Pub Date : 2023-12-01DOI: 10.1093/noajnl/vdad141.015
J. Fukai, Nobuhide Hayashi, H. Nakatogawa, Hiroshi Kawaji, Y. Kodama, T. Shofuda, E. Yoshioka, D. Kanematsu, A. Katsuma, Miho Sumida, Noriyuki Kijima, Y. Okita, K. Mori, Y. Kanemura
Abstract 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.
{"title":"10025-MPC-3 DIFFERENCE AMONG GENERATIONS IN PATIENTS WITH HISTONE H3-MUTATED GLIOMAS","authors":"J. Fukai, Nobuhide Hayashi, H. Nakatogawa, Hiroshi Kawaji, Y. Kodama, T. Shofuda, E. Yoshioka, D. Kanematsu, A. Katsuma, Miho Sumida, Noriyuki Kijima, Y. Okita, K. Mori, Y. Kanemura","doi":"10.1093/noajnl/vdad141.015","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.015","url":null,"abstract":"Abstract 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.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 9","pages":"v4 - v4"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138617018","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 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.
{"title":"10027-CBMS-3 POSTOPERATIVE EPILEPTOGENICITY IN GLIOBLASTOMA ARE ACHIEVED AS THE RESULT OF INTERACTIVE FLUCTUATIONS OF GLUTAMATE AND STEM CELL MARKER","authors":"Kosuke Kusakabe, Akihiro Inoue, Takanori Ohnishi, Yawara Nakamura, Yoshihiro Ohtsuka, Masahiro Nishikawa, Hajime Yano, Junya Tanaka, Hideaki Watanabe, Takeharu Kunieda","doi":"10.1093/noajnl/vdad141.016","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.016","url":null,"abstract":"Abstract 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.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 32","pages":"v4 - v5"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138617547","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/vdad141.061
Yoshiki Shiba, J. Yamaguchi, Yuhei Takido, Daiki Shimizu, Y. Kibe, Sachi Maeda, Tomohide Nishikawa, F. Ohka, K. Motomura, R. Saito
Abstract Ependymoma is an important disease in pediatric brain tumors, but reports with a large number of cases are scarce. In this study, we investigated the clinical course of 12 cases of ependymoma in children treated at our hospital.The median age was 2.5 years (0-15 years), and 10 had posterior fossa and 2 had supratentorial onset. Surgery was performed in all cases, and total resection was achieved in 9 cases (75%). Five cases were diagnosed as ependymoma, Grade II, and seven cases were diagnosed as anaplastic ependymoma, Grade III, according to the WHO revised 4th edition. Adjuvant therapy was administered in 8 patients, 6 with radiotherapy and 2 with combination chemotherapy and radiotherapy. Recurrence was seen in 6 cases, 4 of which were local recurrences and 2 of which were dissemination. The 2-year and 5-year progression-free survival rates were both 60%, and the 2-year and 5-year survival rates were 100% and 66.6%. Progression-free survival/overall survival analysis was performed, and the above results were considered to be equivalent to the published data of 27 cases (Peralia et al. Cell 2022). Progression-free survival tended to be favorable in patients with complete resection (HR = 0.18, 95% CI: 0.025-1.28) and patients with supratentorial disease (HR = 0.18, 95% CI: 0.030-1.11). No difference was seen by WHO grade (HR = 1.022, 95% CI: 0.20-5.24). Our cohort also yielded the same results regarding prognostic factors as previously reported, and WHO grade did not correlate with prognosis. The WHO 5th edition classification adopts molecular diagnosis and further subclassifies ependymoma. Since molecular diagnostics require advanced analytical techniques, there is a problem that it is difficult to put them into practical use, but surrogate markers that can be applied clinically have also been reported. This time, we will reclassify pediatric ependymoma using surrogate markers and compare it with the old classification.
