bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining interventions and metrics to improve diversity in CNS clinical trial participation: A SNO and RANO effort
Authors: Budhu Joshua A , Chukwueke Ugonma N , Jackson Sadhana , Lee Eudocia Q , McFaline-Figueroa J Ricardo , Willmarth Nicole , Dalmage Mahalia , Kawachi Ichiro , Arons David , Chang Susan M , Galanis Evanthia , Hervey-Jumper Shawn L , Wen Patrick Y , Porter Alyx B 
Published: December 2023

Abstract
Despite major strides in cancer research and therapy, these advances have not been equitable across race and ethnicity. Historically marginalized groups (HMG) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black, Hispanic, and Indigenous people represent 30% of the population but only 9% of oncology clinical trial participants. As a result, HMGs lack equitable access to novel therapies, contradicting the principle of distributive justice, as enshrined in the Belmont report, which demands the equitable selection of subjects in research involving human subjects. The lack of clinical trial diversity also leads to low generalizability and potentially harmful medical practices. Specifically, patients with brain cancer face unique barriers to clinical trial enrollment and completion due to disease-specific neurologic and treatment-induced conditions. Collectively, the intersection of these disease-specific conditions with social determinants of health fosters a lack of diversity in clinical trials. To ameliorate this disparity in neuro-oncology clinical trial participation, we present interventions focused on improving engagement of HMGs. Proposals range from inclusive trial design, decreasing barriers to care, expanding trial eligibility, access to tumor profiling for personalized medical trials, setting reasonable metrics and goals for accrual, working with patient community stakeholders, diversifying the neuro-oncology workforce, and development of tools to overcome biases with options to incentivize equity. The diversification of participation amongst neuro-oncology clinical trials is imperative. Equitable access and inclusion of HMG patients with brain tumors will not only enhance research discoveries but will also improve patient care.
10000-SPE-1 STEM CELL-BASED GENE THERAPY FOR MALIGNANT GLIOMA USING GENOME-EDITED HUMAN INDUCED PLURIPOTENT STEM CELLS
Authors: Tamura Ryota , Yo Masahiro , Imai Ryotaro , Okano Hideyuki , Toda Masahiro 
Published: December 2023

Abstract
Glioblastoma is the most aggressive primary brain tumor, and is characterized by diffuse infiltration into the normal brain parenchyma. New therapeutic approaches targeting invasive biological behaviour are warranted. In the present study, we show that neural stem cells (NSCs) derived from CRISRP/Cas9-edited induced pluripotent stem cells (iPSCs) have high tumor-trophic migratory capacity and stable constitutive therapeutic transgene expression, which leads to strong anti-tumor effects against glioma stem cell (GSC) models. The present study provides answers to some important research questions associated with stem cell-based gene therapy. First, the tumor-trophic migratory capacities of human iPSC-derived NSCs (iPSC-NSCs), fetal NSCs, and mesenchymal stem cells (MSCs) were quantitatively evaluated by spatiotemporal methodologies. We demonstrated that iPSC-NSCs have a higher tumor-trophic migratory capacity than MSCs in the brain. Self-repulsive action and pathotropism were important for the migration of iPSC-NSCs: ephrin ligand/receptor mediated repulsion of iPSC-NSCs and CXCL12-CXCR4 interactions between GSCs and iPSC-NSCs. Second, a prodrug converting enzyme fusion gene was selected as a therapeutic gene in human iPSCs. In general, stable constitutive transgene expression by viral vectors was difficult in human iPSCs. Furthermore, viral vectors integrate randomly into the host genome, which raises concerns about transgene silencing, insertional mutagenesis, and oncogene activation. In the present study, several common insertion sites including GAPDH, ACTB, and AAVS1, were compared. The most appropriate gene locus that achieved stable constitutive transgene expression was determined via CRISPR/Cas9-mediated genome editing. Third, we revealed the novel mechanism of action using iPSC-NSCs expressing CD-UPRT, in which ferroptosis was associated with enhanced anti-tumor immune responses. We demonstrated that the established iPSC-NSCs had strong therapeutic efficacy in GSC animal models. Finally, predictive biomarkers for the efficacy of the present treatment strategy were established. We will conduct a clinical trial of this treatment strategy. This research concept can disseminate biological, medical and engineering advances.
10015-NI-1 PREDICTION OF MGMT PROMOTOR METHYLATION STATUS IN GLIOBLASTOMA BY CONTRAST-ENHANCED T1-WEIGHTED IMAGE
Authors: Sanada Takahiro , Kinoshita Manabu , Sasaki Takahiro , Yamamoto Shota , Fujikawa Seiya , Fukuyama Shusei , Hayashi Nobuhide , Fukai Junya , Okita Noriko , Nonaka Masahiro , Uda Takehiro , Arita Hideyuki , Mori Kanji , Ishibashi Kenichi , Takano Koji , Nishida Namiko , Shofuda Tomoko , Yoshioka Ema , Kanematsu Daisuke , Tanino Mishie , Kodama Yoshinori , Mano Masayuki , Kanemura Yonehiro 
Published: December 2023

