bluuebunny/crossref_metadata_2025 huggingface dataset:
NCMP-13. EXPLORING THE PATHOPHYSIOLOGY OF HYDROCEPHALUS IN CHOROID PLEXUS PAPILLOMA
Authors: Harper Stuart , Prabhu Ashna , Perryman Travis , Dudley Lindsey , Delgadillo Alondra , Gor Aidan , Patel Kunal
Published: November 2024

BACKGROUND

Choroid plexus papilloma (CPP) is a benign intraventricular lesion associated with hydrocephalus and ventricular outflow obstruction. However, the molecular mechanism by which cerebrospinal fluid (CSF) is produced by choroid plexus (CP), or by which CSF production is altered in the setting of CPP to cause hydrocephalus, is unknown.

METHODS

A PRISMA systematic literature review was conducted to identify gene targets associated with CSF production. Primary tissue samples of CP and CPP from the same patient were obtained, and expression of target genes was assessed using immunohistochemistry and quantified using QuPath software H-scoring. Single-nucleus sequencing of both CP and CPP was also completed, and differential expression of identified target genes was evaluated by calculating log fold change.

RESULTS

Systematic literature review yielded 25 studies in animal models and 18 unique gene targets. 16 targets were expressed in primary CP and CPP tissue samples upon immunohistochemistry staining. 11 of 18 targets revealed significant differential expression between CP and CPP on single-nucleus sequencing. Genes with notable expression increases in CPP included ion transporters NKCC1 (Na-K-Cl cotransporter) and TRPV4 (non-selective cation channel), as well as carbonic anhydrase II.

CONCLUSIONS

We present evidence that choroid plexus papilloma has altered expression of genes previously implicated in CSF production. Upregulation of membrane transporters and cytoplasmic enzymes involved in Na+, K+, Cl-, and HCO3- transport may provide a mechanistic explanation for the development of hydrocephalus in CPP. Pharmacologic inhibition of CSF production may offer a route for non-surgical management of CPP, as well as other pathologies causing hydrocephalus.
NCMP-14. RADIOGRAPHIC RESPONSE TO BEVACIZUMAB IN TREATING RADIATION NECROSIS AND ASSOCIATED EDEMA IN BRAIN TUMORS
Authors: hee ahn kang
Published: November 2024

OBJECTIVE

This study evaluates the efficacy of bevacizumab in treating radiation necrosis (RN) and associated perilesional edema in brain tumors. We aimed to measure changes in radiologic volumes and clinical performance following treatment.

MATERIALS AND METHODS

We retrospectively reviewed patients treated with radiation therapy and/or stereotactic radiosurgery between September 2017 and August 2023. We identified 10 metastatic brain tumors and one glioblastoma with symptomatic RN. Diagnosis was primarily through MRI, with one case confirmed pathologically. All patients received bevacizumab (7.5 mg/kg every 3 weeks). Volumes of RN and perilesional edema were measured using gadolinium-enhanced T1-weighted and T2-weighted/FLAIR MRI, respectively, analyzed with Brainlab software. Volume changes and clinical symptoms, graded by the ECOG Performance Status (PS) scale, were recorded.

RESULTS

The minimal follow-up was 4 months. The 11 patients received a median of 2 bevacizumab cycles (range, 2-3). Pre-treatment median volumes (ranges) were: tumor/RN 5.45 cc (2.66-13.56), perilesional edema (T2, FLAIR) 53.93 cc (7.46-115.32), 58.01 cc (15.18-131.2). Post-treatment median volumes (ranges) were: tumor/RN 2.5 cc (2.23-7.23), perilesional edema (T2, FLAIR) 4.05 cc (3.08-11.18), 7.38 cc (2.887-17.647). Median percentage volume reductions were: tumor 39%, RN 38%, perilesional edema (T2, FLAIR) 80%, 79%. Significant reductions in edematous volumes were observed. Pre-treatment ECOG PS median was 2 (range 2-3); post-treatment ECOG PS median remained 2 (range 2-3). Clinical performance improved in most patients, with two exception where deterioration occurred after the third cycle despite initial improvement.

CONCLUSION

Bevacizumab is effective in reducing RN and perilesional edema, particularly within the first two cycles of treatment. Most patients showed clinical improvement, though further research is needed to optimize treatment and understand long-term outcomes.
NCMP-16. CNS METASTATIC PATTERNS IN BREAST CANCER TREATED WITH CDK4/6 INHIBITORS: PRELIMINARY RESULTS OF A RETROSPECTIVE ANALYSIS
Authors: Bazer Danielle A , Reiss Justus , Sherief Mohamed , Zhou Yuan , Martinez Daniel Heinemann , Parampil Amy , Torroella Jordina Rincon , Wolff Antonio C , Couzi Rima , Stearns Vered , Wilkinson Mary , Jelovac Danijela , Tao Jessica , Sheng Jenni , Canzoniero Jenna V , Santa-Maria Cesar , Kamson David O , Sahebjam Solmaz
Published: November 2024

BACKGROUND

CDK4/6 inhibitors combined with hormonal therapy or as monotherapy (abemaciclib) play an important role in the management of hormone receptor positive, HER-2 negative breast cancer (BC). To date, these drugs were shown to improve progression-free survival, whereas their comparative effect modulating breast cancer central nervous system metastases (CNSm) has not yet been extensively studied. Here, we present the early findings and analytic plan of our retrospective study to evaluate CNSm patterns and differences among CDK4/6-inhibitors in BC.