{"title":"10154-PEDT-6 RETROSPECTIVE STUDY OF 12 PEDIATRIC EPENDYMOMAS TREATED AT OUR HOSPITAL","authors":"Yoshiki Shiba, J. Yamaguchi, Yuhei Takido, Daiki Shimizu, Y. Kibe, Sachi Maeda, Tomohide Nishikawa, F. Ohka, K. Motomura, R. Saito","doi":"10.1093/noajnl/vdad141.061","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.061","url":null,"abstract":"Abstract Ependymoma is an important disease in pediatric brain tumors, but reports with a large number of cases are scarce. In this study, we investigated the clinical course of 12 cases of ependymoma in children treated at our hospital.The median age was 2.5 years (0-15 years), and 10 had posterior fossa and 2 had supratentorial onset. Surgery was performed in all cases, and total resection was achieved in 9 cases (75%). Five cases were diagnosed as ependymoma, Grade II, and seven cases were diagnosed as anaplastic ependymoma, Grade III, according to the WHO revised 4th edition. Adjuvant therapy was administered in 8 patients, 6 with radiotherapy and 2 with combination chemotherapy and radiotherapy. Recurrence was seen in 6 cases, 4 of which were local recurrences and 2 of which were dissemination. The 2-year and 5-year progression-free survival rates were both 60%, and the 2-year and 5-year survival rates were 100% and 66.6%. Progression-free survival/overall survival analysis was performed, and the above results were considered to be equivalent to the published data of 27 cases (Peralia et al. Cell 2022). Progression-free survival tended to be favorable in patients with complete resection (HR = 0.18, 95% CI: 0.025-1.28) and patients with supratentorial disease (HR = 0.18, 95% CI: 0.030-1.11). No difference was seen by WHO grade (HR = 1.022, 95% CI: 0.20-5.24). Our cohort also yielded the same results regarding prognostic factors as previously reported, and WHO grade did not correlate with prognosis. The WHO 5th edition classification adopts molecular diagnosis and further subclassifies ependymoma. Since molecular diagnostics require advanced analytical techniques, there is a problem that it is difficult to put them into practical use, but surrogate markers that can be applied clinically have also been reported. This time, we will reclassify pediatric ependymoma using surrogate markers and compare it with the old classification.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 11","pages":"v15 - v16"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138618836","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 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.
{"title":"10036-IM-3 SPATIAL AND GENOMIC ANALYSES FOR THE CONSTRUCTION OF TERTIARY LYMPHOID STRUCTURE IN GLIOBLASTOMA","authors":"Ryo Mizuta, Daisuke Muraoka, Ayako Okamura, Takanari Okamoto, Shota Nohira, Yoshihiro Otani, Joji Ishida, K. Fujii, Isao Date, Hirokazu Matsushita","doi":"10.1093/noajnl/vdad141.020","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.020","url":null,"abstract":"Abstract 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.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"110 21","pages":"v5 - v6"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138608608","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/vdad141.093
K. Tateishi, Fukiko Hihara, A. Oshima, Tetsuya Yamamoto, Yukie Yoshii
Abstract High-grade gliomas (HGGs) are highly aggressive brain cancers characterized by the presence of hypoxia within a rapidly-growing tumor mass. Due to invasion to the surrounding brain parenchyma, these tumors commonly recur locally,, and novel local approaches are required. Here, we show a positron emission tomography (PET) integrated local therapy (PETx), to target HGGs. This technique consists of a one-step local theranostic application, followed by PET monitoring, with a hypoxia-targeting radiopharmaceutical64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM). We examined the safety and therapeutic potential of 64Cu-ATSM PETx for HGG patient-derived xenograft (PDX) tumors. PDX models were recapitulated the parent tumor phenotype of high expression of HIF-1 alpha and BNIP3, biomarkers of tissue hypoxia. We confirmed that HIF-1 alpha and BNIP3 were highly upregulated under hypoxia and 64Cu-ATSM was retained with potent cytotoxic effect under hypoxic condition in vitro. We determined that determined the maximum tolerated dose (MTD) to be 3.7 MBq in mouse. PETx using the MTD dose of 64Cu-ATSM indicated high tumor penetration, distribution, and retention of 64Cu-ATSM in PDX tumors, as compared to sham-treated mice. The 64Cu-ATSM PETx promoted DNA double-strand breaks, followed by apoptosis in tumors, and extensively prolonged overall survival with tolerable systemic toxicity. These findings indicate the potential of 64Cu-ATSM PETx to induce high uptake in the hypoxic tumor microenvironment, and strong therapeutic effects in PDX models. These findings establish 64Cu-ATSM PETx as a potential novel theranostic approach to facilitate local control of HGGs.
