Prabhu, Sujit S.

Abstract BACKGROUND Intraoperative electrocorticography (ECoG) may aid localization of language function and help guide eloquent brain tumor resection. However, relevance of ECoG findings to language outcomes remains unclear. METHODS Fifteen patients with brain tumors (Mdn age=60; 67% high-grade glioma) underwent awake craniotomy and intraoperative language mapping. Time-frequency ECoG gamma activity was visualized in real-time followed by direct electrical stimulation (DES) across 3 paradigms (NeuroMapper Tasks: Object, Action, Auditory). Early and late ECoG gamma modulations and positive DES sites were co-registered with postoperative MRI. A subset (N=11) completed expressive language testing (Phonemic and Semantic Fluency, Confrontation Naming) prior to and <2 months following surgery. Correlational analyses and Mann-Whitney U tests examined relationships between test results and surgical impact upon expressive task-elicited gamma activity (Object and Action Naming). RESULTS Across tasks, positive DES sites were identified in 93% of cases (Auditory, 73%; Action, 71%, Object, 57%). No positive DES sites were resected. Early and/or late gamma activations were elicited in all patients, resected in 40%, and within 1 cm of surgical impact in 90%. Four patients (36%) showed reliable decline on at least 1 outcome, which was associated with Action Naming activity <1 cm of surgical impact (phi=.67, p=.035). On individual tests, Confrontation Naming and Phonemic Fluency decline were rare (9% and 18%), though Semantic Fluency declined in 36% of patients. Change in Semantic Fluency was associated with resection of Object Naming gamma sites (Z=-1.83, p=.044) and presence of Action Naming gamma features near surgical impact (Z=-2.25, p=.014). CONCLUSIONS Despite preservation DES sites and sparing of basic confrontation naming ability, verbal fluency declined in a substantial group of patients. Decline was associated with gamma features resected or near surgical impact. While preliminary, findings suggest task-based ECoG can augment DES in informing risk of surgically-acquired language decline.

Abstract BACKGROUND As an adjunct to direct electrical stimulation (DES), intraoperative electrocorticography (ECoG) can aid detection of language-eloquent cortex. However, it is unclear how surgical impact upon mapping findings relates to cognitive-linguistic outcomes. METHODS Ten patients underwent awake craniotomy for tumor resection with ECoG and DES language mapping. Mapping utilized iPad stimulus presentation coupled to an electrode array capable of both recording ECoG activity and delivering DES. Time-frequency gamma band activations were visualized (Early, Long, Late, Double Peak) for 3 naming paradigms (Object, Action, Auditory). DES was also conducted for each task. Mapping results were overlayed on postoperative MRI to examine proximity to parenchymal trauma (cavity, sulcal displacement). Patients completed cognitive-linguistic testing [WAB-R (N=3) or Neuropsychological Assessment (N=7)] prior to surgery and <2 months postoperatively. Patients with persisting aphasia at 6-month follow-up were also identified. RESULTS Postoperative language decline was found in 50% of patients, with 30% showing worsening (>1SD) in Naming and Phonemic Fluency, and 60% in Semantic Fluency. Surgery impacted ECoG features in 60% of patients and DES arrest sites in 30%. A trend was observed where Early and Late Object naming ECoG features were associated with Semantic Fluency decline [rpb(5)=-.69, p=.067]. Arrest during Auditory naming DES <1 cm of surgical effect was associated with decline in Abstraction [rpb(5)=-.83, p=.042; FET, p=.029] and Semantic Fluency [rpb(5)=-.87, p=.012; FET, p=.024]. Excluding the 3 transsulcal surgeries, arrest during Auditory naming DES <1 cm of resection was associated with general language decline [FET, p=.047]. All 3 patients with persisting aphasia had Auditory naming arrest <1 cm of resection and 2/3 patients had Object naming ECoG features resected. CONCLUSIONS While preliminary, results suggest that surgical proximity to ECoG and DES mapping results may inform risk of surgically-acquired cognitive-linguistic decline. Findings support the potential of multimethod-multitask intraoperative language mapping.

