bluuebunny/crossref_metadata_2025_split huggingface dataset:
PATH-48. IMPACT OF DEPRESSION AND ITS TREATMENT ON SURVIVAL AND TUMOR PROGRESSION IN RTK2 GLIOBLASTOMAS: IDENTIFICATION OF A HIGH-RISK SUBGROUP
Authors: Zghaibeh Yahya , Brembach Florian , Silverbush Dana , Gempt Jens , Schüller Ulrich , Monje Michelle , Heiland Dieter Henrik , Drexler Richard , Ricklefs Franz 
Published: November 2024

Abstract

INTRODUCTION
Depressive symptoms are prevalent among glioma patients while the impact on survival is not fully clear and underlying mechanisms remain poorly understood. Here, we investigated the impact of glioblastoma-associated depression as the disease-presenting symptom and the influence of antidepressant pharmacotherapy on glioblastoma progression.

METHODS
We performed a retrospective cohort study on glioblastoma patients treated at our institution. Patients with a new depression as presenting symptom were compared to non-depressive glioblastoma patients employing propensity-matched survival analysis. Additionally, tumor tissues were subjected to DNA methylation analysis (EPIC 850k array). In vitro proliferation assays were performed to investigate the effect of antidepressants on glioma cell growth.

RESULTS
Of 298 glioblastoma patients, 23 patients suffered from a tumor-associated depression and received antidepressants at time of diagnosis (14 SSRI, 3 NaSSA, 4 TCA and 2 unknown). Propensity-matched survival analysis revealed a shorter OS in the depression group (median OS: 8 vs. 14; HR = 2.247; 95% CI: 1 - 5.051; p &lt; 0.05). Methylation subclass analysis indicated a predominance of RTK2 glioblastoma within the depression group (n = 14; 63.6%). Tumors of the depression group originated more likely in the frontal lobe (43.5% vs. 29.2%) and in the midbrain (13% vs. 2.43%). No significant differences in epigenetic neural signatures were found. Treatment with either citalopram or sertraline – the most frequently used antidepressants - significantly increased the proliferation index in RTK2 glioblastoma cultures but not RTK1 glioblastoma cultures.

CONCLUSION
Our study reveals a strong correlation between glioblastoma-associated depression with antidepressant treatment and worse outcome in glioblastoma of the DNA methylation subclass RTK2. These findings may reveal a potential causal link, raising awareness of the increased likelihood of depression and glioblastoma progression in a methylation-dependent manner, which could guide antidepressant treatment for improving patients’ quality of life.
PATH-49. INTRA-OPERATIVE GENETIC ANALYSES FOR DECISION-MAKING DURING TUMOR REMOVAL OF ADULT-TYPE DIFFUSE GLIOMA USING RAPID QUANTITATIVE PCR DEVICE
Authors: Ohka Fumiharu , Maeda Sachi , Shimizu Hiroki , Motomura Kazuya , Takeuchi Kazuhito , Nagata Yuichi , Deguchi Shoichi , Shiba Yoshiki , Yamaguchi Junya , Takido Yuhei , Nakamura Akihiro , Ito Shohei , Saito Ryuta 
Published: November 2024

Abstract

BACKGROUND
Recent comprehensive molecular analyses of central nervous system (CNS) tumors identified several diagnostic or prognostic markers. Especially, for adult-type diffuse glioma, IDH mutation, TERT promoter (pTERT) mutation and CDKN2A homozygous deletion are quite important markers for diagnosis and prognosis of this type of glioma. Intra-operative identification of these molecular alterations could be effective for decision-making of tumor removal strategy.