{"title":"10247-ET-8 HHYPOXIA-TARGETING RADIOPHARMACEUTICAL 64CU-ATSM FOR PET MONITORING WITH LOCAL THERAPY IN HIGH-GRADE GLIOMA PATIENT-DERIVED XENOGRAFT MODEL","authors":"K. Tateishi, Fukiko Hihara, A. Oshima, Tetsuya Yamamoto, Yukie Yoshii","doi":"10.1093/noajnl/vdad141.093","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.093","url":null,"abstract":"Abstract High-grade gliomas (HGGs) are highly aggressive brain cancers characterized by the presence of hypoxia within a rapidly-growing tumor mass. Due to invasion to the surrounding brain parenchyma, these tumors commonly recur locally,, and novel local approaches are required. Here, we show a positron emission tomography (PET) integrated local therapy (PETx), to target HGGs. This technique consists of a one-step local theranostic application, followed by PET monitoring, with a hypoxia-targeting radiopharmaceutical64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM). We examined the safety and therapeutic potential of 64Cu-ATSM PETx for HGG patient-derived xenograft (PDX) tumors. PDX models were recapitulated the parent tumor phenotype of high expression of HIF-1 alpha and BNIP3, biomarkers of tissue hypoxia. We confirmed that HIF-1 alpha and BNIP3 were highly upregulated under hypoxia and 64Cu-ATSM was retained with potent cytotoxic effect under hypoxic condition in vitro. We determined that determined the maximum tolerated dose (MTD) to be 3.7 MBq in mouse. PETx using the MTD dose of 64Cu-ATSM indicated high tumor penetration, distribution, and retention of 64Cu-ATSM in PDX tumors, as compared to sham-treated mice. The 64Cu-ATSM PETx promoted DNA double-strand breaks, followed by apoptosis in tumors, and extensively prolonged overall survival with tolerable systemic toxicity. These findings indicate the potential of 64Cu-ATSM PETx to induce high uptake in the hypoxic tumor microenvironment, and strong therapeutic effects in PDX models. These findings establish 64Cu-ATSM PETx as a potential novel theranostic approach to facilitate local control of HGGs.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 10","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":"138613140","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/vdad141.012
Y. Akasaki, Jun Takei, Yohei Yamamoto, Toshihide Tanaka, A. Teshigawara, Yuko Kamata, Keiichiro Ohara, Shohei Nawate, Tomoya Suzuki, Takaaki Yanagisawa, Yuichi Murayama
Abstract We are conducting a clinical study of immunotherapy using tumor-fused dendritic cells (TFDC) as a modality of multidisciplinary treatment for patients with glioblastoma (GBM). In this study, we analyzed the additional effect of TFDC-immunotherapy for standard therapy. Newly diagnose GBM patients who treated at four of Jikei University Hospitals were analyzed in this study. Adjuvant therapy after tumor removal surgery was maintained according to the Supp's regimen. Bevacizumab (10 mg/kg, every 2 weeks) was added when a recurred tumor was confirmed. TFDC vaccine was generated from cultured tumor cells derived from autologous surgical specimen and dendritic cells from peripheral blood, and were subcutaneously administered in the cervical region for 3-14 times. All patients who had not participated in any other immunotherapy-related clinical studies were compared as a control group in a Propensity score matching analysis. The number of analyzed patients was 55 in the immunotherapy group and 35 in the control group. The 2-year survival rate and 5-year survival rate were 20.9% and 0% in the control group, respectively, while the immunotherapy group was 45.7% and 22.7%, respectively. A statistically significant difference in overall survival was observed between them (p=0.0045). There was no difference in the observed adverse events in the two groups. Specific adverse events for TFDC-immunotherapy was not observed. In the biomarker analysis, low HLA-A expression and lack of CCDC88A, KRT4, TACC2, and TONSL mutations in tumor cells were suggested as biomarkers of better prognosis. We are currently analyzing IDH profile in those patients for further analysis. TFDC-immunotherapy should be adopted as one of the modality of multidisciplinary treatments for GBM because it is expected to have some additional effects for standard therapeutic reagents without adversely affecting them. Since there are a certain number of poor responders for this immunotherapy, predictive biomarkers of therapeutic efficacy are awaited.
