Pub Date : 2023-12-01DOI: 10.1093/noajnl/vdad141.024
Taijun Hana, Satoshi Takahashi, Yuki Kawaguchi, S. Oya
Abstract 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.
{"title":"10048-CO-2 CAN NATURAL LANGUAGE PROCESSING AI BE AN APPROPRIATE “ADVISER” FOR BRAIN TUMOR PATIENTS? CLINICAL APPLICATION AND ISSUES ON CHATGPT","authors":"Taijun Hana, Satoshi Takahashi, Yuki Kawaguchi, S. Oya","doi":"10.1093/noajnl/vdad141.024","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.024","url":null,"abstract":"Abstract 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.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 30","pages":"v6 - v7"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138611483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1093/noajnl/vdad141.057
Haruhiko Takahashi, M. Natsumeda, Y. Tsukamoto, M. Okada, N. Hara, A. Koyama, A. Miyashita, Akihiko Yuki, Hiroshi Shimizu, A. Kakita, Takeshi Ikeuchi, Makoto Oishi
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.
{"title":"10141-GMC-13 MULTIREGIONAL GENOMIC ANALYSIS: A NOVEL APPROACH FOR DETECTING PATHOGENIC DRIVER MUTATION ASSOCIATED WITH MALIGNANT PROGRESSION IN NEUROCUTANEOUS MELANOSIS","authors":"Haruhiko Takahashi, M. Natsumeda, Y. Tsukamoto, M. Okada, N. Hara, A. Koyama, A. Miyashita, Akihiko Yuki, Hiroshi Shimizu, A. Kakita, Takeshi Ikeuchi, Makoto Oishi","doi":"10.1093/noajnl/vdad141.057","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.057","url":null,"abstract":"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.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"111 22","pages":"v14 - v15"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138608635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1093/noajnl/vdad141.088
Y. Miyakita, M. Ohno, Masamichi Takahashi, Shunsuke Yanagisawa, Y. Narita
Abstract PCNSL remains a poor prognosis, with many patients relapsing despite induction high-dose MTX-based chemotherapy and subsequent maintenance therapy. Most recurrences occur in the brain parenchyma, but in rare cases, systemic relapse may occur. We report the clinical and pathological features of the patients with systemic relapse of PCNSL. We examined 165 PCNSLs treated at our hospital since 2005. 102 of the 165 had recurrence, and 11 of these were diagnosed as systemic relapse. The 11 patients at the time of initial diagnosis had 8 males and 3 females, age 49-81 years (median 67), and KPS 50-90 (median 70). The 11 patients at the time of recurrence had age 62-66 years (median 71), KPS 50-100 (median 60), and the sites of recurrence were abdominal lymph nodes in 3 patients, gastrointestinal tract in 3, pleural effusion in 3, and others in 2. The time to systemic relapse ranged from 11.3 to 156.1 months (median 36.4), survival after recurrence ranged from 0.1 to 89 months (median 16.1), and overall survival ranged from 16.5 to 192 months (median 66.5). Tissue sampling at relapse was performed in 9 patients, 8 of whom had DLBCL. Recurrence of PCNSL is often in the brain, and although recurrence outside the CNS occurs in less than 10%, careful follow-up is necessary. Although it has been reported that recurrence in the testes and breast is common, in our case, recurrence in lymph nodes and pleural effusions was common, and genetic histological evaluation, including discussion of the difference from the primary CNS, is considered necessary. Although the prognosis and KPS of PCNSL are poor, there are cases in which a good condition can be maintained with reliable diagnosis and treatment. Detailed clinical information, including genetic analysis at the time of initial onset and at the time of recurrence, is needed.
