bluuebunny/crossref_metadata_2025_split huggingface dataset:
10126-ACT-10 FACTORS AFFECTING THE PATTERN OF RECURRENCE OF IDH-WILDTYPE GLIOBLASTOMA
Authors: Tsuchiya Takahiro , Ohno Makoto , Takahashi Masamichi , Yanagisawa Shunsuke , Osawa sho , Fujita Shohei , Narita Yoshitaka 
Published: December 2023

Abstract

INTRODUCTION
IDH-wildtype glioblastoma is a quite poor prognosis disease with which almost all cases recur in spite of postoperative radiation and chemotherapy. Survival rates are particularly low after dissemination.

METHODS
We included 120 patients with IDH-wild type glioblastoma treated at our hospital from January 2015 to December 2019. Patient backgrounds, MGMT promotor methylation status, imaging findings, and recurrence patterns were analyzed. Subependymal, subarachnoid, and spinal dissemination, plus distant metastasis, were defined as non-local recurrence.

RESULTS
Of 105 patients with a single lesion at diagnosis, 65 had local recurrence and 15 had non-local recurrence. 36 of 65 patients had local recurrence and 12 had non-local recurrence in the second recurrence. 17 of 36 patients had local recurrence and 8 had non-local recurrence in the third recurrence. The cumulative number of non-local recurrences was 54 (45.0%). Surgical ventricular opening and tumor proximity to the ventricles were associated with non-local recurrence (p=0.006, p=0.019). The patients with tumor proximity to the ventricle had non-local recurrence at the first recurrence and those with non-proximity to the ventricle had non-local recurrence at the second or later recurrence (p=0.038). MGMT promotor methylation status and postoperative ischemia were not significantly different from non-local recurrence (p=0.122, p=0.088), but MGMT promotor unmethylation was a risk factor for early non-local recurrence, especially within 1 year (p=0.033). Frontal lobe lesions were less frequently disseminated and more frequently MGMT promotor methylated (p=0.032, p=0.024). Parietal lobe lesions had more MGMT promotor methylation (p=0.006), and temporal lobe lesions had more dissemination (p=0.023). Distant metastasis commonly occurred from the frontal lobe to the ipsilateral or contralateral, and the frontal lobe was frequently associated.

CONCLUSION
IDH-wildtype glioblastoma is characterized by repeated local recurrence and cumulative non-local recurrence. The pattern of recurrence differs depending on the tumor localization, especially adjacent to ventricle, and MGMT promotor methylation status.
10141-GMC-13 MULTIREGIONAL GENOMIC ANALYSIS: A NOVEL APPROACH FOR DETECTING PATHOGENIC DRIVER MUTATION ASSOCIATED WITH MALIGNANT PROGRESSION IN NEUROCUTANEOUS MELANOSIS
Authors: Takahashi Haruhiko , Natsumeda Manabu , Tsukamoto Yoshihiro , Okada Masayasu , Hara Norikazu , Koyama Akihide , Miyashita Akinori , Yuki Akihiko , Shimizu Hiroshi , Kakita Akiyoshi , Ikeuchi Takeshi , Oishi Makoto 
Published: December 2023

Abstract
Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via ventriculo-peritoneal shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three pathogenic mutations, GNAQ R183Q, S1PR3 G89S and NRAS G12V were found. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discover novel driver mutations associated with tumorigenesis and targeted therapy.
10143-COT-16 DIFFUSE BONE MARROW METASTASIS OF HIGH GRADE GLIOMA
Authors: Nitta Naoki , Fukami Tadateru , Yoshida Kazumichi 
Published: December 2023

Abstract

BACKGROUND
Extraneural metastasis of the high grade glioma has rarely been reported and its diffuse bone marrow metastasis is extremely rare. Case description: A 32-year-old man was referred and admitted to Shiga University of Medical Science Hospital for the treatment for three remote recurrent lesions in the brain after the treatment of the primary brain tumor in the right frontal lobe in the referring hospital. One of those lesions was subtotally resected, with histological and immunohistochemical analysis showing a grade 4 glioma, and stereotactic radiation therapy was performed at all three lesions. A lumbar spine MRI showed signal changes in the first and 4th vertebral bodies and the level of LDH was gradually increased during this hospitalization. Three months later, the patient was referred to our hospital again because of intractable lumbago with metastatic lesions in the lumbar vertebrae and the psoae major. Laboratory data showed pancytopenia and extremely elevated level of LDH-1 and LDH-2, suggesting aggressive hemolysis. Abdominopelvic CT also showed slight osteolytic changes in the ilia, sacra, and femurs. Biopsy of the psoas major and iliac bone marrow showed invasion of grade 4 glioma cells. The patient was diagnosed as having diffuse bone marrow metastasis of grade 4 glioma, and died 12 days after the second admission.

