Vorinostat, temozolomide or bevacizumab with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children's Oncology Group Study.

Background: Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly diagnosed HGG who received maintenance temozolomide and bevacizumab. Methods: Patients ≥ 3 and < 22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54-59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy. Results: Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%), and 59.3% (±9.5%), respectively, with no significant difference among treatment arms. Three- and five-year EFS for the entire cohort was 14.8% and 13.4%, respectively, with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (P = .03), whereas H3.3 K27M mutations (P = .0045) and alterations in PIK3CA or PTEN (P = .025) were associated with worse outcomes. Patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors (n = 4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (P = .002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of the telomere maintenance mechanism (P = .0012). Conclusions: Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.

Neuropsychological outcomes after epilepsy surgery: A comparison of stereo electroencephalography and subdural electrodes.

BACKGROUND AND PURPOSE: We analyzed the association of neuropsychological outcomes after epilepsy surgery with the intracranial electrode type (stereo electroencephalography [SEEG] and subdural electrodes [SDE]), and electrical stimulation mapping (ESM) of speech/language. METHODS: Drug-resistant epilepsy patients who underwent comprehensive neuropsychological evaluation before and 1 year after epilepsy surgery were included. SEEG and SDE subgroups were matched by age, handedness, operated hemisphere, and seizure freedom. Postsurgical neuropsychological outcomes (adjusted for presurgical scores) and reliable change indices were analyzed as functions of electrode type and ESM. RESULTS: Ninety-nine patients aged 6-29 years were included with similar surgical resection/ablation volumes in the SEEG and SDE subgroups. Most of the neuropsychological outcomes were comparable between SEEG and SDE subgroups; however, Working Memory and Processing Speed were significantly improved in the SEEG subgroup. Undergoing language ESM was associated with significant improvements in Spelling, Letter-Word Identification, Vocabulary, Verbal Comprehension, Verbal Learning, and Story Memory scores, but a decline in Calculation scores. CONCLUSIONS: Intracranial evaluations with SEEG and SDE are comparable in terms of long-term postsurgical neuropsychological outcomes. Our data suggest that SEEG may be associated with improvements in working memory and processing speed, representing cognitive domains served by spatially distributed networks. Our study also supports wider use of language ESM before epilepsy surgery, preferably using other language tasks in addition to visual naming. Rather than the type of electrode, postsurgical neuropsychological outcomes are driven by whether language ESM was performed or not, with beneficial effects of language mapping.

Evaluating Focal Areas of Signal Intensity (FASI) in Children with Neurofibromatosis Type-1 (NF1) Treated with Selumetinib on Pediatric Brain Tumor Consortium (PBTC)-029B.

BACKGROUND: Understanding the effect of selumetinib on FASI may help elucidate the biology, proliferative potential, and role in neurocognitive changes for these NF1-associated lesions. METHODS: Patients with NF1-associated LGG and FASI treated with selumetinib on PBTC-029B were age-matched to untreated patients with NF1-associated FASI at Cincinnati Children's Hospital Medical Center. Paired bidirectional measurements were compared over time using nonparametric tests. RESULTS: Sixteen age-matched pairs were assessed (age range: 2.8-16.9 years, 60% male). Initial FASI burden was not different between groups (median range 138.7 cm2 [88.4-182.0] for the treated subjects vs. 121.6 cm2 [79.6-181.9] for the untreated subjects; p = 0.98). Over a mean follow-up of 18.9 (±5.9) months, the LGG size consistently decreased with treatment while no consistent change among the treated or untreated FASI size was seen. At the paired time points, the median treated LGG decreased significantly more than the treated FASI (-41.3% (LGG) versus -10.7% (FASI), p = 0.006). However, there was no difference in the median size change in the treated versus untreated FASI (-10.7% (treated FASI) versus -17.9% (untreated FASI), p = 0.08). Among the treated subjects, there was no correlation between the change in LGG and FASI (r = -0.04, p = 0.88). CONCLUSIONS: Treatment with selumetinib did not affect the overall FASI size in children with NF1 treated for progressive low-grade glioma.

Posterior Quadrant Disconnection Procedure for Intractable Epilepsy: A Case Series of 5 Young Pediatric Patients.