Abstract

PURPOSE
The study aims to explore MRI phenotypes that predict the methylation status of the promoter region of MGMT (pMGMT) in glioblastoma.

MATERIALS AND METHODS
202 histologically and molecularly confirmed glioblastoma patients (pMGMT methylated: 103, unmethylated: 99) at the Kansai Network for Molecular Diagnosis of Central Nervous Tumors (KNBTG) were used as a test cohort. 104 patients from the Cancer Imaging Archive (TCIA) / Cancer Genome Atlas (TCGA) dataset (pMGMT methylated: 103, unmethylated: 99) were used as a validation cohort. "Thickened structure" was defined when the solid component of the tumor had either a circumferential extension or occupied more than 50% of the entire volume of the tumor. "Methylated contrast phenotype" was defined by imaging findings with one of the following three features: indistinct enhancing circumferential border, heterogenous enhancement, and nodular enhancement. The inter-rater agreement between three independent blinded raters was first evaluated, and then the relationship between the image findings and pMGMT methylation status was investigated.

RESULTS
Fleiss's Kappa coefficient for "Thickened structure" was 0.68 for the KNBTG cohort and 0.56 for the TCIA cohort and for " Methylated contrast phenotype", 0.32 and 0.35, respectively. The odds ratio of "Methylated contrast phenotype" detecting pMGMT hypermethylation was 2.4 (p = 0.003) for the KNBTG cohort. The odds ratio of "Methylated contrast phenotype" associated with pMGMT methylation was 4.5 (p = 0.001) for those restricted to tumors presenting a "Thickened structure". The odds ratio for pMGMT methylation detected by "Methylated contrast phenotype" was 3.4 (p = 0.005) for the TCIA cohort. It was 7.1 (p = 0.009) when restricting to tumors presenting a "Thickened structure".

CONCLUSION
Glioblastoma showing both a "Thickened structure" structure and "Methylated contrast phenotype" is associated with pMGMT methylation, which may be a clinically useful imaging feature.
10020-ML-1 SENTINEL LESION PRECEDING PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Sasaki Takahiro , Yamoto Toshikazu , Fukai Junya , Nishibayashi Hiroki , Nakao Naoyuki 
Published: December 2023