CONCLUSIONS
We have presented a rare case of diffuse bone marrow metastasis of high grade glioma. LDH elevation might mean hemolysis by bone marrow metastasis in patients with high grade glioma.
10152-PEDT-5 JAPANESE SUBGROUP ANALYSIS OF A PHASE II TRIAL OF DABRAFENIB PLUS TRAMETINIB (D+T) IN BRAF V600-MUTANT PEDIATRIC LOW-GRADE GLIOMA (PLGG) AND RELAPSED/REFRACTORY (R/R) BRAF V600-MUTANT PEDIATRIC HIGH-GRADE GLIOMA (PHGG)
Authors: Terashima Keita , Koga Yuhki , Mukaiyama Akihira , Kurihara Ryohei , Okada Keiko 
Published: December 2023

Abstract

BACKGROUND
pLGG is the most common pediatric brain cancer, and BRAF V600 mutation has been detected in ≈17% of cases. pHGGs comprise ≈10% of pediatric central nervous system tumors and are a leading cause of childhood cancer-related death. The result of a phase II global clinical trial (NCT02684058) of D+T vs carboplatin + vincristine (C+V) in first-line BRAF V600-mutant pLGG and single arm D+T in relapsed/refractory (r/r) BRAF V600-mutant pHGG has already been described. Briefly, the primary endpoint was the independently assessed overall response rate, ORR (CR+PR) using RANO criteria. The ORR was 47% (95% CI, 35%-59%) with D+T vs 11% (95% CI, 3%-25%) with C+V (P&lt;.001; odds ratio, 7.2 [95% CI, 2.3-22.4]) in pLGG and 56.1% (95% CI, 39.7%-71.5%) in pHGG. Safety was consistent with the established profile of D+T in other indications. We report results for the Japanese subgroup.

RESULTS
A total of 6 Japanese pts were included in pLGG (D+T; n=4, C+V; n=2). And a total of 11 Japanese pts with diverse WHO Grade III/IV gliomas were included in r/r pHGG. The best overall response assessed by independent reviewer were as followed; D+T; SD 75% (n=3), PD 25% (n=1), C+V; CR 50% (n=1), PD 50% (n=1) in pLGG and CR 9.1% (n=1), PR 27.3% (n=3), SD 9.1% (n=1), PD 36.4% (n=4) in r/r pHGG. Treatment-related grade &gE;3 adverse events were D+T; 25% (n=1) and C+V; 100% (n=2) in pLGG and 27.3% (n=3) in r/r pHGG.

DISCUSSION AND CONCLUSIONS
Treatment with D+T showed encouraging efficacy in Japanese pLGG and r/r pHGG. Profile of AEs was similar or consistent which is reported in other adult cohorts. Thus, these results suggest that D+T may represent a critical treatment advance for pLGG and r/r pHGG Japanese pts with BRAF V600-mutant.
10159-STMO-7 INTRAOPERATIVE MRI SURGERY FOR POSTERIOR FOSSA LESIONS
Authors: Hanihara Mitsuto , Ogiwara Masakazu , Kazama Hirofumi , Kinouchi Hiroyuki 
Published: December 2023

