bluuebunny/crossref_metadata_2025_split huggingface dataset:
P18.16.A DTI FIBER-TRACKING PARAMETERS ADJACENT TO GLIOMAS: THE ROLE OF TRACT IRREGULARITY VALUE IN OPERATIVE PLANNING, RESECTION, AND OUTCOME
Authors: Armocida D , Pesce A , Salvati M , Cofano F , Frati A , Garbossa D , Santoro A 
Published: October 2024

Abstract

BACKGROUND
The goal of glioma surgery is maximal tumor resection associated with minimal post-operative morbidity. Diffusion tensor imaging-tractography/fiber tracking (DTI-FT) is a valuable white-matter (WM) visualization tool for diagnosis and surgical planning. Still, it assumes a descriptive role since the main DTI metrics and parameters showed several limitations in clinical use. New applications and quantitative measurements were recently applied to describe WM architecture adjacent to the tumor area (BAT), which can be adopted as predictive values and a guide for safe tumor resection.

MATERIAL AND METHODS
This is an observational prospective study on an extensive series of glioma patients who performed magnetic resonance imaging (MRI) with pre-operative DTI-FT analyzed on the BAT by two different software. We examined DTI parameters of Fractional anisotropy (FA mean, min-max), Mean diffusivity (MD), and the shape-metric “tracti irregularity” (TI) grade, comparing it with the surgical series’ clinical, radiological, and outcome data.

RESULTS
The population consisted of 118 patients, with a mean age of 60.6 years. 82 patients suffering from high-grade gliomas (69.5%), and 36 from low-grade gliomas (30.5%). A significant inverse relationship exists between the FA mean value and grading (p=0.001). The relationship appears directly proportional regarding MD values (p=0.003) and TI values (p=0.005). FA mean and MD values are susceptible to significant variations with tumor and edema volume (p=0.05). TI showed an independent relationship with grading regardless of tumor radiological features and dimensions, with a direct relationship with grading, ki67% (p=0,05), PFS (p&lt;0.001), and EOR (p&lt;0.01).

CONCLUSION
FA, MD, and TI are useful predictive measures of the clinical behavior of glioma, and TI could be helpful for tumor grading identification and surgical planning.
P18.18.B EFFICACY AND FAILURE PATTERNS OF SIMULTANEOUS INTEGRATED BOOST INTENSITY- MODULATED RADIOTHERAPY FOR WHO GRADE IV GLIOMAS
Authors: Du X , Huo L , Deng M , Chen Y , Wu S 
Published: October 2024

Abstract

BACKGROUND
We analyzed the efficacy and failure patterns of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) in patients with WHO grade IV gliomas.

MATERIAL AND METHODS
From June 2016 to December 2020, 246 newly diagnosed patients with histologically-proven WHO grade IV gliomas were retrospectively analyzed. All patients were treated with post-operative SIB-IMRT at a total planned dose of 60 Gy for gross tumor volume (PGTV) and 50 Gy for clinical target volume (PCTV), to be given in 28-30 fractions. On progression, recurrent tumors were classified as in-field, marginal, or distant, relative to the 95% isodose line of PGTV.

RESULTS
Median OS and PFS was 23.5 (95% CI 19.9-27.1) and 13.4 (95%CI 11.6-15.2) months, respectively. One-year OS and PFS was 86.4% and 56.1%, respectively. Multivariate analysis identified female sex, gross tumor resection and MGMT promotor methylation as independent predictive factors for better PFS and OS. Of the 98 patients with documented recurrences, 83 patients (84.7%) had an in-field component of treatment failure, 7 (7.1%) had a marginal component, and 18 (18.4%) had a distant component. Seventy-four patients (75.5%) had in-field only recurrence. Of the 100 documented local recurrent lesions, 87% lesions were located within 2 cm-margins of the original GTVs. Patients with multifocal disease were more likely to experience marginal failures (P = 0.041).

CONCLUSION
Post-operative SIB-IMRT is a feasible and safe treatment option for WHO grade IV gliomas with a low rate of marginal recurrence and good survival outcomes.
P18.31.A NIRAPARIB EFFICACY IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA: CLINICAL READOUT OF A PHASE 0/2 ‘TRIGGER’ TRIAL
Authors: Sanai N , Umemura Y , Margaryan T , Molloy J , Zhang H , Knight W , Harmon J , Hong A , Wanebo J , Braun K , Kennedy W , Garcia M , Barani I , Yoo W , Tien A , Tovmasyan A , Mehta S 
Published: October 2024

Abstract

BACKGROUND
Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when a PK threshold is met.

