bluuebunny/crossref_metadata_2025 huggingface dataset:
Surviving the heat: multiwavelength analysis of V883 Ori reveals that dust aggregates survive the sublimation of their ice mantles
Authors: Houge Adrien , Macías Enrique , Krijt Sebastiaan
Published: December 2023

Investigating the response of icy dust aggregates to water ice sublimation is essential for understanding the formation and properties of planetesimals in protoplanetary discs. However, their fate remains unclear, as previous studies suggest that aggregates could either survive or completely fall apart to (sub)μm-sized grains. Protoplanetary discs around stars undergoing accretion outbursts represent a unique laboratory to study the ice sublimation process, as the water snowline is pushed outward to regions accessible to current observatories. In this work, we aim to understand the aggregates’ response to ice sublimation by focusing on V883 Ori, a system currently undergoing a powerful accretion outburst. We present new analysis of archival high-resolution ALMA observations of the protoplanetary disc of V883 Ori at 0.88, 1.3, 2.0, and 3.1 mm, and derive new radial spectral index profiles, which we compare with predictions from one-dimensional dust evolution simulations. In the region of V883 Ori where water ice has sublimated, we find lower spectral indices than previously obtained, indicating the presence of cm-sized particles. Coupled with our dust evolution models, we find that the only way to explain their presence is to assume that they formed before the outburst and survived the sublimation process. The resilience of dust aggregates to such intense events leads us to speculate that it may extend to other environments with more gentle heating, such as pebbles drifting through the water snowline in quiescent protoplanetary discs. In that case, it may alter the formation pathway of dry planetesimals interior to the snowline.
Specific star formation rates in the Mbh-M*,sph diagram and the evolutionary pathways of galaxies across the sSFR-M* diagram
Authors: Graham Alister W , Jarrett T H , Cluver M E
Published: December 2023

It has been suggested that the bulge-to-total stellar mass ratio or feedback from black holes (BHs), traced by the BH-to-(total stellar) mass ratio, might establish a galaxy’s specific star formation rate (sSFR). We reveal that a galaxy’s morphology – reflecting its formation history, particularly accretions and mergers – is a far better determinant of the sSFR. Consequently, we suggest that galaxy formation models which regulate the sSFR primarily through BH feedback prescriptions or bulge-regulated disc fragmentation consider acquisitions and mergers which establish the galaxy morphology. We additionally make several new observations regarding current (z ∼ 0) star-formation rates. (i) Galaxies with little to no star formation have bulges with an extensive range of stellar masses; bulge mass does not dictate presence/absence on the ‘star-forming main sequence’. (ii) The (wet merger)-built, dust-rich S0 galaxies are the ‘green valley’ bridging population between elliptical galaxies on the ‘red sequence’ and spiral galaxies on the blue star-forming main sequence. (iii) The dust-poor S0 galaxies are not on the star-forming main sequence nor in the ‘green valley’. Instead, they wait in the field for gas accretion and/or minor mergers to transform them into spiral galaxies. Mid-infrared sample selection can miss these (primordial) low dust-content and low stellar-luminosity S0 galaxies. Finally, the appearance of the quasi-triangular-shaped galaxy-assembly sequence, previously dubbed the `Triangal', which tracks the morphological evolution of galaxies, is revealed in the sSFR-(stellar mass) diagram.
AGN feedback and star formation in the peculiar galaxy NGC 232: insights from VLT-MUSE observations
Authors: Costa-Souza José Henrique , Riffel Rogemar A , Dors Oli L , Riffel Rogério , da Rocha-Poppe Paulo C
Published: December 2023

We use VLT-MUSE integral field unit data to study the ionized gas physical properties and kinematics as well as the stellar populations of the Seyfert 2 galaxy NGC 232 as an opportunity to understand the role of AGN feedback on star formation. The data cover a field of view of 60 × 60 arcsec2 at a spatial resolution of ∼850 pc. The emission-line profiles have been fitted with two Gaussian components, one associated to the emission of the gas in the disc and the other due to a bi-conical outflow. The spectral synthesis suggests a predominantly old stellar population with ages exceeding 2 Gyr, with the largest contributions seen at the nucleus and decreasing outwards. Meanwhile, the young and intermediate age stellar populations exhibit a positive gradient with increasing radius and a circum-nuclear star-forming ring with radius of ∼0.5 kpc traced by stars younger than 20 Myr, is observed. This, along with the fact that AGN and SF dominated regions present similar gaseous oxygen abundances, suggests a shared reservoir feeding both star formation and the AGN. We have estimated a maximum outflow rate in ionized gas of ∼1.26 M⊙ yr−1 observed at a distance of ∼560 pc from the nucleus. The corresponding maximum kinetic power of the outflow is ∼3.4 × 1041 erg s−1. This released energy could be sufficient to suppress star formation within the ionization cone, as evidenced by the lower star formation rates observed in this region.
Can FSRQ 3C 345 be a very high energy blazar candidate?
Authors: Dar Athar A , Sahayanathan Sunder , Shah Zahir , Iqbal Naseer
Published: December 2023

The recent detection of very high energy (VHE) emissions from flat spectrum radio quasars (FSRQs) at high redshifts has revealed that the universe is more transparent to VHE γ-rays than it was expected. It has also questioned the plausible VHE emission mechanism responsible for these objects. Particularly for FSRQs, the γ-ray emission is attributed to the external Compton (EC) process. We perform a detailed spectral study of Fermi-detected FSRQ 3C 345 using synchrotron, synchrotron self-Compton, and EC emission mechanisms. The simultaneous data available in optical, ultraviolet, X-ray, and γ-ray energy bands is statistically fitted under these emission mechanisms using the χ2-minimization technique. Three high flux states and one low flux state are chosen for spectral fitting. The broad-band spectral energy distribution during these flux states is fitted under different target photon temperatures, and the model VHE flux is compared with the 50 h Cherenkov Telescope Array sensitivity. Our results indicate a significant VHE emission could be attained during the high flux state from MJD 59635−59715 when the target photon temperature is within 900–1200 K. Furthermore, our study shows a clear trend of variation in the bulk Lorentz factor of the emission region as the source transits through different flux states. We also note that during high γ-ray flux states, an increase in external photon temperature demands high bulk Lorentz factors, while this behaviour reverses in case of low γ-ray flux state.
Dust evolution in a supernova interacting with the ISM
Authors: Vasiliev Evgenii O , Shchekinov Yuri A
Published: December 2023