Abstract
Background: Intraoperative MRI (iMRI) is an important modality in brain tumor surgery to identify residual tumors, however, it is problematic due to patient positional limitations. In this study, we investigated the usefulness of iMRI for posterior fossa lesions. Materials and Methods: Of 320 cases of brain tumors removed using iMRI from June 2016 to April 2023, 24 cases of posterior fossa lesions were included. Tumor type, approach method, imaging availability, tumor removal rate, and complications were examined retrospectively. Results: Tumor types included 8 gliomas, 5 epidermoid cysts, 4 meningiomas, 3 metastatic brain tumors, 1 schwannoma, and 3 others. Eleven patients underwent midline suboccipital approach in the supine position, 8 patients underwent lateral suboccipital approach, 2 patients underwent occipital transtentorial approach, and 2 patients underwent anterior transpetrosal approach in the supine position. transpetrosal approach in 2 cases and subtemporal approach in 1 case. iMRI showed residual lesion in 14 of 24 patients. More than half of the gliomas and epidermoid cysts had intraoperative residual disease, whereas only one meningioma did. Total resection was achieved except for one case of intentional residual schwannoma and two cases of glioma. Discussion: iMRI requires the upper body to fit within a gantry, and it is difficult to image in the park bench position. However, various approaches is possible by using a supine-lateral or semi-prone position. In the concorde position, where the fourth ventricle and upper cerebellum are approached, it is useful to insert a mat in the anterior thoracic and raise the upper body. For tumors in the dorsal brainstem and upper cerebellum, the occipital transtentorial approach was used. iMRI is effective in the removal of all tumors, including gliomas in intramedullary tumors and epidermoid cysts in extramedullary tumors. Conclusion: iMRI can be used in posterior cranial fossa lesions.
10167-MET-8 CLINICAL CHARACTERISTICS AND TREATMENT STRATEGY OF CANCER CASES PRESENTING WITH CENTRAL NERVOUS SYSTEM SYMPTOMS
Authors: Hirai Nozomi , Saito Norihiko , Koyahara Yuki , Sato Sho , Hiramoto Yu , Fujita Satoshi , Nakayama Haruo , Hayashi Morito , Ito Keisuke , Sakurai Takatoshi , Iwabuchi Satoshi 
Published: December 2023

Abstract
Metastatic brain tumors were previously reported with prognoses of approximately 6 months. The accuracy of diagnostic imaging and advances in drug therapy have improved the treatment outcomes of various types of cancer. On the other hand, patients with advanced cancer who are detected with neurological symptoms caused by metastatic brain tumors usually face difficulty in deciding on a treatment strategy. In this study, we reported the results of cancer patients who were first detected with central nervous system symptoms in the last 10 years and treated at our hospital.There were 14 patients treated at our hospital from 2013 to 2022 with CNS symptoms as the initial symptom. The mean age was 65.5 years, and the most common primary cancer was lung cancer in 11 cases (9 NSCLC and 2 SCLC). The OS examined in the 11 lung cancer cases was 14 months. Among NSCLC, only 2 cases had EGFR mutation and no cases had ALK fusion gene. The mean Lung-molGPA was 0.89 in 9 patients with NSCLC and 0.75 in 2 patients with SCLC, and the expected survival time was 6.9 months and 2.8 months.With advances in drug therapy, median survival for patients with NSCLC brain metastases has been reported to range from 7 months to 2 years for patients with EGFR mutations and 4 years for patients with ALK fusion gene. Thus, it is necessary to consider treatment strategies according to primary tumor, histology, and genetic information, rather than considering metastatic brain tumors as a single entity.The results of this study suggest that aggressive therapeutic intervention may prolong the survival period expected at the time of initial diagnosis, even in cancer patients who are found to have metastatic brain tumors.
10171-MPC-13 IDH-WILDTYPE LOWER-GRADE ASTROCYTOMA
Authors: Takahashi Yoshinobu , Ogawa Takahiro , Taniyama Ichita , Yamanaka Takumi , Tanigawa Seisuke , Takeuchi Hayato , Hashimoto Naoya 
Published: December 2023

Abstract

BACKGROUND AND PURPOSE
In the WHO 2021 classification, glioblastoma is limited to IDH-wildtype and is diagnosed when microvascular proliferation and necrosis are present. Furthermore, even in the presence of morphologically low-grade findings, the diagnosis of glioblastoma is made if there is either EGFR gene amplification, TERT promoter mutation, or +7/-10 chromosome copy number alterations. Therefore, we investigated IDH wild-type lower-grade astrocytoma.

CASES
10 patients were included in this study. Sanger sequencing was performed for TERT promoter mutations, and MLPA was further implemented using probes for EGFR and PTEN genes in TERT wild-type cases. The threshold values for copy number change were homozygous deletion (x≤0.4), loss of heterozygosity (LOH) (0.4&lt;x≤0.7), gain (1.3≤x&lt;2.0), and amplification (x≥2.0). EGFR gain and PTEN LOH were used as surrogate markers for +7/-10 chromosome copy-number alterations.

RESULTS
Seven of these patients were diagnosed with glioblastoma, IDH-wildtype with a TERT promoter mutation. All three did not meet the diagnostic criteria for glioblastoma. All patients received temozolomide combination radiotherapy and maintenance temozolomide therapy. The median survival time of seven glioblastoma, IDH-wildtype patients was 616 days. Two patients who did not meet the diagnostic criteria for glioblastoma survived 510 and 583 days after initial surgery, respectively, and one patient was given the best supportive care policy at 518 days. Genetic analysis of all three cases showed TP53 LOH.

