Study Design, Setting, and Population
This study is a single-surgeon consecutive case series, where adult patients harboring tumors within the left IFG who underwent awake surgical resection with mapping between July 2018 and August 2020. Tumor location in Broca’s area within the IFG was determined using MR imaging. Broca’s area was anatomically defined to be located at the pT and the pOp, as originally described. Patients were excluded if histopathologic diagnosis was other than glioma, had multifocal disease, were left-handed or had absolute contraindications for awake surgery [7]. Preoperative Karnofsky Performance Status (KPS) and neuropsychological baseline language status were established the day prior to the procedure [8]. Demographic, histologic, imaging, surgical, neuropsychological, and clinical outcomes were included for analysis.
Neuropsychological Evaluation and Intraoperative Functional Language Tasks
All patients underwent baseline language testing using a tablet-based testing platform for intraoperative mapping (NeuroMapper). Administered subsets were individualized to tumor location and the affected white matter tracts, with picture naming, nonword repetition, and digit repetition being the most utilized tests. Accuracy and reaction time data were collected. Items that were answered correctly within a prespecified time to allow for DCS stimulation mapping were selected for intraoperative evaluation (e.g., < 5-7 seconds). Paradigms were administered during stimulation and continuously throughout active resection of the tumors to monitor cognition. Patient performance was considered as stable when error rate was <5% in picture naming responses and cognitive decline was defined as >5% error rate compared to baseline.
Surgical Procedure and Intraoperative Mapping
All patients underwent awake surgery with brain mapping for tumor resection [9,10]. Main surgical goals were to achieve maximal safe resection (MSR) and to obtain tissue for diagnosis. Scalp nerve block was done to ensure analgesia before positioning. After dural opening, direct cortical stimulation (DCS) was carried out, starting at 3mA, increased at 1 mA intervals, until after discharges were present, positive threshold response was established, or reached 9mA with negative mapping with the Ojemann stimulator. All sites were stimulated at least three times. After identifying the most convenient surgical corridor, direct subcortical stimulation (DSS) was done. During DCS and DSS, patients performed a picture naming paradigm where they were required to say “This is a” followed by naming the presented picture. The onset of electrical stimulation was timed to just prior to the presentation of the picture and it was continued until a response was made or until 5-7 seconds with no response. The neuropsychological paradigms were administered continuously and throughout the entire active resection. (Table 3.). Tumor location, positive mapping areas, and patient performance throughout surgery determined the extent of resection (EOR) of the lesions. FLAIR was chased on tumors with high-grade characteristics in preoperative MRI. After achieving maximal safe resection (MSR), hemostasis was secured, and the surgical approach was closed in anatomical layers. Postoperative MRI imaging within the first 24 hours after the procedure.
MR Imaging and Extent of Resection Measurements:
Standard preoperative and immediate postoperative imaging were acquired with and without gadolinium-based contrast. The preoperative and postoperative post-contrast T1-weighted, T2-weighted, and post-contrast FLAIR images were co-registered using a linear affine registration implemented in Statistical Parametric Mapping (SPM) v12 (https://www.fil.ion.ucl.ac.uk/spm/). Masks were created for enhancing tumor (ET) from the post-contrast T1-weighted images, non-enhancing tumor (NET) based on T2-weighted images, and peritumoral edema (PE) based on FLAIR images using ITK-Snap [11]. Using the T1-weighted imaging as reference, normalization to the Montreal Neurological Institute (MNI) template space was performed to generate a transformation warp that was applied to the coregistered T2-weighted, FLAIR images, and segmentation masks.
Total and total residual tumor maps were generated based on the sum of the preoperative and postoperative ET and NET maps, respectively. Individual tumor volume was calculated for each mask. Resection was categorized as follows: gross total resection (GTR): resection above 95%; subtotal resection (STR): between 60-95% tumor resected; partial resection (PR): less than 60% resection [12].Individual total and total residual tumor maps were combined into group-level, preoperative and postoperative tumor masks with an integer value for each voxel representing the number of subjects with tumor in that voxel. Cortical masks from Harvard-Oxford Cortical Atlas were used for preoperative and postoperative tumor volume calculations in the vPMC, pOp, pT, and pOr [13-15].Difference between preoperative and postoperative tumor volume difference was calculated for the evaluation of the extent of tumor resection.
Next, to evaluate the relationship of tumor to critical subcortical white matter structures, a tract atlas was generated in MNI space. Tractography was based on a group-averaged dataset from 1021 subjects in the Human Connectome Project (https://www.humanconnectome.org) which was reconstructed with a q-space diffeomorphic reconstruction [16,17].Individual tracts were then generated in DSI Studio (http://dsi-studio.labsolver.org). Full acquisition details are available at the Human Connectome Project website. Briefly, a multishell diffusion scheme was with b-values of 1000, 2000, and 3000 s/mm2 with 90 diffusion directions per shell. Images were acquired with an isotropic resolution of 1.25 mm. A deterministic fiber tracking algorithm was used [18].Tract data was semi-automated based on prior tractography atlas [19].Topology-informed pruning was applied to the tractography with 3 iterations to remove false connections. The residual tumor group map (thresholded at > 13% or n > 2) was compared to the tract anatomy in DSI Studio [20].
Postoperative Care
Patients were evaluated two weeks after surgery and at follow-up visit at 3 months. Outcome measures of postoperative KPS, EOR, presence of postoperative language deficits, surgical complications, length of hospital stay were collected. Length of hospital stay was from the time of surgery to the day of discharge.
Compliance with Ethical Standards:
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institution and the national research committee. This study was carried out under the IRB number: PR16-009946-01.Informed consent was obtained from all individual participants included in the study.
Statistical Analysis
Descriptive statistics were utilized to detail patient characteristics and postoperative outcomes. Data was expressed as a mean with range for continuous variables and counts with percentages for categorical variables. Student T-test was utilized for continuous data. P<0.05 was considered statistically significant. All analyses were performed using GraphPad Prism 9.0.2 for Windows (Graphpad Software, La Jolla, California, USA).