METHODS
In this study, we established intra-operative gene analysis method using rapid quantitative PCR device, GeneSoC, by which we could obtain genotype of these important genes for 20 minutes in an operating room. Using GeneSoC, we could perform 50 cycles of quantitative PCR for approximately 12 minutes. Results; We established rapid gene analyses of mutations of IDH1 R132H, pTERT C225T, pTERT C250T and homozygous deletion of CDKN2A for adult-type diffuse gliomas. For elution of DNA, we incubated at least 1mg of tumor tissue at 95°for 5 minutes. Combined this boiling method with GeneSoC, we could obtain those genetic alterations for 20 minutes after collection of tumor tissue. In analyses of 111 adult-type diffuse glioma cases, sensitivity and specificity for detection of IDH1 p.R132H are 98% and 98%, respectively, and those of pTERT (C225T or C250T) are 100% and 100%, respectively. In analyses of 50 cases, sensitivity and specificity for detection of CDKN2A homozygous deletion are 100% and 83%, respectively. Conclusion; In this study, we could obtain the genotype of important molecular markers intra-operatively, not only during tumor removal but even during tumor biopsy, using GeneSoC device. This rapid genetic analysis might be effective not only for intra-operative diagnosis but also for detection of boundary between tumor and normal tissue.
PATH-58. SEQUENCING OF DNA RECOVERED FROM BRAIN TUMOR BIOPSY SURGICAL WASTE IMPROVES SENSITIVITY OF RAPID IDH/TP53-MUTANT TUMOR DIAGNOSES
Authors: Wadden Jack , Adam Tiffany , Cartaxo Rodrigo , Niculcea Michael , Kong Seongbae , John Vishal , Tripathy Arushi , Bird Cylaina , Nazarian Javad , Heth Jason , Muraszko Karin , Marupudi Neena , Magge Suresh , Garton Hugh , Al-Holou Wajd , Koschmann Carl 
Published: November 2024

Abstract

BACKGROUND
TP53 and IDH mutations are common in brain tumors and are highly relevant biomarkers for diagnosis and treatment. Thus, biopsy tissue is commonly tested for these mutations via immunohistochemistry (IHC), which is rapid and generally considered highly sensitive. However, IHC only tests for IDH1R132H (80%-90% of IDH mutant disease) and rarer IDH mutations are not covered. p53 nuclear staining is used to identify non-specific p53 upregulation and loss of function but does not test for specific mutations and has a relatively lower overall sensitivity/specificity of ~80%/80-97%. Sequencing can resolve all mutations and improve over IHC, but long turnaround time and high cost prevents this. New advances in rapid sequencing technologies allow same-day, low-cost panel sequencing. However, access to biopsy tissue is zero-sum and obtaining additional tissue for molecular diagnostics confers increased morbidity. We investigate whether tumor DNA recovered from surgical waste (specifically core biopsy needle fluid and non-adherent gauze) is sufficient to diagnose IDH/p53 status of tumors.

METHODS
Surgeons were instructed to save biopsy needle rinse saline, and/or to recover any non-adherent gauze used in specimen handling. Cell-free DNA was extracted and sequenced using a same-day targeted panel protocol and/or TruSight Oncology 500 panel sequencing.

RESULTS
100% of recovered samples yielded enough DNA for targeted sequencing (17/17). In all IDH1R132H IHC positive cases, waste sequencing recapitulated the mutation (4/4). In 7/9 p53 positive cases via IHC (&gt;10% staining), waste sequencing of common hotspot loci was able to identify a specific TP53 mutation. Importantly, sequencing identified alternate IDH mutations in three IHC negative cases (3/13), discovered a rarer TP53 mutation (E286K) in one IHC negative case, and confirmed TP53 negative status in one indeterminate p53 report.

CONCLUSIONS
Surgical waste is an important diagnostic resource that should be leveraged for rapid diagnostic sequencing. Sufficient DNA can be easily recovered from surgical waste and sequenced within the same time-frame–but with increased sensitivity–to IHC.
PATH-66. MOLECULAR FEATURES RELATED TO LONG-TERM SURVIVAL IN GLIOBLASTOMA
Authors: Nisnboym Ziv Michal , Raphael Itay , Drappatz Jan , Marker Daniel F 
Published: November 2024