CONCLUSION
It was suggested that tumors with IDH wild-type low-grade astrocytoma that do not meet the diagnostic criteria for glioblastoma may have a poor prognosis. Although TP53 LOH was common, further investigation of specific genetic abnormalities is needed, and the classification and treatment strategy of these disease groups may be a challenge in the future.
10175-GGE-17 MOLECULAR CHARACTERIZATION OF LOW-GRADE DIFFUSELY INFILTRATIVE TUMOR WITH INI1 DEFICIENCY
Authors: Sugino Hirokazu , Nakashima Takuma , Yamamoto Ryo , Sugihara Yuriko , Ishida Joji , Tateishi Kensuke , Kawamura Atsufumi , Narita Yoshitaka , Nobusawa Sumihito , Suzuki Hiromichi 
Published: December 2023

Abstract
Central nervous system low-grade diffusely infiltrative tumor with INI1 deficiency (CNS LGDIT-INI1) is a pathologically low-grade tumor characterized by the infiltrative growth of INI1-deficient tumor cells. Although CNS LGDIT-INI1 is known to progress to an atypical teratoid/rhabdoid (AT/RT)-like tumor, little is yet known about the molecular characteristics distinguishing CNS LGDIT-INI1 from AT/RT. To elucidate the molecular profile of CNS LGDIT-INI1, we performed whole-genome sequencing (WGS), RNA-seq, and DNA methylation array analysis on three cases (1 child and 2 adults) with CNS LGDIT-INI1, including a paired primary-recurrent case. Additionally, 44 publicly available AT/RT cases were analyzed. All the three cases demonstrate homozygous deletions of the SMARCB1 gene, supporting its fundamental role in the tumorigenesis of CNS LGDIT-INI1. The median number of somatic mutations is 1.3/Mb (1.0-2.8) predominantly comprising age-related C-to-T transitions at the CpG site, which is slightly higher than 0.82/Mb in AT/RT, potentially suggesting an association with advanced age of onset. CNS LGDIT-INI1 exhibits a relatively stable genome where broad copy number variations are extremely rare except for the SMARCB1 region, whereas the AT/RT genome shows multiple copy number alterations. Gene set enrichment analysis based on gene expression reveals that CNS LGDIT-INI1 exhibits relatively lower activation in the cell cycle and protein translational activity compared to AT/RT, which is consistent with the low cell proliferation in CNS LGDIT-INI1. The DNA methylation profile of LGDIT resembles that of AT/RT-MYC, suggesting a common cell of origin between CNS LGDIT-INI1 and AT/RT-MYC. In conclusion, CNS LGDIT-INI1 grows based on the loss of SMARCB1, exhibiting a stable genome and low proliferation activity. Considering the similarity of the DNA methylation profile and SMARCB1 deficiency, it is suggested that CNS LGDIT-INI1 may be a precursor of AT/RT.
10195-MET-11 THE PREDICTIVE FACTORS OF EFFICACY OF PEMBROLIZUMAB IN BRAIN METASTASES OF LUNG CANER
Authors: Kawamura Shinji , Otani Ryohei , Yamada Ryoji , Shimizu Sakura 
Published: December 2023

Abstract
The main treatment for metastatic brain tumors is radiation therapy or surgical removal. Since the pembrolizumab, an anti-PD1 monoclonal antibody, was revealed to be effective for brain metastases of lung cancer, it has been used as a therapeutic option. However, the predictive factors of its efficacy have been unclear. If the efficacy of pembrolizumab can be predicted prior to the treatment of metastatic brain tumors, it will have a significant impact on subsequent treatment strategies. In this study, we performed a retrospective analysis of patients with metastatic brain tumors from lung cancer treated with pembrolizumab to investigate predictive factors of pembrolizumab efficacy. From January 2018 to July 2023, 73 patients were treated with pembrolizumab for brain metastases of lung cancer at our institution. Among them, 16 patients who had received pembrolizumab for at least 1 year were included. Median age was 68 years (45-86), 10 were male (63%), and median period of pembrolizumab treatment was 105 months (49-319). Patients with brain metastasis which was well controlled for at least 2 years after starting pembrolizumab were defined as effective, and those who required new treatment were defined as invalid. There were 11 effective cases and 5 invalid cases. We compared clinical characteristics, genetic characteristics of the primary tumor, and imaging characteristics of metastatic brain tumors between the effective and ineffective cases, and identified predictive factors for efficacy of pembrolizumab.
10199-SPDR-2 PERSONALIZED SYNTHETIC LETHALITY INDUCED BY TARGETING ATR-CHK1 IN MEDULLOBLASTOMAS IDENTIFIED BY IMPLEMENTATION OF SLFN11 IMMUNOHISTOCHEMISTRY
Authors: Nakata Satoshi , NAKATA Aki , Yashima Hideaki , Araki Takuya , Murai Junko , Nobusawa Sumihito , Okada Masayasu , Natsumeda Manabu , Tosaka Masahiko 
Published: December 2023

