The ClearPoint Array Frame: An MRI Compatible System that Supports Non-craniotomy, Multi-trajectory (NCMT) Stereotactic Procedures.

BACKGROUND: With continued evolution in stereotactic techniques and an expanding armamentarium of surgical therapeutic options, non-craniotomy stereotactic procedures in neuro-oncology are becoming increasingly complex, often requiring multi-trajectory approaches. Here we demonstrate that the ClearPoint SmartFrame Array (Solana Beach, California, USA), a second-generation magnetic resonance imaging-compatible stereotactic frame, supports such non-craniotomy, multi-trajectory (NCMT) stereotactic procedures. METHODS: We previously published case reports demonstrating the feasibility of NCMT through the ClearPoint SmartFrame Array. Here we prospectively followed the next 10 consecutive patients who underwent such multi-trajectory procedures to further establish procedural safety and clinical utility. RESULTS: Ten patients underwent complex, multi-trajectory stereotactic procedures, including combinations of needle biopsy ± cyst drainage and laser interstitial thermal therapy targeting geographically distinct regions of neoplastic lesions under the same anesthetic event. The median maximal radial error of stereotaxis was 1.0 mm. In all cases, definitive diagnosis was achieved, and >90% of the intended targets were ablated. The average stereotaxis time for the multi-trajectory procedure was 119 ± 22.2 minutes, comparing favorably to our previously published results of single-trajectory procedures (80 ± 9.59 minutes, P = 0.125). There were no procedural complications. Post-procedure, the neurologic condition of 1 patient improved, while the remaining 9 patients remained stable. All patients were discharged home, with a median hospital stay of 1 day (range: 1-12 days). With a median follow-up of 376 days (range: 155-1438 days), there were no 30-day readmissions or wound complications. CONCLUSIONS: Geographically distinct regions of brain cancer can be safely and accurately accessed through the ClearPoint Array frame in NCMT stereotactic procedures.

Comparison meta-analysis of intraoperative MRI-guided needle biopsy versus conventional stereotactic needle biopsies.

Background: MRI-guided needle biopsy (INB) is an emerging alternative to conventional frame-based or frameless stereotactic needle biopsy (SNB). Studies of INB have been limited to select case series, and comparative studies between INB and SNB remain a missing gap in the literature. We performed a meta-analysis to compare INB and SNB literature in terms of diagnostic yield, surgical morbidity and mortality, tumor size, and procedural time. Methods: We identified 36 separate cohorts in 26 studies of SNB (including both frameless and frame-based biopsies, 3374 patients) and 27 studies of INB (977 patients). Meta-regression and meta-analysis by proportions were performed. Results: Relative to publications that studied SNB, publications studying INB more likely involved brain tumors located in the eloquent cerebrum (79.4% versus 62.6%, P = 0.004) or are smaller in maximal diameter (2.7 cm in INB group versus 3.6 cm in the SNB group, P = .032). Despite these differences, the pooled estimate of diagnostic yield for INB was higher than SNB (95.4% versus 92.3%, P = .026). The pooled estimate of surgical morbidity was higher in the SNB group (12.0%) relative to the INB group (6.1%) (P = .004). Mortality after the procedure was comparable between INB and SNB (1.7% versus 2.3%, P = .288). Procedural time was statistically comparable at 90.3 min (INB) and 103.7 min (SNB), respectively (P = .526). Conclusions: Our meta-analysis indicates that, relative to SNB, INB is more often performed for the challenging, smaller-sized brain tumors located in the eloquent cerebrum. INB is associated with lower surgical morbidity and improved diagnostic yield.

GammaTile® (GT) as a brachytherapy platform for rapidly proliferating glioblastomas: from case series to clinical trials.