Abstract
Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor in adults, with a dismal prognosis that rarely exceeds beyond 2 years of survival despite multimodal treatment. While small fractions of GBM patients seem to display extended survival, the underlying mechanisms for this peculiarity remain largely unknown. Previously published investigations of long-term survivors (LTS) usually incorporate small numbers of patients, non-uniform definition of LTS and rarely provide a comprehensive molecular analysis. With advances in multi-omics technologies and their integration with disease diagnostics, numerous prognostic molecular markers have been proposed. So far, only O6-methylguanine-DNA-methyltransferase (MGMT) gene promotor hypermethylation was linked to outcome and therapy response. We aim to investigate omics characteristics associated with LTS. Molecularly confirmed Isocitrate Dehydrogenase (IDH) wildtype GBM patients, &gt;18 years old, operated and treated at our institution between 2013 and 2020 and living ≥5 years post-diagnosis (LTS = 62) or 1-2 years (STS = 62) were identified. Clinical and demographic characteristics were matched. Tumor tissues was analyzed with targeted next generation sequencing (NGS) and compared between LTS and STS. In addition, methylation analysis was done for all LTS. Results will be presented. We hope to shed a broader light on the molecular drivers behind the LTS in GBM patients, that will provide prognostic markers and potential targets for novel treatments.
NIMG-15. RAPID EARLY PROGRESSION AFTER SURGERY ON PRE-RADIATION PLANNING MRI FOR IDH-WILDTYPE GLIOBLASTOMA
Authors: Sackett Jonathan , Ahmed Khadija , Struve Tim , Pater Luke , Andaluz Norberto , Forbes Jonathan , Chaudhary Rekha , Yogendran Lalanthica , Sengupta Soma , Breneman John , Udstuen Gavin , Wang Kyle 
Published: November 2024

Abstract

BACKGROUND
Use of pre-RT planning MRI for glioblastoma (GBM) is inconsistent and not required by many clinical protocols. We performed a detailed volumetric analysis of rapid early progression (REP) on pre-RT planning MRI’s, hypothesizing that REP is associated with worse survival and more accurately risk stratifies than extent of resection.

METHODS
Patients with IDHwt GBM who had resection (biopsy-only patients excluded) and pre-RT planning MRI ≥2 weeks after postop MRI were included. MRI’s were reviewed by a neuroradiology fellow and attending who measured in 3 dimensions new/increased contrast-enhancing disease between postop and pre-RT MRI. REP was defined as disease ≥1cm in 2 dimensions or ≥0.5cc. Extent of resection was scored 1: gross total (GTR, &gt;95%); 2:near total (NTR, 90-95%); 3:subtotal (STR). The primary endpoint was survival (OS). Cox proportional hazards model analyzed association with age, resection extent, MGMT+ status, short course RT (a surrogate for performance status), and REP.

RESULTS
The final cohort included 77 patients (median age 63), with 9 (12%) receiving short course RT. Surgical extent was GTR in 42 (55%), NTR in 16 (21%), and STR in 19 (25%). REP occurred in 41 patients (53%), with a rate of 29% after GTR, 75% after NTR, and 90% after STR. Age (p=0.24, HR 1.02/yr), short course RT (p=0.64, HR 1.2), and surgical extent (p=0.49, HR 1.1) were not significantly associated with OS on univariate analysis. MGMT+ and REP were associated with survival on both univariate and multivariate (MGMT+ p=0.002, HR 0.4; REP p=0.005, HR 2.3) analyses. Median OS was 1.3 years vs. 1.9 years with vs without REP.

CONCLUSIONS
REP occurs frequently, adds a “growth rate” variable, and is a better prognostic factor than extent of resection. These data have implications for clinical trial design and support pre-RT planning MRI’s as standard of care.
NIMG-16. ASSESSMENT OF RESPONSE TO LOMUSTINE-TEMOZOLOMIDE CHEMOTHERAPY IN ADDITION TO RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA USING FET PET
Authors: Werner Jan-Michael , Wollring Michael M , Tscherpel Caroline , Rosen Elena K , Ceccon Garry , Stetter Isabelle , Lohmann Philipp , Weller Johannes , Stoffels Gabriele , Baues Christian , Celik Eren , Mottaghy Felix M , Goldbrunner Roland , Herrlinger Ulrich , Fink Gereon R , Langen Karl-Josef , Galldiks Norbert 
Published: November 2024

Abstract

BACKGROUND
We examined the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for early response assessment in patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase promoter treated with lomustine-temozolomide chemotherapy in addition to radiotherapy.