BACKGROUND: Posterior quadrant disconnection (PQD) has been described as a treatment for patients with refractory posterior quadrant subhemispheric epilepsy. Surgical outcomes are difficult to interpret because of limited literature. OBJECTIVE: To provide insight regarding the operative technique and postsurgical seizure freedom in young pediatric patients who underwent surgical disconnection for the treatment of posterior quadrant subhemispheric epilepsy at our institution. METHODS: The authors retrospectively analyzed a series of 5 patients who underwent PQD between 2019 and 2021. Charts were reviewed for preoperative workup including noninvasive/invasive testing, operative reports, and postoperative follow-up data which included degree of seizure freedom, completion of disconnection, and complications. RESULTS: Five patients were included in this series. The median age at seizure onset was 12 months (range 3-24 months), and the median age at surgery was 36 months (range 22-72 months). Histopathology confirmed focal cortical dysplasia in 3 of 5 patients (2 patients with type IB; 1 with type IIID). The average length of follow-up after surgery was 16.8 months (range 12-24 months). All patients underwent complete disconnection of the posterior quadrant without complications. Four of 5 patients (80%) had Engel score of I, while the remaining patient had an Engel score of IIB. CONCLUSION: Our early results demonstrate that complete PQD can be successful at providing excellent seizure freedom and functional outcomes in carefully selected young pediatric patients who have concordant seizure semiology, noninvasive/invasive testing, and imaging findings with primary seizure onset zone within the ipsilateral posterior quadrant. Meticulous surgical planning and thorough understanding of the surgical anatomy and technique are critical to achieving complete disconnection.

Comparison of outcomes after stereoelectroencephalography and subdural grid monitoring in pediatric tuberous sclerosis complex.

OBJECTIVE: Patients with tuberous sclerosis complex (TSC) epilepsy present with unique clinical challenges such as early seizure onset and high rates of intractability and multifocality. Although there are numerous studies about the safety and efficacy of stereoelectroencephalography (SEEG), this topic has not been studied in TSC patients who have distinct epilepsy profiles. The authors investigated subdural grid (SDG) and SEEG monitoring to determine whether these procedures lead to similar seizure and safety outcomes and to identify features unique to this pediatric population. METHODS: TSC patients who underwent SDG or SEEG placement and a second epilepsy surgery during the period from 2007 to 2021 were included in this single-center retrospective cohort analysis. Various patient, hospitalization, and epilepsy characteristics were collected. RESULTS: A total of 50 TSC patients were included in this study: 30 were included in the SDG cohort and 20 in the SEEG cohort. Baseline weekly seizure count did not significantly differ between the 2 groups (p = 0.412). The SEEG group had a greater mean baseline number of antiepileptic drugs (AEDs) (3.0 vs 2.0, p = 0.003), higher rate of previous surgical interventions (25% vs 0%, p = 0.007), and larger proportion of patients who underwent bilateral monitoring (50% vs 13.3%, p = 0.005). Despite this, there was no significant difference in seizure freedom between the SDG and SEEG cohorts. The mean reduction in seizure count was 84.9% and 47.8% of patients were seizure free at last follow-up (mean 79.4 months). SEEG trended toward being a safer procedure than SDG monitoring, with a shorter mean ICU stay (0.7 days vs 3.9 days, p < 0.001), lower blood transfusion rate (0% vs 13.3%, p = 0.140), and lower surgical complication rate (0% vs 10%, p = 0.265). CONCLUSIONS: In the comparison of the SDG and SEEG cohorts, the SEEG group included patients who appeared to receive more aggressive management and have a higher rate of multifocality, more prior surgical interventions, more AEDs at baseline, and a higher rate of bilateral invasive monitoring. Despite this, the SEEG cohort had similar seizure outcomes and a trend toward increased safety. Based on these findings, SEEG appears to allow for monitoring of a wider breadth of TSC patients given its minimally invasive nature and its relative simplicity for monitoring numerous regions of the brain.

Functional MRI and electrical stimulation mapping for language localization: A comparative meta-analysis.

