bluuebunny/crossref_metadata_2025 huggingface dataset:
INNV-14. OUTCOMES OF PATIENTS WITH ISOCITRATE DEHYDROGENASE-MUTANT WHO GRADE 4 ASTROCYTOMA TREATED WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY: A REAL-WORLD ANALYSIS
Authors: Connelly Jennifer M , navgeropoulos@novocure.com Nick , Conlon Patrick , Chavez Gordon , Farber Ori
Published: November 2024

BACKGROUND

Tumor Treating Fields (TTFields) therapy is approved for the treatment of patients with newly diagnosed glioblastoma, based on the EF-14 study which demonstrated improvement in progression free survival and overall survival (OS). EF-14 included patients with the isocitrate dehydrogenase (IDH) mutation (IDHmut), which has since been reclassified as IDHmut WHO grade 4 astrocytoma (Astrocytoma IDHmut/G4) and confers a more favorable prognosis than IDH wild type. However, large real-world datasets are lacking. Here, we report real-world outcomes of patients with Astrocytoma IDHmut/G4 treated with TTFields in the US.

METHODS

Utilizing electronic health records from the xCures real-world data platform, patients with newly diagnosed Astrocytoma IDHmut/G4 receiving TTFields in the US from January 1 to December 31, 2019 were analyzed and IDH-mut status was confirmed. Survival was analyzed based on IDH-mut status and TTFields usage, with patients categorized into 2 usage groups (minimum 30 days treatment): high (≥50%) and low (<50%) usage.

RESULTS

Among 1285 patients with known IDH status, 82 had an IDH-mut and were included. The median (range) age of patients was 40.6 (21–75) years, with the majority being men (n=58/71%) and with methylguanine-methyltransferase-promoter methylation (n=48/59%). Median TTFields therapy duration and usage were 9.4 months and 76.8%, respectively. OS at 2 and 4 years was 66% (95% CI: 56–77%) and 44% (34–57%), respectively. Patients with high TTFields usage had increased OS compared to low usage (HR: 0.53 [0.28–1.02], P=0.057, n=80). Among 22 patients with a minimum 4 years of survival, 5 were still on therapy as of the data cutoff.

CONCLUSIONS

These findings demonstrate the utility of the xCures platform in systematically assessing outcomes for a rare glioma subtype in the real-world setting, and suggests that patients with Astrocytoma IDHmut/G4 may benefit from TTFields therapy. Additional patient follow-up and correlative data will be presented.
INNV-17. SAME-DAY DISCHARGE AFTER LASER INTERSTITIAL THERMAL THERAPY: A PROSPECTIVE COHORT PILOT STUDY WITH A MATCHED CONTROL GROUP
Authors: Berke Chandler , Khalafallah Adham , Knott Maxon , Susic Nikola , Gurses Muhammet , Lu Victor , Ivan Michael , Komotar Ricardo , shah Ashish
Published: November 2024

BACKGROUND

Laser interstitial thermal therapy (LITT) has emerged as a minimally invasive treatment modality for intracranial pathologies, offering precision and control over tissue damage. With implementation of enhanced recovery after surgery (ERAS) protocols within neurosurgery, identifying patients amenable for same-day discharge (SDD) is an important step towards streamlining perioperative care following LITT, and correspondingly, we aim to summarize our initial experience.

METHODS

We conducted a prospective study at the University of Miami Hospital of 7 patients who underwent LITT for intracranial pathologies and were discharged on the same day of ablation (post-ablation day 0, PAD0). We then performed a retrospective case-control study against a historic matched PAD1 cohort comparing categorical and continuous variables for statistical significance.

RESULTS

The mean age of the PAD0 cohort was 55 years with 71% males. Preoperative neurological status and comorbidities did not differ significantly between the PAD0 and PAD1 cohorts for KPS (median [IQR]: 80 [80-90] vs. 90 [80-90], p=0.40), mFI-5 (median [IQR]: 1 [1.5] vs. 0 [1], p=0.54), and mFI-11 (median [IQR]: 1 [1.5] vs. 1 [1], p=0.52). PAD0 outcomes demonstrated no immediate complications, neurosurgical readmissions, or significant neurological deficits within 6 months post-procedure and were non-significantly different than PAD1 patients. No PAD0 patient experienced intracranial hemorrhage or vasogenic edema following LITT that necessitated further intervention.

CONCLUSIONS

Our study demonstrates the safety and feasibility of same-day discharge following LITT for intracranial pathologies in the appropriately selected patient. Through meticulous patient selection and optimized perioperative protocols, expedited recovery without compromising patient outcomes was achieved. This approach holds potential for substantial cost savings and resource optimization within healthcare systems. Further research and quality improvement initiatives are warranted to refine patient selection criteria and maximize the benefits of same-day discharge in LITT practice.
INNV-22. CEREBELLOPONTINE EPIDERMOID CYST TO SQUAMOUS CELL CARCINOMA: MALIGNANT TRANSFORMATION, LEPTOMENINGEAL CARCINOMATOSIS, AND MANAGEMENT
Authors: Hennawy Mirna , Fatehi Mostafa , Yip Stephen , Oh Justin , Harrison Rebecca
Published: November 2024

BACKGROUND

Intracranial epidermoid cysts (EDC) are rare, slow-growing, congenital tumors, that generally follow a benign course. EDCs have a rare potential for transformation to squamous cell carcinoma (SCC). We present a case of a malignant EDC transformation to SCC with leptomeningeal (LM) dissemination.

METHODS

Case report and review of literature.