{"title":"10021-IMT-1 A ROLE OF DENDRITIC CELL IMMUNOTHERAPY AS A MODALITY IN MULTIDISCIPLINARY THERAPY FOR GLIOBLASTOMA","authors":"Y. Akasaki, Jun Takei, Yohei Yamamoto, Toshihide Tanaka, A. Teshigawara, Yuko Kamata, Keiichiro Ohara, Shohei Nawate, Tomoya Suzuki, Takaaki Yanagisawa, Yuichi Murayama","doi":"10.1093/noajnl/vdad141.012","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.012","url":null,"abstract":"Abstract We are conducting a clinical study of immunotherapy using tumor-fused dendritic cells (TFDC) as a modality of multidisciplinary treatment for patients with glioblastoma (GBM). In this study, we analyzed the additional effect of TFDC-immunotherapy for standard therapy. Newly diagnose GBM patients who treated at four of Jikei University Hospitals were analyzed in this study. Adjuvant therapy after tumor removal surgery was maintained according to the Supp's regimen. Bevacizumab (10 mg/kg, every 2 weeks) was added when a recurred tumor was confirmed. TFDC vaccine was generated from cultured tumor cells derived from autologous surgical specimen and dendritic cells from peripheral blood, and were subcutaneously administered in the cervical region for 3-14 times. All patients who had not participated in any other immunotherapy-related clinical studies were compared as a control group in a Propensity score matching analysis. The number of analyzed patients was 55 in the immunotherapy group and 35 in the control group. The 2-year survival rate and 5-year survival rate were 20.9% and 0% in the control group, respectively, while the immunotherapy group was 45.7% and 22.7%, respectively. A statistically significant difference in overall survival was observed between them (p=0.0045). There was no difference in the observed adverse events in the two groups. Specific adverse events for TFDC-immunotherapy was not observed. In the biomarker analysis, low HLA-A expression and lack of CCDC88A, KRT4, TACC2, and TONSL mutations in tumor cells were suggested as biomarkers of better prognosis. We are currently analyzing IDH profile in those patients for further analysis. TFDC-immunotherapy should be adopted as one of the modality of multidisciplinary treatments for GBM because it is expected to have some additional effects for standard therapeutic reagents without adversely affecting them. Since there are a certain number of poor responders for this immunotherapy, predictive biomarkers of therapeutic efficacy are awaited.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 2","pages":"v3 - v4"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138614772","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/vdad141.045
Nobuhiro Hata, Yutaka Fujioka, R. Otsuji, Daisuke Kuga, R. Hatae, Yuhei Sangatsuda, T. Amemiya, Naoki Noguchi, Aki Sako, Minoru Fujiki, M. Mizoguchi, Koji Yoshimoto
Abstract BACKGROUND Since the WHO2016 revision, required molecular markers has been increasing, placing a burden on clinical practice of diffuse gliomas. We established an in-house molecular diagnostic platform by Senshin-Iryo (meaning advanced medical care system) and have since been partially modifying the analysis method in accordance with the WHO2021 revision. We review our achievements in total 5 years. METHODS Analyses of IDH, BRAF, and H3 point mutations, loss of heterozygosity on 1p19q and chromosomes 10 and 17, and MGMT methylation were combined into a set and submitted as a Senshin-Iryo "Drug resistance gene testing for anticancer chemotherapy" and approved in August 2018. Subsequently, in October 2021, Sanger sequencing for TERT promotor mutation was added to the set and the LOH analysis was replaced to MLPA, in order to analyze 1p19q codeletion and newly required genetic markers; EGFR, PTEN, CDKN2A, etc. in WHO2021. RESULTS The cumulative number of cases has reached over 200. Among them, 54 cases were analyzed after WHO2021 revision. The laboratory has maintained the diagnostic platform in which molecular diagnoses are steadily confirmed generally within two weeks. The initial expenditure was exceeded the income obtained from the patient co-payment, however, it has gradually been reduced to running costs alone, then is approaching profitability. After WHO2021 revision, diagnoses could be confirmed by molecular markers obtained from Senshin-Iryo in 38 of 54 cases (70.1%). Among the remaining 16, only 4 (7.4%) cases remained diagnosed as diffuse glioma, NEC, exclusionary after 12 cases in which glioblastoma was confirmed by histopathological diagnosis. CONCLUSIONS Our Senshin-Iryo trial has functioned as a salvage system to overcome the current transition period in which the continuing revision of WHO classification causing a clinical dilemma of healthcare system.