METHODS

In this retrospective chart review study, we queried the Johns Hopkins Electronic Medical Record from 1/1/2014 to 4/25/2024 using the following prescreening criteria: 1) Age ≥18 years; 2) Diagnosis and/or problem list including BC; 3) Palbociclib, abemaciclib, or ribociclib included in the medication list. The identified patients were dichotomized based on the presence/absence of ICD10 codes for CNSm and are currently being chart-reviewed. Patients without longitudinal data or confirmed CNS or with CNSm diagnosed before/within 1 month of CDK-inhibitor initiation were excluded. Population: Prescreening identified 1,419 patients (1,055 palbociclib, 301 abemaciclib, 145 ribociclib) of whom 239, 36, and 19 patients had ICD10 codes for brain metastases, respectively. After exclusion of false positives from this cohort, we confirmed 53 patients with CNSm in the palbociclib, 3 in the ribociclib, and 1 in the abemaciclib group.

RESULTS

We present the current data from the first-line palbociclib cohort (N=53) where, median time to CNSm on was 24 months (interquartile range 13-46). Fifty-two (98.1%) patients had documented bone, 31 (58.5%) dural, 7 (13.2%) leptomeningeal, and 33 (62.3%) calvarial involvement. Dural and calvarial metastases were strongly associated with each other (pearson-chi2=10.7; p=0.001).

CONCLUSIONS

This is a work-in-progress, with early preliminary findings showing a high rate of dural and calvarial metastases in this cohort. A more detailed review of the dataset that will also include the CNS-metastasis-free cohort is underway.
NCMP-21. COMPARATIVE ANALYSIS OF VENTRICULOPERITONEAL SHUNT PLACEMENT FOR POST-TREATMENT HYDROCEPHALUS FOLLOWING VESTIBULAR SCHWANNOMA MANAGEMENT: SURGICAL INTERVENTION VERSUS STEREOTACTIC RADIOSURGERY
Authors: Akhavan-Sigari Amirhossein , Persad Amit R L , Kattaa Ahed H , Hori Yusuke S , Emrich Sara C , Ustrzynski Louisa , Tayag Armine , Park David J , Chang Steven D
Published: November 2024

INTRODUCTION

Hydrocephalus may present in patients with vestibular schwannoma (VS) at initial diagnosis, primarily due to the obstructive effects of tumor mass on cerebrospinal fluid (CSF) dynamics. Notably, occurrences of hydrocephalus following either radiosurgery or surgical interventions have also been documented in clinical literature.

OBJECTIVE

To compare the clinical features of patients who have undergone surgical resection or radiosurgery for VS and subsequently developed hydrocephalus necessitating shunt placement.

METHODS

We conducted a retrospective analysis of patients diagnosed with VS who underwent management via surgery or radiosurgery at Stanford Medical Center between 1998 and 2024, focusing on those who subsequently required shunt placement.

RESULTS

A total of 30 patients with VS underwent shunt placement due to hydrocephalus after tumor treatment; 5 patients (16.7%) were managed with radiosurgery and 25 patients (83.3%) with surgery. The median age at treatment was 64 years versus 57 years for the radiosurgery and surgery groups, respectively. There were no significant differences in age, sex, tumor volume, largest diameter at treatment, and tumor Koos grades, between the two groups. Nonetheless, the median time from tumor treatment to shunt placement was significantly longer in the radiosurgery group compared to the surgery group (21.53 versus 1.17 months, p-value=0.002). Regarding CSF parameters, mean white blood cell (WBC) and red blood cell (RBC) counts prior to shunt placement was significantly higher in the surgery versus the radiosurgery group (WBC=83.6 versus 2.0/mm3, p-value=0.001, RBC=3453.4 versus 313.33/mm3, p-value=0.02). CSF protein and glucose were not significantly different between the groups.

CONCLUSION

The median time from VS treatment to shunt placement due to hydrocephalus was longer in the radiosurgery group compared to the surgery group. Furthermore, pre-shunt CSF WBC and RBC counts were higher in the surgery group. Future studies are needed to better understand treatment outcomes and optimize management strategies for these patients.
NCMP-22. CO-OCCURRENCE OF MULTIPLE SCLEROSIS AND HODGKIN LYMPHOMA. IS THERE A COMMON PATHOPHYSIOLOGY?
Authors: Garg Ipshita , Agyei Paunel , Gálvez-Jiménez Néstor , Ranjan Surabhi
Published: November 2024

BACKGROUND

Multiple sclerosis (MS) and Hodgkin lymphoma (HL) share common epidemiology, genetics and immunological factors. Both affect immune activation, cell proliferation and lymphocyte-mediated immunity. However, occurrence of these two distinct clinical conditions is rare. We present a case of a woman with transverse myelitis fulfilling criteria for MS with synchronous HL.

CASE REPORT

A 37-year-old woman presented to the emergency room with bilateral leg weakness, numbness and urinary retention. A contrasted MRI of the brain and thoracic spine showed non-specific, non-enhancing white-matter lesions in the brain, and patchy areas of peripheral contrast-enhancement with T2-hyperintensity in the thoracic cord. Treatment with steroid infusion resulted in mild improvements of leg weakness and numbness. Cerebrospinal fluid (CSF) demonstrated oligoclonal bands (OCB) and increased IgG index. Serum was positive for JCV antibody. Due to the atypical MRI findings, namely the peripheral nature of thoracic contrast-enhancement, we were concerned for other inflammatory or autoimmune etiologies. A computed tomography of the chest, abdomen and pelvis revealed a large mediastinal mass and enlarged lymph nodes. A biopsy revealed classic HL. Three-months later, a follow-up MRI brain showed worsening contrast-enhanced lesions. A repeat CSF study revealed normal OCBs and IgG index. CSF was negative for malignant cells and JC virus DNA. To rule out a rare possibility of central nervous system HL, a biopsy of an enhancing brain lesion was obtained, which showed focal gliosis and focal perivascular lymphocytic infiltrates. No malignant cells were observed. She was diagnosed with multiple sclerosis and started systemic chemotherapy (doxorubicin, bleomycin, dacarbazine and vinblastine) for HL.

