower grade gliomas. 108 patients with newly diagnosed grade-II/III gliomas were included. APTw histogram data were recorded. Routine MRI based descriptors, clinical parameters, and OS were collected. According to the multiple Cox regression models, higher APTw value and IDH-wildtype together showed significant predictive power for shorter OS in the cohort of patients with lower grade gliomas. APTw MRI has potential for preoperative MRI evaluation of lower grade gliomas in terms of predicting patient outcomes.
Purpose
The recent breakthrough in the understanding of genetic features in gliomas, such as isocitrate dehydrogenase (IDH) mutations, has resulted in a reappraisal of the molecular oncogenesis of this group of tumors (1). Notably, a new research direction in cancer imaging, referred to as radiogenomics or imaging genomics, has emerged that focuses on the relationship between imaging phenotypes and genomics (2-4). However, whether certain imaging modality derived biomarkers have a role as prognostic or predictive indicators of clinical outcome in patients is still virtually unaddressed (7). APTw imaging (5, 6), a type of chemical exchange saturation transfer (CEST) imaging (7-11), is a novel molecular MRI technique that generates contrast based mainly on protein content and a few other factors. This technique has shown great diagnostic performance for grading tumor and assessing treatment response in patients with gliomas (12, 13). The purpose of this study was to determine the capability of APTw-MRI to, preoperatively, stratify risk of overall survival in patients with lower grade gliomas.Methods
Subjects:
This retrospective study was approved by the institutional review board, and written, informed consent was waived. Between 5/2013 and 1/2016, 108 newly diagnosed patients (confirmed histopathologically as grade-II or -III gliomas with the IDH1/2 lab test results), were continuously enrolled and had complete APTw and routine MRI assessment before surgery (surgeries were undergone within two weeks after MRI scanning), with the last follow-up more than 30 months after APTw MRI scanning.
MRI Data Acquisition:
All patients were scanned on a Philips 3T MRI system. The sequences used for each patient included T1w, T2w, FLAIR, APTw imaging, and gadolinium-enhanced T1w MRI. A multi-offset, multi-acquisition imaging acquisition scheme (12) was used for APTw imaging (saturation power=2 μT; saturation time=800 ms). APTw images were calculated using a magnetization transfer ratio asymmetry at ±3.5ppm.
Image analysis:
Quantitative APTw image analysis was performed by a neuroradiologist. or each patient, one large ROI covering the whole contour of hyperintensity on FLAIR was drawn. The APTw signal intensities compared with the contralateral normal brain area were reported. The mean APTw value of “tumor core” (core APTw), and APTw intensity histogram metrics (mean, STDV, peak, 10th, 25th, 50th, 75th, 90th percentiles, and interquartile range (IQR)) in “whole tumor” were obtained.
Other Risk factors collection:
Pathological index, routine MRI based descriptors and clinical parameters (Age, gender, Karnofsky performance status (KPS) score, histopathological diagnosis, WHO grade, surgery type and therapeutic regimen) were archived history system. The IDH1/2 mutation status evaluation was determined by immunohistochemical stain and the standard Sanger method for PCR.
Observed data for Survival Analysis:
OS is the primary end point in this study, timing from the date of APTw MRI scanning until the date of death (Event) or the last follow-up examination. Patients alive at the end of the follow-up period were censored.
Statistical analysis:
Cox regression analysis was conducted to identify prognostic factors to OS. Variates associated with overall survival were identified with Kaplan–Meier statistics and log-rank tests were used to compare survival curves. All statistical analyses were performed using SPSS statistical software. The alpha level of all tests was set at P < 0.05 (two-tailed).
Results and Discussion
62 patients were found to be IDH-mutant, and the remaining 46 patients IDH-wildtype. Higher APTw value and IDH-wildtype together showed significant predictive power for shorter OS in the cohort of patients with lower grade gliomas. Especially for 50th percentile APTw and core APTw values, these two predictors independently showed significant association with OS, where age, T2w/FLAIR character, WHO grade, surgery type and therapeutic regimen did not (Figure 1). Figure 2 shows Kaplan-Meier curves comparing OS for patient subgroups as classified by 50th percentile APTw MRI grouping, IDH mutation status and the combination of the two factors. The patients with IDH-mutant or with lower 50th percentile had significant longer OS, compared with patients with IDH-wildtype or higher 50th percentile. Combining 50th percentile APTw MRI grouping and IDH mutation status aids to further stratify prognosis in patients with lower grade gliomas with statistical significance.
A main merit of our study is that it shows that APTw MRI
features are predictive for the prognosis of patients with lower grade gliomas.
Moreover, this presented study is one of a few studies where IDH1 and IDH2
mutations were simultaneously analyzed.
Conclusion
Our findings suggest that APTw MRI has potential implications for preoperatively predicting outcomes for patients with lower grade gliomas.Acknowledgements
No acknowledgement found.References
1. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360:765-73.
2. Diehn M, Nardini C, Wang DS, et al. Identification of noninvasive imaging surrogates for brain tumor gene-expression modules. Proc Natl Acad Sci (USA) 2008;105:5213-8.
3. Pope WB, Chen JH, Dong J, et al. Relationship between gene expression and enhancement in glioblastoma multiforme: Exploratory DNA microarray analysis. Radiology 2008;249:268-77.
4. Choi C, Ganji SK, DeBerardinis RJ, et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in subjects with IDH-mutated gliomas. Nat Med 2012;18:624-9.
5. Zhou J, Payen J, Wilson DA, Traystman RJ, van Zijl PCM. Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nature Med 2003;9:1085-90.
6. Zhou J, Lal B, Wilson DA, Laterra J, van Zijl PCM. Amide proton transfer (APT) contrast for imaging of brain tumors. Magn Reson Med 2003;50:1120-6.
7. Ward KM, Aletras AH, Balaban RS. A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J Magn Reson 2000;143:79-87.
8. Vinogradov E, Sherry AD, Lenkinski RE. CEST: From basic principles to applications, challenges and opportunities. J Magn Reson 2013;229:155-72.
9. Kogan F, Hariharan H, Reddy R. Chemical exchange saturation transfer (CEST) imaging: Description of technique and potential clinical applications. Curr Radiol Reports 2013;1:102-14.
10. Zaiss M, Bachert P. Chemical exchange saturation transfer (CEST) and MR Z-spectroscopy in vivo: a review of theoretical approaches and methods. Phys Med Biol 2013;58:R221-R69.
11. Zhou J, Tryggestad E, Wen Z, et al. Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides. Nature Med 2011;17:130-4. 12. Wen Z, Hu S, Huang F, et al. MR imaging of high-grade brain tumors using endogenous protein and peptide-based contrast. NeuroImage 2010;51:616-22. 13. Togao O, Yoshiura T, Keupp J, et al. Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades. Neuro-Oncology 2014;16:441-8.
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