bluuebunny/crossref_metadata_2025_split huggingface dataset:
INNV-27. LOW/ULTRA-LOW RADIO FREQUENCY MAGNETIC FIELD THERAPIES FOR THE TREATMENT OF CNS TUMORS: RGBM AND DIPG – PAST AND CURRENT RESULTS USING THE EMULATE THERAPEUTICS INC. TECHNOLOGY
Authors: Figueroa Xavier 
Published: November 2023

Abstract
EMulate Therapeutics, Inc. (EMTx) has developed a technology that emulates the effects of chemical compounds, via an alternating magnetic field. Our research has led to the development of a radio frequency energy (RFE) signal (A1A) that emulates the effects of paclitaxel. Pre-clinical and animal studies demonstrate an effect in slowing down and inhibiting tumor growth. EMTx has developed a portable medical device that allows for continuous delivery of our A1A signal for up to 14 hours before recharging. The device can be used in combination with current best-supportive-care (BSC) and new investigational treatments. Our technology has been tested in recurrent glioblastoma (rGBM) with very encouraging results in overall survival (OS), especially in combination with BSC. Phase II OS alone was equivalent to BSC (7.2 months BSC OS vs. 7.0 months A1A alone OS) and a considerably improved OS when combined with conventional drug treatment (7.2 months BSC OS versus 10.0 months A1A + BSC OS). EMTx is in the process of seeking humanitarian device exemption (HDE) from the US Food & Drug Administration (FDA) for the Hælo® therapeutic system, our pediatric treatment option. Diffuse intrinsic pontine gliomas (DIPG) are a rare pediatric central nervous system (CNS) tumor. Survival is measured in under 12 months, with no clinical trials demonstrating a significant increase in overall survival in 20 years (9 months median survival post radiation therapy). EMTx’s compassionate use program demonstrated safety and suggested a clinical benefit, with 12 of 14 patients surviving more than 12 months. EMTx is committed to run and complete a pivotal pediatric trial for children diagnosed with DMG/DIPG. The trial will recruit study patients from both the US and India. A total of 35-40 patients will be recruited to participate in this pediatric neuro-oncology trial, which will be a best-supportive-care + single therapy (Hælo®) clinical trial.
INNV-32. RELIABILITY OF SERIAL NEUROPATHOLOGICAL ASSESSMENT TO DIFFERENTIATE TUMOR PROGRESSION FROM PSEUDO-PROGRESSION IN GLIOMA
Authors: Khoury Lara , Harrison William , Ramkissoon Shakti , Stogner-Underwood Kimberly , Mott Ryan T , Miller James , Lesser Glenn , Chan Michael , Cramer Christina , Tatter Steven , Laxton Adrian , White Jaclyn , Tavolara Thomas , Hsu Fang-Chi , Strowd Roy 
Published: November 2023