METHODS
Thirty-one patients (29-74 years) were treated according to the CeTeG/NOA-09 phase-3 trial. FET PET and anatomical MRI were performed at baseline and follow-up after the third cycle. We obtained mean and maximum tumor-to-brain ratios (TBR) and metabolic tumor volumes (MTV). Thresholds derived from FET PET were defined using receiver operating characteristic analyses to predict progression-free survival (PFS) of ≥12 months. The predictive value of FET PET parameters was subsequently evaluated using univariate and multivariate survival estimates. MRI response assessment was based on the RANO 1.0 criteria. FET PET data were also used to estimate response according to the PET RANO 1.0 criteria.

RESULTS
Patients received a median number of 6 cycles of lomustine-temozolomide chemotherapy (3-6 cycles). After treatment initiation, the median follow-up was 17.2 months (7.2-59.4 months). As of April 2024, we confirmed tumor progression according to the RANO 1.0 criteria in 24 patients (77%). After three cycles of lomustine-temozolomide chemotherapy, a reduced mean TBR value by ≥10% predicted a significantly longer PFS (31.0 vs. 10.4 months; P=0.039). In contrast, changes in maximum TBR values, MTV, the RANO 1.0 criteria, and the PET RANO 1.0 criteria were not predictive for response (P&gt;0.05). Multivariate survival analysis revealed that changes in mean TBR values predicted a significantly prolonged PFS independent of age, the extent of resection, and the Karnofsky Performance Status (P=0.036; HR, 3.892; 95% CI, 1.242-17.230).

CONCLUSION
Our results suggest that FET PET is clinically valuable for identifying responders to lomustine-temozolomide chemotherapy in addition to radiotherapy early after treatment initiation. The evaluation of FET PET’s value in predicting a significantly longer overall survival is ongoing.
NIMG-18. RAPID INTRAOPERATIVE DIFFERENTIATION OF PRIMARY CNS LYMPHOMA FROM COMMON CNS TUMORS USING STIMULATED RAMAN HISTOLOGY AND DEEP LEARNING
Authors: Reinecke David , Maroouf Nader , Alber Daniel , Smith Andrew , Hollon Todd C , Neuschmelting Volker , Golfinos John G , Orringer Daniel A 
Published: November 2024

Abstract
Accurate intraoperative diagnosis is crucial for decision-making during tumor surgery and stereotactic-guided biopsies. Differentiating between primary CNS lymphoma (PCNSL) and non-PCNSL entities such as gliomas and metastatic cancers presents significant challenges due to overlapping histomorphological features, time constraints, and the differing further therapy strategies required. Our study utilized deep learning and stimulated Raman histology (SRH) to address this challenge. We imaged unprocessed, label-free tissue samples intraoperatively using a portable Raman scattering microscope, generating virtual H&E-like images within less than five minutes. Our training set comprised over 54,000 SRH tumor patch images, including various brain tumors. We developed a deep learning pipeline utilizing a ResNet-50 feature extractor and the BYOL (Bootstrap Your Own Latent) self-supervised learning algorithm. We trained a binary linear classifier to distinguish between PCNSL and non-PCNSL entities. Data were collected from New York University (NYU), the University of Cologne (UKK), and the University of Michigan (UM), including 263 SRH whole slide images from 177 patients sourced from surgical resections and stereotactic-guided biopsies. In an international bicentric test cohort (N = 100, NYU and UKK), the model achieved an overall accuracy of 91.1%, an area under the receiver operating characteristic curve (AUROC) of 0.983, a sensitivity of 89.3%, and a specificity of 100% compared to the final formalin-fixed, paraffin-embedded-based diagnosis. Our algorithm can accurately extract typical histomorphological features to help differentiate between PCNSL and non-PCNSL tumors. These results underscore the potential of deep learning models to enhance the accuracy of intraoperative diagnoses for PCNSL and non-PCNSL entities, thereby improving intraoperative decision-making and further treatment strategies by supporting neuropathologists and surgeons.
NIMG-29. EARLY REDUCTION IN MRI DIFFUSION APPARENT DIFFUSION COEFFICIENT (ADC) STRONGLY PREDICTS LONG TERM RESPONSE TO ONC201 THERAPY IN PATIENTS WITH H3K27M-DMG
Authors: Lau Benison , Ajaero Diala , Hoff Benjamin , Galban Craig , Parmar Hemant , Ibrahim Mohannad , Koschmann Carl 
Published: November 2024

