Ammar Shaikhouni and E. Antonio Chiocca
M. Necmettin Pamir, Koray Özduman, Erdem Yıldız, Aydın Sav and Alp Dinçer
The authors had previously shown that 3-T intraoperative MRI (ioMRI) detects residual tumor tissue during low-grade glioma and that it helps to increase the extent of resection. In a proportion of their cases, however, the ioMRI disclosed T2-hyperintense areas at the tumor resection border after the initial resection attempt and prompted a differential diagnosis between residual tumor and nontumoral changes. To guide this differential diagnosis the authors used intraoperative long-TE single-voxel proton MR spectroscopy (ioMRS) and tested the correlation of these findings with findings from pathological examination of resected tissue.
Patients who were undergoing surgery for hemispheric or insular WHO Grade II gliomas and were found to have T2 changes around the resection cavity at the initial ioMRI were prospectively examined with ioMRS and biopsies were taken from corresponding localizations. In 14 consecutive patients, the ioMRS diagnosis in 20 voxels of interest was tested against the histopathological diagnosis. Intraoperative diffusion-weighted imaging (ioDWI) was also performed, as a part of the routine imaging, to rule out surgically induced changes, which could also appear as T2 hyperintensity.
Presence of tumor was documented in 14 (70%) of the 20 T2-hyperintense areas by histopathological examination. The sensitivity of ioMRS for identifying residual tumor was 85.7%, the specificity was 100%, the positive predictive value was 100%, and the negative predictive value was 75%. The specificity of ioDWI for surgically induced changes was high (100%), but the sensitivity was only 60%.
This is the first clinical series to indicate that ioMRS can be used to differentiate residual tumor from nontumoral changes around the resection cavity, with high sensitivity and specificity.
Koray Özduman, Erdem Yıldız, Alp Dinçer, Aydın Sav and M. Necmettin Pamir
The goal of surgery in high-grade gliomas is to maximize the resection of contrast-enhancing tumor without causing additional neurological deficits. Intraoperative MRI improves surgical results. However, when using contrast material intraoperatively, it may be difficult to differentiate between surgically induced enhancement and residual tumor. The purpose of this study was to assess the usefulness of intraoperative dynamic contrast-enhanced T1-weighted MRI to guide this differential diagnosis and test it against tissue histopathology.
Preoperative and intraoperative dynamic contrast-enhanced MRI was performed in 21 patients with histopathologically confirmed WHO Grade IV gliomas using intraoperative 3-T MRI. Standardized regions of interest (ROIs) were placed manually at 2 separate contrast-enhancing areas at the resection border for each patient. Time-intensity curves (TICs) were generated for each ROI. All ROIs were biopsied and the TIC types were compared with histopathological results. Pharmacokinetic modeling was performed in the last 10 patients to confirm nonparametric TIC analysis findings.
Of the 42 manually selected ROIs in 21 patients, 25 (59.5%) contained solid tumor tissue and 17 (40.5%) retained the brain parenchymal architecture but contained infiltrating tumor cells. Time-intensity curves generated from residual contrast-enhancing tumor and their preoperative counterparts were comparable and showed a quick and persistently increasing slope (“climbing type”). All 17 TICs obtained from regions that did not contain solid tumor tissue were undulating and low in amplitude, compared with those obtained from residual tumors (“low-amplitude type”). Pharmacokinetic findings using the transfer constant, extravascular extracellular volume fraction, rate constant, and initial area under the curve parameters were significantly different for the tumor mass, nontumoral regions, and surgically induced contrast-enhancing areas.
Intraoperative dynamic contrast-enhanced MRI provides quick, reproducible, high-quality, and simply interpreted dynamic MR images in the intraoperative setting and can aid in differentiating surgically induced enhancement from residual tumor.
M. Necmettin Pamir, Koray Özduman, Alp Dinçer, Erdem Yildiz, Selçuk Peker and M. Memet Özek
The authors describe the first shared-resource, 3-T intraoperative MR (ioMR) imaging system and analyze its impact on low-grade glioma (LGG) resection with an emphasis on the use of intraoperative proton MR spectroscopy.
The Acibadem University ioMR imaging facility houses a 3-T Siemens Trio system and consists of interconnected but independent MR imaging and surgical suites. Neurosurgery is performed using regular ferromagnetic equipment, and a patient can be transferred to the ioMR imaging system within 1.5 minutes by using a floating table. The ioMR imaging protocol takes < 10 minutes including the transfer, and the authors obtain very high–resolution T2-weighted MR images without the use of intravenous contrast. Functional sequences are performed when needed. A new 5-pin headrest–head coil combination and floating transfer table were specifically designed for this system.