PURPOSE: Radiation plays a central role in glioblastoma treatment. Logistics related to coordinating clinic visits, radiation planning, and surgical recovery necessitate delay in radiation delivery from the time of diagnosis. Unimpeded tumor growth occurs during this period, and is associated with poor clinical outcome. Here we provide a pilot experience of GammaTile ® (GT), a collagen tile-embedded Cesium-131 (131Cs) brachytherapy platform for such aggressive tumors. METHODS: We prospectively followed seven consecutive patients (2019-2023) with newly diagnosed (n = 3) or recurrent (n = 4) isocitrate dehydrogenase wild-type glioblastoma that grew > 100% in volume during the 30 days between the time of initial diagnosis/surgery and the radiation planning MRI. These patients underwent re-resection followed by GT placement. RESULTS: There were no surgical complications. One patient developed right hemiparesis prior to re-resection/GT placement and was discharged to rehabilitation, all others were discharged home-with a median hospital stay of 2 days (range: 1-5 days). There was no 30-day mortality and one 30-day readmission (hydrocephalus, requiring ventriculoperitoneal shunting (14%)). With a median follow-up of 347 days (11.6 months), median progression free survival of ≥ 320 days (10.6 months) was achieved for both newly and recurrent glioblastoma patients. The median overall survival (mOS) was 304 and 347 days (10 and 11.5 mo) for recurrent and newly diagnosed glioblastoma patients, respectively. CONCLUSION: Our pilot experience suggests that GT offers favorable local control and safety profile for patients afflicted with rapidly proliferating glioblastomas and lay the foundation for future clinical trial design.

Magnetic Resonance Imaging-Aided SmartFlow Convection Delivery of DNX-2401: A Pilot, Prospective Case Series.

BACKGROUND: The Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects (CAPTIVE) study is a phase II clinical trial testing the efficacy of a recombinant adenovirus DNX-2401 combined with the immune checkpoint inhibitor pembrolizumab. Here, we report the first patients in this study who underwent viral delivery through real-time magnetic resonance imaging (MRI) stereotaxis-guided SmartFlow convection delivery of DNX-2401. METHODS: Patients who underwent real-time MRI-guided DNX-2401 delivery through the SmartFlow convection catheter were prospectively followed. RESULTS: Precise catheter placement was achieved in all patients treated, and no adverse events were noted. Average radial error from target was 0.9 mm. Average procedural time was 3 hours 16 minutes and was comparable to other convection-enhanced delivery techniques. In 2 patients, delivery of DNX-2401 was visualized as >1 cm maximal diameter of T1 hypointensity infusate on MRI obtained immediately after completion of viral infusion. These patients exhibited partial response based on Response Assessment in Neuro-Oncology assessment. The remaining patient showed <1 cm maximal diameter of infusate on immediate postinfusion MRI and showed disease progression on subsequent MRI. CONCLUSIONS: Our pilot case series supports compatibility of the SmartFlow system with oncolytic adenovirus delivery and provides the basis for future validation studies.

Comparison of Gamma Knife (GK) and Linear Accelerator (LINAC) radiosurgery of brain metastasis resection cavity: a systematic review and proportional meta-analysis.

PURPOSE: Stereotactic radiosurgery (SRS) to the resection cavity is essential in the treatment of brain metastasis (BM) amenable to surgical resection. The two most common platforms for SRS delivery include Gamma Knife (GK) and LINAC. Here we collated the available peer-reviewed literature and performed a meta-analysis on clinical outcomes after GK or LINAC resection cavity SRS. METHODS: Following PRISMA Guidelines, a search on PUBMED and MEDLINE was performed to include all studies evaluating each post-operative SRS modality. Local control, overall survival, radiation necrosis, and leptomeningeal disease were evaluated from the available data. A proportional meta-analysis was performed via R using the metafor package to pool the outcomes of studies and a moderator effect to assess the significance between groups. RESULTS: We identified 21 GK studies (n = 2009) and 28 LINAC studies (n = 2219). The radiosurgery doses employed were comparable between GK and LINAC studies. The pooled estimate of 1-year local control, 1-year overall survival, and risk of leptomeningeal disease were statistically comparable between GK and LINAC (81.7 v 85.8%; 61.4 v 62.7%; 10.6 v 12.5%, respectively). However, the risk of radiation necrosis (RN) was higher for LINAC resection cavity SRS (5.4% vs. 10%, p = 0.036). The volume of the resection cavity was a significant modifying factor for RN in both modalities (p = 0.007) with a 0.5% and 0.7% increase in RN risk with every 1 cm3 increase in tumor volume for GK and LINAC, respectively. CONCLUSIONS: Our meta-analysis suggests that GK and LINAC SRS of resection cavity achieve comparable 1-year local control and survival. However, resection cavity treated with GK SRS was associated with lowered RN risk relative to those treated with LINAC SRS.