Abstract
It has been reported that there are rare cases of spontaneous resolution, which are referred to as sentinel lesions in the early stages of primary malignant lymphoma of the central nervous system (PCNSL). In this study, we examined cases of PCNSL that presented with a sentinel lesion. Of the 43 PCNSL cases biopsied at our institution between 2011 and 2022, three cases were difficult to diagnose on initial biopsy. No preoperative steroids were used in all patients, and postoperative CT or MRI confirmed that the lesions were appropriately sampled from the targeted lesions. Since the diagnosis was not confirmed by the initial biopsy and symptoms were stable, the patients were followed up without chemotherapy, but symptoms worsened around 6 months later, and MRI showed recurrent large lesions. Another biopsy was performed in all patients, and a definitive diagnosis of diffuse large B-cell lymphoma (DLBCL) was finally obtained. It has been reported that sentinel lesions in PCNSL are characterized by demyelination or nonspecific inflammation on initial pathology and spontaneous resolution of lesions, which are estimated to be changes mediated by immunological mechanisms. In the present study, the course of symptoms was characterized by a relatively slow progression, and diffusion-weighted images at the initial onset did not show as high a signal as in usual PCNSL. Multiple biopsies are required to make a definitive diagnosis, and careful follow-up of symptoms and images and determination of the appropriate timing of biopsy are important.
10022-MET-2 CLINICAL FEATURES OF RENAL CELL CARCINOMA BRAIN METASTASES COMPARED WITH OTHER CARCINOMAS
Authors: Yamamoto Yohei , Tanaka Toshihide , Takei Jun , Teshigawara Akihiko , Nawate Shohei , Tomoto Kyoichi , Ishi Takuya , Hasegawa Yuzuru , Akasaki Yasuharu , Murayama Yuichi 
Published: December 2023

Abstract

INTRODUCTION
In recent years, the positioning of surgical treatment for metastatic brain tumors has changed. To extract conditions suitable for surgical treatment, the background factors for each primary lesion were verified by retrospective analysis of our case.

SUBJECTS AND METHODS
From 2014 to 2022, 425 patients with metastatic brain tumors diagnosed and treated at our university were included. There were 219 lung cancers, 46 breast cancers, 64 gastrointestinal cancers, 26 renal cell carcinomas, and 70 others. First, the tumor volume and edema volume were measured, and the ROC curve was drawn for the presence or absence of symptoms to determine the cutoff value. After that, statistical analysis was performed on the following items for each primary lesion. The items were tumor volume (T), edema volume (E), tumor edema ratio (E/T), age, KPS, hemorrhage, cyst formation, meningitis, metastasis to other organs, posterior fossa, simultaneous detection, and single tumor.

RESULTS
The symptomatic cutoff was 1514mm3 for tumor volume (sensitivity 0.86 specificity 0.74) and 15616 mm3 for edema volume (sensitivity 0.85 specificity 0.85). The tumor edema ratio was significantly higher in renal cell carcinoma. Factors with significant differences were older age and multiple lesions in lung cancer, younger age and posterior fossa in breast cancer, lower KPS in gastrointestinal cancer, and solitary cases and bleeding in renal cell carcinoma.

DISCUSSION/CONCLUSION
In this analysis, many cases of brain metastasis from renal cell carcinoma are solitary, and because they exhibit extensive edema that seems to be affected by VEGF, they tend to develop symptoms while they are small, and they are characterized by hemorrhage easily during the course. These findings suggest that patients with brain metastases from renal cell carcinoma should be given priority for surgical treatment.
10024-CO-1 A MULTICENTER PERFORMANCE COMPARISON STUDY OF AN IDH STATUS PREDICTION MODEL USING THE VISUAL TRANSFORMER MODEL
Authors: Takahashi Satoshi , Takahashi Masamichi , Kinoshita Manabu , Miyake Mototaka , Kobayashi Kazuma , Sese Jun , Ichimura Koichi , Narita Yoshitaka , Hamamoto Ryuji , Diagnosis Consortium Glioma Molecular 
Published: December 2023

Abstract

PURPOSE
To compare the performance and explainability of the visual transformer (ViT) and convolutional neural network (CNN) architectures in predicting genomic mutations from brain MRI.