Supernovae (SNe) explosions are thought to be an important source of dust in galaxies. At the same time strong shocks from SNe are known as an efficient mechanism of dust destruction via thermal and kinetic sputtering. A critically important question of how these two hypotheses of SNe activity control the dust budget in galaxies is still not quite clearly understood. In this paper, we address this question within 3D multifluid hydrodynamical simulations, treating separately the SNe injected dust and the dust pre-existed in ambient interstellar gas. We focus primarily on how the injected and the pre-existing dust is destroyed by shock waves and hot gas in the SN bubble depending on the density of ambient gas. Within our model, we estimate an upper limit of the SN-produced dust mass which can be supplied into interstellar medium. For an SN progenitor mass of 30 M⊙ and the ejected dust mass Md = 1 M⊙, we constrain the dust mass that can be delivered into the ISM as ≥0.13 M⊙, provided that the SN has injected large dust particles with a ≥ 0.1 µm.
Constraints on sub-terrestrial free-floating planets from Subaru microlensing observations
Authors: DeRocco William , Smyth Nolan , Profumo Stefano
Published: December 2023

The abundance of protoplanetary bodies ejected from their parent star system is presently poorly constrained. With only two existing optical observations of interstellar objects in the 108–1010 kg mass range and a small number of robust microlensing observations of free-floating planets (FFPs) in the 1024–1025 kg mass range, there is a large range of masses for which there are no existing measurements of the unbound population. The three primary microlensing surveys currently searching for FFPs operate at a cadence greater than 15 min, which limits their ability to observe events associated with bodies with a mass much below an Earth mass. We demonstrate that existing high-cadence observations of M31 with the Subaru Hyper Suprime-Cam place constraints on the abundance of unbound objects at sub-terrestrial masses, with peak sensitivity at 10−4 M⊕ for Milky Way lenses and 10−1 M⊕ for lenses in M31. For a fiducial $\frac{dn}{dM}\propto M^{-2}$ mass distribution, we find that the abundance of unbound objects is constrained to $n_\text{unbound} \lt 1.4 \times 10^{7} ~\rm {pc}^{-3}$ for masses within 1 dex of 10−4 M⊕. Additionally, we compute limits on an artificial ‘monochromatic’ distribution of unbound objects and compare to existing literature, demonstrating that the assumed spatial distribution of lenses has very significant consequences for the sensitivity of microlensing surveys. While the observations ultimately do not probe abundances suggested by current models of planetary formation, our limits place direct observational constraints on the unbound population in the sub-terrestrial mass range and motivate new observational strategies for microlensing surveys.
10005-ANGI-1 REGULATION OF ALTERNATIVE ANGIOGENIC FACTORS IN BEVACIZUMAB THERAPY FOR GLIOBLASTOMA
Authors: Ezaki Taketo , Tanaka Toshihide , Tamura Ryota , Yamamoto Yohei , Takei Jun , Morimoto Yukina , Imai Ryotaro , Kuranari Yuki , Akasaki Yasuharu , Murayama Yuichi , Miyake Keisuke , Sasaki Hikaru
Published: December 2023

The elucidation of the mechanism of action and resistance is imperative to overcome resistance to Bev and develop a more effective therapy. This study aims to investigate the status and change of alternative angiogenic factors regarding Bev usage using human specimens. The present study used 54 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naive Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory/autopsied Bev group). Importantly, naive Bev-refractory Bev of 22 specimens in 11 cases (including 4 autopsy specimens and 7 salvage surgery specimens) were obtained as paired specimens from the same patient. The expression of alternative angiogenic factors including basic fibroblast growth factor (bFGF), placental growth factor (PlGF), Angiopoietin1 (Ang-1), Angiopoietin2(Ang-2) and EphrinA2 were investigated via immunohistochemistry. PlGF expression was higher in the effective group than in the Naive group (p=0.048), and Ang-2 (0.047) and EphA2 (p=0.028) were higher in the relapse group than in the Naive group. Interestingly, in paired specimens, PlGF expression was higher in the refractory group than in the Naive group (p=0.036). This suggests that angiogenic factors other than VEGF are involved in recurrence. We provide the first clinicopathological evidence of the status of alternative angiogenic pathway after the Bev usage. These in situ observations will help to optimize therapy.
10006-PEDT-1 PEDIATRIC LOWER GRADE GLIOMA SURGERY IN THE ERA OF GENOMIC MEDICINE
Authors: Gomi Akira , Oguma Hirofumi , Kawai Kensuke
Published: December 2023

INTRODUCTION

In the new WHO Brain Tumor Classification of 2021, pediatric-type gliomas are classified separately from adult-type tumors. Additionally, with the advancement of cancer genomics, treatment options have expanded. Here we consider surgery for pediatric low-grade gliomas.

METHODS

We retrospectively analyzed 41 cases of low-grade gliomas or glioneuronal tumors in patients under 18 years of age who underwent surgery at our institute from 2002 to March 2023. We discussed surgical strategies based on molecular classification.