CONCLUSIONS

We report a case of an atypical transverse myelitis with HL. Although familial genetic clustering has been described, other potential common risk-factors between MS and HL are Epstein-Barr Virus infection and immunologic overlap, particularly in the context of lymphocyte-mediated immunity.
NCMP-24. GLIOMA-RELATED EPILEPSY: ANTI-SEIZURE REGIMENS, TOLERABILITY AND SYMPTOM BURDEN
Authors: Patel Shrey , Akintola Oluwatosin
Published: November 2024

AIMS

Seizures are often the presenting symptom in 30-40% of glioma patients, and play a significant role in patients’ quality of life and symptom burden. Many complex factors are considered when selecting anti-seizure medications (ASM) for the individual patient. This single institution study investigates physician practices, seizure control and adverse effect profiles of ASM regimens in glioma patients.

METHOD

A retrospective review was undertaken of the electronic health records of glioma patients from 2020-2022 who were followed at the University of Vermont Medical Center.

RESULTS

Ninety-four patients (90 glioblastoma IDH-WT, 1 astrocytoma, 2 oligodendroglioma, 1 radiological diagnosis of glioma) were included. Levetiracetam was the first line ASM in 93 patients including seizure prophylaxis patients per neurosurgical practice. 30 of the patients presented with seizures and required long term ASMs. 21 required a second-line ASM, 3 required a third-line ASM, and 20 experienced at least one adverse drug effect. 11.4% of patients experienced mood disturbances on levetiracetam, ranging from anxiety to mania. 5% of patients experienced generalized weakness and gait imbalance issues on levetiracetam. 25% of patients experienced breakthrough seizures over the course of their illness despite therapeutic levetiracetam > 1000mg/day. 10.4% of patients presented with breakthrough status epilepticus following the initiation of levetiracetam therapy. No statistically significant differences were seen in rates of breakthrough seizures based on extent of resection, functional status or sex.

CONCLUSIONS

Seizures are a major cause of morbidity in glioma patients. The overwhelming majority of patients included in this study were placed on levetiracetam as a first-line ASM. Most patients on long-term levetiracetam experienced at least one neuropsychiatric adverse effect. Further studies are required to investigate the efficacy and tolerability of ASM regimens in glioma patients and to understand methods for ASM regimen individualization for varying disease courses.
NCMP-27. NEUROLOGICAL COMPLICATIONS IN LUNG CANCER THERAPIES: UNVEILING THE ELEVATED RISKS IN CHEMOTHERAPY AND TARGETED TREATMENT APPROACHES
Authors: Manne Swetha , Currie Joshua
Published: November 2024

BACKGROUND

Neurological complications due to lung cancer treatments are a common side effect, with prevalence ranging from 19% to over 80% depending on the drug administered. Peripheral neuropathy is the most common manifestation of chemotherapy associated neurotoxicity, but there are potential central nervous system impacts as well, such as seizures, dementia, and generalized cognitive impairment. Occurrence of similar effects is less commonly reported with targeted gene therapy for cancer, however the exact prevalence has not been determined.

DESIGN/METHODS

We searched the US Collaboration network through TriNetX for all cases of lung cancer, identified by ICD-10 code C34. Cohort A was defined as adults 18-70 years old that had lung cancer treated with cisplatin or etoposide. Cohort B was defined as adults 18-70 that had lung cancer treated with crizotinib, alectinib, or epidermal growth factor receptor tyrosine kinase inhibitors. Outcomes were evaluated from 1 day to 5 years after the indexed event.

RESULTS

We reported 15,268 patients with lung cancer that were prescribed chemotherapy agents matched with 6,490 patients with lung cancer that were prescribed tyrosine kinase inhibitors. Patients prescribed chemotherapy agents were at significantly higher risk for neurological complications post treatment when compared to those treated with tyrosine kinase inhibitors (p < 0.0001).

CONCLUSIONS

Patients diagnosed with lung cancer on chemotherapy 18-70 years old displayed higher associated risk of various neurological disorder diagnoses. Patients undergoing chemotherapy should be educated about this increased risk and talk with their providers about alternative treatments. Further research should be conducted on the range of potential neurological complications associated with chemotherapy regimens.
NCMP-29. BRAIN LESIONS IN A TEEN WITH NEWLY DIAGNOSED T-CELL ALL AND SARS-COV-2 INFECTION
Authors: Aspromonte Salvatore , Ehidom Clinton , Khan Shama , Perez Julio Arevalo , Pascual Juan , Greenfield Jeffrey , Hohl Tobias , Haque Sofia , Khakoo Yasmin , Trippett Tanya
Published: November 2024

T-cell Lymphoblastic Leukemia (T-cell ALL) accounts for up to 15% of all newly diagnosed cases of acute lymphoblastic leukemia in pediatric patients (0-18 years old). Patients are at risk of opportunistic infections during induction therapy with up to 2% developing blood stream infections when their absolute neutrophil count is above 1,500. We report a case of a 15-year-old female with High-Risk T-cell ALL, CNS1 (negative CNS disease), presenting with three days of headaches, photophobia, and non-neutropenic fever. She completed induction chemotherapy one week earlier with vincristine, daunorubicin, calaspargase and a 28-day course of dexamethasone. On physical exam, she had no focal deficits or changes in sensation or strength. CBC was notable for a white blood cell count: 7500, hemoglobin: 8.6, platelets: 328,000 and ANC (Absolute Neutrophil Count): 4700. The patient was also COVID positive on admission. A contrast enhanced MRI brain demonstrated multiple diffusion restricting and peripherally enhancing lesions, concerning for intracranial abscesses. Neurosurgery performed a burr hole craniotomy and aspirated 5 mL of purulent drainage, the culture of which grew Aspergillus fumigatus complex. The patient was started empirically on Voriconazole, in addition to broad spectrum antibiotic coverage pending culture results, due to excellent CNS penetration and proven superiority to amphotericin-based therapy for invasive aspergillosis. Micafungin was added due to CT chest demonstrating nodular infiltrates, suggesting primary pulmonary aspergillosis with CNS dissemination. The patient improved symptomatically without further sequelae. Patients with COVID-19 on prolonged courses of corticosteroids are at higher risk of developing fungal co-infections regardless of neutrophil count. While pulmonary aspergillosis is the most common location of a COVID-19 aspergillus coinfection, there have been documented reports of intracranial micro-abscesses. Contrast-enhanced brain MRI should be obtained in any patient with a recent history of COVID-19 presenting with new neurological symptoms, especially in a patient with a recent history of corticosteroids.
NCOG-08. A RARE PRIMARY CNS T-CELL LYMPHOMA CASE: 12-YEAR FOLLOW-UP AFTER CHEMOTHERAPY
Authors: Cheng Amory , Bota Daniela A , Kong Xiao-Tang
Published: November 2024