Abstract BACKGROUND Few studies have examined concordance between intraoperative electrocorticography (ECoG) and direct electrical stimulation (DES) language mapping, especially across varied naming tasks. METHODS Twelve patients (Mdn age=59; 75% HGG) underwent awake craniotomy with ECoG and DES language mapping. Mapping utilized iPad stimulus presentation coupled to a 4x8 electrode array for both ECoG and DES. Time-frequency ECoG gamma band activity (Early and Late) was visualized for 3 naming paradigms (Object, Action, Auditory). Bipolar DES was also conducted for each task at each electrode pair. ECoG activations and DES hits were overlayed on preoperative MRI. DES hits represented ground truth for eloquence. ECoG accuracy was examined for each task with 3 different criteria: exact (identical electrodes for ECoG activation and DES hits), adjacent (ECoG <1cm of DES hits), and adjacent within a predefined peritumoral region of interest (<2 cm from boundaries). RESULTS 32 DES hits (40% Auditory, 32% Action, 28% Obj) were observed across patients. Exact ECoG-DES accuracy ranged from 78%-90% [Object: Sens=11%, Spec=91%, PPV=6%, NPV=95%; Action: Sens=40%, Spec=93%, PPV=24%, NPV=97%; Auditory: Sens=69%, Spec=78%, PPV=19%, NPV=78%]. Adjacent ECoG-DES accuracy ranged from 82%-91% [Object: Sens=33%, Spec=92%, PPV=18%, NPV=97%; Action: Sens=44%, Spec=93%, PPV=25%, NPV=97%; Auditory: Sens=91%, Spec=81%, PPV=37%, NPV=99%]. When restricted to the peritumoral region, adjacent ECoG-DES accuracy ranged from 94%-97% [Object: Sens=14%, Spec=99%, PPV=25%, NPV=97%; Action: Sens=25%, Spec=99%, PPV=25%, NPV=99%; Auditory: Sens=100%, Spec=94%, PPV=54%, NPV=100%]. For patients with DES hits (N=10), all had at least 1 task activation <1 cm of DES hits, with 7/10 having convergence of activations across at least 2 tasks. CONCLUSIONS Negative ECoG mapping is strongly predictive of non-eloquence confirmed by DES for all naming tasks. Additionally, gamma band activation elicited by auditory naming within the peritumoral region is strongly predictive of eloquence. Findings support task-based ECoG language mapping for prediction of eloquence and identification of targets for DES confirmation.

Abstract INTRODUCTION Accurately mapping sensorimotor regions is crucial for preserving motor and sensory functions in the treatment of gliomas located in the peri-Rolandic areas of the brain. OBJECTIVE We examined the use of high-density electrocorticography (ECoG) for passive mapping of sensorimotor regions in treating peri-Rolandic gliomas by analyzing the spatial-temporal and spectral features of real-time somatosensory evoked potentials (SSEPs), and their spectral patterns in differentiating states of consciousness. METHODS During surgery, SSEPs were recorded using high-density ECoG on fourteen patients (n=14), both in anesthetized and awake states. Neural data from 0.6Hz median nerve stimulation were captured at 2.4kHz and processed in real-time using MATLAB Simulink. The system displayed SSEPs’ peak activations as a 2D heat map on a screen, particularly around the 20ms time point (N20), and generated the spectral power in the gamma range using the Stockwell transform. Accuracy in delineating the central sulcus (CS) was assessed using the ROC curve, and paired t-tests compared gamma oscillations between states of consciousness. RESULTS Patients consistently showed clear discrimination between anterior and posterior channels at the 20ms time point, with 93.6±14.9% accuracy. Color contrast delineated the CS, correlating with the sulcus in the 3D reconstructed magnetic resonance imaging of each patient. Late gamma (60–250 Hz) modulation occurred 50 ms after stimulation onset, extending up to 250 ms in the primary somatosensory area. It was suppressed in the anesthetized state and significantly increased in the awake state (delineation accuracy: 81±10.3% and 91±13.4%, respectively). CONCLUSIONS These results demonstrate that SSEPs and gamma modulations can delineate sensorimotor areas and assess consciousness, significantly impacting neurosurgical planning.

Abstract Treatment options for glioblastoma remain limited, particularly for those who are not eligible for traditional resection, whether due to lesion location or inability to tolerate open craniotomy. Maximal-safe resection followed by radiation with concurrent and adjuvant temozolomide offers the best outcomes for patients. Unfortunately, not all tumors are amenable to conventional surgical resection at the time of diagnosis with only about 1/3 of patients able to receive a gross-total resection and 15-25% of patients receiving biopsy only, thus reducing their projected overall survival to 9 months. Laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive tool, that has demonstrated safety as a surgical approach to treat primary brain tumors. METHODS Data from LAANTERN prospective multicenter registry (NCT02392078) was analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma (N=89). Demographics, intraprocedural data, adverse events, KPS, health-economics, and survival data were prospectively collected then analyzed separately for newly diagnosed GBM (N=29) and recurrent GBM (N=60). RESULTS Median overall-survival was 9.73 months (95% CI: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 (6.94, 12.36) months for recurrent patients. Median overall-survival for newly diagnosed patients receiving post-LITT chemoradiotherapy was 16.14 months (6.11, not reached). The median length of hospital stay was 50 hours and 80% of patients were discharged to home. CONCLUSIONS LITT offers an effective cytoreductive approach for patients with newly diagnosed and recurrent IDH wild-type glioblastoma. Importantly, its use in newly diagnosed patients who receive post-LITT chemoradiotherapy leads to a median OS similar to that of patients treated with conventional surgical resection. LITT remains an important alternative for patients with inoperable tumors or those not amenable to resection. Enrollment in LAANTERN is ongoing and these cohorts will be revisited as data continues to mature. Benefits beyond cytoreduction are also being actively explored.