Abstract
Histopathology is the gold standard for distinguishing tumor recurrence from treatment-induced necrosis but differentiating pseudoprogression from true recurrence is challenging in tumors with ambiguous morphological features. Prior research reported a 36% inter-rater agreement during suspected recurrence (Holdhoff et al., 2019). While serial radiographic and laboratory assessments are common, serial histopathological assessments are not. This study evaluated agreement and factors influencing assessment of active and inactive tumors through single and multiple time-point histopathological assessments. Patients who underwent initial and subsequent reoperation were identified, and their available histology slides were examined retrospectively. Four independent neuropathologists conducted two types of reviews: single time-point reviews using most recent biopsy/surgery slides, and multiple time-point reviews comparing images from initial and repeat biopsies taken 1-3 months apart. Neuropathologists completed a questionnaire assessing various tumor characteristics. Assignments were categorized as "active tumor," "treatment effect," or "unable to classify." 324 assessments were conducted (108 single time-point, 216 multiple time-point). Intraclass correlation coefficients for single vs. multiple time-point assessments were 0.72-0.93 for active tumors and 0.57-0.86 for inactive tumors. Pathologists' assessment of % inactive tumor was influenced by mitotic activity (p= 0.0028), cellularity (p&lt; 0.0001), hyalinized vessels (p= 0.0019), and necrosis (p= 0.0046). Evaluation of % active tumor was influenced by hyalinized vessels (p= 0.0006), mitotic activity (p&lt; 0.0001), cellularity (p&lt; 0.0001), and microvascular proliferation (p= 0.0093), with the latter three factors specifically affecting final sign-out pathology. Serial histopathological assessment didn’t affect determination of % active or inactive tumor. No association between % inactive tumor and fibrinoid necrosis for single time-point (p= 0.34) but a strong negative association was seen for serial assessment (p= 0.0006). Inter-rater agreement was higher for identifying active tumors than inactive tumors in both case reviews. Changes in necrosis between tissue samples in single vs. multiple timepoint assessments influenced pathologists' assessment of % inactive tumor.
INNV-35. IMPLEMENTATION OF A NATIONAL ADOLESCENT AND YOUNG ADULT MOLECULAR TUMOR BOARD: REPORT FROM THE CANADIAN AYA NEURO-ONCOLOGY NETWORK
Authors: Lim-Fat Mary-Jane , Das Sunit , Climans Seth , MacDonald Maria , Perreault Sébastien , Yip Stephen , Harrison Rebecca , Lapointe Sarah , Chan Aimee , Massey Natalie , Erker Craig , MacNeil Mary , Ironside Sarah , Tsang Derek , Hawkins Cynthia , Tabori Uri , Bennett Julie 
Published: November 2023

Abstract

BACKGROUND
The adolescent and young adult (AYA) population (15-39 years) is a unique and understudied population and their care requires multidisciplinary expertise. Current challenges in AYA neuro-oncology include fragmented care across pediatric and adult hospitals, low inclusion in clinical trials, unique survivorship considerations and a lack of standard-of-care therapies for this population.

METHODS
We will report on a two-and-a-half-year national effort from the Canadian AYA Neuro-Oncology Network (CANON) to implement national clinical and molecular AYA rounds. The aims of the rounds are to provide a platform for standardized diagnostics and multidisciplinary recommendations benefiting from the expertise of pediatric and adult providers across several tertiary and community centers.

RESULTS
Since April 2021, the Canadian national AYA rounds have occurred biweekly on a virtual secure platform. As of April 2023, 132 cases have been discussed from 25 sites; 15 cases (11%) involved pediatric patients and 117 (89%) were patients aged &gt; 18 and treated at adult hospitals. Cases discussed included adult (n =34, 26%) and pediatric type (n = 22, 17%) low-(n=25, 19%) and high-grade (n=30, 23%) glioma, medulloblastoma (n=14, 10.5%), ependymoma (n=6, 5%) and other tumors (glioneuronal tumors, pineal tumors, germinoma). A total of 175 providers and 70 trainees across 32 Canadian institutions have attended the rounds, spanning adult and pediatric neurosurgery, neuropathology, neuro-oncology, radiation oncology and radiology. The updated results of an ongoing prospective database of cases presented at our AYA rounds, outlining themes around molecular characterization, choice of therapies and relevant clinical outcomes will be presented at the meeting.

CONCLUSIONS
Virtual national AYA-neuro-oncology multi-disciplinary rounds is an effective platform that has raised awareness of current gaps and has facilitated nation-wide solutions to improve the care of AYA brain tumors, leveraging research and clinical collaborations.
INNV-38. PREDICTING THE CLINICAL PHENOTYPE IN NF2 RELATED SCHWANNOMATOSIS PATIENTS
Authors: Borghi Arianna , Rosati Nayma , Paterra Rosina , Vetrano Igrazio , Nazzi Vittoria , Moscatelli Marco , Silvani Antonio , Eoli Marica 
Published: November 2023