OBJECTIVE: This systematic review and meta-analysis evaluated the diagnostic validity of functional magnetic resonance imaging (fMRI) compared to electrical stimulation mapping (ESM) for pre-surgical language mapping. METHODS: A structured literature search was performed and studies with electrode-level data comparing fMRI and ESM for language localization were analyzed. Outcome measures included pooled estimates of diagnostic odds ratio (DOR), sensitivity, and specificity. Sources of heterogeneity were explored with a meta-regression framework. RESULTS: Nine studies were included in the analysis having 5-40 patients with mean age 11.3-43.4 years. Verb generation and picture naming were the most common fMRI tasks, while picture naming was the most common ESM task. Sensitivity (0.37-0.95), specificity (0.36-0.97), and DOR (1.9-44.6) for fMRI compared to ESM varied widely across studies with statistically significant heterogeneities. Pooled estimates were: sensitivity 0.71 (95% confidence interval 0.54, 0.83), specificity 0.74 (0.58, 0.85), and DOR 7.0 (3.5, 13.8), from a valid meta-analysis (area under the summary receiver-operating-curve 0.78). fMRI was noted to have higher sensitivity in studies using higher maximal ESM currents. fMRI variables could not be included in the meta-regression because of substantial methodological differences among studies. CONCLUSIONS: fMRI is moderately sensitive and moderately specific for language localization compared to ESM in well-designed studies. However, because the confidence limits for sensitivity and DOR are close to the line of no effect, and there is high unmeasured heterogeneity, fMRI cannot perhaps be used as the only modality for language localization to inform neurosurgical decisions at present.

Responsive neurostimulation device therapy in pediatric patients with complex medically refractory epilepsy.

OBJECTIVE: Pediatric epilepsy is characterized as drug resistant in 20%-30% of patients and defined as persistent seizures despite adequate treatment with two first-line antiepileptic medications. The American Academy of Neurology advocates surgical options earlier in the treatment of epilepsy to provide long-term seizure reduction. The new development of minimally invasive approaches has recently allowed for surgical options to patients not previously deemed surgical candidates. These may include patients with bilateral, deep, eloquent, or poorly localizing epileptogenic foci. To this end, responsive neurostimulation (RNS) is an FDA-approved closed-loop neuromodulation device for adjuvant treatment of adults with medically intractable epilepsy arising from one or multiple foci. METHODS: In this study, the authors describe their initial institutional experience with the use of RNS in pediatric patients with drug-resistant epilepsy. An IRB-approved retrospective review was conducted of 8 pediatric patients who underwent RNS implantation at Cincinnati Children's Hospital Medical Center between 2019 and 2021. RESULTS: Eight patients met the inclusion criteria for the study. The average age at the time of surgery was 14.7 years (range 8-18 years) with a mean follow-up of 16.5 months. All patients underwent invasive monitoring with stereo-EEG, subdural grid placement, or a combination of both. All patients had either bilateral or eloquent cortex targets. Trajectories were based on noninvasive (phase 1) and invasive (phase 2) seizure onset zone localization data. Four (50%) of the 8 patients underwent surgical intervention for epilepsy prior to RNS placement. RNS electrodes were placed with robot-assisted guidance in a hybrid operating room with intraoperative CT and electrocorticography. The authors demonstrated individualized RNS electrode trajectory and placement with targets in the amygdala/hippocampus, bilateral insula, bilateral parietal and occipital targets, and frontoparietal regions for a total of 14 implanted electrodes. One adverse event occurred, a wound infection requiring return to the operating room for removal of the RNS implant. All patients demonstrated a reduction in seizure frequency. All patients achieved > 50% reduction in seizure frequency at last follow-up. CONCLUSIONS: RNS implantation in carefully selected pediatric patients appears safe and efficacious in reducing seizure burden with a low rate of operative complications.

Phase I study of ribociclib and everolimus in children with newly diagnosed DIPG and high-grade glioma: A CONNECT pediatric neuro-oncology consortium report.

Background: Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of CDK4/6 and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG. Methods: Patients were enrolled according to a Rolling-6 design and received ribociclib and everolimus once daily for 21 and 28 days, respectively. All patients with HGG and biopsied DIPG were screened for retinoblastoma protein presence by immunohistochemistry. Pharmacokinetics were analyzed. Results: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each dose level 1 and 2 without dose-limiting toxicities (DLT). Thirteen patients were enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy before cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9 ± 0.9-fold higher than single-agent administration. Median overall survival for 15 patients with DIPG was 13.9 months; median event-free survival for four patients with HGG was 10.5 months. Two longer survivors had tumor molecular profiling identifying CDKN2A/B deletion and CDK4 overexpression. Conclusion: The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m2 and everolimus 1.5 mg/m2. Results will inform a molecularly guided phase II study underway to evaluate efficacy.