INTRODUCTION

Primary central nervous system (CNS) T-cell lymphoma (PCNSTL) is a rare hematological malignancy. There is mere literature to guide the treatment.

CASE REPORT

This study is an update on our previously reported case at SNO in 2012 after a 12-year follow-up, detailing the long-term outcome of our chemotherapy treatment for a case of PCNSTL. In 2011, a 26-year-old immunocompetent patient presented with severe headache, vomiting, and lethargy. The brain MRI found more than a dozen masses on his bilateral cerebral hemispheres. Brain biopsy discovered T-cell lymphoma. The patient was started biweekly high-dose-methotrexate (HD-MTX) in 2011. After three doses, there was no noticeable improvement on his brain MRI. His treatment was switched to HD-MTX plus high dose cytarabine regimen (Ferreri et al, The Lancet, 2009). The patient could not tolerate cytarabine; thus, was changed back to HD-MTX. The patient responded to the rest of HD-MTX well. He completed 8 doses of biweekly HD-MTX induction therapy and 2 doses of monthly HD-MTX maintenance therapy. His brain MRI showed complete resolution of enhancement on one-year follow-up image. The patient has been off-treatment and monitored under surveillance of brain MRIs since 2012. He has had no lymphoma recurrence over the past 12 years. His physical functions have been preserved with a Karnofsky Performance Status scale of 80%. Neuropsychological evaluations in 2015, 2018, and 2023 showed mild cognitive impairment with gradual improvements in his working memory and semantic fluency. His Mini-Mental Status Exam scores have remained stable to mild improvement, recording 27/30 in 2015, 26/30 in 2018, 27/30 in 2023 and 28/30 in 2024.

DISCUSSION

The patient, who is now 38 years old, has surpassed a 12-year survival mark. Our experience emphasizes the feasibility of treating PCNSTL through chemotherapy only, which might be potentially beneficial in surviving and preserving major aspects of brain function.
NCOG-13. ASSESSING CAREGIVER OUTCOMES OF PRIMARY BRAIN TUMOR PATIENTS: A SYSTEMATIC REVIEW OF THE LITERATURE
Authors: Walbert Tobias , Cachia David , Hertler Caroline , Sherwood Paula , Dirven Linda , Young Jacob , Stockdill Macy , Almaraz Eduardo Rodriguez , Pill Karin , Boele Florien
Published: November 2024

BACKGROUND

Family caregivers in neuro-oncology are known to have high levels of unmet support needs. Intervention trials and effective support options are scarce. The Response Assessment in Neuro-Oncology (RANO-) Cares working group has been established to determine standards of caregiver outcomes (CO) research reporting in neuro-oncology. We present the current state of methodological quality of reporting on neuro-oncology caregiver outcomes in randomized controlled trials (RCTs).

METHODS

A systematic literature review (PubMed/Medline, Embase, Web of Science, Emcare, Cochrane Library, PsycINFO; July 2023) was performed to assess to what degree RCTs assessing outcomes of family caregivers of adult primary brain tumor patients adhere to established reporting standards. Using Covidence, screening and data extraction was independently performed by two researchers, with a third guiding consensus. A 33-item checklist (23 applicable to secondary analysis reports) based on the International Society for Quality of Life (ISOQOL) Research criteria for patient-reported outcome reporting was utilized to assess reporting standards. Risk of bias was assessed per RCT.

RESULTS

Fifteen publications (12 unique RCTs) included 684 neuro-oncology caregivers, with low overall risk of bias. Ten publications (66%) reported on COs as a primary aim and eight (80%) of these satisfied ≥2/3 of the key methodological criteria. Of the five secondary analysis reports (33%) two met ≥2/3 of applicable key criteria. Criteria often missed are related to sample size calculations, details on statistical approaches, discussion of limitations and clinical significance of studies. Only three of the 12 RCTs were definitive trials aimed at improving COs and five should be considered as pilot or feasibility studies.

CONCLUSION

RCTs investigating neuro-oncology COs have high reporting standards and risk of bias was low. Future studies should focus on specific caregiver interventions to reduce high caregiver burden and with that patients’ quality of life.
NCOG-14. THE ROLE OF POSTOPERATIVE BLOOD PRESSURE MANAGEMENT IN EARLY POSTOPERATIVE HEMORRHAGE IN AWAKE CRANIOTOMY GLIOMA PATIENTS
Authors: Kerschbaumer Johannes , Demetz Matthias , Kriger Aleksandrs , Pinggera Daniel , Klingenschmid Julia , Thomé Claudius , Freyschlag Christian
Published: November 2024

INTRODUCTION

Awake surgery is widely used to maximize the extent of resection and enhance neuro-oncological outcome in gliomas. Postoperative hemorrhage can severely deteriorate the patients’ neurological outcome. Higher postoperative blood pressure can increase the risk of postoperative hemorrhage, but optimal perioperative patient and blood pressure management is unclear. The aim of this study was to investigate the role of postoperative blood pressure and other common radiological and epidemiological features with the incidence of postoperative hemorrhage.