RESULTS

Among the cases, there were 34 gliomas and 7 glioneuronal tumors. According to the new WHO classification, they corresponded to 1) Adult-type diffuse gliomas, 2) Pediatric-type diffuse low-grade gliomas, 3) Circumscribed astrocytic tumors, or 4) Glioneuronal and neuronal tumors. Cases without molecular diagnosis were also considered in light of the new WHO classification.

DISCUSSION

Among molecularly diagnosed astrocytomas involving the cerebral hemisphere, brain stem, spinal cord, there were no cases of 1), and 2) 3) were the main cases. It is important in surgical selection to note that these cases generally have a more favorable prognosis compared to the adult type and have usefulness in diagnosing MAPK pathway abnormalities leading to the selection of molecularly targeted drugs. 3) includes pilocytic astrocytoma, subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma. Among these, in the treatment of pilocytic astrocytomas located in the optic pathway and hypothalamus, biopsy becomes necessary for molecular diagnosis and the selection of appropriate therapeutic agents. Conversely, for unilateral optic nerve gliomas, options other than resection may be considered. 4) is primarily associated with epilepsy-related tumors. Surgical resection holds the promise of controlling epilepsy in these cases. However, various genetic abnormalities have been identified, which could prove useful in diagnosis and treatment.

CONCLUSION

Based on the new WHO classification, a reevaluation of treatment strategies for pediatric brain tumors is necessary.
10008-CBMS-1 THE NOVEL MDM4 INHIBITOR CEP-1347 ACTIVATES THE P53 PATHWAY AND BLOCKS MALIGNANT MENINGIOMA GROWTH IN VITRO AND IN VIVO
Authors: Mitobe Yuta , Sonoda Yukihiko , Kitanaka Chifumi
Published: December 2023

A significant proportion of meningiomas are clinically aggressive, but there is currently no effective chemotherapy for meningiomas. An increasing number of studies have been conducted to develop targeted therapies, yet none have focused on the p53 pathway as a potential target. In this study, we aimed to determine the in vitro and in vivo effects of CEP-1347, a small-molecule inhibitor of MDM4 with known safety in humans. The effects of CEP-1347 and MDM4 knockdown on the p53 pathway in human meningioma cell lines with and without p53 mutation were examined by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 was examined in vitro and in a mouse xenograft model of meningioma. In vitro, CEP-1347 at clinically relevant concentrations inhibited MDM4 expression, activated the p53 pathway in malignant meningioma cells with wild-type p53, and exhibited preferential growth inhibitory effects on cells expressing wild-type p53, which was mostly mimicked by MDM4 knockdown. CEP-1347 effectively inhibited the growth of malignant meningioma xenografts at a dose that was far lower than the maximum dose that could be safely given to humans. Our findings suggest targeting the p53 pathway with CEP-1347 represents a novel and viable approach to treating aggressive meningiomas.
10014-CBMS-2 CONCURRENT TARGETING OF MDM4 AND MDM2 USING CEP-1347 AS AN EFFECTIVE THERAPEUTIC STRATEGY FOR P53 WILD-TYPE MALIGNANT BRAIN TUMORS
Authors: Mitobe Yuta , Sonoda Yukihiko , Kitanaka Chifumi
Published: December 2023

The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study using CEP-1347, an inhibitor of MDM4 protein expression. The effects of CEP-1347, the genetic and/or pharmacological inhibition of MDM2, and their combination on the p53 pathway in malignant brain tumor cell lines expressing wild-type p53 were investigated by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 alone or in combination with MDM2 inhibition were examined by dye exclusion and/or colony formation assays. The treatment of malignant brain tumor cell lines with CEP-1347 markedly increased MDM2 protein expression, while blocking CEP-1347-induced MDM2 overexpression by genetic knockdown augmented the effects of CEP-1347 on the p53 pathway and cell growth. Blocking the MDM2-p53 interaction using the small molecule MDM2 inhibitor RG7112, but not MDM2 knockdown, reduced MDM4 expression. Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest CEP-1347-induced MDM2 overexpression combined with the selective inhibition of MDM2's interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells.
10018-COT-4 COMPARATIVE VOLUMETRIC ANALYSES FOLLOWING BEVACIZUMAB THERAPY FOR A PATIENT WITH CO- INCIDENCE OF GLIOBLASTOMA, MENINGIOM
Authors: Teshigawara Akihiko , Tanaka Toshihide , Tomoto Kyoichi , Hasegawa Yuzuru , Murayama Yuichi
Published: December 2023

BACKGROUND

Given that glioblastoma, meningioma and dural arteriovenous fistura (dAVF) represent angiogenic disease mainly caused by high expression of vascular endothelial growth factor (VEGF), bevacizumab is expected to be effective for these diseases. We experienced a patient with co-incidence of these 3 diseases was given neoadjuvant bevacizumab which provided a volume reduction of glioblastoma with improvement of clinical symptoms.

CASE REPORT

An eighty five year-old man has suffered from aphasia and dementia. Brain MRI showed a ring enhanced intraaxial tumor with perifocal edema in left temporal lobe, a dural-attached extraaxial tumor in the left sphenoid ridge and dAVF at left transverse-sigmoid sinus. Due to elderly with poor general condition, he was treated by administrate bevacizumab rather than the resection to confirm histological diagnosis. Three days after the administration, he began to walk and speech.

RESULTS

For comparison of the reactivity to bevacizumab among these three diseases, we calculated the volumetric quantitative assessment of glioblastoma and meningioma by the contrast-enhanced MRI and made a qualitative assesment for the dAVF by digital subtraction angiography (DSA) and MRA with comparison between before and afterbevacizumab administration. The volume reduction rates 1 and 5 months later after bevacizumab administration in glioblastoma and in meningioma were 0.34% and 94.5%, 13.7%, 6.8%, respectively. The volume reduction rate of glioblastoma was significantly larger than of Mg. The DSA showed the dAVF did not change even though bevacizumab therapy.