CASE PRESENTATION

A 44-year-old female presented for evaluation of left-sided tinnitus and sensorineural hearing loss, which revealed a left cerebellopontine angle (CPA) tumor. She underwent a subtotal resection at age 47. One year later, she had rapid symptomatic recurrence of the cyst, as well as LM deposits of the right internal acoustic canal bundle, the left trigeminal nerve, and along the lumbar and sacral spine. She underwent repeat resection of the CPA lesion, with pathology now consistent with SCC, with CDKN2A loss. She received focal radiation therapy at the posterior fossa and the lumbar spine. SCC-directed chemotherapy with pembrolizumab and carboplatin followed by 5 cycles of pembrolizumab monotherapy was given as adjuvant therapy, prior to her developing symptomatic LM disease.

CONCLUSION

Malignant transformation of intracranial EDC is a rare occurrence in these typically benign tumours. Prognosis is especially poor when there is associated LM involvement, with median survival noted to be 10 months. Awareness of this phenomenon amongst clinicians is needed to ensure appropriate surveillance and aggressive treatment if it remains within patient wishes, though there is no consensus on recommendations for treatment. The patient presented has maintained disease stability with LM dissemination for over 10 months and ongoing, with a regimen of chemoradiotherapy informed by therapeutic approach to systemic SCC. To our knowledge, this is the first reported case of EDC to SCC transformation and LM dissemination stabilized with chemoradiotherapy using an immune-checkpoint inhibitor.
INNV-24. CONGENITAL EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES AND TREATMENT IN A NEWBORN
Authors: Casey Jessica , Raman Sarina , Lasky Joseph , Gupta Sumit
Published: November 2024

BACKGROUND

Embryonal Tumor with Multilayered Rosettes (ETMR) is a rare but deadly pediatric brain tumor with no standard of care treatment. We present a unique case of congenital ETMR and treatment strategy using intrathecal topotecan and no radiation therapy. Case report: A term baby was admitted to NICU at 12 hours of life with respiratory arrest requiring intubation. CT of the brain revealed a 4.2x3.9x3.5cm left posterior fossa hyperdense hemorrhagic mass with moderate hydrocephalus. She underwent posterior fossa craniotomy for biopsy and evacuation at two days of life. Pathology was consistent with an ETMR. MRI brain after first resection was not concerning. She underwent re-resection at 3 months of age due to re-growth (2x3x3cm). She was then treated as per Head Start 4 chemotherapy regimen with vincristine, cisplatin, etoposide, cyclophosphamide, and methotrexate, followed by consolidation with three tandem auto-hemopoietic stem cell transplants (HSCT) with carboplatin and thiotepa conditioning. Maintenance treatment consisted of intrathecal topotecan every four weeks (0.2mg per dose <1 year old, 0.25mg per dose when ≥1 year old) for 12 doses. She also received oral vorinostat (100mg PO QD) and isotretinoin (80mg/m2 divided BID) during maintenance for 1 year. No radiation was given. The treatment course was complicated by mucositis, febrile neutropenia, pseudomonas sepsis and an episode of respiratory arrest secondary to choking from epistaxis. The patient is currently doing well and continues to remain in remission for over seven months after end of treatment.

CONCLUSION

We present a case of congenital ETMR with a unique treatment option and strategy using Head Start 4 therapy with three tandem auto-HSCT as consolidation, followed by 12 months of maintenance therapy with intrathecal topotecan, oral vorinostat, and isotretinoin, without any radiation, leading to sustained remission.
INNV-25. POST-OPERATIVE LOW DOSE VERSUS STANDARD DOSE DEXAMETHASONE FOR MANAGEMENT OF CEREBRAL EDEMA: A RANDOMIZED, DOUBLE-BLINDED FEASIBILITY STUDY IN PATIENTS WITH PRIMARY OR METASTATIC BRAIN TUMORS UNDERGOING CRANIOTOMY FOR TUMOR RESECTION
Authors: Portnow Jana , Filipov Aleksandr , Blanchard M Suzette , Stiller Tracey , Kilpatrick Julie , Kelii Danalle , Feldman Lisa , Badie Behnam
Published: November 2024

INTRODUCTION

Although dexamethasone is effective for controlling cerebral edema during the peri-operative period, its immunosuppressive properties can inhibit responses to immunotherapy. We hypothesized that patients with mild to moderate cerebral edema could be safely managed post-operatively with lower doses of dexamethasone.

METHODS

Eligible patients with brain tumors who had less than 10 mm of midline shift on their pre-operative brain MRIs were randomized 1:1 to the standard or low dose dexamethasone arm, each tapering double blinded through post-op day 8. The double blind was maintained using equivalent volumes for IV doses and capsules containing dexamethasone or placebo. By post-op day 9, participants received the same dose of dexamethasone and continued tapering to off by day 14. Additional doses of dexamethasone were allowed if needed, based on specified symptom criteria. Lack of feasibility was defined as a participant requiring 18 mg or more of dexamethasone in addition to the planned total dose of dexamethasone (low dose: 49 mg; standard dose: 112 mg). Brain MRIs were performed on post-operative days 1, 3, and 8 to evaluate changes in cerebral edema. Manual segmentation and computer-assisted techniques were used to quantitatively measure cerebral edema volume.

RESULTS

Twenty-six patients were randomized and treated within tumor type strata (primary versus metastatic), of which 25 were evaluable. None of the participants on the low dose dexamethasone arm met the criteria for lack of feasibility. The quantitative assessment of differences in cerebral edema between the arms is ongoing and will be presented.