{"title":"10223-ML-12 SYSTEMIC RELAPSE OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA","authors":"Y. Miyakita, M. Ohno, Masamichi Takahashi, Shunsuke Yanagisawa, Y. Narita","doi":"10.1093/noajnl/vdad141.088","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.088","url":null,"abstract":"Abstract PCNSL remains a poor prognosis, with many patients relapsing despite induction high-dose MTX-based chemotherapy and subsequent maintenance therapy. Most recurrences occur in the brain parenchyma, but in rare cases, systemic relapse may occur. We report the clinical and pathological features of the patients with systemic relapse of PCNSL. We examined 165 PCNSLs treated at our hospital since 2005. 102 of the 165 had recurrence, and 11 of these were diagnosed as systemic relapse. The 11 patients at the time of initial diagnosis had 8 males and 3 females, age 49-81 years (median 67), and KPS 50-90 (median 70). The 11 patients at the time of recurrence had age 62-66 years (median 71), KPS 50-100 (median 60), and the sites of recurrence were abdominal lymph nodes in 3 patients, gastrointestinal tract in 3, pleural effusion in 3, and others in 2. The time to systemic relapse ranged from 11.3 to 156.1 months (median 36.4), survival after recurrence ranged from 0.1 to 89 months (median 16.1), and overall survival ranged from 16.5 to 192 months (median 66.5). Tissue sampling at relapse was performed in 9 patients, 8 of whom had DLBCL. Recurrence of PCNSL is often in the brain, and although recurrence outside the CNS occurs in less than 10%, careful follow-up is necessary. Although it has been reported that recurrence in the testes and breast is common, in our case, recurrence in lymph nodes and pleural effusions was common, and genetic histological evaluation, including discussion of the difference from the primary CNS, is considered necessary. Although the prognosis and KPS of PCNSL are poor, there are cases in which a good condition can be maintained with reliable diagnosis and treatment. Detailed clinical information, including genetic analysis at the time of initial onset and at the time of recurrence, is needed.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 7","pages":"v22 - v22"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138618436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1093/noajnl/vdad141.054
Mitsuhiro Anan, Rolando Del Maestro, Nobihiro Hata, Minoru Fujiki
Abstract In this study, the epigenetic heterogeneity of GBM was investigated by evaluating the methylation status of the O6-methylguanine methyltransferase (MGMT) promoter in individual clones of a single cell derived from GBM cell lines. Cell lines, U251 and U373, were used for the experiments from the Brain Tumour Research Centre of the Montreal Neurological Institute. To evaluate the methylation status of the MGMT promoter, pyrosequencing and methylation-specific PCR (MSP) were used. A total of 12 U251 and 12 U373 clones were isolated. The methylation status of 83 of 97 CpG sites in the MGMT promoter were evaluated by pyrosequencing, and 11 methylated CpG sites and 13 unmethylated CpG sites were evaluated by MSP. The results demonstrate tumor heterogeneity among individual clones derived from a single GBM cell.
{"title":"10125-GGE-10 EVALUATION OF MGMT PROMOTER METHYLATION STATUS OF GBM CELL LINE CLONAL POPULATION.","authors":"Mitsuhiro Anan, Rolando Del Maestro, Nobihiro Hata, Minoru Fujiki","doi":"10.1093/noajnl/vdad141.054","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.054","url":null,"abstract":"Abstract In this study, the epigenetic heterogeneity of GBM was investigated by evaluating the methylation status of the O6-methylguanine methyltransferase (MGMT) promoter in individual clones of a single cell derived from GBM cell lines. Cell lines, U251 and U373, were used for the experiments from the Brain Tumour Research Centre of the Montreal Neurological Institute. To evaluate the methylation status of the MGMT promoter, pyrosequencing and methylation-specific PCR (MSP) were used. A total of 12 U251 and 12 U373 clones were isolated. The methylation status of 83 of 97 CpG sites in the MGMT promoter were evaluated by pyrosequencing, and 11 methylated CpG sites and 13 unmethylated CpG sites were evaluated by MSP. The results demonstrate tumor heterogeneity among individual clones derived from a single GBM cell.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 2","pages":"v14 - v14"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138618867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1093/noajnl/vdad141.092