{"title":"10098-MPC-10 HOW SHOULD WE RESPOND TO REPEATED WHO REVISIONS? IN-HOUSE MOLECULAR DIAGNOSIS SYSTEM BY ADVANCED MEDICAL SYSTEM","authors":"Nobuhiro Hata, Yutaka Fujioka, R. Otsuji, Daisuke Kuga, R. Hatae, Yuhei Sangatsuda, T. Amemiya, Naoki Noguchi, Aki Sako, Minoru Fujiki, M. Mizoguchi, Koji Yoshimoto","doi":"10.1093/noajnl/vdad141.045","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.045","url":null,"abstract":"Abstract BACKGROUND Since the WHO2016 revision, required molecular markers has been increasing, placing a burden on clinical practice of diffuse gliomas. We established an in-house molecular diagnostic platform by Senshin-Iryo (meaning advanced medical care system) and have since been partially modifying the analysis method in accordance with the WHO2021 revision. We review our achievements in total 5 years. METHODS Analyses of IDH, BRAF, and H3 point mutations, loss of heterozygosity on 1p19q and chromosomes 10 and 17, and MGMT methylation were combined into a set and submitted as a Senshin-Iryo \"Drug resistance gene testing for anticancer chemotherapy\" and approved in August 2018. Subsequently, in October 2021, Sanger sequencing for TERT promotor mutation was added to the set and the LOH analysis was replaced to MLPA, in order to analyze 1p19q codeletion and newly required genetic markers; EGFR, PTEN, CDKN2A, etc. in WHO2021. RESULTS The cumulative number of cases has reached over 200. Among them, 54 cases were analyzed after WHO2021 revision. The laboratory has maintained the diagnostic platform in which molecular diagnoses are steadily confirmed generally within two weeks. The initial expenditure was exceeded the income obtained from the patient co-payment, however, it has gradually been reduced to running costs alone, then is approaching profitability. After WHO2021 revision, diagnoses could be confirmed by molecular markers obtained from Senshin-Iryo in 38 of 54 cases (70.1%). Among the remaining 16, only 4 (7.4%) cases remained diagnosed as diffuse glioma, NEC, exclusionary after 12 cases in which glioblastoma was confirmed by histopathological diagnosis. CONCLUSIONS Our Senshin-Iryo trial has functioned as a salvage system to overcome the current transition period in which the continuing revision of WHO classification causing a clinical dilemma of healthcare system.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 1","pages":"v11 - v12"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138619190","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/vdad141.017
S. Ohba, E. Sugihara, Seiji Yamada, Daijiro Kojima, Kazutaka Nakao, Eiji Fujiwara, Masanobu Kumon, Masahiro Joko, Y. Nishiyama, Jun Muto, S. Nakae, K. Adachi, Masato Abe, Hideyuki Saya, Yuichi Hirose
Abstract 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,
{"title":"10031-GGE-2 GENOMIC ANALYSIS OF MENINGIOMA USING GENE PANEL TESTING","authors":"S. Ohba, E. Sugihara, Seiji Yamada, Daijiro Kojima, Kazutaka Nakao, Eiji Fujiwara, Masanobu Kumon, Masahiro Joko, Y. Nishiyama, Jun Muto, S. Nakae, K. Adachi, Masato Abe, Hideyuki Saya, Yuichi Hirose","doi":"10.1093/noajnl/vdad141.017","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.017","url":null,"abstract":"Abstract 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,","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"21 3","pages":"v5 - v5"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138621303","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/vdad141.019
Ryohei Otani, Masachika Ikegami, Ryoji Yamada, H. Yajima, Shinji Kawamura, Sakura Shimizu, S. Tanaka, Shunsaku Takayanagi, H. Takami, Tatsuro Yamaguchi
Abstract 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.