Characteristics of children ≤36 months of age with DIPG: A report from the international DIPG registry.

BACKGROUND: Children ≤36 months with diffuse intrinsic pontine glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes. METHODS: Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed. RESULTS: Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (P = .018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation. CONCLUSIONS: Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.

Volumetric endpoints in diffuse intrinsic pontine glioma: comparison to cross-sectional measures and outcome correlations in the International DIPG/DMG Registry.

BACKGROUND: Cross-sectional tumor measures are traditional clinical trial endpoints; however volumetric measures may better assess tumor growth. We determined the correlation and compared the prognostic impact of cross-sectional and volumetric measures of progressive disease (PD) among patients with DIPG. METHODS: Imaging and clinical data were abstracted from the International DIPG Registry. Tumor volume and cross-sectional product (CP) were measured with mint Lesion™ software using manual contouring. Correlation between CP and volume (segmented and mathematical [ellipsoid] model) thresholds of PD were assessed by linear regression. Landmark analyses determined differences in survival (via log-rank) between patients classified as PD versus non-PD by CP and volumetric measurements at 1, 3, 5, 7, and 9 months postradiotherapy (RT). Hazard ratios (HR) for survival after these time points were calculated by Cox regression. RESULTS: A total of 312 MRIs (46 patients) were analyzed. Comparing change from the previous smallest measure, CP increase of 25% (PD) correlated with a segmented volume increase of 30% (R2 = 0.710), rather than 40% (spherical model extrapolation). CP-determined PD predicted survival at 1 month post-RT (HR = 2.77), but not other time points. Segmented volumetric-determined PD (40% threshold) predicted survival at all imaging timepoints (HRs = 2.57, 2.62, 3.35, 2.71, 16.29), and 30% volumetric PD threshold predicted survival at 1, 3, 5, and 9 month timepoints (HRs = 2.57, 2.62, 4.65, 5.54). Compared to ellipsoid volume, segmented volume demonstrated superior survival associations. CONCLUSIONS: Segmented volumetric assessments of PD correlated better with survival than CP or ellipsoid volume at most time points. Semiautomated tumor volume likely represents a more accurate, prognostically-relevant measure of disease burden in DIPG.

Extraneural Metastases of Diffuse Midline Glioma, H3 K27M-Mutant at Diagnosis: Case Report, Review of the Literature, and Identifying Targetable Alterations.

Extraneural metastases are rare in pediatric high-grade gliomas and little is known about the genomic profiles of tumors that disseminate beyond the central nervous system. We describe a pediatric patient with H3 K27M-mutant diffuse midline glioma of the brain and spine with biopsy-confirmed osseous metastases present at diagnosis and suspected metastatic parenchymal pulmonary disease. Several potentially clinically and/or therapeutically relevant genomic alterations were identified, including H3F3A and TP53 mutations as well as MET, CDK6, EMSY, and PIK3CG amplifications. Sequencing is critical to improve our understanding of the molecular drivers of distant metastases and discover therapeutic targets that penetrate all disease sites.

Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.

Hypoalbuminaemia as a Prognostic Biomarker of First-Line Treatment Resistance in Metastatic Non-small Cell Lung Cancer.