Naoki Kagawa, Y. Oji, Ryuichi Hirayama, Noriyuki Kijima, Y. Oka, H. Sugiyama, H. Kishima
Abstract PURPOSE Our clinical trials show the safety and clinical efficacy of Wilms' tumor 1 (WT1) human leukocyte antigen (HLA) class I (Izumoto S et al. J Neurosurg. 2008) and class II (Tsuboi A et al. Cancer Immunol Immunother. 2019) peptide vaccination for recurrent malignant gliomas have been established. We have developed a cocktail vaccine (WT1 trio) containing two class I peptides (HLA-A*24:02 and HLA-A*02:01) and one II class peptide to improve more effective immunological response and improve patient's prognosis. Clinical trial of a cocktail vaccination using WT1 HLA class I and II peptides for recurrent malignant gliomas is planned to verify its safety, clinical efficacy and usefulness of surrogate markers. Patients and METHODS Twenty-three patients with recurrent malignant gliomas, which showed WT1-positive in tumor samples and HLA-A*24:02 or HLA-A*02:01-positive in blood sample, were enrolled. These patients (age: 26-72 years old, average: 49.4) included 15 cases of glioblastomas and 8 of anaplastic astrocytomas. Patients received a WT1 trio vaccine intradermally, 7 times at 2-week intervals during 3 months.WT1-DTH and WT1-IgG antibody were regularly measured. Vaccine-related adverse events, best clinical response and the transfer rate of long-term administration of WT1 trio vaccination were estimated. RESULTS WT1-DTH positive cases were 12, WT1-IgG antibody positive were in 11. In most patients, WT1 -DTH positiveness coincided with that of WT1-IgG antibody. 9 of 11 cases showed stable disease at 3 months and transferred long-term administration of WT1 trio vaccination. Transfer rate in GBM and AA of long-term administration was 33% and 25%, respectively. Grade1 skin eruption was observed at the injection sites in 15 cases, but no significant adverse events related with vaccination were shown. Conclusion: WT1-DTH and WT1-IgG antibody may be useful surrogate markers. Long-term outcome of WT1 trio vaccination was verified for recurrent malignant gliomas.
摘要目的临床试验表明，Wilms' tumor 1 (WT1) human leukocyte antigen (HLA) class I (Izumoto S et al.)的安全性和临床疗效。J neurosurgery . 2008)和II类(Tsuboi A et al.)。Cancer Immunol Immunother. 2019)的多肽疫苗接种治疗复发性恶性胶质瘤已经建立。我们开发了一种鸡尾酒疫苗(WT1三联疫苗)，含有两种I类肽(HLA-A*24:02和HLA-A*02:01)和一种II类肽，以提高更有效的免疫应答，改善患者预后。计划使用WT1 HLA I类和II类肽鸡尾酒疫苗治疗复发性恶性胶质瘤的临床试验，以验证其安全性、临床疗效和替代标记物的有用性。患者与方法入选肿瘤标本wt1阳性、血液标本HLA-A*24:02或HLA-A*02:01阳性的复发性恶性胶质瘤患者23例。患者年龄26-72岁，平均49.4岁，其中胶质母细胞瘤15例，间变性星形细胞瘤8例。患者在3个月内接受皮内注射WT1三联疫苗，每隔2周注射7次。定期检测WT1-DTH、WT1-IgG抗体。评估疫苗相关不良事件、最佳临床反应和长期接种WT1三联疫苗的转移率。结果WT1-DTH阳性12例，WT1-IgG抗体阳性11例。在大多数患者中，WT1 -DTH阳性与WT1- igg抗体阳性一致。11例中有9例在3个月时病情稳定，并转入长期接种WT1三联疫苗。长期给药组GBM和AA的转移率分别为33%和25%。15例在注射部位观察到1级皮肤出疹，但未显示与接种疫苗相关的显著不良事件。结论:WT1-DTH和WT1-IgG抗体可能是一种有用的替代标志物。WT1三联疫苗接种对复发性恶性胶质瘤的长期疗效得到证实。
{"title":"10243-IMT-3 LONG-TERM OUTCOME OF A COCKTAIL WILMS' TUMOR 1 (WT1) VACCINATION USING TWO HLA CLASS I PEPTIDES AND ONE CLASS II PEPTIDE AGAINST RECURRENT MALIGNANT GLIOMAS","authors":"Naoki Kagawa, Y. Oji, Ryuichi Hirayama, Noriyuki Kijima, Y. Oka, H. Sugiyama, H. Kishima","doi":"10.1093/noajnl/vdad141.092","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.092","url":null,"abstract":"Abstract PURPOSE Our clinical trials show the safety and clinical efficacy of Wilms' tumor 1 (WT1) human leukocyte antigen (HLA) class I (Izumoto S et al. J Neurosurg. 2008) and class II (Tsuboi A et al. Cancer Immunol Immunother. 