Preoperative Versus Postoperative Radiosurgery of Brain Metastases: A Meta-Analysis.

OBJECTIVE: While postoperative resection cavity radiosurgery (post-SRS) is an accepted treatment paradigm for brain metastasis (BM) patients who undergo surgical resection, there is emerging interest in preoperative radiosurgery (pre-SRS) followed by surgical resection as an alternative treatment paradigm. Here, we performed a meta-analysis of the available literature on this matter. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a search of all studies evaluating pre-SRS and post-SRS was completed. Local recurrence (LR), overall survival (OS), radiation necrosis (RN), and leptomeningeal disease (LMD) were evaluated from the available data. Moderator analysis and pooled effect sizes were performed using a proportional meta-analysis with R using the metafor package. Statistics are presented as mean [95% confidence interval]. RESULTS: We identified 6 pre-SRS and 33 post-SRS studies with comparable tumor volume (4.5-17.6 cm3). There were significant differences in the pooled estimates of LR and LMD, favoring pre-SRS over post-SRS. Pooled aggregate for LR was 11.0% [4.9-13.7] and 17.5% [15.1-19.9] for pre- and post-SRS studies (P = 0.014). Similarly, pooled estimates of LMD favored pre-SRS, 4.4% [2.6-6.2], relative to post-SRS, 12.3% [8.9-15.7] (P = 0.019). In contrast, no significant differences were found in terms of RN and OS. Pooled estimates for RN were 6.4% [3.1-9.6] and 8.9% [6.3-11.6] for pre- and post-SRS studies (P = 0.393), respectively. Pooled estimates for OS were 60.2% [55.8-64.6] and 60.5% [56.9-64.0] for pre- and post-SRS studies (P = 0.974). CONCLUSIONS: This meta-analysis supports further exploration of pre-SRS as a strategy for the treatment of BM.

Neurosurgery residency match for international medical graduates in the United States.

OBJECTIVE: Training of international medical graduates (IMGs) offers opportunities for the US neurosurgery community to engage the global talent pool and impact national and international healthcare. Here, the authors analyzed the time trend of IMGs matching into US neurosurgery programs and identified potential opportunities for enhancing IMG engagement. METHODS: The authors analyzed the National Resident Matching Program (NRMP) match results, NRMP program director (PD) surveys, and applicant surveys from 2013 to 2022. Regression methods were used to analyze time trends. RESULTS: Between 2013 and 2022, the number of US neurosurgery residency positions increased by 17.6% (from 204 to 240). During this period, the percentage of IMGs matching into neurosurgery increased from 3.5% to 7%, translating into a 6.8% increase in the likelihood of a successful IMG match per year (95% CI 0.3%-13.8%, p = 0.042). The likelihoods of a successful match for US MDs and IMGs scoring > 260 on the USMLE Step 1 were > 90% and approximately 55%, respectively. In PD surveys, approximately 90% of PDs indicated that they seldom/never interview or rank IMGs. In terms of factors that influenced the PD decision for interviewing/ranking, IMGs are disadvantaged in several categories, including the ability to secure an audition elective/rotation, and proper letters of recommendation, as well as the influence of the culture on the preconceived perception of poor interpersonal skills. CONCLUSIONS: The number of IMGs matching successfully in neurosurgery has increased marginally during the past decade. The authors outline the challenges that IMGs encounter in this process and suggest strategies for considerations of IMG training in NRMP-associated institutions.

Comparison of Stereotactic Radiosurgery and Hypofractionated Radiosurgery for Vestibular Schwannomas: A Meta-Analysis of Available Literature.