Abstract
ONC201 is the first monotherapy to improve outcomes in H3K27M- diffuse midline glioma (DMG) beyond radiation. Despite impressive early efficacy in H3K27M-DMG, individual response to ONC201 is variable and no radiographic biomarkers predict long term response. Previous studies demonstrated baseline MRI diffusion apparent diffusion coefficient (ADC) is lower in DMG with H3K27M compared to wildtype but change after radiation therapy was not correlated with improved OS or PFS. We hypothesize ADC will enable stratification of patients more likely to respond to ONC201. Imaging and clinical data were abstracted from chart review of patients treated with ONC201 at University of Michigan. Two neuroradiologists performed centralized review for RAPNO measurements and mean ADC was assessed using ROI measured in consistent anatomic locations, with areas of cystic degeneration or necrosis excluded. Sixty-one patients were identified for review. Preliminary analysis was performed on twenty-three patients, with upfront ONC201 therapy, median age 14.8 years old (5-25yo), primary site includes pontine (n=15), thalamic (n=7). Baseline characteristics of age, ADC and size at diagnosis or follow-up RAPNO scored size were not statistically significant. Patients with longer than median survival (334 days) demonstrated increased ADC (+58.25x10-6mm2/s) from baseline to cycle 2 whereas patients with shorter than median survival demonstrated decreased ADC (-174.8x10-6mm2/s) (p = 0.0076). Further, patients with decreased ADC demonstrated mean OS of 302.8 days and patients with increased ADC had mean OS of 588.0 (p = 0.0054). In H3K27M-DMG patients treated with ONC201, increased ADC after two cycles of ONC201 was strongly predictive of longer overall survival. Our recent work demonstrated that ONC201 disrupts metabolic and epigenetic pathways to restore pathognomonic H3K27me3 reduction, which may underline greater change in ADC. Ongoing work will validate these findings in an independent external cohort and integrate histogram analysis, parametric assessments, MRI perfusion and liquid biopsy biomarkers (cf-tDNA and metabolomics).
NIMG-44. ELEVATED TRANSLOCATOR PROTEIN 18KDA BINDING IN LOW MEAN DIFFUSIVITY CLUSTERS IS A FEATURE OF THE TRANSFORMING GLIOMA AND IDH MUTANT GLIOMA MICROENVIRONMENT
Authors: Breese James , Agushi Erjon , Lewis Daniel , Hinz Rainer , Alfaifi Bandar , Jackson Alan , Waqar Mueez , Coope David 
Published: November 2024