Abstract

BACKGROUND
Different genetic scores have been proposed to predict the phenotype of NF2 related Schwannomatosis (NF2 -SCHW MIM # 101000) , a rare autosomal dominant familial cancer syndromes caused by pathogenic variants of the NF2 gene. The UK NF2 Reference Group proposed the Genetic Severity Score (GSS) based on the type and location of NF2 germline variant observed. Catasus et al. suggested a new score based also on a functional assay of Merlin and its downstream pathways (FGSS). Recently Teranish et al. used targeted deep sequencing to predict functional prognosis in those patients. Material and

METHODS
70 patients (median age 40) were identified by scanning the electronic NF2-SCHW patient database at Fondazione IRCCS C. Besta,. The median follow-up was 14 yrs. Clinical diagnosis was established following the Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis”. All patients underwent NF2, SMARCB1 and LZTR1 mutational screening by NGS and MPLA analysis using blood DNA or the tissue of two different tumors when available. NF2 gene germline pathogenic were found in 45 subjects (64%), in most cases NF2 point mutations, but in 4 cases and whole gene deletions was observed and in 2 a ring NF2 chromosome was identified, in four cases a mosaic NF2-SCH was identified and in 21 (30%) patients no pathogenic variant was found. We assessed NF2 clinical phenotype in relation to the UK GSS and FGSS to validate their use.

RESULTS
The disease phenotype differed significantly depending both on clinical and genetic factors.. GSS and FGSS showed significant correlation with several measures, allowing stratification of patients with severe and mild disease but not with moderate phenotype. Furthermore, we provided evidence on correlation between whole NF2 deletion extent and phenotype severity. Large cohorts of NF2-SCHW patients are needed to identify more accurate scores.
PATH-18. MORE UNUSUAL FEATURES IN H3 K27M-MUTANT GLIOMAS
Authors: DeMasters B K , Guzman Samuel , Ormond David 
Published: November 2023

Abstract
Diffuse midline glioma, H3 K27M-altered, WHO grade 4 is an infiltrating midline glioma; however, H3 K27M mutation can also be seen in midline circumscribed, non-infiltrating gliomas and rarely in non-midline tumors. We report 2 unusual examples. A 37-year-old female developed a right posterior frontal infiltrating glioma; resection showed infiltrative tumor with brisk mitotic activity, elevated MIB-1 (20%), negative p53 expression, ATRX retention, but no necrosis or microvascular proliferation. Molecular workup showed neither IDH1/2/TERT promoter mutations or co-deletion 1p, 19q; further testing showed gain of whole chromosome 7 + loss of whole chromosome 10, meeting molecular criteria for glioblastoma. Recurrent tumor 2 years later in the same area prompted re-resection again of infiltrating tumor devoid of necrosis or microvascular proliferation; molecular testing now revealed a H3F3A (p.K28M) mutation. Both tumors showed protein expression by H3 K27M IHC+. She succumbed post-therapy at 3 ½ years. A 30-year-old woman developed a circumscribed, non-enhancing third ventricular mass; resection demonstrated circumscribed, non-infiltrating glioneuronal tumor with monotonous rounded tumor nuclei, synaptophysin IHC+, negative GFAP, H3 K27M IHC+, and low MIB-1. Molecular testing identified alterations in H3F3A p. K28M and FGFR1 p.N546K. She was treated, but lost to follow-up, until she re-presented 5 years later with hemorrhagic left frontal lobe tumor contiguous with the midline, with dorsal midbrain and 4th ventricular involvement. After resection, tumor now showed infiltrative features, necrosis and microvascular proliferation, diffuse GFAP IHC+, retention of nuclear ATRX, p53 (20%), MIB-1 (22%), and H3 K27M IHC+. New tumor had no FGFR1 alteration or PDGFRA amplification to suggest radiation-induced tumor, instead manifesting PTPRZ1-MET fusion. She survives at 5 years. These cases offer new insights into survival of a non-midline example and transformation of a circumscribed, non-infiltrating tumor to secondary infiltrating H3 K27-altered tumor with new molecular alterations, possibly representing second independent tumor development.
PATH-20. IDH MUTANT ASTROCYTOMAS WITHOUT RECEIVING ADJUVANT TREATMENT DO NOT DEVELOP HYPERMUTATION OR SPECIFIC GENE MUTATION AND MYC, CDKN2A AND PDGFRA ARE INVOLVED IN MALIGNANT TRANSFORMATION
Authors: Li Kay Ka-Wai , Shi Zhi-Feng , Kwan Johnny Sheung-Him , Chan Danny Tat-Ming , Ng Ho-Keung 
Published: November 2023