{"title":"10035-GMC-1 PTPN11 VARIANT MAY BE A PROGNOSTIC INDICATOR OF IDH-WILDTYPE GLIOBLASTOMA IN A COMPREHENSIVE GENOMIC PROFILING COHORT","authors":"Ryohei Otani, Masachika Ikegami, Ryoji Yamada, H. Yajima, Shinji Kawamura, Sakura Shimizu, S. Tanaka, Shunsaku Takayanagi, H. Takami, Tatsuro Yamaguchi","doi":"10.1093/noajnl/vdad141.019","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.019","url":null,"abstract":"Abstract 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.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":"53 2","pages":"v5 - v5"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138623433","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/vdad141.023
K. Mitsuya, S. Deguchi, Takahiro Suzuki, N. Hayashi
Abstract BACKGROUND Management of leptomeningeal metastasis-related hydrocephalus (LM-H) is particularly challenging to control severe symptoms by intracranial hypertension. The aim of this study is assessment the outcomes of CSF diversion followed by systemic therapy for LM-H in patients with solid cancer. METHODS The authors reviewed 80 patients with LM-H required CSF diversion between October 2008 and May 2023. CSF diversion followed by chemotherapy and/or radiotherapy was indicated when a patient had (1) controlled extra-CNS metastases and (2) systemic life expectancy longer than three months after control of LM. The outcomes were analyzed with Kaplan-Meier estimates. RESULTS The patients consisted of 49 women and 31 men with a mean age of 57 years (range 35-81) . Primary cancers were lung (NSCLC) in 47 (59%), breast (BC) in 16 (20%), gastric (GC) in 10 (13%), cholangiocarcinoma 1 and other cancer in 6. Forty patients (50%) underwent whole brain radiotherapy, 17 patients (21%) cranio-spinal irradiation, and 45 patients (56%) were administrated systemic chemotherapy after CSF diversion. CSF diversion yielded a rapid improvement of their performance status (PS) in 90%. The median OS was significantly longer in patients with maintenance chemotherapy than in those without chemotherapy (4.5 versus 2 months, p<0.001). The patients were classified with EANO-ESMO clinical practice guideline (cytology, MR findings and clinical findings). Type A (linear) in 34, B (Nodular) in 14, C (linear and nodular) in 13 ID (normal) in 19. Linear enhancement groups (IA+IC) were shorter survival than other nodular (IB) and normal findings (ID) (p=0.0038) in long survivor over 6 months. Post-surgical complications were infection in 3, peritoneal dissemination in 2, and shunt malfunction in 1. CONCLUSION Combination of CSF diversion and systemic therapy is a safe and effective strategy in patients with LM-H.
{"title":"10045-MET-4 CEREBROSPINAL FLUID DIVERSION FOLLOWED BY SYSTEMIC THERAPY FOR LEPTOMENINGEAL METASTASIS-RELATED HYDROCEPHALUS IN PATIENTS WITH SOLID CANCER: ASSESSMENT WITH CLASSIFICATION OF EANO-ESMO CLINICAL PRACTICE GUIDELINE","authors":"K. Mitsuya, S. Deguchi, Takahiro Suzuki, N. Hayashi","doi":"10.1093/noajnl/vdad141.023","DOIUrl":"https://doi.org/10.1093/noajnl/vdad141.023","url":null,"abstract":"Abstract BACKGROUND Management of leptomeningeal metastasis-related hydrocephalus (LM-H) is particularly challenging to control severe symptoms by intracranial hypertension. The aim of this study is assessment the outcomes of CSF diversion followed by systemic therapy for LM-H in patients with solid cancer. METHODS The authors reviewed 80 patients with LM-H required CSF diversion between October 2008 and May 2023. CSF diversion followed by chemotherapy and/or radiotherapy was indicated when a patient had (1) controlled extra-CNS metastases and (2) systemic life expectancy longer than three months after control of LM. The outcomes were analyzed with Kaplan-Meier estimates. RESULTS The patients consisted of 49 women and 31 men with a mean age of 57 years (range 35-81) . Primary cancers were lung (NSCLC) in 47 (59%), breast (BC) in 16 (20%), gastric (GC) in 10 (13%), cholangiocarcinoma 1 and other cancer in 6. Forty patients (50%) underwent whole brain radiotherapy, 17 patients (21%) cranio-spinal irradiation, and 45 patients (56%) were administrated systemic chemotherapy after CSF diversion. CSF diversion yielded a rapid improvement of their performance status (PS) in 90%. The median OS was significantly longer in patients with maintenance chemotherapy than in those without chemotherapy (4.5 versus 2 months, p<0.001). The patients were classified with EANO-ESMO clinical practice guideline (cytology, MR findings and clinical findings). Type A (linear) in 34, B (Nodular) in 14, C (linear and nodular) in 13 ID (normal) in 19. Linear enhancement groups (IA+IC) were shorter survival than other nodular (IB) and normal findings (ID) (p=0.0038) in long survivor over 6 months. Post-surgical complications were infection in 3, peritoneal dissemination in 2, and shunt malfunction in 1. CONCLUSION Combination of CSF diversion and systemic therapy is a safe and effective strategy in patients with LM-H.","PeriodicalId":19138,"journal":{"name":"Neuro-oncology Advances","volume":" 492","pages":"v6 - v6"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138611062","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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