BACKGROUND: Stereotactic radiosurgery (SRS) and recently, hypofractionated radiosurgery (hSRS) are increasingly utilized as treatment for vestibular schwannomas (VS). We performed a meta-analysis of literature comparing these modalities. METHODS: The PubMed database of articles was searched for studies that compared SRS and hSRS in patients with VS. Variables analyzed include tumor control, hearing preservation, facial nerve preservation, trigeminal nerve preservation, and total complications. Heterogeneity across the studies was gauged using Higgins's inconsistency index. Funnel plots and Egger's regression intercept test were used to address the publication bias. RESULTS: Thirteen studies that satisfied the search criteria were selected for meta-analysis. The studies identified in our study included 353 SRS and 511 hSRS-treated patients. Analysis of heterogeneity showed that hSRS is employed for relatively larger tumor sizes in comparison to SRS. Pooled meta-analysis estimates showed no significant differences between SRS and hSRS in terms of tumor control (odds ratio [OR], 0.620; 95% confidence interval [CI], 0.21-1.86, P = 0.39), hearing preservation (OR, 1.07; 95% CI, 0.59-1.93, P = 0.83), facial nerve preservation (OR, 0.53; 5% CI, 0.23-1.21, P = 0.13), or trigeminal nerve preservation (OR, 0.67; 95% CI, 0.24-1.89, P = 0.49) at a mean follow-up of 39 months. Statistically significant heterogeneity was found across the studies only for tumor diameter (Higgins's inconsistency index = 65.69%, P = 0.003) but not for other variables. CONCLUSIONS: Meta-analysis of thirteen studies comparing SRS and hSRS as treatment for VS showed comparable tumor control, hearing preservation, facial nerve preservation, and trigeminal nerve preservation.

Comparison of peripheral leukocyte parameters in patients receiving conventionally and hypofractionated radiotherapy schemes for the treatment of newly diagnosed glioblastoma.

Introduction: Treatment for glioblastomas, aggressive and nearly uniformly fatal brain tumors, provide limited long-term success. Immunosuppression by myeloid cells in both the tumor microenvironment and systemic circulation are believed to contribute to this treatment resistance. Standard multi-modality therapy includes conventionally fractionated radiotherapy over 6 weeks; however, hypofractionated radiotherapy over 3 weeks or less may be appropriate for older patients or populations with poor performance status. Lymphocyte concentration changes have been reported in patients with glioblastoma; however, monocytes are likely a key cell type contributing to immunosuppression in glioblastoma. Peripheral monocyte concentration changes in patients receiving commonly employed radiation fractionation schemes are unknown. Methods: To determine the effect of conventionally fractionated and hypofractionated radiotherapy on complete blood cell leukocyte parameters, retrospective longitudinal concentrations were compared prior to, during, and following standard chemoradiation treatment. Results: This study is the first to report increased monocyte concentrations and decreased lymphocyte concentrations in patients treated with conventionally fractionated radiotherapy compared to hypofractionated radiotherapy. Discussion: Understanding the impact of fractionation on peripheral blood leukocytes is important to inform selection of dose fractionation schemes for patients receiving radiotherapy.

Management Strategies of Plasma Cell Granuloma Involving the Central Nervous System: A Systematic Review of the Literature.

BACKGROUND: Plasma cell granuloma (PCG) is a rare clinical entity seen in the neurosurgical literature. It has often been referred to as inflammatory myofibroblastic tumor or inflammatory pseudotumor. No well-defined management guidelines exist in the literature. METHODS: Using PRISMA guidelines, we systematically reviewed the literature in PubMed and Google Scholar using MeSH terms: intracranial plasma cell granuloma, myofibroblastic tumor, intracranial pseudotumor, spinal plasma cell granuloma. We analyzed the clinical presentation, treatment strategies, clinical outcomes, and follow-up across different studies. RESULTS: Eighty-three studies were included presenting 108 cases. Primary extracranial disease was seen in 4 patients and primary central nervous system (CNS) disease in 104. In the combined cohort, multicompartmental disease was seen in 22 (20.8%) patients. Headache (n=40, 42.59%) was the most common clinical symptom. Surgical excision (n=86, 79.6%) was the most common primary treatment used. Radiation therapy, steroids, and chemotherapy (methotrexate/6-mercaptopurine/rituximab) were also used. Disease recurrence was noted in 25 (33.3%) patients and residual disease in 33 (30.5%). Mortality was seen in 4 (3.7%) patients. In the cranial PCG subgroup (n=87), 81 (93.1%) patients had solitary lesions, and 6 (6.8%) had multiple lesions. Recurrence after primary surgery was noted in 27.58% (n=24). In the spinal PCG subgroup (n=17), the thoracic spine was the most common location (n=9, 52.9%) and recurrence was seen in 5.84% (n=1). CONCLUSIONS: Combination of multiple treatment modalities is needed when approaching this complex disease. Spinal PCGs respond favorably to gross total excision, with a low recurrence rate. Cranial PCGs warrant intense follow-up with secondary chemotherapy/radiation/steroids in recurrent cases.