2019) peptide vaccination for recurrent malignant gliomas have been established. We have developed a cocktail vaccine (WT1 trio) containing two class I peptides (HLA-A*24:02 and HLA-A*02:01) and one II class peptide to improve more effective immunological response and improve patient's prognosis. Clinical trial of a cocktail vaccination using WT1 HLA class I and II peptides for recurrent malignant gliomas is planned to verify its safety, clinical efficacy and usefulness of surrogate markers. Patients and METHODS Twenty-three patients with recurrent malignant gliomas, which showed WT1-positive in tumor samples and HLA-A*24:02 or HLA-A*02:01-positive in blood sample, were enrolled. These patients (age: 26-72 years old, average: 49.4) included 15 cases of glioblastomas and 8 of anaplastic astrocytomas. Patients received a WT1 trio vaccine intradermally, 7 times at 2-week intervals during 3 months.WT1-DTH and WT1-IgG antibody were regularly measured. Vaccine-related adverse events, best clinical response and the transfer rate of long-term administration of WT1 trio vaccination were estimated. RESULTS WT1-DTH positive cases were 12, WT1-IgG antibody positive were in 11. In most patients, WT1 -DTH positiveness coincided with that of WT1-IgG antibody. 9 of 11 cases showed stable disease at 3 months and transferred long-term administration of WT1 trio vaccination. Transfer rate in GBM and AA of long-term administration was 33% and 25%, respectively. Grade1 skin eruption was observed at the injection sites in 15 cases, but no significant adverse events related with vaccination were shown. Conclusion: WT1-DTH and WT1-IgG antibody may be useful surrogate markers. Long-term outcome of WT1 trio vaccination was verified for recurrent malignant gliomas.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"20 24","pages":"v23 - v23"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138624408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1093/noajnl/vdad141.031
Takuma Nakashima, Yusuke Funakoshi, Ryo Yamamoto, Yuriko Sugihara, Shohei Nambu, Yoshiki Arakawa, S. Tanaka, Joji Ishida, R. Saito, R. Hanaya, Koji Yoshimoto, Y. Narita, Hiromichi Suzuki
Abstract Glioblastoma (GBM) is the most common and highly resistant malignant brain tumor. Although the previous large-scale genomic analyses identified numerous driver genes, limited progress has been achieved in the development of novel treatments. To obtain further insights into the molecular mechanisms underlying the development of GBM, an integrated analysis including epigenetic and transcriptomic analyses, known to regulate malignant tumor progression, is imperative. We analyzed 289 whole-genome sequencing (WGS) including 159 unpublished deep WGS (≥ ×120 coverage) along with RNA-seq, DNA methylation array, whole-genome bisulfite sequencing, and assay for transposase-accessible chromatin with sequencing (ATAC-seq).Mutational analysis identified known driver alterations exhibiting inter-tumoral heterogeneity. Deep WGS enables us to delineate a fine view of clonal architecture demonstrating distinct mutational signatures between clonal and subclonal mutations, suggesting different mutational processes contribute to GBM pathogenesis depending on the developmental stage. Genetic alterations are strongly associated with gene expression subtypes and DNA methylation patterns. Transcriptional deconvolution analysis reveals the heterogeneous proportion of differentiated and stem-like cell states among cases. Tumors predominantly comprised of differentiated cells display genetic and epigenetic profiles that align with the classical subtype, whereas tumors predominantly composed of stem-like cells exhibit profiles consistent with the proneural subtype. Genome-wide chromatin accessibility patterns are well associated with expression subtypes of GBM. Motif enrichment analysis of open chromatin sites identified specific transcription factor binding sites, such as the SOX10 motif in the proneural subtype, known to regulate cell states, and the CREB motif in the mesenchymal and classical subtypes, which promote cell proliferation and angiogenesis through TGF-beta regulation. These findings support a model in which the difference in chromatin structure also regulates the progression of GBM.Our analysis encompassing multilayer molecular mechanisms reveals that GBM evolves through harboring genetic alterations and epigenetic modifications depending on the tumor initiation stage and cellular differentiation status.