CONCLUSIONS

Administration of lower doses of dexamethasone post-operatively to brain tumor patients with mild to moderate cerebral edema is feasible. Treatment with lower doses of dexamethasone post-operatively should be considered in this patient population when peri-operative administration of immunotherapy is planned.
INNV-27. TEMOZOLOMIDE FOR PATIENTS WITH AGGRESSIVE PITUITARY TUMORS: A CASE SERIES
Authors: White Jessica , Baykal Duru , Ser Hazal , Uhm Joon , Ruff Michael , Lachance Daniel , Neth Bryan , Van Gompel Jamie , Giannini Caterina , Raghunathan Aditya , Erickson Dana , Sener Ugur
Published: November 2024

BACKGROUND

Pituitary adenomas are often effectively managed with medical therapy, surgery, and radiation therapy. However, up to 15% of pituitary neoplasms exhibit rapid growth, invasive behavior, or, rarely, metastasize despite optimal standard treatments. Temozolomide is associated with a survival benefit for patients with these aggressive pituitary tumors.

METHODS

We present a case series of 8 patients with an aggressive pituitary tumor (APT) or pituitary carcinoma (PC) treated with temozolomide.

RESULTS

Eight patients (3 female, median age at diagnosis 44) with APT (n=6) or PC (n=2) were treated. A variety of pituitary tumor types were represented (1 prolactinoma, 5 corticotroph adenomas, 1 gonadotroph adenoma, 1 thyrotropinoma). Prior to temozolomide initiation, patients underwent a median 5 treatments including medical management (n=4), surgery (n=7), radiation therapy (n=7). Temozolomide was started at median 3.5 recurrence. Median treatment duration was 6 cycles (n=6, 150-200 mg/m2 days 1-5, 28-day cycles; n=1, 75 mg/m2, days 1-21, 28-day cycles). Seven patients experienced progression after temozolomide treatment, median progression-free survival (PFS) was 4 months. One patient remains on treatment, progression-free at 5 months. MGMT methylation status was assessed for 3 tumors. Among 2 patients with MGMT promoter methylated tumors, PFS was 4 months for one patient, the other remains on treatment. For one patient with MGMT promoter unmethylated corticotroph adenoma, PFS was 9 months. No ≥ grade 4 toxicities were noted. Most common toxicities were nausea (n=5), thrombocytopenia (n=3), and fatigue (n=2).

CONCLUSION

In this group of heavily pretreated patients, temozolomide monotherapy was well-tolerated and associated with median PFS of 4 months. Interestingly, PC patients had longer PFS at 9 months and 24 months. Our findings support use of single-agent temozolomide chemotherapy for patients with APT/PC, but further prospective analysis is needed to identify patients more likely to benefit from treatment and optimal timing of chemotherapy initiation.
INNV-29. PATIENT BARRIERS AND PREFERENCES FOR EXERCISE FOLLOWING A BRAIN TUMOR DIAGNOSIS
Authors: Fogh Shannon , Mishra Kavita , Hoffer Naomi , Destri Mary , Chang Susan , Taylor Jennie
Published: November 2024

BACKGROUND

Exercise has shown benefit in patients with cancer, however patients with brain tumors often experience deficits in cognition, motor skills and other symptoms, further exacerbated by treatment, which can make exercise challenging. Yet, the literature supports positive impact of exercise on symptoms and prognosis within this patient population. Our study aims to understand patient’s motivations and preferences for exercise.

METHODS

We surveyed patients with primary brain tumors within a single, quaternary medical center. Questions were extrapolated from published questionnaires and were accessed through flyers containing a QR code. Questions assessed current practices, attitudes, knowledge, motivating factors and barriers for integrating exercise into treatment.

RESULTS

Twenty-nine patients completed the survey. Nearly 70% reported that exercise has been important throughout their life in maintaining good health and quality of life. Walking emerged as the predominant mode of physical activity (55%). Thirty-one percent of patients reported the intensity of their current routine was light activity, 24% moderate activity, and 7% vigorous activity.The primary motivators for patients initiating or sustaining an exercise regimen included having someone monitor their progress (28%), complimentary access to a workout facility (21%) and awareness of the beneficial impact of exercise on symptoms and prognosis (51%). The most prevalent physical barriers to exercise included trouble with balance (34%), fatigue (34%) and headaches (21%). Other barriers included lack of transportation (38%), space (21%), cost (21%) and time (14%). Sixty-six percent of patients were more likely to participate in an exercise program if mentioned by their healthcare provider or healthcare team during a visit.

CONCLUSION

Findings from this study help to expand our understanding of barriers and facilitators to incorporating exercise interventions into brain cancer treatment and can inform the implementation of a structured exercise programs.
INNV-30. TOXICITIES AND OUTCOME AFTER CD19-DIRECTED CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY FOR NEUROLYMPHOMATOSIS
Authors: Kaulen Leon D , Karschnia Philipp , Doubrovinskaia Sofia , Wick Wolfgang , Martinez-Lage Maria , Shankar Ganesh , Abramson Jeremy S , Frigault Matthew J , Dietrich Jorg
Published: November 2024

BACKGROUND

Lymphomatous infiltration of the peripheral nervous system (PNS), termed neurolymphomatosis, represents a distinct extranodal non-Hodgkin lymphoma variant with dismal outcome. CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy has emerged as a safe and effective treatment for B-cell lymphomas. We aimed to assess toxicity and efficacy of CD19-CAR T-cells in neurolymphomatosis.

METHODS

Neurolymphomatosis treated with CD19-CAR T-cells were retrospectively identified at Massachusetts General Hospital over a six-year period. Toxicities were graded according to the ASTCT classification. Management, and response rates were recorded.