Survey Assessment of Utility in Preoperative Magnetic Resonance (MR) Tractography Surgical Planning.

BACKGROUND: Although tractography-guided surgery is used by many surgeons, there is controversy in the published literature as it relates to its clinical utility. Here we adopted a survey-based approach with the goal of attaining a broader view of how tractography influence preoperative planning in a sampling of practicing neurosurgeons. METHODS: Three cases were prepared where the presence of a tumor distorted the optic radiation (case 1), arcuate fasciculus (case 2), and corticospinal tract (case 3). This survey was administered at the Medtronic Cranial Consortium attended by 20 practicing neurosurgeons. To avoid commercial bias, we used both the Brainlab and Medtronic platform to compute tractography. Each participant is asked to vote on a surgical trajectory before and after seeing the tractography images, as well as whether tractography added value in validating their surgical approach. RESULTS: In the 3 cases surveyed, 16%-44% of the surgeons changed the surgical corridor selected after seeing the tractography images. The most common finding associated with a change in surgical corridor involved intersection of the surgical corridor with visualized tracts. Consistently, >80% of the surgeons surveyed felt that tractography added value in their surgical planning. CONCLUSIONS: The clinical utility of tractography in preoperative planning varies as a function of surgeon and the tumor anatomy, with >80% of the participating surgeons believing that tractography added value in preoperative surgical planning.

Increased risk for ex-vacuo ventriculomegaly with leukoencephalopathy (EVL) in whole brain radiation therapy and repeat radiosurgery treated brain metastasis patients.

INTRODUCTION: Cerebral atrophy with leukoencephalopathy is a known morbidity after whole brain radiation therapy (WBRT), resulting in ex-vacuo ventriculomegaly with leukoencephalopathy (EVL). Here we studied the correlation between WBRT, stereotactic radiosurgery (SRS), and risk for EVL in brain metastases patients. METHODS: In a retrospective study, we identified 195 patients (with 1,018 BM) who underwent SRS for BM (2007-2017) and had > 3 months of MRI follow-up. All patients who underwent ventriculoperitoneal shunting were excluded. Cerebral atrophy was measured by ex-vacuo-ventriculomegaly, defined based on Evans' criteria. Demographic and clinical variables were analyzed using logistic regression models. RESULTS: Ex-vacuo ventriculomegaly was observed on pre-radiosurgery imaging in 29.7% (58/195) of the study cohort. On multivariate analysis, older age was the only variable associated with pre-radiosurgery ventriculomegaly. Of the 137 patients with normal ventricular size before radiosurgery, 27 (19.7 %) developed ex-vacuo ventriculomegaly and leukoencephalopathy (EVL) post-SRS. In univariate analysis, previous whole brain radiation therapy was the main factor associated with increased risk for developing EVL (OR = 5.08, p < 0.001). In bivariate models that included prior receipt of WBRT, both the number of SRS treatments (OR = 1.499, p = 0.025) and WBRT (OR = 11.321, p = 0.003 were independently associated with increased EVL risk. CONCLUSIONS: While repeat radiosurgery contributes to the risk of EVL in BM patients, this risk is ∼20-fold lower than that associated with WBRT.

Stereotactic Radiosurgery as Treatment for Brain Metastases: An Update.

Stereotactic radiosurgery (SRS) is a mainstay treatment option for brain metastasis (BM). While guidelines for SRS use have been outlined by professional societies, consideration of these guidelines should be weighed in the context of emerging literature, novel technology platforms, and contemporary treatment paradigms. Here, we review recent advances in prognostic scale development for SRS-treated BM patients and survival outcomes as a function of the number of BM and cumulative intracranial tumor volume. Focus is placed on the role of stereotactic laser thermal ablation in the management of BM that recur after SRS and the management of radiation necrosis. Neoadjuvant SRS prior to surgical resection as a means of minimizing leptomeningeal spread is also discussed.