Introduction: Despite significant advances in systemic anticancer therapy (SACT) for non-small cell lung cancer (NSCLC), many patients still fail to respond to treatment or develop treatment resistance. Albumin, a biomarker of systemic inflammation and malnutrition, predicts survival in many cancers. We evaluated the prognostic significance of albumin in patients receiving first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC. Methods: All patients treated with first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC at a regional Scottish cancer centre were identified. Serum albumin at pre-treatment, after 12-weeks of treatment, and at the time of progressive disease were recorded. The relationship between albumin (≥ 35g/L v <35g/L) and overall survival (OS) was examined. Results: Data were available for 389 patients of both targeted therapy cohort (n = 159) and immunotherapy-based therapy cohort (n = 230). Pre-treatment albumin was predictive of OS in each cohort at HR1.82 (95%CI 1.23-2.7) (p =0.003) and HR2.55 (95%CI 1.78-3.65) (p < 0.001), respectively. Pre-treatment albumin <35 g/L was associated with a significantly higher relative risk of death within 12 weeks in each cohort at RR9.58 (95%CI 2.20-41.72, p = 0.003) and RR3.60 (95%CI 1.74-6.57, p < 0.001), respectively. The 12-week albumin was predictive of OS in each cohort at HR1.88 (95%CI 1.86-4.46) (p < 0.001) and HR2.67 (95%CI 1.74-4.08) (p < 0.001), respectively. 46 out of 133 (35%) evaluable patients treated with targeted therapy and 43 out of 169 (25%) treated with immunotherapy-based therapy crossed over albumin prognostic groups between pre-treatment and 12-week. The prognostic value of 12-week albumin was independent of pre-treatment albumin status. A majority of patients had albumin <35g/L at the time of progressive disease when it was also predictive of survival following progressive disease at HR2.48 (95%CI 1.61-3.82) (p < 0.001) and HR2.87 (95%CI 1.91-4.31) (p < 0.001) respectively). Conclusions: Albumin is a reliable prognostic factor in patients with metastatic NSCLC, predicting survival independent of the class of drug treatment at various time points during the patient journey. Tracking albumin concentrations during systemic therapy may indicate disease activity or treatment response over time.

A distributed network supports spatiotemporal cerebral dynamics of visual naming.

OBJECTIVE: Cerebral spatiotemporal dynamics of visual naming were investigated in epilepsy patients undergoing stereo-electroencephalography (SEEG) monitoring. METHODS: Brain networks were defined by Parcel-Activation-Resection-Symptom matching (PARS) approach by matching high-gamma (50-150 Hz) modulations (HGM) in neuroanatomic parcels during visual naming, with neuropsychological outcomes after resection/ablation of those parcels. Brain parcels with >50% electrode contacts simultaneously showing significant HGM were aligned, to delineate spatiotemporal course of naming-related HGM. RESULTS: In 41 epilepsy patients, neuroanatomic parcels showed sequential yet temporally overlapping HGM course during visual naming. From bilateral occipital lobes, HGM became increasingly left lateralized, coursing through limbic system. Bilateral superior temporal HGM was noted around response time, and right frontal HGM thereafter. Correlations between resected/ablated parcels, and post-surgical neuropsychological outcomes showed specific regional groupings. CONCLUSIONS: Convergence of data from spatiotemporal course of HGM during visual naming, and functional role of specific parcels inferred from neuropsychological deficits after resection/ablation of those parcels, support a model with six cognitive subcomponents of visual naming having overlapping temporal profiles. SIGNIFICANCE: Cerebral substrates supporting visual naming are bilaterally distributed with relative hemispheric contribution dependent on cognitive demands at a specific time. PARS approach can be extended to study other cognitive and functional brain networks.

Categorizing cortical dysplasia lesions for surgical outcome using network functional connectivity.

OBJECTIVE: Focal cortical dysplasia (FCD) is often associated with drug-resistant epilepsy, leading to a recommendation to surgically remove the seizure focus. Predicting outcome for resection of FCD is challenging, requiring a new approach. Lesion-symptom mapping is a powerful and broadly applicable method for linking neurological symptoms or outcomes to damage to particular brain regions. In this work, the authors applied lesion network mapping, an expansion of the traditional approach, to search for the association of lesion network connectivity with surgical outcomes. They hypothesized that connectivity of lesion volumes, preoperatively identified by MRI, would associate with seizure outcomes after surgery in a pediatric cohort with FCD. METHODS: This retrospective study included 21 patients spanning the ages of 3 months to 17.7 years with FCD lesions who underwent surgery for drug-resistant epilepsy. The mean brain-wide functional connectivity map of each lesion volume was assessed across a database of resting-state functional MRI data from healthy children (spanning approximately 2.9 to 18.9 years old) compiled at the authors' institution. Lesion connectivity maps were averaged across age and sex groupings from the database and matched to each patient. The authors sought to associate voxel-wise differences in these maps with subject-specific surgical outcome (seizure free vs persistent seizures). RESULTS: Lesion volumes with persistent seizures after surgery tended to have stronger connectivity to attention and motor networks and weaker connectivity to the default mode network compared with lesion volumes with seizure-free surgical outcome. CONCLUSIONS: Network connectivity-based lesion-outcome mapping may offer new insight for determining the impact of lesion volumes discerned according to both size and specific location. The results of this pilot study could be validated with a larger set of data, with the ultimate goal of allowing examination of lesions in patients with FCD and predicting their surgical outcomes.