Abstract
Around 95% of low-grade gliomas undergo anaplastic de-differentiation into high-grade gliomas, a process only partially understood from in vivo clinical imaging. 11 patients with suspected transforming gliomas underwent a combined magnetic resonance imaging (MRI) and positron emission tomography (PET) protocol, incorporating post-contrast T1-weighted/FLAIR acquisition for tumour delineation and diffusion tensor imaging. The PET radiotracer [11C]-(R)-PK11195 assessed translocator protein 18kDa (TSPO) distribution, whose upregulation is associated with inflammation/glioma progression. [11C]-(R)-PK11195 binding potential (BPND) maps were generated using the simplified reference tissue model, with the grey-matter cerebellar time-activity curve serving as the reference tissue input function. KMeans clustering of mean diffusivity (MD) intensity values defined spatially distinct “habitats” of high/low MD voxels within the glioma microenvironment. BPND values within high/low MD clustering habitats were evaluated, across glioma grades and isocitrate dehydrogenase (IDH) mutational status. Across all grade 2 and 3 gliomas (n= 6), mean TSPO BPND values in low MD habitats (0.0383 ±0.102) were significantly greater than high MD habitats (-0.045 ±0.142) (p= 0.003). In grade 4 gliomas (n= 5), no significant difference was observed in mean BPND values between low (0.514 ±0.176) and high (0.465 ±0.296) MD habitats (p= 0.543). IDH mutant gliomas (n= 7) exhibited significantly higher mean BPND in low MD habitats (0.116 ±0.225), relative to high habitats (0.052 ±0.287) (p= 0.021). IDH wildtype gliomas (n= 4) showed no significant differences between BPND values in low (0.498 ±0.199) and high MD habitats (0.424 ±0.325) (p= 0.467). Our novel findings demonstrate spatial heterogeneity in TSPO expression within 2/3/IDH mutant gliomas, a characteristic absent from grade 4/IDH wildtype varieties. Regions of restricted diffusion with high TSPO signal in grade 2/3/IDH mutant tumours indicate the heterogenous distribution of active TSPO-expressing immune/neoplastic cell populations, contrasting the homogenous distribution in grade 4/IDH wildtype gliomas, highlighting differences between their inflammatory profile and pathological features.
NIMG-53. MRI-BASED RADIOMICS FOR DIFFERENTIATION BETWEEN PERIFOCAL EDEMA AND NON-CONTRAST-ENHANCING GLIOBLASTOMA FOCI
Authors: Thiele Frederic , Saviolli Felipe , Biczok Annamaria , Stöcklein Veit , Stöcklein Sophia , Schichor Christian , Thon Niklas , Weller Jonathan 
Published: November 2024

Abstract

OBJECTIVE
Various intracranial tumors can lead to the development of perifocal edema. Differentiating edema from tumor on MRI might be easy in metastases and meningiomas but can be challenging in patients with glioblastoma. We set out to compare and characterize perifocal edema and non-contrast-enhancing glioblastoma foci by means of radiomic feature analysis.

METHODS
In this single-center, retrospective study, patients with intracranial tumors and perifocal edema on preoperative T2/FLAIR-sequences were included. Patients diagnosed with brain metastasis, meningioma or glioblastoma were eligible. Tumor and edema volumes were semi-automatically segmented and extracted. After image registration, contrast-enhancing tumor and necrosis on T1-weighted sequences were subtracted from T2/FLAIR-hyperintense tumor and perifocal edema. Radiomic features were computed. Distribution of radiomic features were tested using the Shapiro-Wilk test. ANOVA or Kruskal-Wallis tests were applied to compare the features. Significant features were identified based on p-values (&lt;0.05) and post-hoc Tukey’s Honest Significant Difference (HSD) tests were conducted.

RESULTS
The cohort comprised n=60 patients and was split in three groups according to histopathology (metastases, meningioma, glioblastoma). Each subgroup comprised n=20 patients (33.3%). 107 radiomic features of the T2-hyperintensity, after subtraction of contrast-enhancing tumor and necrosis, were tested for each patient. 18 radiomic features (17%) that mainly comprised measures of shape, texture and intensity distribution, e.g., sphericity (p&lt;0.01), surface/volume (p&lt;0.01), entropy (p&lt;0.01), skewness (p&lt;0.01) and kurtosis (p&lt;0.01), showed no significant difference between metastases and meningiomas but differed significantly from the T2-hyperintensity of glioblastoma. The textual complexity of glioblastoma was significantly higher (p&lt;0.01).

CONCLUSION
Radiomic feature analysis unraveled many features that might be helpful in differentiating perifocal edema from tumor infiltration. Future studies should aim at validating our results and further exploring the T2-hyperintensity of glioblastoma patients, e.g., suspected edema versus suspected tumor infiltration zone.