DISCUSSION

As previously reported, the VEGF concentration in the glioblastoma was significantly higher than that in other types of tumors including meningioma. In dAVF, other angiogenic factors would be produced in addition to VEGF.

CONCLUSIONS

Based on these evidences and the current rare case with co-incidence of glioblastoma, meningioma, and dAVF, it suggested that the effectiveness of bevacizumab therapy would be depend on the expression level of the VEGF concentration.
10025-MPC-3 DIFFERENCE AMONG GENERATIONS IN PATIENTS WITH HISTONE H3-MUTATED GLIOMAS
Authors: Fukai Junya , Hayashi Nobuhide , Nakatogawa Hirokazu , Kawaji Hiroshi , Kodama Yoshinori , Shofuda Tomoko , Yoshioka Ema , Kanematsu Daisuke , Katsuma Asako , Sumida Miho , Kijima Noriyuki , Okita Yoshiko , Mori Kanji , Kanemura Yonehiro
Published: December 2023

OBJECT

This study investigates clinical and molecular features, including the survival outcomes, of patients with histone H3-mutant gliomas and the differences among generations: children (-13 years), adolescence and young adult (AYA) (14-39 years), and older adult (40- years) patients. Particularly, we focused on the older adult cases.

METHODS

We collected pediatric and adult glioma cases harboring histone H3 mutations (K27M and G34R/G34V) enrolled in Kansai Network (118 cases) and retrospectively analyzed clinical characteristics and genetic status, including overall survival times (OS). Additionally, the differences between the older adult (40- years) and the younger generations (-39 years) were evaluated.

RESULTS

The older adult patients were not infrequently enrolled in the H3 K27-mutant glioma group (n = 47) (40-79 years old)), although H3 G34-mutant glioma cases belonged to around AYA generation (11-45 years old). Most popular location was brainstem in children (8/15, 53%) and thalamus in AYA (29/56, 52%), while cerebrum as well as brainstem and thalamus were common in the older adults (15/47, 32%; 15/47, 32%; 11/47, 24%). Histologically, diagnosis of non-GBM was not uncommon (63/105, 60%). There were no significant age-specific differences in genetic status (IDH1/2, TERT promoter, MGMT promoter, TP53, BRAF, FGFR1, EGFR). In general, tumor biopsy followed by radiation and chemotherapy was the main treatment regimen regardless of patient age (92/115, 80%). Particularly in the H3 K27-mutant gliomas, there was no statistically significant difference in OS among generations (median OS of children/AYA/older adult, 16.6/18.4/15.9 months).

CONCLUSIONS

We report clinicopathological features and survival outcomes of histone H3-mutated glioma patients in Kansai Network cohort. Histone H3 mutation could exist in the older adult cases with diffuse gliomas at cerebral location. There was a little difference in clinical and pathological features among generations. The prognosis of the older adults was as poor as those of children and AYA.
10027-CBMS-3 POSTOPERATIVE EPILEPTOGENICITY IN GLIOBLASTOMA ARE ACHIEVED AS THE RESULT OF INTERACTIVE FLUCTUATIONS OF GLUTAMATE AND STEM CELL MARKER
Authors: Kusakabe Kosuke , Inoue Akihiro , Ohnishi Takanori , Nakamura Yawara , Ohtsuka Yoshihiro , Nishikawa Masahiro , Yano Hajime , Tanaka Junya , Watanabe Hideaki , Kunieda Takeharu
Published: December 2023

BACKGROUND AND OBJECTIVE

In our recent Glioblastoma multiforme (GBM) cases, postoperative epilepsy mostly occurred later than twenty-eight days after surgery. CD44, a stem cell marker, is known to relate with tumor cell invasiveness, however, little are known with epilepsy nor glutamate (Glu). We investigated the relationship between CD44 and the pathophysiology of this post operative late-phase epilepsy.

MATERIALS AND METHODS

A total of 10 GBM cases received surgery and postoperative treatment at our institute were divided into two groups; 4 cases of epilepsy onset, group E, and 6 cases without, group NE. In each group, the tumor was separated into core and periphery, from which Glu was measured (Amino Acid Analyzer L8900; Hitachi High-Tech Corporation) with expression of xCT, EAAT2 and CD44 examined (Western blot). The same objects were also examined on our three glioma stem-like cell (GSC) lines. In addition, we figured Factor X (F-X) as a key related factor, and evaluated the same objects on the GSCs under conditioned F-X (under submission).

RESULTS

Group E showed higher Glu than group NE both in the core and periphery. CD44 expression was significantly higher in group E in the periphery, and xCT was higher in group E both in the core and periphery. EAAT2 was lower in group E both in the core and periphery. Among the GSCs, GSC-2 had the highest CD44 expression while having the lowest xCT and extracellular Glu, and the highest EAAT2. In addition, CD44 knockdown in GSC-2 resulted in significant increase of xCT expression and extracellular Glu. Furthermore, changing the concentration of F-X low to high led to decreased expression of CD44 and increased xCT.