METHODS
Presumed newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 (cohort 1) or 8-10 hours (cohort2) following the last dose. Tumor tissue (Gadolinium enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation of surgical vs non-irradiated tissue. A PK ‘trigger’ determined eligibility for the Phase 2 component of the study and was defined as unbound [niraparib] &gt; 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors in excess of the PK threshold were eligible for Phase 2 dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib monotherapy.

RESULTS
All patients in the Phase 0 analysis population (n=46) met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 335.1 nM (n=43) for cohort 1 and 331.9 nM (n=3) for cohort 2. PAR suppression after ex vivo radiation was observed in 73% of the patients (24/33). Twenty of 28 (71.4%) patients with unmethylated tumors were enrolled into Phase 2. Five patients in Phase 2 experienced Grade 4 thrombocytopenia related to niraparib. All adverse events resolved without sequelae. Median progression-free survival was 14.9 months and median overall survival was 20.3 months.

CONCLUSIONS
Niraparib achieves pharmacologically relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. Accompanying PD effects were observed in patient tumor tissue and long-term clinical efficacy data is promising. A global Phase 3, open-label, randomized 2-arm study comparing niraparib versus temozolomide in adult patients with newly diagnosed, MGMT unmethylated glioblastoma is underway.
P18.48.B THE TRANSFORMATION AND RECURRENCE PATTERN OF TARGET VOLUME FOR GLIOMA ON THE MR-LINAC
Authors: Chen Y , Yin X , Guo L , Ding S , Wang Y , Deng M , Liu Z , Mu Y 
Published: October 2024

Abstract

BACKGROUND
Glioma, which carries a poor prognosis, stands as the most prevalent primary tumor of the central nervous system. The magnetic resonance (MR) linear accelerator (Linac) was increasingly used in the treatment of glioma, allowing for the collection of MRI images before each radiotherapy session, facilitating real-time adjustments to target volume.

MATERIAL AND METHODS
The authors retrospectively reviewed the patients with newly diagnosed glioma who underwent adaptive radiotherapy by means of 1.5 T MR-linac between August 2021 and December 2022 at Sun Yat-sen University Cancer Center, and analyzed changes in target volume (GTV), Dice Similarity Coefficient, Hausdorff distance (HD), relative GTV volume, and recurrence pattern.

RESULTS
A total of 20 patients were treated, including 18 with high-grade glioma and 2 with low-grade glioma. In 18 high-grade gloma patients, 10 had a recurrence, with 50% (5/10) exhibiting in-field recurrence, 40% (4/10) ex-field, and 10% (1/10) in/ex-field recurrence. The median progression-free survival (PFS) was 6 months (range, 2-13 months). Among 3 patients with initial GTV HD greater than first radiation therapy session for 15mm, all had ex-field recurrence. Of 9 patients who underwent complete resection, 44.4% (4/9) experienced recurrence (3 in-field, 1 ex-field), while 66.7% (6/9) experienced recurrence (2 in-field, 4 in/ex-field) in the other 9 patients. In 17 patients, MGMT methylation IDH1/2 mutation status was evaluated. 50% (4/8) of the MGMT methylated population occurred recurrence (3 in-field, 1 ex-field); 66.7% (6/9) of the MGMT unmethylated population occurred recurrence (2 in-field, 3 ex-field, 1 in/ex-field). 75% (9/12) IDH1/2wt patients developed recurrence (4 in-field, 4 ex-field, 1 in/ex-field), whereas only 20% (1/5) IDH1/2mut patients developed in-field recurrence. All patients tolerated MR-linac radiotherapy well, with minimal complications or toxicity. Notably, while preparing for radiotherapy of one patient, whose radiotherapy was scheduled after reoperation due to recurrence. During the radiotherapy, 3 patients occurred recurrence, then received prompting adjustments to target volume and drug treatments, resulting in successful recovery.

CONCLUSION
The implementation of MR-linac offers a novel approach for precise radiotherapy to glioma. Among patients who received adaptive radiotherapy on the MR-linac, the incidence of in-field recurrence decreased compared to previous research, likely attributable to precise irradiation of GTV. Nevertheless, longer follow-up is necessary to determine survival benefits. Future research should focus on increasing sample sizes to explore the relationship between target volume deformation and recurrence pattern in radiotherapy, as well as developing new modes of target volume delineation and optimizing target volume dosages.
P19.16.A THE EFFECT OF TARGETING CCNB1 ON THE RADIOSENSITIVITY OF MALIGNANT MENINGIOMA
Authors: Gong Z , Ma P , Zhou D , Xu T , Fang Y 
Published: October 2024

Abstract

BACKGROUND
While most meningiomas are benign with favorable outcomes, malignant meningiomas are challenging due to high recurrence rates. The standard treatment involves surgical resection followed by radiotherapy. However, radiotherapy resistance is common, underscoring the need for novel targets to improve radiotherapy outcomes. Cyclin B1 (CCNB1) serves as a key regulator at the G2/M checkpoint of the cell cycle. It plays a significant role in DNA damage repair pathways, intimately linked to various cancers’ development and radiosensitivity.