MATERIAL & METHODS

In this retrospective analysis, we included all patients who underwent awake surgery between 2010 and 2023 at our institution. We assessed the blood pressure both intra- and postoperatively as well as the heart rate for the first 12 hours. We compared a cohort with postoperative hemorrhage, who required further treatment (surgical revision or intravenous antihypertensive therapy), with a cohort with no postoperative hemorrhage.

RESULTS

We included 48 patients with a median age of 39 years. 9 patients (19%) showed a preoperative history of arterial hypertension, 8 of them were on antihypertensive treatment. 23 patients (48%) showed signs of a hemorrhage on early postoperative MRI, of whom 9 (19%) required further treatment, which was surgery in 2 cases and conservative therapy in 7 cases. Patients with postoperative hemorrhage showed significantly higher postoperative systolic blood pressure during the hours 3-12 (p<0.05) as well as intraoperatively during the hours 1-5 (p<0.05). In ROC and Youden Test, a strong impact of systolic blood pressure over 140 mmHg during the early postoperative course could be shown.

DISCUSSION

Postoperative hemorrhage is a serious complication in awake surgery glioma patients. However, with early treatment, no significant difference in Performance scores at follow-up could be found. To avoid postoperative hemorrhage, treating physicians should aim strictly on systolic blood pressure of under 140 mmHg for the postoperative course.
NCOG-18. META-ANALYSIS OF DIRECT ENDOVASCULAR THROMBECTOMY VS BRIDGING THERAPY IN THE MANAGEMENT OF ACUTE ISCHEMIC STROKE WITH LARGE VESSEL OCCLUSION
Authors: Shafique Muhammad Ashir , Lucke-Wold Brandon , Mustafa Muhammad Saqlain , Ali Syed Muhammad Sinaan
Published: November 2024

Debates persist when using intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) for acute ischemic stroke (AIS) due to large-vessel occlusion (LVO). This systematic review and meta-analysis synthesized evidence on outcomes in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO), comparing bridging therapy (BT) with MT alone.

METHOD

We conducted searches of PubMed, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials from inception to July 2023 to identify pertinent clinical trials and observational studies.

RESULT

76 studies, involving 37,658 patients, revealed no significant difference in 90-day functional independence between DEVT and BT. However, a trend favoring BT for achieving functional independence with a modified Rankin Scale (mRS) of 0–1 was observed, having Odds ratio (OR) of 0.75 (95% CI 0.66–0.86; p < 0.001). DEVT was associated with higher postprocedural mortality (OR 1.44;95% CI 1.25–1.65; p < 0.001), but a lower risk of symptomatic intracranial hemorrhage compared to BT (OR 0.855; 95% CI 0.621–1.177; p = 0.327). Successful recanalization rates favored BT, emphasizing the importance of individualized treatment decisions (OR 0.759; 95% CI 0.594–0.969; p = 0.027). Sensitivity analyses were conducted to identify key contributors to heterogeneity.

CONCLUSION

Our meta-analysis underscores the intricate equilibrium between functional efficacy and safety in the evaluation of DEVT and BT for ACS-LVO. Fundamentally, while BT appears more efficacious, concerns about safety arise due to the superior safety profile demonstrated by DEVT. Individualized treatment decisions are imperative, and further trials are warranted to enhance precision in clinical guidance.
NCOG-30. FACTORS ASSOCIATED WITH COGNITIVE IMPAIRMENT IN LONG-TERM IDH-MUTANT GLIOMA SURVIVORS
Authors: Lanman Tyler , Gross Hana , Faria Caylin M , Miller Julie , Cahill Daniel P , Shih Helen , Zarella Giuliana , Dietrich Jorg , Parsons Michael
Published: November 2024

BACKGROUND

Cognitive deficits are less frequent in patients with IDH mutant (IDHm) than wild-type glioma at time of diagnosis, but less is known about factors that influence cognition for long-term survivors. We evaluated long-term neuropsychological outcomes of patients with IDHm glioma.

METHODS

Patients with IDHm glioma who underwent clinical neuropsychological assessment at Massachusetts General Hospital 3+ years after diagnosis were included and compared to a previously published cohort of IDHm patients tested prior to surgery/diagnosis (Wefel et al., 2016).

RESULTS

Sixty-three patients were included for analysis (54% male; median age 45 [range 21-75], 16 years of education, and 7 years from diagnosis [range 3-28]). Thirty-eight patients (60%) had astrocytoma and 24 (40%) had oligodendroglioma; 28 (44%) were grade 2, 31 (49%) grade 3, and 4 (6%) grade 4. Fifty-five patients (87%) received radiation and 51 (81%) received chemotherapy. Cognitive impairment (defined as Z score ≤-1.5 on at least two tests) was present in 30 patients (48%) and was associated with lower scores in neurologic aspects of quality of life (QoL; p<0.01), grade 3/4 relative to grade 2 (p=0.01), older age (p=0.03), left-sided lateralization (p=0.02), and less education (p=0.01). Prior radiation (p=0.07) and photon relative to proton radiation (p=0.06) trended toward poorer function. Tumor type, disease duration, and extent of resection were not significant factors (p>0.05). Compared to the pre-diagnosis IDHm cohort, impairment was significantly more common on tests of processing speed and language. Learning/memory, executive, and visuospatial function trended toward more frequent impairment but were not significant. Attention had comparable frequency of impairment.