METHODS
The performances of the ViT and CNN classification models in predicting the IDH mutation status of gliomas were compared. The two models were fine-tuned on the TCIA dataset. The fine-tuned models were evaluated on the TCIA dataset and an external independent dataset, namely the Japanese Cohort (JC) dataset. To evaluate their explanatory power, the gradient-weighted class activation mapping (Grad-CAM) visualization of the CNNs model and attention map visualization of the ViT model were compared.

RESULTS
The visual transformer model consistently outperforms the convolutional neural network on both the TCIA and JC datasets (p-value = 0.021, p-value &lt; 0.001, statistically different). The attention map of the ViT model accurately highlighted the tumor, and the Grad-CAM of the CNN model sometimes highlighted non-tumor areas.

CONCLUSION
The ViT model was more robust against differences in the image domain. The ViT model's attention map had superior explainability.
10037-SPE-3 APPROACH TO SAFE AND RELIABLE BRAIN TUMOR SURGERY APPLYING INTRAOPERATIVE GAMMA OSCILLATION REGULARITY ANALYSIS
Authors: Kobayashi Yusuke , Satou Yosuke , Kawauchi Yuta , Kon Takashi , Tanioka Daisuke , Shimizu Katsuyoshi , Mizutani Tohru 
Published: December 2023

Abstract
In primary brain tumors, the complexity of Electroencephalogram (EEG) has been reported to be higher compared to healthy individuals. In gliomas, a significant decrease in gamma oscillation regularity in the tumor-surrounding brain cortex has been demonstrated. It is considered acceptable to remove the areas with significantly decreased gamma oscillation regularity as non-functional regions with deteriorated normal brain function. This article introduces the practical application of safe and reliable brain tumor surgery using an approach from non-functional regions through intraoperative analysis of gamma oscillation regularity. The patient had undergone a partial resection surgery for a left temporal lobe tumor at another hospital and was diagnosed with a glioblastoma. Upon transfer to our hospital, the patient exhibited mild motor aphasia but had good comprehension. Language dominance was determined to be on the left side through the WADA test. Approximately 50% of the tumor, which was enhanced near the Broca's area and Wernicke's area, remained after the first surgery. We performed a non-awake extraction surgery for the residual tumor using intraoperative analysis of gamma oscillation regularity. By depicting a non-functional field during the operation, almost all of the tumors to be contrasted were removed without exacerbation of symptoms. Since the non-functional field can be depicted intraoperatively, surgery can be performed safely even in patients who cannot tolerate awake surgery. Brain tumor surgery using intraoperative analysis of gamma oscillation regularity is considered highly beneficial.
10038-ANGI-2 NEW ANTI-ANGIOGENIC THERAPY WITH THE ANTI-DEPRESSANT TOWARD TUMOR DERIVED ENDOTHELIAL CELLS (TDECS)
Authors: Michiue Hiroyuki , Tsuboi Nobushige , Otani Yoshihiro , Uneda Atsuhito , Suruga Yasuki , Yuji Matsumoto , Joji Ishida , Fujii Kentaro , Kurozumi Kazuhiko , Date Isao 
Published: December 2023

Abstract

BACKGROUND
Anti-angiogenic therapy has been reported to prolong patient survival in some malignancies, but has not been shown to be effective in glioblastoma. We focused on the relationship between the differentiation of glioma stem-like cells (GSCs) into tumor-derived endothelial cells (TDECs) and resistance to anti-angiogenic therapy. In particular, we elucidated the mechanism of drug resistance of TDECs to anti-angiogenesis inhibitors, and identified and elucidated the efficacy of novel anti-angiogenesis inhibitors with potential clinical application.

METHODS
005 mouse GSCs were differentiated into TDECs under hypoxic conditions and analyzed by RNA-Seq over time. Furthermore, novel angiogenesis inhibitors for glioblastoma were evaluated by tube formation assay and existing blood-brain barrier permeable drugs. Novel angiogenesis inhibitors were administered in vitro to differentiated TDECs and in vivo to the 005 mouse brain tumor model and evaluated by RNA-Seq, immunohistochemistry, MRI imaging, and survival.