Subtraction ictal SPECT co-registered to MRI (SISCOM) patterns in children with temporal lobe epilepsy.

OBJECTIVE: We evaluated SISCOM patterns and their relationship with surgical outcome in children with temporal lobe epilepsy (TLE) who had undergone a temporal lobe surgery. METHODS: This was an observational study evaluating SISCOM patterns in 40 children with TLE. We classified SISCOM patterns into 4 categories; (i) unilateral anteromesial and/or anterolateral temporal pattern; (ii) unilateral anteromesial and/or anterolateral temporal plus posterior extension pattern; (iii) bilateral anteromesial and/or anterolateral temporal pattern; and (iv) atypical pattern. Determinants of SISCOM pattern and correlation between postoperative outcomes and SISCOM patterns were evaluated. RESULTS: Pattern (i), (ii), (iii), and (iv) were identified in 10 (25%), 14 (35%), 0 (0%), and 16 (40%) patients, respectively. There was no significant correlation between patterns and postoperative outcomes. SISCOM patterns significantly associated with the presence of hippocampal sclerosis and type of focal cortical dysplasia (p-value = 0.048 and 0.036, respectively). Patients with HS had 5 times the odds of having unilateral temporal pattern, compared to patients with other neuropathology (OR = 5, 95% CI 0.92 to 27.08). Patients with FCD type 2 had 9.71 times the odds of having atypical pattern, compared to patients with other types of FCD (OR = 9.71, 95% CI 0.92 to 103.04). Lobar concordance of SISCOM and ictal and interictal scalp EEG significantly correlated with postoperative outcomes (p-value = 0.018 and 0.013, respectively). CONCLUSION: Three SISCOM patterns were seen. Patients with HS had increased odds of having unilateral temporal pattern while patients with FCD type 2 had increased odds of having atypical pattern. However, there was no significant correlation between SISCOM patterns and postoperative outcomes. Lobar concordance of SISCOM and ictal and interictal scalp EEG significantly correlated with postoperative outcome. SIGNIFICANCE: This study shows that the distribution of SISCOM patterns and their relationship with postoperative outcomes in children with TLE are different from adult population. Besides, SISCOM may add only limited diagnostic and prognostic information in children with drug-resistant TLE undergoing epilepsy surgery. Further evaluation to identify patient populations that may benefit from SISCOM is desirable.

Fast Automated Stereo-EEG Electrode Contact Identification and Labeling Ensemble.

INTRODUCTION: Stereotactic electroencephalography (SEEG) has emerged as the preferred modality for intracranial monitoring in drug-resistant epilepsy (DRE) patients being evaluated for neurosurgery. After implantation of SEEG electrodes, it is important to determine the neuroanatomic locations of electrode contacts (ECs), to localize ictal onset and propagation, and integrate functional information to facilitate surgical decisions. Although there are tools for coregistration of preoperative MRI and postoperative CT scans, identification, sorting, and labeling of SEEG ECs is often performed manually, which is resource intensive. We report development and validation of a software named Fast Automated SEEG Electrode Contact Identification and Labeling Ensemble (FASCILE). METHODS: FASCILE is written in Python 3.8.3 and employs a novel automated method for identifying ECs, assigning them to respected SEEG electrodes, and labeling. We compared FASCILE with our clinical process of identifying, sorting, and labeling ECs, by computing localization error in anteroposterior, superoinferior, and lateral dimensions. We also measured mean Euclidean distances between ECs identified by FASCILE and the clinical method. We compared time taken for EC identification, sorting, and labeling for the software developer using FASCILE, a first-time clinical user using FASCILE, and the conventional clinical process. RESULTS: Validation in 35 consecutive DRE patients showed a mean overall localization error of 0.73 ± 0.15 mm. FASCILE required 10.7 ± 5.5 min/patient for identifying, sorting, and labeling ECs by a first-time clinical user, compared to 3.3 ± 0.7 h/patient required for the conventional clinical process. CONCLUSION: Given the accuracy, speed, and ease of use, we expect FASCILE to be used frequently for SEEG-driven epilepsy surgery. It is freely available for noncommercial use. FASCILE is specifically designed to expedite localization of ECs, assigning them to respective SEEG electrodes (sorting), and labeling them and not for coregistration of CT and MRI data as there are commercial software available for this purpose.