{"title":"10064-GGE-6 A MULTI-OMIC LANDSCAPE OF GLIOBLASTOMA, IDH-WILD TYPE","authors":"Takuma Nakashima, Yusuke Funakoshi, Ryo Yamamoto, Yuriko Sugihara, Shohei Nambu, Yoshiki Arakawa, S. Tanaka, Joji Ishida, R. Saito, R. Hanaya, Koji Yoshimoto, Y. Narita, Hiromichi Suzuki","doi":"10.1093/noajnl/vdad141.031","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.031","url":null,"abstract":"Abstract Glioblastoma (GBM) is the most common and highly resistant malignant brain tumor. Although the previous large-scale genomic analyses identified numerous driver genes, limited progress has been achieved in the development of novel treatments. To obtain further insights into the molecular mechanisms underlying the development of GBM, an integrated analysis including epigenetic and transcriptomic analyses, known to regulate malignant tumor progression, is imperative. We analyzed 289 whole-genome sequencing (WGS) including 159 unpublished deep WGS (≥ ×120 coverage) along with RNA-seq, DNA methylation array, whole-genome bisulfite sequencing, and assay for transposase-accessible chromatin with sequencing (ATAC-seq).Mutational analysis identified known driver alterations exhibiting inter-tumoral heterogeneity. Deep WGS enables us to delineate a fine view of clonal architecture demonstrating distinct mutational signatures between clonal and subclonal mutations, suggesting different mutational processes contribute to GBM pathogenesis depending on the developmental stage. Genetic alterations are strongly associated with gene expression subtypes and DNA methylation patterns. Transcriptional deconvolution analysis reveals the heterogeneous proportion of differentiated and stem-like cell states among cases. Tumors predominantly comprised of differentiated cells display genetic and epigenetic profiles that align with the classical subtype, whereas tumors predominantly composed of stem-like cells exhibit profiles consistent with the proneural subtype. Genome-wide chromatin accessibility patterns are well associated with expression subtypes of GBM. Motif enrichment analysis of open chromatin sites identified specific transcription factor binding sites, such as the SOX10 motif in the proneural subtype, known to regulate cell states, and the CREB motif in the mesenchymal and classical subtypes, which promote cell proliferation and angiogenesis through TGF-beta regulation. These findings support a model in which the difference in chromatin structure also regulates the progression of GBM.Our analysis encompassing multilayer molecular mechanisms reveals that GBM evolves through harboring genetic alterations and epigenetic modifications depending on the tumor initiation stage and cellular differentiation status.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"331 4","pages":"v8 - v8"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138625810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1093/noajnl/vdad141.085
K. Miyake, Yutaka Yamauchi, Tomono Fuke, Masaki Tatano, Momo Ishikawa, Takahiro Kanda, Kenta Suzuki, Takeshi Fujimori, Yasunori Toyota, D. Ogawa, T. Hatakeyama, M. Okauchi, M. Kawanishi
Abstract In recent years, R-MPV therapy has been widely used for treatment of primary central nervous system lymphoma (PCNSL). Although a high response rate and favorable prognosis have been reported with R-MPV therapy using multiple drugs, the treatment strategy for cases refractory to induction therapy has not been established. High-dose radiotherapy is currently recommended for refractory cases, however, the efficacy and frequency of adverse events such as leukoencephalopathy are not yet clear. Tirabrutinib has been available for recurrent or refractory PCNSL cases since 2020. However, there have been few reports on the results of tilabrutinib in these refractory cases. We have been using tirabrutinib for these refractory cases since its introduction. Here, we compared the results of tirabrutinib with those before the introduction of tirabrutinib. We investigated 30 cases with PCNSL treated with R-MPV at our hospital since 2013. 5 (16.7%) of the 30 cases revealed refractory to R-MPV. Two cases were promptly treated with irradiation (total 40-45 Gy) and both remitted, but one (a 70's male) had extensive white matter changes. One case (40's female) also had white matter changes but maintained CR for 4 years and 8 months. All three patients treated with tirabrutinib achieved CR or PR immediately, and two patients (a 60's woman and a 70's man) received whole brain irradiation of 23.4 Gy at 26 and 28 days after tirabrutinib introduction and remained in remission for 2 years 3 months and 2 years 4 months respectively with no significant white matter changes. The results suggest that tirabrutinib may be useful for cases refractory to R-MPV therapy. Because the long-term results of tirabrutinib are not yet clear, careful consideration should be given to the necessity of radiotherapy for cases who have achieved remission with tirabrutinib.