CONCLUSION

The postoperative epileptogenicity could be gained by the increase of Glu which results from the alterations of CD44, xCT and EAAT2. F-X could enhance the ability of Glu discharge.
10031-GGE-2 GENOMIC ANALYSIS OF MENINGIOMA USING GENE PANEL TESTING
Authors: Ohba Shigeo , Sugihara Eiji , Yamada Seiji , Kojima Daijiro , Nakao Kazutaka , Fujiwara Eiji , Kumon Masanobu , Joko Masahiro , Nishiyama Yuya , Muto Jun , Nakae Shunsuke , Adachi Kazuhide , Abe Masato , Saya Hideyuki , Hirose Yuichi
Published: December 2023

Recently, cancer gene panel tests have been covered by insurance and their usefulness has been reported. In addition to the cancer gene panel tests covered by insurance, we are conducting the PleSSision-Rapid test, a cancer gene panel test that can measure 143 genes, as a clinical research project. The former has been used for 14 cases brain tumors, and the latter has been used for brain tumors in about 100 cases, respectively. The PleSSision-Rapid test has now completed analysis of 87 cases, with gliomas accounting for 33, meningiomas for 29, and metastatic brain tumors for 14 cases. Tumor mutation burden (TMB) was high in 18 cases, and microsatellite instability was high in none. NTRK gene fusion was observed in 1 case. Of the 29 meningiomas, 9 were male and 20 female, ranging in age from 31 to 79 years (mean 57). Twenty of the cases were located at the skull base. Twenty four were primary cases, whereas 5 were recurrent cases. WHO grade 1, 2, and 3 were 23, 4, and 2, respectively. There was no difference in TMB among grades, and Ki-67 values increased with increasing grade. Comparing grade 1 and grade 2/3, NF2 and KDM6A were found to be significantly different in the rate of gene mutations. Grade 2/3 patients had a significantly higher frequency of copy number aberrations such as genes related to DNA repair, histone modification, and chromatin remodeling, than grade 1 patients,
10033-IM-2 IDENTIFICATION OF THERAPEUTIC TARGET ANTIGENS USING PATIENT DERIVED GLIOBLASTOMA AND THEIR APPLICATION TO CAR-T THERAPY
Authors: Kuroda Hideki , Kijima Noriyuki , Tachi Tetsuro , Murakami Koki , Nakagawa Kanji , Kawamoto Yuki , Utsugi Reina , Hirayama Ryuichi , Okita Yoshiko , Kagawa Naoki , Hosen Naoki , Kishima Haruhiko
Published: December 2023

Introduction: New therapies for glioblastoma (GBM) are urgently needed due to its poor prognosis and chimeric antigen receptor T (CAR-T) cell therapy is one of the promising strategies. CAR-T cell therapy targeting EGFRvIII,HER2, and IL13Rα2 have been tested for GBM, but have limited efficacies. To further develop CAR-T cell therapy, cell surface targets that is highly specific for GBM cells are needed. In this study, we applied this strategy to search for GBM-specific cell surface targets using patient derived tumor spheres. Methods: Patient derived tumor spheres was established from GBM surgical specimens, and immunized to Balb/c mice. The B cells from the mice were fused with myeloma cells, immortalized, and cultured nonclonally to obtain a number of monoclonal antibodies reacted GBM cells. The obtained antibodies were reacted with GBM cells and normal brain cells, and those that specifically react to GBM were selected by flowcytometry to obtain antibody candidates that could be specifically expressed on the surface of GBM cells. Then, we generated CAR-T cells derived from the obtained antibody and confirmed anti-tumor effect of CAR-T cells in vitro by ELISA. Results: Approximately 25,000 antibody-producing strains were generated. Within these candidates, we identified antibody X, which reacted with several GBM samples and does not reacted with several normal brain cells. The antibody X is a reported to be a cell adhesion molecule. The CAR-T cells derived from the antibodies X produced IL-2 and IFNγ significantly in co-culture with GBM cells. Conclusion: In this study, we identified antigen X and analyzed its anti-tumor effect in vitro. The antigen X has been reported to be associated with the progression of solid tumors and is expected to be a tumor-specific antigen. Further studies are necessary to examine whether the CAR-T cells targeting antigen X have anti-tumor effect in vivo.
10035-GMC-1 PTPN11 VARIANT MAY BE A PROGNOSTIC INDICATOR OF IDH-WILDTYPE GLIOBLASTOMA IN A COMPREHENSIVE GENOMIC PROFILING COHORT
Authors: Otani Ryohei , Ikegami Masachika , Yamada Ryoji , Yajima Hirohisa , Kawamura Shinji , Shimizu Sakura , Tanaka Shota , Takayanagi Shunsaku , Takami Hirokazu , Yamaguchi Tatsuro
Published: December 2023

Glioblastoma (GBM) is the most common type of primary malignant brain tumor and has a poor prognosis. Identifying novel targets and stratification strategies is urgently needed to improve patient survival. The present study aimed to identify clinically relevant genomic alterations in IDH-wildtype GBM using data from comprehensive genomic profiling (CGP) assays performed nationwide in Japan. The CGP assay results of 392 IDH-wildtype GBM cases performed between October 2019 and February 2023 obtained from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were retrospectively analyzed. The median patient age was 52.5 years, and 207 patients (53%) were male. In the 286 patients for whom survival information was available, a protein-tyrosine phosphatase non-receptor type 11 (PTPN11) variant detected in 20 patients (6.8%) was extracted as the gene associated with significantly shorter overall survival (OS) (p = 0.002). Multivariate analysis demonstrated that the PTPN11 variant and poor PS were independent prognostic indicators. In contrast, no prognostic impact was observed in the cohort in The Cancer Genome Atlas data. The discrepancy in the prognostic impact of the PTPN11 variant from these two pools might have resulted from differences in the biases affecting the survival of patients who underwent a CGP assay, including left-truncation and right-censored bias. However, survival simulation done to adjust for these biases showed that the prognostic impact of the PTPN11 variant was also significant, suggesting that the PTPN11 variant was a negative prognostic indicator of IDH-wildtype GBM in the patient cohort with the CGP assay.
10036-IM-3 SPATIAL AND GENOMIC ANALYSES FOR THE CONSTRUCTION OF TERTIARY LYMPHOID STRUCTURE IN GLIOBLASTOMA
Authors: Mizuta Ryo , Muraoka Daisuke , Okamura Ayako , Okamoto Takanari , Nohira Shota , Otani Yoshihiro , Ishida Joji , Fujii Kentaro , Date Isao , Matsushita Hirokazu
Published: December 2023

BACKGROUND

Recently, the presence of tertiary lymphoid structure (TLS), composed mainly of intratumoral B cells, has been reported as a favorable prognostic factor in various types of cancer. However, in glioblastoma, TLS has not been well studied though increased B-cell infiltration was likely to be related to improved prognosis. In this study, we performed spatial and genomic analyses in human glioblastoma, focusing on TLS.