Abstract
It is known that temozolomide treatment induces hypermutation and malignant transformation in IDH-mutant astrocytomas at recurrences and “wait-and-see” after resection is acceptable post-operative management. Although a small number of adjuvant-treatment-naive IDH-mutant low-grade astrocytomas have been embedded in well known series of longitudinal gliomas, little specific information is available about the natural evolution of IDH-mutant astrocytoma without selection pressures of temozolomide and irradiation. We studied 19 patients for tissues from primary and recurrent IDH-mutant 1p19q non-deleted Grade 2 gliomas and where no alkylating therapy or radiation was given between primary tumors and malignantly transformed recurrences (2 patients with multiple recurrences). Mean and median follow-ups were 123.1 and 138.8 months. We performed FISH for amplifications for MYC, PDGFRA, homozygous deletion (HD) for CDKN2A and for Alternative Lengthening for Telomeres (ALT). In the paired tumors from 12 patients, panel sequencing was performed. ATRX, p53, IDH mutations and ALT co-occurred in both primary and recurrent tumors for the same patients. MYC was found in tumors from 5/19 patients, three of which were found in the recurrences but not primary tumors. PDGFRA amplification was seen in tumors from six patients, four only in recurrences. Tumors from 11/19 patients showed either CDKN2A HD, MYC or PDGFRA amplification at recurrences. No hypermutated tumors could be found. Only 131 of a total 255 mutations were acquired in the recurrences. NOTCH1 mutation was found only in tumors from 2 patients. No recurrence-specific mutation was identified. p53 mutations when occurring in the primary tumors were associated with a shorter PFS (p=0.011). No mutation of the mismatch repair genes was found and only one POLE mutation was found. CONCLUSION: IDH-mutant low grade astrocytomas not being treated with temozolomide or irradiation do not develop hypermutation or specific gene mutation for their natural evolution and malignant transformation.
PATH-21. GPX4 IS CRUCIALLY IMPLICATED IN THE PATHOBIOLOGY OF GLIOBLASTOMA AND A PUTATIVE ACTIONABLE TARGET
Authors: Purkait Suvendu , Behera Minakshi , Sahu Rabi N , Ghosh Amit 
Published: November 2023

Abstract

BACKGROUND
Glioblastoma(GBM) is the most common malignant primary brain tumor with a dismal prognosis. Glutathione-mediated inhibition of the ferroptotic form of cell death is crucially implicated in various malignancies, which is principally regulated by glutathione peroxidase 4 (GPX4). However, there is limited data on GBM. The present study evaluated the expression of GPX4 in GBM and its implications in tumor biology, clinical outcome, and therapeutic potentials.

METHODS
The mRNA and protein expression was assessed by qRT-PCR and immunohistochemistry, respectively, in 75 cases of adult hemispheric GBMs (IDH wild type). For comparison, 21 lower-grade astrocytomas (IDH-mutant, grade-2/3) [LGA] and 20 cases were also evaluated. In-vitro analysis was performed on U87MG and LN229 glioma cell line.