RESULTS

Eleven neurolymphomatosis cases, who had received a median 2 prior PNS-directed treatments (range: 1-3) before CD19-CAR T-cell exposure, were identified. Neurolymphomatosis localized to the nerve roots (8/11, 73%), plexus (5/11, 45%), peripheral (4/11, 36%) and cranial nerves (5/11, 45%). Low grade cytokine release syndrome was detected in 8/11 (73%; grade 1: N = 7; grade 2: N =1) cases. Low- and high-grade immune cell-associated neurotoxicity syndrome were recorded in 5/11 (45%; grade 1: N = 4; grade 2: N = 1) and 1/11 (9%; grade 4) patients, respectively. Seven of eleven neurolymphomatosis patients (64%) responded to CD19-CAR T-cells. Complete remissions were achieved in three cases (27%), of which two are still sustained now 9 and 46 months after CD19-CAR T-cell infusion. All radiographic responses were associated with remission of neurological symptoms.

CONCLUSIONS

CD19-CAR T-cell treatment was well tolerated and yielded promising efficacy in recurrent neurolymphomatosis, a difficult to treat condition with unmet medical need. Findings suggest that CD19-CAR may sufficiently penetrate the blood-nerve barrier, and toxicity and outcomes were overall similar to CAR-T cell therapy in CNS lymphoma.
INNV-33. ADVANCING PRECISION TREATMENT FOR DIFFUSE MIDLINE GLIOMA: THE DMG LEARNING HUB INITIATIVE
Authors: Lyons Nicole , Mehta Misha , Ward Lisa
Published: November 2024

Diffuse Midline Glioma (DMG) poses a significant challenge in neuro-oncology due to its heterogeneous presentation and limited therapeutic options. Clinical trials often serve as the primary avenue for treatment, yet families encounter numerous barriers in navigating and selecting appropriate trials. Health disparities, including disparities in medical literacy and access to specialized medical centers, further complicate decision-making processes. Existing registries lack comprehensive data integration, focusing on isolated perspectives of either research or clinical data, neglecting the holistic patient profile. Evaluation of treatment endpoints beyond Progression-Free Survival (PFS) and Overall Survival (OS) remain inconsistent, despite being a priority for families. The DMG Learning Hub emerges as a transformative platform designed to empower families by offering informed options and guidance while fostering a collaborative environment where patient families actively contribute to shaping the landscape of clinical trials. Leveraging AI-assisted matching, the platform assists families in navigating the complex decision-making process surrounding clinical trial participation. The inclusion of a patient-reported outcome journal feature enables families to track vital information such as symptom changes and supplement usage, with autonomy over the timing of shared data. Using real-time data sharing facilitates invaluable insights for researchers, bridging gaps that would otherwise be overlooked and enriching the collective understanding of DMG. Harmonizing molecular, imaging, and clinical data within the platform equips care teams with comprehensive, near-real-time information crucial for personalized treatment strategies. This integrated approach not only supports the inclusion of n-of-1 arms in current trials but also extends therapeutic opportunities to patients previously ineligible for studies due to specific disease markers or progression patterns. The DMG Learning Hub represents a significant stride towards precision oncology by synergizing patient-centric priorities with cutting-edge technology, integrating harmonized data, and fostering collaborative efforts, the initiative heralds a promising era of personalized treatment for DMG and beyond the neuro-oncology community.
INNV-35. DATA-DRIVEN MODELING OF EMERGING TRENDS AND COLLABORATIVE NETWORKS ACROSS BRAIN METASTASES RESEARCH: THE PAST DECADE OF INNOVATION
Authors: Durrani Sulaman , Cote Ian , Carpintieri Sabrina , Martinez Joseph , Metzler Ashley , Graciolli Joacir , Shah Ashish , Oermann Eric , Komotar Ricardo , Ivan Michael , Benjamin Carolina , Sheehan Jason , Kondziolka Douglas , Tecle Najib El
Published: November 2024

With recent significant growth in brain metastases literature output, more comprehensive research is necessary to understand emerging trends and novel methods of diagnosis and treatment. We aimed to address this by providing a contemporary systematic global analysis of emerging brain metastases research in the last decade while visually depicting the international collaborative environment among its researchers. Data mining was performed on all brain metastases publications across the last decade indexed in Elsevier’s Scopus database. Our Scopus search revealed 6,362 publications from 1,184 sources from 2013-2022. Of those, 252 were identified as high-impact articles with an annual citation rate (CR) > 10. The compounded annual growth rate (CAGR) of brain metastases publications was 7.2% per year since 2013. There was an acceleration of scientific production, from 5.9% CAGR across 2013-2018 to 9.6% across 2019-2022. Authors per document increased from 7.2% to 8.5% while international co-authorships increased from 16.6% to 18.3% in the same periods, respectively. Recent trending topics were noted to be artificial intelligence, understanding the brain microenvironment, exosomes, novel mechanisms of diagnosis (such as circulating tumor cells), and targeted treatments. High-impact articles tended to revolve around specific therapies or biomarkers as opposed to general synopses. Clustering analysis revealed three separate pivotal collaborative communities centered around Brown PD/Sahgal A, Ahluwalia MS, and Wang Y, with Brown PD as most notable for high impact research. While the top institutional collaborative group centered around Mayo Clinic, the highest impact research centered around the Dana-Farber Cancer Institute. Sub-analyses revealed that studies involving multiple countries tended to have a higher impact. The median overall survival of brain metastases, by primary source, was illustrated across the last five decades. Overall, significant growth in scientific production is driven by the integration of novel technologies (such as artificial intelligence), interdisciplinary approaches, and collaboration across global communities.
PATH-08. MOLECULAR DIVERGENCE RATES DIFFER BETWEEN BRAIN METASTASES AND EXTRACRANIAL DISEASE SITES ACROSS PRIMARY TUMOR HISTOLOGIES
Authors: Morshed Ramin , Khela Harmon , Nguyen Minh , Young Jacob , Goldschmidt Ezequiel , McDermott Michael , Malik Noor , Parney Ian , Chang Edward , Berger Mitchel , Theodosopoulos Philip , Hervey-Jumper Shawn , Huppert Laura , Aghi Manish , Vasudevan Harish
Published: November 2024