{"title":"10215-ML-7 CLINICAL OUTCOME OF TIRABRUTINIB IN PCNSL REFRACTORY TO R-MPV THERAPY","authors":"K. Miyake, Yutaka Yamauchi, Tomono Fuke, Masaki Tatano, Momo Ishikawa, Takahiro Kanda, Kenta Suzuki, Takeshi Fujimori, Yasunori Toyota, D. Ogawa, T. Hatakeyama, M. Okauchi, M. Kawanishi","doi":"10.1093/noajnl/vdad141.085","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.085","url":null,"abstract":"Abstract In recent years, R-MPV therapy has been widely used for treatment of primary central nervous system lymphoma (PCNSL). Although a high response rate and favorable prognosis have been reported with R-MPV therapy using multiple drugs, the treatment strategy for cases refractory to induction therapy has not been established. High-dose radiotherapy is currently recommended for refractory cases, however, the efficacy and frequency of adverse events such as leukoencephalopathy are not yet clear. Tirabrutinib has been available for recurrent or refractory PCNSL cases since 2020. However, there have been few reports on the results of tilabrutinib in these refractory cases. We have been using tirabrutinib for these refractory cases since its introduction. Here, we compared the results of tirabrutinib with those before the introduction of tirabrutinib. We investigated 30 cases with PCNSL treated with R-MPV at our hospital since 2013. 5 (16.7%) of the 30 cases revealed refractory to R-MPV. Two cases were promptly treated with irradiation (total 40-45 Gy) and both remitted, but one (a 70's male) had extensive white matter changes. One case (40's female) also had white matter changes but maintained CR for 4 years and 8 months. All three patients treated with tirabrutinib achieved CR or PR immediately, and two patients (a 60's woman and a 70's man) received whole brain irradiation of 23.4 Gy at 26 and 28 days after tirabrutinib introduction and remained in remission for 2 years 3 months and 2 years 4 months respectively with no significant white matter changes. The results suggest that tirabrutinib may be useful for cases refractory to R-MPV therapy. Because the long-term results of tirabrutinib are not yet clear, careful consideration should be given to the necessity of radiotherapy for cases who have achieved remission with tirabrutinib.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"34 1","pages":"v21 - v22"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138626904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Brain tumor is a major shock at diagnosis for patients and their families, and is likely to have physical, emotional, financial, and social impacts to them. These impacts are not limited to during treatment, but affect their lives even after the treatment is over. Therefore, continuous support is a must for brain tumor patients and their families. The Japan Brain Tumor Alliance (JBTA) was established in 2006 and provides nationwide patient support. Our main activities are 1) support for patients and their families, 2) provision of the latest information and networking, 3) contribution to advocacy and science, and 4) awareness-raising activities. In (1), we hold monthly social gatherings where patients and their families can share their daily problems and challenges. In (2), JBTA actively collaborated with other patient groups in Japan and abroad, and in (4), continues to provide up-to-date information via website and social media. JBTA has been particularly active in 3) by holding the seminars by health care professionals and the meetings with neurosurgeons in Japan Clinical Oncology Group to discuss newly planned clinical trials. Our cooperation with rehabilitation therapists and nurses resulted in a brochure for patients, "Brain Tumor Support Book". As members of the committee of supportive care for brain tumor patients which was established in the Japan Society of Neuro-Oncology, collaboration with various health care professionals was made to prepare leaflets for supportive care including advance care planning. Since April 2023, a survey to find out the needs of patients and caregivers is on-going. The interim report as of June 2023 showed that patients and their caregivers have difficulties to share their concerns and problems, and that they have few opportunities to receive support from multidisciplinary professionals. Therefore, more supports for brain tumor patients and their families are needed in their daily lives.