RESULTS
The mRNA expression of GPX-4 was significantly higher in GBM than LGA, and normal brain (NB) [p-values 0.028, and 0.001, respectively]. Normal brain cases were negative for GPX4. Almost half of the GBMs (49.3%) showed strong immunoreactivity, which was higher than LGAs (23.8%) [p-value -0.04]. Inhibition of GPX-4 in-vitro by 1S-RSL3 & FIN56 was associated with decreased cell survival, proliferation, migration, invasion, and increased cell death. GPX-4 expression was not significantly associated with overall survival in GBM.

CONCLUSION
GPX-4 is crucial for the tumor cells' survival and aggressive biological behavior. Considering its immune-positivity only in the neoplastic cell and strong positivity in GBM it may be a useful adjunct to the diagnosis. The present study emphasized its role as a potential therapeutic target in the form of 1S-RSL3 & FIN56.
PATH-24. A CASE SERIES OF LONGER THAN EXPECTED SURVIVAL IN IDH-WILDTYPE, MGMT-UNMETHYLATED GLIOBLASTOMA PATIENTS
Authors: Lomax Jerica , Kong Xiao-Tang , Bota Daniela 
Published: November 2023

Abstract
Despite interventions with surgery, radiation, and chemotherapy, Glioblastoma (GBM) remains a difficult cancer to treat. Only 6.9% of patients survive five years post-diagnosis1 and the median overall survival is reported to be in the range of 14-15 months.2Glioblastoma patients who harbor an IDH-mutation have a known improved survival rate over their IDH-wildtype counterparts and under the recent WHO 2021 Classification of CNS tumors, IDH-mutational status is now an established criteria for the classification of high-grade gliomas. MGMT methylation status is also a well-described prognostic factor in GBM. MGMT methylated patients have a more favorable prognosis and better response to conventional treatment with temozolomide.3 It is rare but there are some IDH-wildtype, MGMT-unmethylated GBM patients who survive longer than 4 years. Therefore, it is important to identify other potential favorable factors for longer survival in the unfavorable cohort of patients with IDH-wildtype and MGMT-unmethylated GBM. Case Series: Eighty-five GBM patients who had next generation sequencing completed at the University of California, Irvine were reviewed. Of 85 patients, 4 patients (4.7%) were IDH-wildtype, MGMT-unmethylated and lived longer than 4 years. We evaluated the pathology, clinical characteristics, treatment course, and molecular findings of these 4 long term GBM survivors with IDH-wildtype and MGMT-unmethylated status. Discussion: This case series of 4 cases of patients with IDH-wildtype, MGMT-unmethylated GBM with longer than expected survival did not reveal a ubiquitously prevalent molecular marker for long term survival based on review of next-generation sequencing results. 2 out of the 4 patients harbored an uncommon MTAP copy number loss mutation, which may warrant further investigation into the significance of this mutation on prognosis. 3 out of 4 patients received a vaccine-based intervention through clinical trial which may support ongoing investigation into the additional benefit this specific population of GBM patients may have from vaccine-based therapy.
PATH-27. DROPLET DIGITAL PCR ENHANCES DETECTION OF HOTSPOT MUTATIONS IN CIRCULATING TUMOR DNA FROM CEREBROSPINAL FLUID OF PATIENTS WITH HIGH-GRADE GLIOMA
Authors: Tartaro Marlene , Nandakumar Subhiksha , Hertz Charli Ann , Holle Bridget , Hill Katherine , Lapshina Maria , Farina Andrea , Arcila Maria , Miller Alexandra , Mellinghoff Ingo 
Published: November 2023