Genomic alterations and molecular subgroups between extracranial disease sites and brain metastases often differ, yet the prevalence and clinical significance of divergent evolution in brain metastases is not fully understood. This study examined genomic alterations and molecular subgroup divergence rates between matched brain metastases and extracranial disease sites. A retrospective, two-center study was conducted on patients who underwent resection of brain metastases between 2014-2022 with clinical and matched genomic data and/or molecular markers available. The overall cohort comprised 256 patients with matched tumors from multiple cancer types, most commonly from breast (n=108, 42.2%), melanoma (n=83, 32.4%), and NSCLC (n=43, 16.8%). Targeted next-generation sequencing of over 500 oncogenes was performed on resected tumors as part of clinical care (n=41 patients with matched specimens). Molecular subgroups for breast, melanoma, and non-small cell lung cancer were also assessed by immunohistochemistry to evaluate rates of molecular subgroup discordance between sites. Subgroup discordance by immunohistochemistry was observed most frequently across breast cancer (22.2%, n=24/108) with loss of the estrogen receptor (ER) and progesterone receptor (PR) and gain of HER2 most frequently observed within brain metastases. Molecular subgroup discordance was rare within melanoma (7.3%, n=6/82) and NSCLC (14.0%, n=6/43) patients. When evaluating oncogenomic alterations from targeted DNA sequencing in 41 patients with matched specimens, 80.5% (33/41) of brain metastases demonstrated a unique oncogene alteration profile compared to an extracranial disease site. Fourteen patients (34.1%) had a gain of at least 1 targetable alteration within a brain metastasis that was not observed in an extracranial disease site. Brain metastases demonstrated high rates of genomic divergence compared to primary and extracranial metastatic disease sites. This data supports obtaining brain metastasis tissue and conducting molecular profiling of this tissue to help select optimal CNS penetrant systemic therapies for each patient.
PATH-11. TECTAL GLIOMA: CLINICAL, PATHOLOGICAL, AND MOLECULAR FEATURES
Authors: Imoto Ryoji , Otani Yoshihiro , Ishida Joji , Hirano Shuichiro , Kemmotsu Naoya , Suruga Yasuki , Mizuta Ryo , Kegoya Yasuhito , Inoue Yohei , Washio Kana , Yanai Hiroyuki , Tanaka Shota , Satomi Kaishi , Ichimura Koichi , Date Isao
Published: November 2024

Tectal glioma (TG) is a rare lower-grade glioma (LrGG) that occurs in the tectum, mainly affecting children. The clinical course is usually indolent, with common symptoms including headache, gait disturbance, and ataxia resulting from obstructive hydrocephalus. TG shares pathological similarities with pilocytic astrocytoma (PA), but recent genetic analyses have revealed distinct features, such as alterations in KRAS and BRAF. Here, we report the clinical, radiological, pathological, and molecular characteristics of TG cases in our hospital. We conducted a retrospective review of cases clinically diagnosed as TG and surgically treated at our institute between January 2005 and March 2023. Molecular analysis, including genome-wide DNA methylation profiling, was performed. Six cases were identified and the median age at diagnosis was 30.5 years (range: 6–45 years). The mean tumor diameter was 22.8 mm (range: 14.7–33.2 mm), with obstructive hydrocephalus observed in all cases. Contrast enhancement of the tumor was noted in four cases and cyst formation occurred in two cases. Four patients underwent biopsy or biopsy with endoscopic third ventriculostomy, and two patients underwent tumor resection. Postoperatively, three patients received radiotherapy and two were treated with chemotherapy. The median overall survival was 6.2 years (range: 1.4–7.3 years), and the median progression-free survival was 3.4 years (range: 1.4–7.3 years). Histological diagnoses included three cases of PA, one case of astrocytoma, and two cases of high-grade glioma. Among the three patients who underwent molecular evaluation, including genome-wide methylation analysis, two had KRAS mutation and one had H3-3A K27M mutation. Our results demonstrate the diverse histological and molecular characteristics of TG distinct from other LrGGs. Given the heterogeneous pathological background and the risk of pathological progression in TG, we emphasize the importance of comprehensive diagnosis, including molecular evaluation.
PATH-15. DIGITAL PCR ANALYSIS FOR DETECTINGTERT PROMOTOR MUTATION IN MENINGIOMAS
Authors: Shimizu Yuzaburo , Kodama Takuma , Miyahara Ryo , Suzuki Mario , Akiyama Osamu , Ogino Ikuko , Kondo Akihide
Published: November 2024