Diffusion tensor imaging in children following prenatal myelomeningocele repair and its predictive value for the need and timing of subsequent CSF diversion surgery for hydrocephalus.

OBJECTIVE: The aim of this study was to investigate diffusion tensor imaging (DTI), an objective and noninvasive neuroimaging technique, for its potential as an imaging biomarker to predict the need and timing of CSF diversion surgery in patients after prenatal myelomeningocele (MMC) repair. METHODS: This was a retrospective analysis of data based on 35 pediatric patients after prenatal MMC repair (gestational age at birth 32.68 ± 3.42 weeks, range 24-38 weeks; 15 females and 20 males). A logistic regression analysis was used to classify patients to determine the need for CSF diversion surgery. The model performance was compared between using the frontooccipital horn ratio (FOHR) alone and using the FOHR combined with DTI values (the genu of the corpus callosum [gCC] and the posterior limb of the internal capsule [PLIC]). For patients who needed to be treated surgically, timing of the procedure was used as the clinical outcome to test the predictive value of DTI acquired prior to surgery based on a linear regression analysis. RESULTS: Significantly lower fractional anisotropy (FA) values in the gCC (p = 0.014) and PLIC (p = 0.037) and higher mean diffusivity (MD) values in the gCC (p = 0.013) were found in patients who required CSF diversion surgery compared with those who did not require surgery (all p values adjusted for age). Based on the logistic regression analysis, the FOHR alone showed an accuracy of performance of 0.69 and area under the receiver operating characteristic curve (AUC) of 0.60. The performance of the model was higher when DTI measures were used in the logistic regression model (accuracy = 0.77, AUC = 0.84 for using DTI values in gCC; accuracy = 0.75, AUC = 0.84 for using DTI values in PLIC). Combining the DTI values of the gCC or PLIC and FOHR did not improve the model performance when compared with using the DTI values alone. In patients who needed CSF diversion surgery, significant correlation was found between DTI values in the gCC and the time interval between imaging and surgery (FA: ρ = 0.625, p = 0.022; MD: ρ = -0.6830, p = 0.010; both adjusted for age and FOHR). CONCLUSIONS: The authors' data demonstrated that DTI could potentially serve as an objective biomarker differentiating patients after prenatal MMC repair regarding those who may require surgery for MMC-associated hydrocephalus. The predictive value for the need and timing of CSF diversion surgery is highly clinically relevant for improving and optimizing decision-making for the treatment of hydrocephalus in this patient population.

Overcoming barriers to establishing autopsy procurement programs in pediatric patients with central nervous system tumors: a call to develop regional centers.

BACKGROUND: While autopsy-repository programs with a variety of pediatric central nervous system (CNS) tumor types are a critical resource for preclinical neuro-oncology research, few exist and there is no published guidance on how to develop one. The goal of this prospective Pediatric Brain Tumor Repository (PBTR) study was to develop such a program at Cincinnati Children's Hospital Medical Center (CCHMC) and then publish the quantitative and experiential data as a guide to support the development of similar programs. METHODS: Protocols and infrastructure were established-to educate oncologists and families, establish eligibility, obtain consent, address pre- and post-autopsy logistics (e.g., patient and tissue transportation), process and authenticate tissue samples, and collect and analyze data. RESULTS: Of the 129 pediatric CNS tumor patients at CCHMC who died between 2013 and 2018, 109 were eligible for our study. Of these, 74% (81 of 109) were approached for PBTR donation, and 68% (55 of 81) consented. In the final year of the study, approach and consent rates were 93% and 85%, respectively. Median time from death to autopsy (postmortem interval, PMI) was 10 h (range, 1.5-30). In the outpatient setting, PMI increased with distance (from the hospice/home where the patient died to CCHMC). In all patients, PMI appeared to be lower, when consent was obtained more than 24 h before death. CONCLUSIONS: Procurement of autopsy specimens need not be a barrier in neuro-oncology research. Regional centers, strict timing-of-consent, patient education, and dedicated staff are all needed to minimize PMI and, thereby, increase the value of the procured tissue for an array of basic and translational research applications.