Abstract
Survival in medulloblastoma varies widely between molecular subgroups, and risk-adapted treatment stratification is necessary. Schlafen family member 11 (SLFN11) defines sensitivity to DNA-damaging therapies in a variety of cancers and may be useful in stratifying medulloblastomas. We previously showed that SLFN11 immunohistochemistry identifies poor-prognosis groups that lack expression; however, the additional treatment for these groups has not been fully elucidated. The serine/threonine kinase ATR (ataxia telangiectasia and Rad3-related) binds to single-stranded DNA upon DNA damage competing with SLFN11 and leads to cell cycle arrest and DNA repair process via Chk1 phosphorylation. Although therapeutic effects of ATR/Chk1 inhibitors on SLFN11-deficient cell lines have been reported in other carcinomas, little is known on brain tumors. In the present study, we investigated the effect of ATR/Chk1 inhibition on SLFN11-negative medulloblastomas. ATR knockdown was introduced to the medulloblastoma cell line DAOY and the isogenic SLFN11-knockout line DYB9, and only DYB9 showed increased sensitivity to cisplatin (Prestoblue assay, p &lt; 0.05, t-test). The ATR inhibitor ceralasertib and the Chk1 inhibitor prexasertib also increased cisplatin and camptothecin sensitivity in DYB9 and SLFN11-low Group 3 medulloblastoma D425. Furthermore, combination therapy with cisplatin and prexasertib inhibited the growth of D425 cerebellar tumors (Akaluc IVIS imaging, p &lt; 0.05, t-test) and prolonged survival of the mice (p &lt; 0.05, Log-rank). Combination therapy with irradiation is currently under investigation. Evaluation of SLFN11 expression in medulloblastoma may lead to new treatment strategies, such as reduced radiation dose for the SLFN11-high groups and the combination therapy with ATR/Chk1 inhibitors for the low-expressing groups.
10203-ML-6 TIRABRUTINIB FOR PRIMARY CNS LYMPHOMA: A SINGLE INSTITUTE RETROSPECTIVE ANALYSIS
Authors: Matsutani Tomoo , Hirono Seiichirou , Kobayashi Masayoshi , Higuchi Yoshinori 
Published: December 2023

Abstract
In 2020, Tirabrutinib (TIR) was approved in Japan as a novel treatment for primary CNS lymphoma (PCNSL). However, the position of TIR in relation to the existing therapy, methotrexate (MTX)-based therapy, is still unclear. We are currently using TIR for patients who have insensitivity to MTX, have short-term recurrence after MTX, or have difficulty receiving MTX, with the principle of readministering MTX-based therapy to patients with recurrent disease. The subjects were ten patients treated with TIR at our institute, 6 with multiple relapses, 3 with inability to MTX, and 1 with difficulty in MTX treatment, and the mean number of relapses was 3.8 when Tirabrutinib was used. The mean number of treatments was 104 days, and 7 patients discontinued treatment due to tumor progression, while 3 patients discontinued due to severe skin problems. The median progression-free survival was 99 days, and only one patient was controlled for more than one year. 4 patients received the best supportive care for recurrence after TIR, and one patient received radiotherapy. The four patients in the MTX-based retreatment group had two progressions and two no progressions at the time of the abstract, with a progression-free survival of 133 days, and two patients had CTCAE grade 4 hematologic toxicities that had not occurred with previous therapy. One patient treated surgically died of postoperative pneumocystis pneumonia. Tirabrutinib showed a high early response rate, but the duration of tumor control tended to be shorter than with MTX-based retreatment. This may be due to its use in our institution after multiple relapses and its aggressive administration in MTX-naive patients. It is also important to note that chemotherapy after TIR use is associated with increased hematologic toxicity.