The WHO Classification of Brain Tumors 5th edition requires the evaluation of TERT promoter mutations and CDKN2A/B homozygous deletions for the diagnosis of malignant meningiomas. Digital PCR (dPCR) is an emerging method for highly sensitive quantitative analysis. In this study, we performed TERT promoter mutation analysis using Pyrosequencing and dPCR in specimens with atypical and anaplastic meningiomas to investigate its utility and clinical significance. Adult patients diagnosed with atypical or anaplastic meningiomas after tumor resection between January 2009 and June 2023 were included. Genomic DNA was extracted from the excised specimens. TERT promoter mutations was analyzed by using the Pyrosequence and dPCR methods and compared with the clinical course. A total of 37 meningioma cases (13 males and 24 females) with 64 specimens were included. Atypical meningioma, grade II (WHO 2016) at diagnosis was 53 specimens (83%) and anaplastic meningioma, grade III (WHO 2016) was 11 specimens (17%). Of these, 7 (10%) were diagnosed with TERT promoter mutations by pyrosequencing, and one case with a low frequency (15%) of mutations by dPCR that tested negative by pyrosequencing had repeated recurrences in a short period of time. The dPCR method is highly sensitive in detecting low frequency TERT promoter mutations in tumor cell subpopulations and may contribute to the determination of treatment by predicting the malignant course of the disease. The results suggest that dPCR could contribute to therapeutic decision-making by detecting low-frequency TERT promoter mutations in tumor cell subpopulations.
PATH-16. MOLECULAR ALTERATIONS IN IDH-MUTANT ASTROCYTOMA: A MULTI-INSTITUTIONAL RETROSPECTIVE STUDY
Authors: Lam Keng , Ozkizilkaya Hanim , Den Milton ái , Dono Antonio , Kumar Vinodh , Johnson Jason , Esquenazi Yoshua , Patel Chirag , Ballester Leomar
Published: November 2024

BACKGROUND

Many molecular alterations are being identified for diagnosis and prognosis in patients with isocitrate dehydrogenase (IDH)-mutant astrocytoma. However, contemporary survival data for these tumors with respect to their molecular alterations are lacking. Moreover, the prognostic value of histologic grading in IDH-mutant astrocytomas remains controversial.

METHODS

This was a retrospective study of adult IDH-mutant diffuse astrocytoma patients in whom clinical and molecular alteration data were collected. Overall survival (OS) was estimated using the Kaplan-Meier method. Group differences in OS were assessed by the log-rank test and associations between OS and measures of interest were evaluated using Cox proportional hazards regression models.

RESULTS

We identified 241 eligible patients with median age of 33 years (range, 16-73 years). The most frequent mutations were in IDH1 (98%), TP53 (91%), ATRX (70%), ARID1A (8%), BRCA2 (6%), TSC2 (6%), CDKN2A (6%), and CREBBP (6%). IDH2 mutations were identified in 2% of cases. By univariate analysis, age >40 years (hazard ratio [HR], 2.02; 95% CI, 1.19-3.43; P =.009) was associated with worse OS. BRCA2 wild-type status compared with mutated BRCA2 (HR, 0.42; 95% CI, 0.20-0.90; P =.024) and histology-based grade 2 compared with grade 3 astrocytoma (HR, 0.41; 95% CI, 0.23-0.74; P =.003) were associated with improved OS. In multivariable analysis, age>40 years (HR, 2.14; 95% CI, 1.22-3.75; P =.008) was associated with worse OS. Patients with WHO grade 2 astrocytoma remained associated with improved OS compared to those with grade 3 disease (HR, 0.45; 95% CI, 0.24-0.84; P =.013).

CONCLUSIONS

Age and histological grade remain essentials for risk stratification among IDH-mutant astrocytoma patients. Further studies are warranted to determine the role of BRCA2 mutation in prognosis.
PATH-24. NOVEL MOLECULAR SUBTYPES IDENTIFIED IN INTRACRANIAL GERM CELL TUMORS SHOWED UNIQUE WHOLE-GENOME METHYLATION PROFILE
Authors: Li Bo , Qiu Xiaoguang
Published: November 2024

BACKGROUND

By integrating whole-genome sequencing (WGS) and RNA-seq data, we found that intracranial germ cell tumors (IGCTs) can be divided into three distinct molecular subtypes: immune-hot, MYC/E2F, and SHH, each characterized by a unique profile of genomic abnormalities. To further define these subtypes, we subsequently performed whole-genome bisulfate sequencing (WGBS) on IGCT tumors

METHODS

Within our prior discovery cohort (n=110), DNA from 84 samples was available for profiling methylation levels using Whole Genome Bisulfite Sequencing (WGBS). Fastq data was aligned to the human reference genome (hg19), with duplicates removed, and DNA methylation was extracted using bismark pipeline (ver0.24.0). After quality control, weight methylation level was calculated for each CpG island as the sum of methylated reads divided by coverage. To identify IGCTs molecular groups, we applied hierarchical consensus k-means clustering to the most variant methylated CpG island (n=1000) across 84 IGCTs tumor tissues. The methylation level of RNA-seq subtypes was visualized to further clarify the molecular subtypes of IGCTs

RESULTS

Unsupervised clustering revealed that IGCTs can be divided into three groups based on the CpG island methylation levels: hypomethylation group (n=32), moderate methylation group (n=27), and hyper methylation group (n=25). The hypomethylation and moderate methylation group are predominantly observed in germinoma (>90%). In contrast, hypermethylation group comprises the majority of non-germinomatous germ cell tumors. Furthermore, these subgroups derived from methylation analysis are highly consistent with the molecular subtypes previously defined through gene transcription profile analysis. We observed that the majority of MYC/E2F subtype (24/33) belonged to the hypomethylation group, whereas the majority of immune-hot subtype (14/23) fell into the moderate methylation group. The SHH subtype was the most common within the hypermethylation group (18/26)

CONCLUSIONS

The three molecular IGCT subtypes showed unique methylation profile. These results indicate different mechanisms of tumorigenesis among the subtypes and pave the way for the clinical application of methylation-based subtyping.
PATH-31. COMPLETE TUMOR DISAPPEARANCE ON BRAIN MRI AFTER STANDARD CHEMORADIATION THERAPY FOR A MOLECULAR GLIOBLASTOMA
Authors: Ahn Jeffrey , Bow Hansen , Eapen Ann , Kong Xiao-Tang
Published: November 2024

INTRODUCTION

Glioblastoma (GBM) is the most aggressive brain tumor. The WHO CNS5 classification has newly incorporated three molecular criteria in diagnosing molecular GBM, including a concurrent gain of chromosome 7 and loss of chromosome 10 (+7/-10), TERT promoter mutation, or EGFR amplification. Despite new classification, the Stupp protocol remains the standard of care for all GBMs. However, it is unclear if the treatment response of the molecular GBM with low grade features is the same as the limited response of the traditional histopathological GBM.