FINDINGS
In the GSCs005 brain tumor model, inhibition of the Vascular Endothelial Growth Factor (VEGF) pathway had no anti-tumor effect and conversely increased TDECs. A drug screening by Existing Drugs Redevelopment showed that the antidepressant sertraline inhibited TDEC tube formation. Sertraline decreased the expression of Lama4 and Ang2 in TDECs, which play an important role in non-VEGF-mediated angiogenesis in tumors. sertraline in combination with VEGF pathway inhibitors showed prolonged survival in the 005 model.

CONCLUSION
Diversity of tumor vascular endothelial cells across VEGF and non-VEGF pathways was shown to induce anti-angiogenic resistance. The combination of sertraline and VEGF pathway inhibitors with antidepressants was an effective anti-angiogenic therapy for glioblastoma and could be applied safely and cost-effectively.
10045-MET-4 CEREBROSPINAL FLUID DIVERSION FOLLOWED BY SYSTEMIC THERAPY FOR LEPTOMENINGEAL METASTASIS-RELATED HYDROCEPHALUS IN PATIENTS WITH SOLID CANCER: ASSESSMENT WITH CLASSIFICATION OF EANO-ESMO CLINICAL PRACTICE GUIDELINE
Authors: Mitsuya Koichi , Deguchi Shoichi , Suzuki Takahiro , Hayashi Nakamasa 
Published: December 2023

Abstract

BACKGROUND
Management of leptomeningeal metastasis-related hydrocephalus (LM-H) is particularly challenging to control severe symptoms by intracranial hypertension. The aim of this study is assessment the outcomes of CSF diversion followed by systemic therapy for LM-H in patients with solid cancer.

METHODS
The authors reviewed 80 patients with LM-H required CSF diversion between October 2008 and May 2023. CSF diversion followed by chemotherapy and/or radiotherapy was indicated when a patient had (1) controlled extra-CNS metastases and (2) systemic life expectancy longer than three months after control of LM. The outcomes were analyzed with Kaplan-Meier estimates.

RESULTS
The patients consisted of 49 women and 31 men with a mean age of 57 years (range 35-81) . Primary cancers were lung (NSCLC) in 47 (59%), breast (BC) in 16 (20%), gastric (GC) in 10 (13%), cholangiocarcinoma 1 and other cancer in 6. Forty patients (50%) underwent whole brain radiotherapy, 17 patients (21%) cranio-spinal irradiation, and 45 patients (56%) were administrated systemic chemotherapy after CSF diversion. CSF diversion yielded a rapid improvement of their performance status (PS) in 90%. The median OS was significantly longer in patients with maintenance chemotherapy than in those without chemotherapy (4.5 versus 2 months, p&lt;0.001). The patients were classified with EANO-ESMO clinical practice guideline (cytology, MR findings and clinical findings). Type A (linear) in 34, B (Nodular) in 14, C (linear and nodular) in 13 ID (normal) in 19. Linear enhancement groups (IA+IC) were shorter survival than other nodular (IB) and normal findings (ID) (p=0.0038) in long survivor over 6 months. Post-surgical complications were infection in 3, peritoneal dissemination in 2, and shunt malfunction in 1.

CONCLUSION
Combination of CSF diversion and systemic therapy is a safe and effective strategy in patients with LM-H.
10049-GGE-3 CHARACTERISTICS OF CHROMOSOMAL ABERRATIONS IN GLIOMAS AND THEIR IMPACT ON RECURRENCE
Authors: Negoto Tetsuya , Yoshitake Hidenobu , Hashimoto Aya , Moritsubo Mayuko , Furuta Takuya , Sakata Kiyohiko , Nakamura Hideo , Morioka Motohiro 
Published: December 2023

Abstract

INTRODUCTION
Chromosome instability is the inability to evenly distribute sister chromatids during mitosis, which leads to chromosomal numerical/structural abnormalities and increases the genetic heterogeneity of the tumor. In this study, we investigated the association between chromosome aberration characteristics and recurrence in clinical specimens of gliomas using the Spectral Karyotyping.