MATERIAL AND METHODS
87 meningiomas (15 WHO Grade I, 63 WHO Grade II, 9 WHO Grade III) and 9 normal dural tissue microarrays were constructed for immunohistochemical and subsequent survival analyses. The malignant meningioma cell line IOMM-Lee was used to develop CCNB1 knockdown and overexpression models. In vitro assays included cell migration, proliferation, clonogenicity, apoptosis, cell cycle analysis, and DNA damage repair pathway assessments. In vivo, CCNB1’s impact on radiosensitivity was evaluated using an orthotopic meningioma model in nude mice, assessing post-irradiation tumor growth through bioluminescence imaging, and survival rates were analyzed.

RESULTS
Immunohistochemical analysis on tissue microarrays revealed that CCNB1 expression was minimal in normal dural tissues but significantly elevated in meningioma tissues, with higher expression particularly noted in high-grade tumors compared to low-grades. Survival analysis indicated that high CCNB1 expression correlates with a shorter progression-free survival (PFS) in patients. In vitro, CCNB1 knockdown in IOMM-Lee cells markedly reduced migration and proliferation compared to controls. Conversely, CCNB1 overexpression led to increased migration and proliferation compared to controls. The apoptotic rate in knockdown cells increased significantly post-irradiation to 11.43±0.40% from 6.27±0.34% in controls (p &lt; 0.01). Additionally, a pronounced increase in G2/M phase arrest was observed, with cells exhibiting 66% in G2/M phase at 8 hours post-irradiation, compared to 48% in controls, indicating enhanced radiosensitivity. In vivo studies further confirmed these findings, demonstrating significant tumor growth suppression and prolonged survival in xenografted nude mice with CCNB1 knockdown tumors. These comprehensive results underline the significant role of CCNB1 in modulating DNA damage response pathways, particularly the ATR-Chk1 pathway, and its potential as a prognostic marker and therapeutic target in high-grade meningiomas.

CONCLUSION
CCNB1 is a pivotal factor in the radiosensitivity of malignant meningiomas. Targeting CCNB1 may improve the efficacy of radiotherapy, providing a potential therapeutic avenue to combat the high recurrence and mortality rates of these tumors.
P20.05.B BELZUTIFAN TREATMENT OF VON HIPPEL-LINDAU-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA
Authors: Thomsen A , Valerius A , Uhm J H , Ruff M , Baykal D , Caron S , White J D , Neth B J , Webb M J , Pichurin P N , Sener U 
Published: October 2024

Abstract

BACKGROUND
Von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease associated with tumors in multiple organs. VHL is characterized by mutation of the VHL gene which leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. Conventional management of VHL-associated tumors involves surgical resection and radiation therapy. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). Belzutifan was approved by the United States Food and Drug Administration (FDA) in August 2021 as a targeted therapy option for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Our objective here is to report on our clinical experience with use of belzutifan for VHL-associated CNS hemangioblastomas.

MATERIAL AND METHODS
We retrospectively chart reviewed our institutional (Mayo Clinic Rochester) experience of belzutifan in adults (18 years or older) with VHL and craniospinal hemangioblastomas not amenable to surgery. The study period was October 2021 to March 2024.

RESULTS
Nine adults (5 female, 4 male) were included in the study. Of those able to continue the therapy without interruption (6 patients), the median duration of therapy at last follow-up was 11.5 months (range 3-22 months). Seven had radiographic response to therapy after a median of 3 months (1-5 months), with a maximal response to therapy after a median of 13 months (3-29 months). One patient had a mixed radiographic response, and 1 patient had tumor progression while on belzutifan noted at 5 months. The most common adverse effect was fatigue. Seven patients reported fatigue, 4 patients experienced anemia, and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects, specifically fatigue and hypoxia. One patient had to take multiple medication pauses, once due to seizure and once due to kidney injury, but resumed treatment with dose reduction.