Since the facility became operational in June 2004, 56 LGG resections have been performed using ioMR imaging, and > 19,000 outpatient MR imaging procedures have been conducted. First-look MR imaging studies led to further resection attempts in 37.5% of cases as well as a 32.3% increase in the number of gross-total resections. Intraoperative ultrasonography detected 16% of the tumor remnants. Intraoperative proton MR spectroscopy and diffusion weighted MR imaging were used to differentiate residual tumor tissue from peritumoral parenchymal changes. Functional and diffusion tensor MR imaging sequences were used both pre- and postoperatively but not intraoperatively. No infections or other procedure-related complications were encountered.
This novel, shared-resource, ultrahigh-field, 3-T ioMR imaging system is a cost-effective means of affording a highly capable ioMR imaging system and increases the efficiency of LGG resections.
Cemaliye B. Akyerli, Şirin Yüksel, Özge Can, E. Zeynep Erson-Omay, Yavuz Oktay, Erdal Coşgun, Ege Ülgen, Yiğit Erdemgil, Aydın Sav, Andreas von Deimling, Murat Günel, M. Cengiz Yakıcıer, M. Necmettin Pamir and Koray Özduman
Recent studies have established that hemispheric diffuse gliomas may be grouped into subsets on the basis of molecular markers; these subsets are loosely correlated with the histopathological diagnosis but are strong predictors of clinical tumor behavior. Based on an analysis of molecular and clinical parameters, the authors hypothesized that mutations of the telomerase promoter (TERTp-mut) mark separate oncogenic programs among isocitrate dehydrogenase 1 and/or 2 (IDH) mutant (IDH-mut) and IDH wild-type (IDH-wt) diffuse gliomas independent of histopathology or WHO grade.
Four molecular subsets of the combined statuses of IDH and TERT-promoter mutations (double mutant, IDH only, TERT only, and double negative) were defined. Differences in age, anatomical location, molecular genetics, and survival rates in a surgical cohort of 299 patients with a total of 356 hemispheric diffuse gliomas (WHO Grade II, III, or IV) were analyzed.
TERTp-mut were present in 38.8% of IDH-mut and 70.2% of IDH-wt gliomas. The mutational status was stable in each patient at 57 recurrence events over a 2645-month cumulative follow-up period. Among patients with IDH-mut gliomas, those in the double-mutant subset had better survival and a lower incidence of malignant degeneration than those in the IDH-only subset. Of patients in the double-mutant subset, 96.3% were also positive for 1p/19q codeletions. All patients with 1p/19q codeletions had TERTp-mut. In patients with IDH-mut glioma, epidermal growth factor receptor or phosphatase and tensin homolog mutations were not observed, and copy-number variations were uncommon. Among IDH-wt gliomas, the TERT-only subset was associated with significantly higher age, higher Ki-67 labeling index, primary glioblastoma-specific oncogenic changes, and poor survival. The double-negative subset was genetically and biologically heterogeneous. Survival analyses (Kaplan-Meier, multivariate, and regression-tree analyses) confirmed that patients in the 4 molecular subsets had distinct prognoses.
Molecular subsets result in different tumor biology and clinical behaviors in hemispheric diffuse gliomas.
Ege Ülgen, Özge Can, Kaya Bilguvar, Yavuz Oktay, Cemaliye B. Akyerli, Ayça Erşen Danyeli, M. Cengiz Yakıcıer, O. Uğur Sezerman, M. Necmettin Pamir and Koray Özduman
Processes that cause or contribute to cancer, such as aging, exposure to carcinogens, or DNA damage repair deficiency (DDRd), create predictable and traceable nucleotide alterations in one’s genetic code (termed “mutational signatures”). Large studies have previously identified various such mutational signatures across cancers that can be attributed to the specific causative processes. To gain further insight into the processes in glioma development, the authors analyzed mutational signatures in adult diffuse gliomas (DGs).
Twenty-five DGs and paired blood samples were whole exome sequenced. Somatic mutational signatures were identified using 2 different methods. Associations of the signatures with age at diagnosis, molecular subset, and mutational load were investigated. As DDRd-related signatures were frequently observed, germline and somatic DDR gene mutations as well as microsatellite instability (MSI) status were determined for all samples. For validation of signature prevalence, publicly available data from The Cancer Genome Atlas (TCGA) were used.
Each tumor had a unique combination of signatures. The most common signatures were signature 1 (88%, aging related), signature 3 (52%, homologous recombination related), and signature 15 (56%, mismatch repair related). Eighty-four percent of the tumors contained at least 1 DDRd signature. The findings were validated using public TCGA data. The weight of signature 1 positively correlated with age (r = 0.43) while cumulative weight of DDRd signatures negatively correlated with age (r = −0.16). Each subject had at least 1 germline/somatic alteration in a DDR gene, the most common being the risk single nucleotide polymorphism rs1800734 in MLH1. The rs1800734-AA genotype had a higher cumulative DDRd weight as well as higher mutational load; TP53 was the most common somatically altered DDR gene. MSI was observed in 24% of the tumors. No significant associations of MSI status with mutational load, rs1800734, or the cumulative weight of DDRd signatures were identified.
Current findings suggest that DDRd may act as a fundamental mechanism in gliomagenesis rather than being a random, secondary event.