Abstract
Molecular profiling of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) has the potential to enhance diagnosis, prognosis, and longitudinal monitoring for glioma patients through a minimally invasive approach. We previously detected somatic mutations from gliomas in CSF samples using MSK-IMPACT™, a 505-gene FDA-authorized next-generation DNA sequencing panel, and detected tumor-derived mutations in 50% of samples of patients with high-grade gliomas (HGG). To investigate whether we could enhance sensitivity of CSF ctDNA profiling and biomarker detection, we tested MSK-IMPACT™ pre-capture NGS residual DNA libraries from 43 CSF ctDNA samples by droplet digital PCR (ddPCR) for detection of key recurrent alterations in IDH1, BRAF, TERT, H3F3A, and TP53 using previously validated probes. Residual libraries contained a median of 18.0ng of DNA library (range, 0.0153-18.0ng). Of the 7 samples positive for IDH1 R132H, TERT C228T, or TERT C250T mutations in MSK-IMPACT™, we found that ddPCR accurately detected all mutations (7/7, 100%), confirming sensitivity of ddPCR in CSF ctDNA. We also tested 36 mutation-negative samples by MSK-IMPACT™ for the corresponding undetected mutations, of which 7 were tested for two mutations. Overall, ddPCR detected 41.9% (18/43) of previously undetected mutations. Specifically, we found that ddPCR rescued hotspot mutations such as BRAF V600E (2/3, 66.7%), IDH1 R132G/H (3/8, 37.5%), TERT C228T (11/26, 42.3%), and TERT C250T (2/4, 50.0%). Collectively, our results suggest that a combined-modality approach involving MSK-IMPACT™ and ddPCR enables comprehensive assessment of limited CSF ctDNA samples with high sensitivity and provides a minimally invasive methodology to molecularly profiling glioma.
PATH-31. RECURRENT COPY NUMBER CHANGES IN GLIOBLASTOMA, IDH-WILDTYPE: ARE OTHER +7/-10 PATTERNS CLINICALLY RELEVANT?
Authors: Choate Lauren , Pazdernik Vanessa , Kollmeyer Thomas , Praska Corinne , Jenkins Robert , Ida Cristine 
Published: November 2023

Abstract
Glioblastoma (GBM), IDH-wildtype (WT) is currently defined as an IDH-WT and H3-WT diffuse astrocytic glioma with molecular diagnostic features including whole +7/−10, TERT promoter (TERTp) mutation, and EGFR amplification and/or morphological diagnostic features such as necrosis and microvascular proliferation. To further understand the diversity of copy number signatures of GBM, IDHWT and evaluate the diagnostic utility of other recurrent copy number changes, we analyzed paired chromosomal microarray and next-generation sequencing mutational profiling data from 418 adult IDH-WT and H3-WT tumors with GBM morphological diagnostic features. The most common molecular features were TERTp mutations (85%), CDKN2A/B heterozygous/homozygous deletion (78%/66%), +7/-10 (63%), EGFR amplification (41%), +19 (36%), PTEN mutations (35%), partial -13 (33%), partial -14 (33%), +20 (32%), TP53 mutations (32%), and partial -22 (29%). At least one molecular diagnostic biomarker was present in 92% (n=385) of cases, and 29% (n=121) of cases had all three. The +7/-10 biomarker was the most frequent chromosomes 7/10 copy number change (68%, n=265). Other +7/-10 patterns were seen in 30% (n=125) of cases and included isolated +7 or -10, combinations of +7 and -10 with partial +7, partial -10 or 10 copy neutral loss of heterozygosity (cnLOH). Overall, 93% (390/418) of cases had whole and other chromosome 7/10 copy number changes. In comparison to tumors with +7/-10, tumors with other +7/-10 patterns were significantly enriched for partial 13 loss (Bonferroni adjusted p=0.04) but were not associated with significant difference in patient overall survival (p=0.30, 158/418 had available survival data). Our findings reiterate and expand the spectrum of copy number changes associated with GBM, IDH-WT. The similar overall survival rates between cases with the +7/-10 biomarker and those with other +7/-10 patterns suggest that other +7/-10 patterns may be functionally equivalent to +7/-10 and diagnostically relevant as a molecular diagnostic biomarker for this tumor type.