CASE REPORT

A 74-year-old male presented in August of 2023 with new onset left-sided facial numbness. The numbness resolved spontaneously that day. Brain MRI was notable for a diffuse left frontal T2/Flair hyperintense lesion extending across the corpus callosum into the right frontal lobe without definite enhancement. Brain biopsy from 8 sites of the tumor demonstrated a subset of areas with mild hyper-cellularity, suggesting a low-density infiltrating glioma. However, TERT promoter mutation (-124C>T), was detected along with wild-type IDH1, supporting molecular GBM. Studies also found unmethylated MGMT gene promotor. Brain MRIs after 3 and 6 months showed no tumor progression. The patient has remained asymptomatic apart from baseline mild forgetfulness. He was started on the 6-week standard concomitant temozolomide and radiation therapy. Follow-up brain MRI after the above treatment showed complete imaging resolution of the tumor.

DISCUSSION

It is very rare for complete imaging resolution of GBM on brain MRI after standard 6-week chemoradiation therapy. Our case suggests that molecular GBM with low-grade features on imagine and pathology might have a better response to the standard treatment than traditional histopathological GBM even though the molecular GBM patient has unfavorable prognostic factors such as unmethylated MGMT and older age (>70 years old). Our experience emphasizes the heterogenous response of molecular GBM to the current standard treatment.
PATH-37. A NEW SUBTYPE OF DIFFUSE MIDLINE GLIOMA, H3 K27 AND BRAF/FGFR1 CO-ALTERED, EXHIBITS SPECIFIC BIOLOGICAL CHARACTERISTICS AND NEW THERAPEUTIC VULNERABILITIES
Authors: Auffret Lucie , Barry Clémentine , Ajlil Yassine , Tauziède-Espariat Arnault , Mayr Lisa , Simbozel Marie , Kergrohen Thomas , Puiseux Chloé , Riffaud Laurent , Blouin Pascale , Bertozzi Anne-Isabelle , Leblond Pierre , Blomgren Klas , Froelich Sébastien , Picca Alberto , Touat Mehdi , Sanson Marc , Beccaria Kevin , Blauwblomme Thomas , Dangouloff-Ros Volodia , Boddaert Nathalie , Gojo Johannes , Filbin Mariella , Varlet Pascale , Debily Marie-Anne , Grill Jacques , Castel David
Published: November 2024

Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumor type is classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System tumors. However, we recently identified a new subtype of DMG by assembling a retrospective cohort of 60 adult and pediatric DMG cases harboring BRAF or FGFR1 mutations in addition to the H3K27M mutation or EZHIP overexpression. Comprehensive clinical, histological, radiological, and genomic, analyses allowed to identify distinct genotype-phenotype characteristics. Contrary to other DMG, these tumors occur more frequently in the thalamus (27% vs. 70% for BRAFV600E or 58% for FGFR1MUT), and in adults in the case of FGFRMUT tumors. Importantly, these patients display a longer overall survival with a median above three years. Unsupervised analysis of DNA methylation profiles regrouped these MAPK-altered DMG in a methylation cluster distinct from other DMG H3K27, but also lower-grade midline tumors driven by FGFR1 or BRAF mutations Additionally, this new DMG subtype harbors atypical radiological and histopathological profiles with calcification and/or a solid tumor component both for BRAFV600E and FGFR1MUT cases that can suggest this differential diagnosis. Further analyses of the transcriptome of these tumors compared to canonical DMG H3K27-altered showed an expression signature of senescence with activation of a TP53/CDKN1A axis, together with a strong upregulation of the PI3K/AKT/MTOR pathway. Our current modelling of the drug response using patient-derived models of these specific DMG will permit to rapidly prioritize treatment strategies. Additionally, our clinical experience in treating these patients suggests a higher response to everolimus and imipridone ONC201 in this specific subtype. In conclusion, DMG H3 K27 and BRAF/FGFR1 co-altered, represent a new subtype of DMG with distinct specific characteristics compared to canonical DMG H3K27 and data accumulated strongly support their separate stratification in clinical trials and specific therapeutic managements.
PATH-39. AI-BASED IDENTIFICATION OF GLIOMA IDH MUTATIONAL STATUS FROM H&E-STAINED WHOLE SLIDE IMAGES
Authors: Innani Shubham , Baheti Bhakti , Nasrallah MacLean P , Bell W Robert , Bakas Spyridon
Published: November 2024

INTRODUCTION

Isocitrate-dehydrogenase (IDH) mutational status is diagnostically critical in adult gliomas, with prognostic and therapeutic implications. IDH status cannot be determined by sole histologic assessment and requires molecular testing. We hypothesize that AI-based analysis can accurately predict IDH mutational status in glioma, by retrieving sub-visual cues in H&E-stained digitized tissue sections.

MATERIALS AND METHODS

A retrospective discovery cohort of 1,534 cases (756/778 IDH-wildtype/IDH-mutant, including all available grades) from the TCGA-LGG/TCGA-GBM collections was used for model development with 10-fold cross-validation (CV). A replication cohort of 114 cases (82/32 IDH-wildtype/IDH-mutant) from the University of Pennsylvania Health System (UPHS) was used for independent hold-out evaluation. Each 20X magnification whole slide image (WSI) underwent comprehensive curation for elimination of artifactual content, followed by partitioning into 256x256 patches, and feature extraction using pre-trained i) ImageNet weights (baseline), and ii) self-supervised vision transformer (ViT). A weakly-supervised attention-based multiple-instance-learning framework distinguished cases as IDH-wildtype or IDH-mutant, while generating visually interpretable attention heatmaps.