CONCLUSIONS

In this cohort of IDHm glioma survivors, neurocognitive deficits were common, related to QoL, and associated with some expected clinical factors, but not length of survival. These findings emphasize the need for future research on interventions aimed at supporting patients’ neurocognitive abilities and QoL.
NCOG-35. IDENTIFYING PROGNOSTIC FACTORS IN PEDIATRIC DIFFUSE MIDLINE GLIOMAS, H3 K27-ALTERED
Authors: Yang Yufan , Govind Sachin , Wadhwani Nitin , Brat Daniel , Stupp Roger , Sachdev Sean , DeCuypere Michael
Published: November 2024

INTRODUCTION

Diffuse midline gliomas, H3 K27-altered (DMG) are rare, grade 4 tumors localized to the diencephalon, brainstem, and cervical spine. DMGs, characterized by a K27M missense mutation in histone H3, often cannot be safely resected and predominantly present with poor outcomes in children. Few prognostic factors for DMGs have been identified and/or need to be further elucidated, including adolescent age of onset, re-irradiation status, and tumor molecular profile (i.e., PIK3CA mutation). Herein, we describe the clinical outcomes of DMG patients at our institution.

METHODS

Pediatric patients (<18 y/o) between 2015 and 2023 with biopsy-proven DMG were reviewed. Demographic, treatment, and tumor characteristics (histologic and molecular) were recorded. Adolescent-onset DMGs were defined as patients ≥10 y/o at diagnosis and early-onset DMGs were defined as patients <10 y/o. Progression free survival (PFS) and overall survival (OS) were calculated according to the Kaplan Meier-method. Multivariate regression analyses were performed.

RESULTS

Twenty-one patients were included (median age=9 y/o). Early-onset DMGs (n=13) progressed significantly earlier and experienced significantly greater mortality than adolescent-onset DMGs (n=8); PFS and OS at 12 months was 7.7% and 23% for early-onset DMGs and 50% and 87.5% for adolescent-onset DMGs (PFS: p<0.01, OS: p<0.02). Patients that received re-irradiation for progressive disease (n=9, mean=84Gy) had an OS of 75% at 12 months, which was significantly greater than an OS of 23% at 12 months (p<0.05) for patients that received no re-irradiation (n=12, mean=53Gy). PIK3CA mutation status was identified as an independent predictor of survival, with PIK3CA-mutant DMGs (n=7) having a median survival of 4.1 months versus 9.7 months for PIK3CA-WT DMGs.

CONCLUSION

We describe a pediatric cohort that presents several possible prognostic factors of survival in DMGs. Our findings on adolescent age of onset, if further corroborated, has the potential to inform the design and enrollment of DMG clinical trials.
EXTH-02. MODIFYING CAR T CELL EPIGENETIC PROGRAMS TO IMPROVE THEIR PERSISTENCE AGAINST GROUP 3 MEDULLOBLASTOMAS
Authors: Ward Meghan , Senaoui Linda , Youngblood Ben , Roussel Martine , Krenciute Giedre
Published: November 2024

BACKGROUND

Safe, effective therapies are desperately needed to improve outcomes for patients with medulloblastoma (MB), a malignant pediatric brain cancer. Chimeric antigen receptor (CAR)-T cells are a promising therapeutic option as they target T-cell cytotoxicity exclusively to tumor associated antigens. B7 homolog 3 (B7-H3) is an ideal target for CAR-T cell therapy as all MB subtypes express B7-H3 but healthy tissues do not. However, a major roadblock to tumor clearance and control is the inability of CAR-T cells to persist, suggesting that improving persistence will improve therapeutic efficacy. The goal of this study was to compare head-to-head the impact of knocking out TET2 and DNMT3A negative epigenetic regulators of CAR-T cell persistence against group 3 MB (G3MB), the most malignant MB subtype.

METHODS

We generated B7-H3 CAR-T cells with CD28ζ signaling domain and performed CRISPR/Cas9 knockout (KO) of TET2, DNMT3A, and AAVS1 as a control. We compared resulting CAR-T cell persistence via repeat stimulation assays in vitro against G3MB cell lines with varying B7-H3 antigen density (D341low, HDMB03mid, and D425high). We further compared KO CAR-T cells in vivo against D341low, HDMB03mid, and D425high orthotopic xenografts.

RESULTS

Our data shows that DNMT3A KO, but not TET2 KO, consistently improves the persistence and expansion of CAR-T cells against G3MB in vitro. In vivo, KO of epigenetic regulators, improves CAR-T cell therapy against highly aggressive D341low, HDMB03mid, and D425high but is insufficient to elicit curative responses.

CONCLUSIONS

Our study demonstrates that genetic KO of negative epigenetic regulators of CAR-T cell persistence can improve anti-tumor function against G3MB. We conclude that for the B7-H3.CD28ζ CAR, DNMT3A KO is superior for improving persistence over TET2 KO, but that DNMT3A KO is insufficient in vivo.
EXTH-19. AN INTERNATIONAL ACCELERATOR PROGRAMME FOR RESEARCHERS DEVELOPING NOVEL THERAPIES FOR BRAIN TUMOURS
Authors: Aitken Charlotte , Huskens Nicky , Bushby Katie , Noble Karen , Hamerlik Petra , Kaye Edward , Kobayashi Dione , Mathew Ryan , McCall John , Nazarian Javad , Plummer Ruth , Rahman Ruman , Lopez Juanita , Nagaraju Kanneboyina
Published: November 2024