CONCLUSION
Among patients with VHL-associated CNS hemangioblastomas, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to FDA approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, duration of treatment, and effects of cessation after long-term use.
P20.09.A CLINICAL, PATHOLOGICAL AND MOLECULAR DISEASE CHARACTERISTICS OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Le Rhun E , Bink A , Felsberg J , Gramatzki D , Brandner S , Benhamida J K , Wick A , Tonn J C , Mohme M , Tabatabai G , Capper D , Snuderl M , Razis E , Ronellenfitsch M , Neidert N , Ng H , Pohl U , Bale T A , Quach S , Rieger D , Schüller U , Drüschler K , Healy E , Graham M , Paine S M L , Medici V , Sievers P , Schrimpf D , Wick W , Sahm F , Reifenberger G , von Deimling A , Weller M 
Published: October 2024

Abstract

BACKGROUND
Diffuse hemispheric glioma, histone 3 (H3) G34-mutant, is a pediatric-type diffuse high-grade glioma newly defined in the World Health Organization (WHO) classification of central nervous system tumors 2021. Here we sought to define the prognostic roles of clinical, neuroimaging, pathological and molecular features of these tumors.

MATERIAL AND METHODS
We retrospectively assembled a cohort of 114 patients with diffuse hemispheric glioma, H3 G34-mutant and profiled the imaging presentation and the molecular landscape of their tumors.

RESULTS
Compared with glioblastoma, H3 G34-mutant tumors exhibited less avid contrast enhancement, less necrosis and less edema on magnetic resonance imaging (MRI). Comprehensive analyses of mutational and DNA copy number profiles revealed recurrent mutations in TP53 and ATRX, homozygous deletions of CDKN2A/B, and amplifications of PDGFRA, EGFR, CCND2 and MYCN. MGMT promoter methylation was detected in 79 tumors (75%). Median survival was 21.5 months (95% CI 15.3-27.7) and 8 patients (7.0%) survived for ≥ 5 years. Female sex, gross total resection, and MGMT promoter methylation were prognostic factors on univariate analysis. Among pathological and radiological features, presence of microvascular proliferation and absence of pial invasion were prognostic factors on univariate analyses.

CONCLUSION
This study refines the clinical and molecular landscape of H3 G34-mutant diffuse hemispheric gliomas. Dedicated trials for this novel tumor type are urgently needed.
P20.10.B CLINICAL, PATHOLOGICAL, AND GENOMIC FEATURES OF INFRATENTORIAL IDH-MUTANT GLIOMAS
Authors: WANG L 
Published: October 2024

Abstract

BACKGROUND
Isocitrate dehydrogenase (IDH) 1/2 mutations are rare in infratentorial gliomas, which of clinico-molecular characteristics of infratentorial IDH-mutant gliomas have not been well characterized.

MATERIAL AND METHODS
In the current study, a series of 12 cases of infratentorial IDH-mutant gliomas were described for clinical, pathological, and genomic characteristics.

RESULTS
The median age of this cohort at diagnosis was 41-year-old (range: 10-67). 9 tumors were located in posterior fossa, including 5 (41.7%) were only in the brainstem and 4 (33.3%) were present in both brainstem and cerebellum, and 3 (25%) in spinal cord. Histopathologic diagnosis of twelve cases are all diffuse astrocytoma. Eight cases were low-grade astrocytoma (WHO grade 2) including one with concomitant KIAA1549-BRAF fusion and IDH mutation in pediatric spinal cord astrocytoma, and four high-grade astrocytoma (WHO grade 3). Comprehensive genomic profiling revealed that Non-canonical IDH (50%, 6/12) and TP53 (75%, 9/12) mutations were more frequent in infratentorial IDH-mutant astrocytomas than supratentorial cases. While ATRX mutation (33.3%, 4/12) and MGMT promoter methylation (41.7%, 5/12) were less frequent (p&lt;0.005). No mutations of H3.1, H3.3, TERT, homozygous deletion of CDKN2A/B, or co-deletion of 1p/19q were detected.

CONCLUSION
Our data revealed infratentorial IDH-mutant gliomas have distinct clinical, pathological, molecular, and prognostic characteristics, differed from supratentorial cases.
P20.12.B INTEGRATED GENETIC ANALYSES OF IMMUNODEFICIENCY-ASSOCIATED EPSTEIN-BARR VIRUS- (EBV) POSITIVE PRIMARY CNS LYMPHOMAS
Authors: Kaulen L D , Denisova E , Hinz F , Hai L , Friedel D , Henegariu O , Hoffmann D , Ito J , Kourtesakis A , Lehnert P , Doubrovinskaia S , Karschnia P , von Baumgarten L , Kessler T , Baehring J , Brors B , Sahm F , Wick W 
Published: October 2024

Abstract

BACKGROUND
Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV+) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies.

MATERIAL AND METHODS
In this study, a comprehensive genetic analysis of 22 EBV+ PCNSL, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. Deconvolution of bulk RNA sequencing data was performed using CIBERSORTx to characterize the tumor microenvironment.

RESULTS
EBV+ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24-217) and 2 insertions/deletions (range 0-22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79-53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV- PCNSL. Instead, EBV+ PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV+ PCNSL.

CONCLUSION
In addition to novel insights into the pathobiology of EBV+PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.