METHODS

We evaluated lymphocytic infiltration by immunostaining in 54 cases. Flow cytometry was conducted on 12 prospective samples. RNA-sequencing (RNA-seq) was performed in 43 cases to compare those with and without TLS by differential gene expression (DGE) analysis and Gene Set Enrichment Analysis (GSEA).

RESULTS

TLS was detected in 5 (9.3%) of the 54 cases. Flow cytometry showed that 3 cases with TLS by immunostaining had higher numbers of T and B cells than those without TLS. DGE analysis showed increased gene expression related to the T cell activation marker (TNFRSF9), chemokine (CCL5), etc., in patients with TLS. GSEA also confirmed the activation of immune responses such as adaptive immune response and B cell receptor signaling pathway. We are currently validating these data with spatial transcriptome analysis and investigating the TLS formation in detail.

DISCUSSION

Although several TLS signatures and TLS components have been reported so far, the formation mechanism of TLS is still unknown. In addition, to our knowledge, there are no reports yet on spatial transcriptome analysis in multiple cases of glioblastoma focusing on the presence of TLS.

CONCLUSION

We analyzed a total of 54 glioblastoma cases by immunostaining. RNA-seq and spatial transcriptome analysis were performed to assess TLS in glioblastoma comprehensively.
10048-CO-2 CAN NATURAL LANGUAGE PROCESSING AI BE AN APPROPRIATE “ADVISER” FOR BRAIN TUMOR PATIENTS? CLINICAL APPLICATION AND ISSUES ON CHATGPT
Authors: Hana Taijun , Takahashi Satoshi , Kawaguchi Yuki , Oya Soichi
Published: December 2023

INTRODUCTION

Brain tumors affect approximately 20,000 individuals annually in Japan, with some cases requiring urgent treatment. However, the medical knowledge of non-medical individuals (the general public) is often limited, resulting in delays in seeking treatment even when neurological symptoms are evident. Having appropriate advisors who can encourage medical consultations could potentially improve this situation. While Natural Language Processing AI (NLP-AI) is widely used, its full integration into healthcare remains a work in progress. ChatGPT, a prominent NLP-AI, possesses extensive knowledge and is accessible 24/7 online. We explored the potential of leveraging its advanced capabilities and accessibility in the field of brain tumor management.

METHODS

To evaluate its ability to guide hospital visits effectively, we simulated various symptoms associated with primary brain tumors and consulted ChatGPT(GPT3.5) as patients. We also assessed how ChatGPT handled unnecessary noise information (unrelated symptoms) during symptom consultations.

RESULTS

ChatGPT consistently recommended hospital visits for all simulated brain tumor patients and provided appropriate advice regarding the urgency and relevant medical department. Notably, even when patients expressed hesitation and refusal hospital visits, ChatGPT persistently persuaded them to visit the hospital despite the user(patient)'s intention. Despite the introduction of noise information, ChatGPT accurately identified and emphasized the importance of relevant symptoms, prompting appropriate medical attention. However, accuracy declined when excessive noise was present. Additionally, ChatGPT generated concise summaries of medical histories for presentation during hospital visits.

DISCUSSION

While AI is widely utilized in medical imaging, the comprehensive integration of conversational AI in healthcare is still in progress. ChatGPT, despite not being a healthcare professional, holds potential as an "advisor" with extensive medical knowledge, accessible for consultations at any time, to support brain tumor patients. However, challenges related to accountability and expanding knowledge capabilities remain to be addressed.
10053-MNG-1 STRATIFICATION OF TUMOR VOLUME GROWTH RATE USING RISK FACTORS IN SUPRATENTORIAL MENINGIOMAS
Authors: Hirayama Ryuichi , Yamada Shuhei , Iwata Takamitsu , Kawamoto Yuki , Nakagawa Kanji , Murakami Kouki , Utsugi Reina , Tachi Tetsuro , Kuroda Hideki , Kijima Noriyuki , Okita Yoshiko , Kagawa Naoki , Kishima Haruhiko
Published: December 2023

BACKGROUND

The natural history of meningiomas is still unclear, and no guidelines have been established based on objective indices regarding the necessity and timing of therapeutic intervention. Objective: We attempted to provide statistics on the characteristics of tumor volume change, stratify tumor growth by risk factors, and generate a predictive tumor volume curve based on the statistics, with the aim of describing the natural history of meningiomas.

METHODS

313 cases were included in the study, with the origin of meningioma being the circumflex and parasagittal sinus areas and the cerebral sickle region, and with multiple MRI scans performed at intervals of at least 3 months. Relative growth rate (RGR) and annual volume change (AVC) were calculated by tumor volume, and the patients were classified into three groups according to the combination of gender, age, and MRI T2WI signal intensity, and compared.

RESULTS

The median RGR and AVC of the entire cohort were 6.1% and 0.20 cm3/year, respectively, and there were significant differences between groups in gender (p=0.018) and MRI T2WI (p < 0.001) for RGR and tumor location (p=0.025) and initial tumor volume (p < 0.001)for AVC. The median RGR and AVC in the classification were 17.5% and 1.05 cm3/year for the very high growth group, 8.2% and 0.33 cm3/year for the high growth group, and 3.4% and 0.04 cm3/year for the low growth group, showing significant differences between the groups (p < 0.001). The predicted tumor volume curve showed an average 2.24-fold or 5.24 cm3 increase in volume over 5 years in the very high-growth group, while little tumor volume change was observed in the low-growth group.