Developing a comprehensive translational programme for brain tumours involves navigating numerous challenges, including robustness of preclinical studies, safety, clinical trial design, understanding and addressing regulatory requirements, and funding. Recognising the difficulty of this journey, the Brain Tumour Research Novel Therapeutics Accelerator (BTR-NTA) was launched in 2023. The BTR-NTA is an accelerator programme providing independent expert guidance to de-risk drug or device development through systematic evaluation. The international, multidisciplinary BTR-NTA Committee spans expertise across the entire therapeutic development pipeline. Supported by Brain Tumour Research, the BTR-NTA programme is free for academic applicants. Researchers at any stage of therapeutic development may apply to BTR-NTA. Accepted applicants proceed as follows: 1. Applicants outline their current and prospective data and findings. The proposal and all supporting materials are covered under a confidentiality agreement that protects applicants’ intellectual property; 2. Proposals are reviewed by the BTR-NTA Committee; 3. Applicants and BTR-NTA Committee meet in-person to constructively evaluate the work; and 4. Applicants receive a comprehensive report with feedback on strengths, identification of potential risks, and guidance on next steps. The BTR-NTA Committee dedicates time for in-person meetings with each applicant, and extensive time pre- and post-meeting. Since the launch of BTR-NTA in 2023,14 international groups have applied to the programme and seven therapies have been advanced to the in-person review by the BTR-NTA Committee. Of the applicants who provided feedback on the BTR-NTA programme, all intended to adjust or refine their future work based on the Committee’s input and the average rating of the programme’s helpfulness was 9.5 out of 10. The ultimate goal of BTR-NTA is to help researchers with a potential therapy for brain tumours to navigate the development journey and reach the clinic in an efficient way. This programme will support the development of novel therapies to improve outcomes for patients with brain tumours.
EXTH-48. ADENO-ASSOCIATED VIRUS TARGETING OF THE TUMOR MICROENVIRONMENT TO IMPROVE LYMPHOCYTE RECRUITMENT IN GLIOBLASTOMA
Authors: von Roemeling Christina , Patel Jeet , Carpenter Savannah , Yegerov Oleg , Yang Changling , Bhatia Alisha , Doonan Bently , Golde Todd , Mitchell Duane
Published: November 2024

BACKGROUND

Glioblastoma (GBM) is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment, infiltration, and activation. We have developed a novel recombinant adeno-associated virus (AAV) gene therapy strategy that enables focal and stable reconstitution of the GBM tumor microenvironment (TME) with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for cytotoxic T lymphocytes (CTLs). By increasing lymphocyte recruitment in GBM, we HYPOTHESIZE that these tumors will be more responsive to immunotherapy.

METHODS

3D fluorescence microscopy was used to characterize the distribution, tropism, and durability of AAV6 transgene expression in preclinical GBM. Flow cytometry and 3D fluorescence microscopy was used to quantify T cell infiltration and visualize their biodistribution in preclinical GBM treated with AAV-CXCL9 in combination with anti-PD-1 immune checkpoint blockade (ICB). Single-cell RNA sequencing was used to characterize intratumor lymphocyte subsets following treatment. Survival studies with and without lymphocyte depletion were done to evaluate immunogenic responsiveness of therapy.

RESULTS

Focal delivery of CXCL9 with AAV6 results in stable transduction of peri-tumoral astrocytes. When combined with anti-PD-1 ICB, lymphocyte infiltration was improved, with cells found disseminated across the tumor stroma and within the tumor parenchyma. CXCR3, the chemokine receptor for CXCL9, was expressed across lymphocyte subsets and NKT cells, validating treatment selectivity of AAV6-CXCL9 for lymphocytes. Combination treatment considerably improved overall survival in two distinct GBM models, with durable responses dependent on CD8 T-lymphocyte infiltration.

CONCLUSIONS

By manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by CD8-postive cytotoxic lymphocytes, sensitizing GBM to anti-PD-1 ICB. These effects are accompanied by immunologic signatures evocative of an inflamed and responsive TME. These findings support targeted AAV gene therapy as a promising adjuvant strategy for reconditioning GBM immunogenicity given its excellent safety profile, TME-tropism, modularity, and off-the-shelf capability.
EXTH-49. DEVELOPMENTAL ANTIGENS CAN TARGET EMBRYONAL PEDIATRIC BRAIN CANCERS IN ADOPTIVE CELLULAR THERAPY
Authors: Pham Christina , Sebastian Mathew , Reid Alexandra , Love Caitland , Drake Jeffery , Mitchell Duane , Flores Catherine
Published: November 2024

Mutations in tumor neoantigens have shown promise in immunotherapies for many cancers, yet pediatric brain tumors, which typically have a lower mutational burden, offer fewer opportunities to capitalize on these targeted therapies. Studies indicate that medulloblastoma (MB) and brain stem gliomas (BSG) originate from abnormal reactivation of post-natal developmental processes. This led us to investigate whether proteins expressed during the early post-natal development of the mouse cerebellum and brainstem could be powerful antigens to fight MB and BSG, respectively. We performed both in vitro and in vivo studies in mice with the RNA of developmental antigens from the brain stem and cerebellum in an adoptive cellular therapy (ACT) platform. We evaluated the reactivity and therapeutic efficacy of these treatments as sustainable antigenic targets against BSG and MBs. We demonstrate that T cells activated towards these non-mutated, tissue-specific developmental antigens can recognize distinct subtypes of MB and BSG, and activate specifically without cross-reacting to the normal brain. This conferred a survival benefit in established orthotopic models of these pediatric brain tumor types. Our research exhibits the value developmental antigens can offer when serving as tumor rejection antigens in MB and BSG.
EXTH-52. SIMULTANEOUS TARGETING OF TUMOR CELLS AND TUMOR-ASSOCIATED MACROPHAGES TO REPROGRAM GLIOBLASTOMA BY TUMOR-SUPPRESSIVE MICRORNA
Authors: Nguyen Grace , Noh MinHye , Miller Alexandra , Huang Minxin , Dai Yulin , Zhao Zhongming , Yoo Ji Young , Lee Tae Jin
Published: November 2024