GammaTile® (GT) as a brachytherapy platform for rapidly growing brain metastasis.

Background: A subset of brain metastasis (BM) shows rapid recurrence post-initial resection or aggressive tumor growth between interval scans. Here we provide a pilot experience in the treatment of these BM with GammaTile® (GT), a collagen tile-embedded Cesium 131 (131Cs) brachytherapy platform. Methods: We identified ten consecutive patients (2019-2023) with BM that showed either (1) symptomatic recurrence while awaiting post-resection radiosurgery or (2) enlarged by >25% of tumor volume on serial imaging and underwent surgical resection followed by GT placement. Procedural complication, 30-day readmission, local control, and overall survival were assessed. Results: For this cohort of ten BM patients, 3 patients suffered tumor progression while awaiting radiosurgery and 7 showed >25% tumor growth prior to surgery and GT placement. There were no procedural complications or 30-day mortality. All patients were discharged home, with a median hospital stay of 2 days (range: 1-9 days). 4/10 patients experienced symptomatic improvement while the remaining patients showed stable neurologic conditions. With a median follow-up of 186 days (6.2 months, range: 69-452 days), no local recurrence was detected. The median overall survival (mOS) for the newly diagnosed BM was 265 days from the time of GT placement. No patients suffered from adverse radiation effects. Conclusion: Our pilot experience suggests that GT offers favorable local control and safety profile in patients suffering from brain metastases that exhibit aggressive growth patterns and support the future investigation of this treatment paradigm.

Integrated analysis of single-cell chromatin state and transcriptome identified common vulnerability despite glioblastoma heterogeneity.

In 2021, the World Health Organization reclassified glioblastoma, the most common form of adult brain cancer, into isocitrate dehydrogenase (IDH)-wild-type glioblastomas and grade IV IDH mutant (G4 IDHm) astrocytomas. For both tumor types, intratumoral heterogeneity is a key contributor to therapeutic failure. To better define this heterogeneity, genome-wide chromatin accessibility and transcription profiles of clinical samples of glioblastomas and G4 IDHm astrocytomas were analyzed at single-cell resolution. These profiles afforded resolution of intratumoral genetic heterogeneity, including delineation of cell-to-cell variations in distinct cell states, focal gene amplifications, as well as extrachromosomal circular DNAs. Despite differences in IDH mutation status and significant intratumoral heterogeneity, the profiled tumor cells shared a common chromatin structure defined by open regions enriched for nuclear factor 1 transcription factors (NFIA and NFIB). Silencing of NFIA or NFIB suppressed in vitro and in vivo growths of patient-derived glioblastomas and G4 IDHm astrocytoma models. These findings suggest that despite distinct genotypes and cell states, glioblastoma/G4 astrocytoma cells share dependency on core transcriptional programs, yielding an attractive platform for addressing therapeutic challenges associated with intratumoral heterogeneity.

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Comparable safety profile between neuro-oncology procedures involving stereotactic needle biopsy (SNB) followed by laser interstitial thermal therapy (LITT) and LITT alone procedures.