METHODS
Chromosome karyotypes were analyzed for a total of 121 cells from 26 gliomas (Glioblastoma 14, PXA 3, Astrocytoma 5, Oligodendroglioma 3, Ependymoma 1, 18 primary cases and 8 recurrent cases) removed at our hospital. In addition, each case was quantitatively analyzed for numerical aberrations/ cell (AS: Aneuploidy score), structural abnormalities/ cell (SS: Structural abnormality score), and karyotype concordance rate between cells /case (HS: Heterogeneity Score) were quantitatively analyzed.

RESULTS
In the analysis of all cases, numerical aberrations in chromosomes X and 7 (21.5%/16.9%) and structural aberrations in chromosomes 1, 4, and 5 (&gt;10.0%) were highly prevalent, with structural aberrations in large chromosomes and numerical aberrations in small chromosomes. On the other hand, quantitative analysis showed that the mean for the first occurrence (18 cases); AS: 2.22±0.94/ SS: 1.48±0.96/ HS: 22.2±7.41, and for the recurrence (8 cases); AS: 4.68±1.75/ SS: 7.50±1.44/ HS: 55.0±11.1, indicating that numerical and structural abnormalities were more common in the recurrent lesions The recurrent lesions showed more numerical and structural abnormalities and higher intra-tumor heterogeneity. In addition, in cases in which the primary/recurrent lesions were analyzed in pairs, the frequency of numerical and structural chromosomal abnormalities was higher in the recurrent lesions.

DISCUSSION
This study clarified the characteristics of chromosomal aberrations in each pathological classification of gliomas and suggested the involvement of chromosomal instability in the recurrence process. We look forward to further clarification of the pathogenesis of gliomas with a focus on chromosomal instability.
10050-TB-1 ADDITIONAL RAS/MAPK PATHWAY ACTIVATION ALLOWS CELLS TO DIFFERENTIATE DURING TUMORIGENESIS.
Authors: Miki Shunichiro , Koga Tomoyuki , Furnari Frank 
Published: December 2023

Abstract
Activation of the RAS/MAPK pathway has been introduced in most of the glioblastoma models reported to date. To examine the roles of this pathway in tumorigenesis from different cells of origin, we differentiated human induced pluripotent stem cells (hiPSCs) with CDKN2A/2B null, PTEN null, and TERT promoter mutation (TPM), which we have previously generated, into neural stem cells (NPCs) and astrocytes, and also prepared cell lines with lentiviral EGFRvIII overexpression in both. 4 cell lines were transplanted into the brains of immunodeficient mice, and differences in tumorigenesis were compared between NPCs and astrocyte states with and without MAPK/RAS pathway activity. In NPCs, overexpression of EGFRvIII significantly shortened the time required for tumorigenesis. In Astrocytes, however, tumor formation was observed only in cells with EGFRvIII overexpression. RNA sequencing revealed the primary spheres formed from the tumors with EGFRvIII overexpression clustered similarly regardless of whether they were derived from NPCs or astrocytes, suggesting that similar tumors were formed from both sources. To further clarify the effect on the RAS/MAPK pathway, we prepared CDKN2A/2B null, PTEN null, TPM, and NF1 null iPSCs. Tumor formation was also confirmed when the cell line was differentiated into astrocytes and transplanted into immunodeficient mice. Although the cell of origin of glioblastoma is still controversial, recent reports indicate that tumorigenesis itself starts from undifferentiated cells. Our results suggest that the RAS/MAPK pathway activation in glioblastoma enhances tumorigenesis, allows cells to differentiate during the process, and also enables cells to transform even after differentiation by acquiring the activation.