RESULTS

Evaluation on discovery and replication cohorts with the ViT yield accuracy of 90.84% (AUCDiscovery=97.16%) and 93.94% (AUCReplication=97.36%), respectively, with high sensitivity (i.e., high confidence in correctly predicting IDH-wildtype glioma). Comparison of the ViT with the baseline model on the replication cohort indicates the ViT superiority by improvements of 8% and 9.5% in accuracy and AUC, respectively. Histologic assessment of heatmaps indicates IDH-wildtype tumors exhibiting distinct regions of significant pleomorphism and microvascular proliferation, while IDH-mutant tumors exhibit dense nodular cell concentrations, microcystic architecture, and gemistocytic cells.

CONCLUSION

Our accurate H&E-based computational determination of glioma IDH status, with interpretations aligned with human-identifiable features, can contribute to obviating the need for molecular analyses and enable expedited diagnosis even in community healthcare settings. This study robustly identifies morpho-IDH correlates and could enable expedited patient prognostic stratification.
PATH-42. METASTATIC ADENOID CYSTIC CARCINOMA OF BREAST WITH BRAIN METASTASES AND LEPTOMENINGEAL DISEASE
Authors: Farooq Shama , Correia Carlos Eduardo Silva
Published: November 2024

INTRODUCTION

Adenoid cystic carcinoma (ACC) of the breast rarely metastasizes to the brain and leptomeninges. ACC is a rare type of breast cancer, accounting for less than 0.1% of cases. It is usually triple negative, but has a good prognosis when it is confined to the breast. Lymph node involvement is uncommon, occurring in less than 2% of cases, and distant metastases to the brain are extremely rare. Leptomeningeal disease has not been reported yet. Case: In this case, we describe a 57-year-old woman diagnosed with triple-negative ACC of the right breast, which had spread to the axillary lymph nodes and distant metastases to the lung. The diagnosis was confirmed by biopsies of both metastatic sites. The patient received vinorelbine and cisplatin treatment for 11 cycles followed by right needle localized lumpectomy. While awaiting for the next steps in treatment she was admitted to the hospital for altered mental status, saddle anesthesia, and urinary incontinence. Neuraxis MRI revealed numerous hemorrhagic and non-hemorrhagic brain metastasis with diffuse leptomeningeal disease. Cerebrospinal fluid analysis confirmed leptomeningeal disease with positive cytology for atypical epithelioid malignant cells. The patient underwent whole brain radiation and focal radiation treatment to specific areas of leptomeningeal disease. Although she initially improved after the first month of radiation, her condition deteriorated rapidly, preventing the initiation of the next line of treatment with high-dose methotrexate or capecitabine.

DISCUSSION

Adenoid cystic carcinoma of the breast is exceedingly rare however with a very good overall prognosis. It is uncommon for ACC to spread to regional lymph nodes, and even rarer for distant metastasis. Brain metastasis is also infrequently reported. There are no documented cases of metastatic ACC with leptomeningeal disease, so there is no consensus on the best course of treatment.
PATH-46. DETECTION OF CDKN2A/B HOMOZYGOUS DELETION BY DNA METHYLATION AND DNA NEXT GENERATION SEQUENCING: A COMPARISON
Authors: Galbraith Kristyn , Dhasmana Neha , Schroff Chanel , McLennan Sam , Yang Yiying , Shen Guomiao , Snuderl Matija
Published: November 2024

CDKN2A/B homozygous deletion status is critical for grading of several central nervous system (CNS) tumors, including IDH mutant astrocytoma, pleomorphic xanthoastrocytoma, and meningioma. CDKN2A/B status can be assed using variety of methods, but the accuracy varies due to technical and analytical variables. Here we sought to compare sensitivity of CDKN2A/B homozygous deletion detection by NGS and DNA methylation array derived copy number analysis. We retrospectively analyzed 100 CNS tumors diagnosed at NYU Langone Health between 2020 and 2023. All tumors were profiled by whole genome DNA methylation profiling using the Illumina EPIC array. Copy numbers were analyzed using the ‘conumee’ R package and visual inspection. Next-generation sequencing (NGS) analysis was performed by NYU Langone Genome PACT, a 510(k) FDA cleared (K202304) matched tumor-normal 607 gene panel. Variant allele frequency of canonical driver mutations was used to molecularly estimate tumor cell content. Discrepant cases were assed using targeted qPCR. Our cohort of 100 CNS tumors included glioblastoma (N=75), IDH mutant astrocytoma (N=14), oligodendroglioma (N=4), pleomorphic xanthoastrocytoma (N=2), meningioma (N=1), infantile hemispheric glioma (N=1), central neurocytoma (N=1), diffuse midline glioma K27-altered (N=1), and anaplastic pilocytic astrocytoma (N=1). By DNA methylation, CDKN2A/B homozygous deletion was detected in 54 cases, hemizygous deletion was detected in 13 cases, and no deletion was detected in 33 cases. By NGS, CDKN2A/B homozygous deletion was detected in 31 cases, hemizygous deletion was detected in 28, and no deletion was detected in 41 cases. DNA methylation detected a homozygous deletion in 23 cases that were not detected by NGS. All cases of homozygous deletion detected by NGS were also detected by DNA methylation. DNA methylation derived copy number assessment is more sensitive for CDKN2A/B homozygous deletion than next generation sequencing.