CONCLUSION

The combination of growth risk factors allowed stratification of tumor growth and provided a predictive tumor volume curve for each county. The results may assist in the treatment of supratentorial meningiomas.
10054-STMO-1 5-ALA INTENSITY ANALYSIS OF NON-NEOPLASTIC LESIONS BY IMAGE J
Authors: Kon Takashi , Kobayashi Yusuke , Shimizu Katsuyoshi , Mizutani Tohru , Sato Yosuke
Published: December 2023

PURPOSE

We used 5-ALA during surgery for malignant brain tumors, and analyzed the brightness using Image J for positive findings during surgery. We report on three cases that were positive for intraoperative 5-ALA and had high brightness but were diagnosed as non-tumor, including the results of brightness analysis by Image J.

METHODS

5-ALA was administered according to the protocol, and intraoperative 5-ALA-positive findings were analyzed with Image J (Wayne Rasband: NIH), brightness was measured with histograms, and maximum brightness was compared.

RESULTS

Case 1 was suspected malignant tumor before surgery, but the diagnosis was inflammation, different from lymphoma. The intraoperative maximum brightness was as high as 239, but there was no finding of' blazing fire' characteristic of malignant tumors, and the lesion and its surroundings were uniformly red. Case 2 required differentiation between metastatic brain tumor and radiation necrosis, and case 3 required differentiation between recurrent anaplastic astrocytoma and radiation necrosis, both of which had high intraoperative brightness (113,166).

CONCLUSION

Measuring the brightness of 5-ALA-positive findings during surgery can help in the rapid pathological diagnosis of tumors and the determination of peripheral edema.
10060-MET-5 LEPTOMENINGEAL METASTASES FROM HER2 POSITIVE SALIVARY GLAND CARCINOMATREATED WITH CRANIOSPINAL IRRADIATION FOLLOWED BY INTRATHECAL TRASTUZUMAB
Authors: Tabei Yusuke , Tada Yuichiro , Oyama Kenichi , Matsuno Akira
Published: December 2023

We report our experience with a case of intrathecal trastuzumab (Tmab) after craniospinal irradiation for leptomeningeal metastases (LM) of HER2-positive salivary gland carcinoma. The patient was a 46-year-old male with postoperative extensive cervical recurrence of left parotid carcinoma (salivary gland conduit carcinoma, HER2 positive) treated with intravenous Tmab and docetaxel. He was hospitalized for headache and nausea, and diagnosed as LM by MRI and CSF cytology. He received whole brain irradiation of 30Gy/10Fr and whole spinal cord irradiation of 30Gy/10Fr. Because of HER2 positive cancer, we applied to the ethics committee and started Tmab intrathecal treatment(IT) . The initial dose was 20 mg, which was administered intrathecally once every 3 weeks, and the dose was increased by 20 mg in 20 mg increments up to 60 mg while checking for post-dose side effects. The side effect was discomfort in the extremities during IT, which resolved by slowing down the administration rate. The time from diagnosis of LM to CNS deterioration was 9 months. Tmab IT may be effective in treating LM in HER2-positive salivary gland carcinoma. Further clinical studies are needed to evaluate efficacy and safety.
10073-CBMS-6 CURCUMIN ANALOG B EXHIBIT ANTI-TUMOR ACTIVITY AGAINST GLIOBLASTOMAAT LOWER CONCENTRATIONS THAN CURCUMIN
Authors: Inai Kyoko , Hamabe-Horiike Toshihide , Ono Masaya , Iwashimizu Sonoka , Ito Ryo , Sunagawa Yoichi , Katanasaka Yasufumi , Arakawa Yoshiki , Hasegawa Koji , Morimoto Tatsuya
Published: December 2023

PURPOSE

Glioblastoma (GBM) has a high risk of recurrence and a poor prognosis due to the difficulty of surgical resection and resistance to the standard treatment, temozolomide. Therefore, the development of noble therapeutic agents against GBM is required. This study investigated the anti-tumor activity of the curcumin (Cur) analog Compound B (ComB) against GBM.

METHODS AND RESULTS

To evaluate anti-tumor activity against GBM, we performed an MTT assay. The human glioblastoma cell lines U87-MG and U251 were pre-treated with Cur or ComB, and then cell viability was examined using a cell counting kit, and IC50 values were calculated. The IC50 value for U87-MG of Cur was 9.78 μM, and that of ComB was1.28 μM. The IC50 value for U251 of Cur was 9.50 μM, and that of ComB was 0.64 μM. To examine the effects of ComB on normal cells, the same MTT assay was performed on primary cultured astrocytes prepared from neonatal rats. ComB did not reduce cell viability in astrocytes at concentrations that had an anti-tumor effect on GBM cells. Next, a cell cycle analysis was performed with Propidium Iodide (PI) staining and an apoptosis assay with Annexin V/PI staining using flow cytometry. ComB induced cell cycle G2/M arrest and apoptosis at lower concentrations than Cur. qPCR showed that mRNA expression levels of CDK1 and CyclinB1, which play an essential role in the progression from the G2 phase to the M phase, decreased by ComB at lower concentrations than Cur.