{"title":"10264-NQPC-10 ACTIVITY RECORD OF THE JAPAN BRAIN TUMOR ALLIANCE, AND THE NEEDS OF BRAIN TUMOR PATIENTS AND FAMILIES","authors":"Keiko Nomura, Hisato Tagawa, Shuji Yamaguchi, Laureline Gatellier","doi":"10.1093/noajnl/vdad141.098","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.098","url":null,"abstract":"Abstract Brain tumor is a major shock at diagnosis for patients and their families, and is likely to have physical, emotional, financial, and social impacts to them. These impacts are not limited to during treatment, but affect their lives even after the treatment is over. Therefore, continuous support is a must for brain tumor patients and their families. The Japan Brain Tumor Alliance (JBTA) was established in 2006 and provides nationwide patient support. Our main activities are 1) support for patients and their families, 2) provision of the latest information and networking, 3) contribution to advocacy and science, and 4) awareness-raising activities. In (1), we hold monthly social gatherings where patients and their families can share their daily problems and challenges. In (2), JBTA actively collaborated with other patient groups in Japan and abroad, and in (4), continues to provide up-to-date information via website and social media. JBTA has been particularly active in 3) by holding the seminars by health care professionals and the meetings with neurosurgeons in Japan Clinical Oncology Group to discuss newly planned clinical trials. Our cooperation with rehabilitation therapists and nurses resulted in a brochure for patients, \"Brain Tumor Support Book\". As members of the committee of supportive care for brain tumor patients which was established in the Japan Society of Neuro-Oncology, collaboration with various health care professionals was made to prepare leaflets for supportive care including advance care planning. Since April 2023, a survey to find out the needs of patients and caregivers is on-going. The interim report as of June 2023 showed that patients and their caregivers have difficulties to share their concerns and problems, and that they have few opportunities to receive support from multidisciplinary professionals. Therefore, more supports for brain tumor patients and their families are needed in their daily lives.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"119 8","pages":"v24 - v25"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138608407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1093/noajnl/vdad141.055
Takahiro Tsuchiya, M. Ohno, Masamichi Takahashi, Shunsuke Yanagisawa, Sho Osawa, Shohei Fujita, Y. Narita
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.
{"title":"10126-ACT-10 FACTORS AFFECTING THE PATTERN OF RECURRENCE OF IDH-WILDTYPE GLIOBLASTOMA","authors":"Takahiro Tsuchiya, M. Ohno, Masamichi Takahashi, Shunsuke Yanagisawa, Sho Osawa, Shohei Fujita, Y. Narita","doi":"10.1093/noajnl/vdad141.055","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.055","url":null,"abstract":"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.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"102 15","pages":"v14 - v14"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138608849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1093/noajnl/vdad141.058
N. Nitta, Tadateru Fukami, Kazumichi Yoshida
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.
{"title":"10143-COT-16 DIFFUSE BONE MARROW METASTASIS OF HIGH GRADE GLIOMA","authors":"N. Nitta, Tadateru Fukami, Kazumichi Yoshida","doi":"10.1093/noajnl/vdad141.058","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.058","url":null,"abstract":"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.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"105 7","pages":"v15 - v15"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138609048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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