INTRODUCTION: Tissue diagnosis through stereotactic needle biopsy (SNB) is often needed prior to laser interstitial thermal therapy (LITT). Whether these procedures should be performed in the same surgery or in separate settings remain unclear. As a first step to address this question, we assess safety profile of procedures involving LITT alone versus SNB + LITT. METHODS: Using International Classification of Disease (ICD) codes, we queried the National Readmissions Database (NRD, 2010-2018) for malignant brain tumor patients who underwent either (1) LITT alone or (2) elective LITT in combination with SNB (SNB + LITT). Survey regression methods were utilized. Additionally, the procedural outcome of LITT or SNB + LITT performed by the senior surgeon (2014-2022) were reviewed. RESULTS: During the study period, an estimated 678 malignant brain tumor patients underwent LITT alone versus 373 patients that underwent SNB + LITT. Patients undergoing LITT and SNB + LITT exhibited statistically comparable median lengths of hospital stay (IQR; LITT = 2 day [1, 3]; SNB + LITT = 1 day [1, 3]; p = 0.405) and likelihood of routine discharge (LITT = 73.5%; SNB + LITT = 81.1%; p = 0.068). The odds of 30-day medical or neurological readmissions were comparable between LITT and SNB + LITT treated patients (all p ≥ 0.793). In the single surgeon experience of 218 procedures performed over an eight year period (2014-2022), the complications (LITT = 3.9%; SNB + LITT = 2.6%, p = 0.709), discharge within 48 h (LITT = 84.5%; SNB + LITT = 87.8%; p = 0.556), routine discharge (LITT = 91.3%; SNB + LITT = 93.9%; p = 0.604), and unplanned 30-day readmission (LITT = 3.9%; SNB + LITT = 1.7%; p = 0.423) were similarly comparable between LITT and SNB + LITT. CONCLUSION: The length of hospital stay, the likelihood of routine discharge, and 30-day readmission for malignant brain tumor patients who underwent LITT and SNB + LITT were comparable.

Main Manuscript for Cell migration simulator-based biomarkers for glioblastoma.

Glioblastoma is the most aggressive malignant brain tumor with poor survival due to its invasive nature driven by cell migration, with unclear linkage to transcriptomic information. Here, we applied a physics-based motor-clutch model, a cell migration simulator (CMS), to parameterize the migration of glioblastoma cells and define physical biomarkers on a patient-by-patient basis. We reduced the 11-dimensional parameter space of the CMS into 3D to identify three principal physical parameters that govern cell migration: motor number - describing myosin II activity, clutch number - describing adhesion level, and F-actin polymerization rate. Experimentally, we found that glioblastoma patient-derived (xenograft) (PD(X)) cell lines across mesenchymal (MES), proneural (PN), classical (CL) subtypes and two institutions (N=13 patients) had optimal motility and traction force on stiffnesses around 9.3kPa, with otherwise heterogeneous and uncorrelated motility, traction, and F-actin flow. By contrast, with the CMS parameterization, we found glioblastoma cells consistently had balanced motor/clutch ratios to enable effective migration, and that MES cells had higher actin polymerization rates resulting in higher motility. The CMS also predicted differential sensitivity to cytoskeletal drugs between patients. Finally, we identified 11 genes that correlated with the physical parameters, suggesting that transcriptomic data alone could potentially predict the mechanics and speed of glioblastoma cell migration. Overall, we describe a general physics-based framework for parameterizing individual glioblastoma patients and connecting to clinical transcriptomic data, that can potentially be used to develop patient-specific anti-migratory therapeutic strategies generally.

Cooperativity between H3.3K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars.

Diffuse midline glioma (DMG) is a leading cause of brain tumor death in children. In addition to hallmark H3.3K27M mutations, significant subsets also harbor alterations of other genes, such as TP53 and PDGFRA. Despite the prevalence of H3.3K27M, the results of clinical trials in DMG have been mixed, possibly due to the lack of models recapitulating its genetic heterogeneity. To address this gap, we developed human iPSC-derived tumor models harboring TP53R248Q with or without heterozygous H3.3K27M and/or PDGFRAD842V overexpression. The combination of H3.3K27M and PDGFRAD842V resulted in more proliferative tumors when gene-edited neural progenitor (NP) cells were implanted into mouse brains compared to NP with either mutation alone. Transcriptomic comparison of tumors and their NP cells of origin identified conserved JAK/STAT pathway activation across genotypes as characteristic of malignant transformation. Conversely, integrated genome-wide epigenomic and transcriptomic analyses, as well as rational pharmacologic inhibition, revealed targetable vulnerabilities unique to the TP53R248Q; H3.3K27M; PDGFRAD842V tumors and related to their aggressive growth phenotype. These include AREG-mediated cell cycle control, altered metabolism, and vulnerability to combination ONC201/trametinib treatment. Taken together, these data suggest that cooperation between H3.3K27M and PDGFRA influences tumor biology, underscoring the need for better molecular stratification in DMG clinical trials.