Glioblastoma (GBM) is the most aggressive type of primary brain tumors due in part to cell-intrinsic and cell-extrinsic mechanisms. The ability of GBM tumor to not only resist conventional therapies but also induce an immunosuppressive tumor microenvironment (TME) is thought to underlie the failure of immunotherapies. Thus, strategies to target both tumor cells and immunosuppressive immune cells, such as tumor-associated macrophages (TAMs), are of great interest. The ability of microRNA (miRNA) to target multiple genes is favorable to alter the character of the TME and cancer cells. Previously, we have shown that tumor suppressive miRNA, miR-138, can effectively regulate the genes in GBM cells relating to cell proliferation and viability. The exogenous delivery of miRNAs, however, has been limited due to the lack of delivery mechanisms that minimize off target effects. We argue that extracellular vesicles (EVs) are an ideal modality of targeted delivery for therapeutic miRNA, which we can accomplish by decorating the EV surface with cancer specific ligands, such as folate. Here, we report that trypsin digestion of the EV surface can increase the surface labeling efficiency for cancer targeting ligands. Folate-labeled trypsinized EVs effectively targeted folate receptor (FR) positive GBM cells and TAMs, delivering miR-138 in in vitro and in vivo orthotopic intracranial murine models of GBM. This simultaneous delivery decreased cancer cell proliferation and altered macrophage polarization through the inhibition of known target genes, phenotypically reprogramming both cancer cells and TAMs. To our knowledge, this is the first preclinical study attempting to target both tumor cells and innate immunity by delivering tumor suppressive miR-138 using a trypsinized EV-based RNA delivery system. These findings can be rapidly translated into a novel therapeutic option for GBM patients.
EXTH-57. EXPLORING NOVEL ROUTES FOR NON-INVASIVE DRUG ADMINISTRATION: INTRADERMAL DELIVERY FOR THE TREATMENT OF BRAIN TUMORS
Authors: Kim Seunghyun , Mahajan Akanksha , Jarvis Rachel , Stegh Alexander
Published: November 2024

Effective non-invasive drug delivery to brain tumors remains challenging, despite extensive exploration of these methods, due to the blood-brain barrier (BBB). Intranasal drug delivery has emerged as a promising alternative approach, as it circumvents limitations on tumor access imposed by the BBB when administering therapeutics systemically and limits the occurrence of systemic toxic responses to treatment. The intranasal route of administration allows therapeutic access to brain tumors through pathways involving the olfactory and trigeminal nerves (TNs) that connect the nasal passage to the brain. However, effective nose-to-brain delivery is impeded by rapid mucosal drug clearance in the nasal cavity, drug aspiration, and ingestion. Since the TN arises from the brainstem and its branches innervate the facial skin, in addition to muscles, meninges, and respiratory mucosa, we tested the hypothesis that facial intradermal administration targeting the V2 branch of the TN could be an alternative strategy to harness TN-mediated brain delivery to bypass the BBB. Here, we developed Spherical Nucleic Acids (SNAs) consisting of a 15nm spherical gold nanoparticle core functionalized with radially oriented fluorophore-tagged ssDNA as a model therapeutic. We observed the delivery of the SNAs to the brain starting 4 hours post intradermal injection, with the SNA accumulation in the tumor persisting over time. Using ex vivo fluorescent imaging, comprehensive immunofluorescence microscopy, and flow cytometry we confirmed the SNA accumulation in the brain, dura, TN, and cervical lymph nodes. In particular, we demonstrated that SNAs were enriched in the neuronal cell bodies of the trigeminal ganglia and within the epineurium and perineurium of the TN. The SNAs were also enriched in CD45-positive immune cells. In conclusion, this study credentialed facial intradermal administration of SNAs as a promising non-invasive method for brain drug delivery to target intracranial tumors.
EXTH-68. EPIGENETIC EDITING BY MRNA-BASED CRISPROFF ENABLES FLEXIBLE AND DURABLE TARGETING OF GLIOBLASTOMA DRIVERS MGMT AND TERT
Authors: Lin Katie , Zou Christopher , Goudy Laine , Sharma Rohit , Stevers Nicholas O , Pak Joanna , Foster Kyla , Payne Emily , Shai Anny , Ozawa Tomoko , de Groot John F , Vasudevan Harish , Phillips Joanna J , Raleigh David R , Costello Joseph F , Murthy Niren , Gilbert Luke A , Berger Mitchel , Liu S John
Published: November 2024

Alterations in cis-regulatory elements, such as hypomethylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter and activating mutations within the telomerase reverse transcriptase (TERT) promoter, are pervasive drivers of glioblastoma (GBM) tumorigenesis that are challenging to target. CRISPRoff is an engineered CRISPR/Cas9 system that can potently and heritably silence cis-regulatory elements through DNA methylation. Here, we develop an mRNA-based CRISPRoff platform to target the MGMT and TERT promoters in GBM, and we establish proof-of-principal in vivo targeting through lipid nanoparticles (LNP). Epigenetic editing in GBM cells and primary GBM organoids was performed using either electroporation or LNP encapsulation of CRISPRoff mRNA and sgRNAs. Target gene silencing and functional phenotypes were assessed by bisulfite sequencing, RT-qPCR, RNA-seq, western blot, cell viability/apoptosis, and telomere restriction fragment assays. In vivo efficacy was demonstrated using intracranial GBM xenografts, first through transplantation of cells with CRISPRoff delivered ex vivo, then with direct delivery of LNPs using convection enhanced delivery (CED) coupled with immunofluorescence/ immunohistochemistry. CRISPRoff targeting of MGMT promoter resulted in >99% reduction in MGMT expression in MGMT unmethylated primary GBM organoids, inducing up to 150-fold sensitization to temozolomide. Temozolomide sensitization was retained after intracrania transplantation, and silencing was durable in clonally isolated GBM cells continuously passaged for over 8 months after transient delivery of CRISPRoff. CRISPRoff targeting of the TERT promoter in primary GBM cultures harboring the G228A TERT promoter mutation silenced TERT expression by up to 99%, overcoming constitutive activation of TERT, and induced telomere shortening sufficient for complete replicative senescence. CED of mRNAs encapsulated by LNPs based on cKK-E12 or Lipid A9 resulted in tumor-selective uptake of mRNA transcripts, establishing a foundation for direct delivery of CRISPRoff in vivo bypassing the blood-brain-barrier. In summary, we establish a flexible and durable epigenetic editing system against multiple regulatory elements driving GBM, leveraging LNPs with potential for in vivo application.