DISCUSSION

These results suggest that ComB, at lower concentrations than Cur, has an anti-tumor effect without affecting normal cells by inducing cell cycle arrest and apoptosis against GBM. Further detailed analysis and in vivo studies are expected to lead to the development of novel therapeutic agents for GBM.
10074-COT-10 A NEW PREOPERATIVE PREDICTIVE SCORING SYSTEM FOR SUPRATENTORIAL NEWLY DIAGNOSED ISOCITRATE DEHYDROGENASE-WILD TYPE GLIOBLASTOMA TREATED WITH RADIOTHERAPY PLUS CONCOMITANT AND ADJUVANT TEMOZOLOMIDE
Authors: Mtsuda Ryosuke , Maeoka Ryosuke , Morisaki Yudai , Yokoyama Shohei , Park Young-Soo , Nakagawa Ichiro
Published: December 2023

We aimed to evaluate the usefulness of a preoperative predictive score for assessing overall survival in patients with supratentorial newly diagnosed isocitrate dehydrogenase (IDH)-wild type glioblastoma (GBM) treated with radiotherapy plus concomitant and adjuvant temozolomide. In this study, 104 patients with newly diagnosed supratentorial IDH-wild type GBM were enrolled between May 2007 and April 2021. Four prognostic factors were evaluated preoperatively: age, initial symptoms, neutrophil/lymphocyte ratio (NLR), and contact of the tumor with the ventricles on magnetic resonance imaging (MRI). A scoring system of 0-6 points was created, with 2, 1, 2, and 1 points assigned to age > 75 years, no seizure onset, NLR > 2.23, and ventricular c ontact. The median follow-up period after surgery was 15 months (range: 1-146 months). The total score was 0, 1, 2, 3, 4, 5, and 6 points for 6, 6, 18, 15, 43, 6, and 10 patients respectively. Patients with 0-2, 3-4, and 5-6 points were assigned to groups 1, 2, and 3, respectively. The median survival time from surgery was 20 months in the entire cohort and 34, 19, and 10 months in groups 1, 2, and 3, respectively. The three groups showed significant differences in the median survival time (p< 0.001), with lower scores corresponding to longer survival times. We propose a new preoperative prognostic scoring system for newly diagnosed patients with supratentorial IDH-wild GBM. The prognostic information obtained using this system can help determine the intensity of treatment for the patient.
10075-CO-3 PREDICTION OF KPS DETERIORATION IN GLIOBLASTOMA USING MULTIMODAL LEARNING WITH PRE- AND POST-OPERATIVE MRI IMAGES AND CLINICAL INFORMATION
Authors: Mineharu Yohei , Sasagasako Tomoki , Ueda Akihiko , Mochizuki Yusuke , Numa Arisa , Doi Soichiro , Arakawa Yoshiki , Okuno Yasushi
Published: December 2023

BACKGROUND

Previous AI studies on glioblastoma have mostly focused on predicting genetic subtypes or survival outcomes using preoperative imaging alone. We aimed to investigate the feasibility of utilizing postoperative imaging in combination with clinical chart data for multimodal learning, to evaluate systemic functional outcome.

METHODS

We included 77 glioblastoma cases that received treatment at Kyoto University between December 2001 and January 2022. These cases had both pre- and postoperative MRI images, including T1WI, CE-T1WI, FLAIR, ADC, and DWI. Molecular diagnoses were confirmed for all cases. First, using external data (BRaTS2020), we constructed models for tumor segmentation prediction from MRI images followed by an image feature extraction model using an autoencoder (VAE), extracting 192 image feature variables from preoperative and postoperative images. These variables were combined with 24 clinical variables, and 6 variables of radiologists' findings. We built a CNN model to predict a decrease of 30% or more KPS at 6 months and evaluated its accuracy using the AUC. Feature importance was calculated using PermutationImportance.

RESULTS

When predicting KPS deterioration using only clinical data, the AUC was 0.79. When combined with radiologists' findings, the AUC increased to 0.84. Combination with preoperative image features resulted in an AUC of 0.78. On the other hand, when combined with both pre- and postoperative image features, the AUC increased to 0.94. Both pre- and post-operative images were identified as important features.

DISCUSSION

Our findings demonstrate the utility of incorporating postoperative imaging into multimodal learning for predicting systemic functional outcomes in glioblastoma patients. Further validation in independent cases from different medical facilities is warranted to confirm these results.
10077-NI-4 POSTOPERATIVE DISAPPEARANCE OF LEPTOMENINGEAL ENHANCEMENT AROUND THE BRAINSTEM IN GLIOBLASTOMA
Authors: Inoue Hirotaka , Kuroda Jun-ichiro , Uetani Hiroyuki , Matsuyama Tomohiko , Kaku Yasuyuki , Shinojima Naoki , Hirai Toshinori , Mukasa Akitake
Published: December 2023

BACKGROUND AND PURPOSE

Leptomeningeal enhancement (LME) suggests leptomeningeal dissemination (LMD) of tumor cells, which is an end-stage glioblastoma complication associated with a poor prognosis. However, magnetic resonance imaging (MRI) occasionally indicates the disappearance of peri-brainstem LME after surgical resection of glioblastoma. Since preoperative LMD may affect treatment indication, we aimed to analyze the clinical significance of preoperative LME of the brainstem on glioblastoma, focusing on imaging examinations and patient outcomes.

METHODS

We retrospectively collected clinical and radiological data obtained from consecutive patients with glioblastoma and preoperative LME of the brainstem, who were treated at our hospital between 2017 and 2020.

RESULTS AND CONCLUSIONS

Among 112 patients with glioblastoma, nine (8%) showed preoperative LME of the brainstem. Tumors with LME were relatively large (median size, 59 cm; range, 47-83 cm) and frequently located in the temporal lobe (temporal lobe: n = 4, 44%; frontal lobe: n = 1; parietal lobe: n = 2; corpus callosum: n = 2). Notably, among six patients who underwent surgical resection for glioblastoma with peri-brainstem LME, four showed significant radiological disappearance of the LME on postoperative MRI. This suggests that the LME did not result from LMD in these cases. Moreover, these four patients lived longer than would be expected from the presence of LMD. This LME disappearance was not observed after biopsy or chemoradiotherapy. These findings suggest that preoperative LME does not necessarily indicate the presence of untreatable LMD; moreover, LME may disappear after surgical tumor resection. Thus, transient preoperative LME could be attributed to other mechanisms, including impaired venous flow due to intratumoral arteriovenous shunts, which can be resolved by reducing the tumor burden.