Abstract Background Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma. Methods Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers. Results A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc. Conclusions Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.

Abstract Background There is recognition that breast cancer is a collection of heterogeneous diseases divided in subtypes based on combined molecular features such as hormonal receptors (HR) and human epidermal growth factor receptor 2 (HER2) status. We aimed to study clinical differences among biological subtypes in brain metastasis from breast cancer after targeted therapy introduction. Methods This was a retrospective study with 406 consecutive patients with brain metastasis from breast cancer treated at MD Anderson Cancer Center from 1998 to 2013. Overall, 315 of these patients met the study criteria and were analyzed. Subtypes were classified as HER2-/HR+ (96 patients), HER2+/HR+ (57 patients), HER2+/HR- (63 patients), and triple negative (HER2-/HR-) (99 patients). End points were time to development of brain metastasis (TDBM), brain metastasis-free survival (BMFS), and overall survival from start of treatment of brain metastasis (OSBM). Univariate and multivariate Cox proportional hazard regression models were used to analyze the data. Results TDBM was 41 months for HER2-/HR+; 58 months for HER2+/HR+; 30 months for HER2+/HR-; and 27 months for triple negative (P < .001). BMFS was 9 months for HER2-/HR+; 24 months for HER2+/HR+; 9 months for HER2+/HR-; and 7 months for triple negative (P = .06). OSBM was 20 months for HER2-/HR+; 22 months for HER2+/HR+; 24 months for HER2+/HR-; and 9 months for triple negative (P < .001). On multivariate analyses, triple negative showed lower OSBM compared with other subtypes, with a hazard ratio of 1.9 (P < .001). Conclusion Comparing all breast cancer subgroups we noticed that HR and HER2 are the most significant biomarkers in brain metastasis behavior. Patients who received targeted therapy had better outcomes, but not in the triple negative group. Prospective studies with different treatment modalities for each subgroup are recommended.

Abstract Introduction Recent advances in stereotactic radiosurgery (SRS) have improved clinical outcomes in patients with limited intracranial metastases. As a result of this high-dose radiation delivery to a focal area within the brain, tissue structural and functional changes within the treatment field are often difficult to distinguish from local tumor recurrence based on conventional imaging techniques. Here, we demonstrate that elevation of circulating cells of myeloid origin, the key regulators of inflammation and immune responses, can serve as a potential surrogate marker to differentiate radiation-induced tissues changes from local tumor recurrence. Materials and Methods We retrospectively identified 96 patients who were initially treated with Gamma-knife radiosurgery at MD Anderson Cancer Center from 2009-2013 for brain metastases, and subsequently underwent surgical resection of previous irradiated lesions after presenting with clinical symptoms and radiographic findings suggestive of tumor progression. All surgical specimens were centrally reviewed by neuropathology. Pre-operative circulating blood cell profiles were analyzed for monocytic, granulocytic and lymphocytic sub-populations. Results A total of 11 and 85 patients who underwent surgical resection after prior SRS for brain metastasis were pathologically confirmed to have radiation-induced changes or tumor recurrence, respectively. Among patients with confirmed recurrence vs. those with radiation-induced changes, the number of circulating immature granulocytes (mean = 0.093 × 103ul−1 vs 0.032 × 103ul−1, p = 0.075) and monocytes (mean = 0.632 × 103ul−1 vs 0.401 × 103ul−1, p = 0.007) were elevated when compared to patients with radiation-induced changes (combined: mean = 0.71 × 103ul−1 vs 0.43 × 103ul−1, p = 0.002). No statistically significant differences were observed among mature granulocytic or lymphocytic populations between the two groups. Receiver operating characteristic analysis showed significant discriminative utility of pre-operative myeloid cell count when compared to reference line of no discrimination (AUC = 0.774, p = 0.003). The cut-point for myeloid cell population was found be &gt; = 0.5 × 103ul−1, which corresponds to a detection sensitivity of 73.3% and specificity of 72.7% for tumor recurrence. Conclusion Bone marrow cells of myeloid origin play important roles in mediate acute inflammatory reactions and in regulating adaptive immunity. We showed here that certain primitive cells of myeloid lineage may potentially be used to aid the differentiation of tumor recurrence from radiation-induced changes in patients who had SRS for brain metastasis. The identification of potential circulating biomarkers that can complement traditional imaging to distinguish the two distinct pathological entities has significant implications in the management of these patients. Note: This abstract was not presented at the meeting. Citation Format: Wen Jiang, Yvo Rodriguez, Nicolas S. Boehling, Sujit S. Prabhu, Betty Y.S. Kim, Patrick Hwu, Erik P. Sulman, Paul D. Brown, Jing Li. Circulating myeloid precursor profile as potential marker to differentiate radiation changes from tumor recurrence after brain stereotactic radiosurgery. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 532. doi:10.1158/1538-7445.AM2015-532