211 results on '"Yoshitaka Narita"'
Search Results
2. High-grade neuroepithelial tumor with EP300::BCOR fusion and negative BCOR immunohistochemical expression: a case report
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Hirokazu Sugino, Kaishi Satomi, Taisuke Mori, Yuuki Mukai, Mai Honda-Kitahara, Yuko Matsushita, Koichi Ichimura, Yoshitaka Narita, and Akihiko Yoshida
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Cancer Research ,Oncology ,Neurology (clinical) ,General Medicine - Published
- 2023
3. Utility of real-time polymerase chain reaction for the assessment of CDKN2A homozygous deletion in adult-type IDH-mutant astrocytoma
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Yuzaburo Shimizu, Mario Suzuki, Osamu Akiyama, Ikuko Ogino, Yuko Matsushita, Kaishi Satomi, Shunsuke Yanagisawa, Makoto Ohno, Masamichi Takahashi, Yasuji Miyakita, Yoshitaka Narita, Koichi Ichimura, and Akihide Kondo
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Cancer Research ,Oncology ,Neurology (clinical) ,General Medicine - Published
- 2023
4. Safety and efficacy of tumour-treating fields (TTFields) therapy for newly diagnosed glioblastoma in Japanese patients using the Novo-TTF System: a prospective post-approval study
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Ryo Nishikawa, Fumiyuki Yamasaki, Yoshiki Arakawa, Yoshihiro Muragaki, Yoshitaka Narita, Shota Tanaka, Shigeru Yamaguchi, Akitake Mukasa, and Masayuki Kanamori
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Cancer Research ,Oncology ,Radiology, Nuclear Medicine and imaging ,General Medicine - Abstract
Background Tumour-treating fields therapy is a locoregional, anti-cancer treatment. Efficacy and safety of tumour-treating fields therapy in adults with newly diagnosed glioblastoma were demonstrated in the pivotal phase 3 EF-14 study (NCT00916409). Here, we report post-approval data of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma. Methods Unsolicited post-marketing surveillance data from Japanese patients with newly diagnosed glioblastoma treated with tumour-treating fields therapy (December 2016–June 2020) were retrospectively analysed. The primary endpoints were skin, neurological and psychiatric adverse events. The secondary endpoints were 1- and 2-year overall survival rates, and the 6-month progression-free survival. adverse events were analysed using MedDRA v24.0. The overall survival and progression-free survival were assessed using the Kaplan–Meier survival analysis (log-rank testing). The Cox proportional hazard regression analyses were also performed. Results Forty patients with newly diagnosed glioblastoma were enrolled (62.5% male; median age 59 years; median baseline Karnofsky Performance Scale score 90). The most common tumour-treating-fields-therapy-related adverse event was beneath-array local skin reaction (60% of patients). The adverse events were mostly mild to moderate in severity. Neurological disorders were observed in 2.5% patients (one patient reported dysesthesia). No psychiatric disorders were reported. The 1- and 2-year overall survival rates were 77.9% (95% CI 60.6–88.3) and 53.6% (35.5–68.7%), respectively. The 6-month progression-free survival was 77.5% (61.2–87.6%). These survival rates compare favourably with those in the EF-14 trial (1- and 2-year overall survival rates: 73% [69–77%] and 43% [39–48%], respectively; 6-month progression-free survival rate: 56% (51–61%). Conclusion This post-approval, real-world evidence study revealed no new safety signals and suggests the safety and efficacy of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma.
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- 2023
5. Assessment of radiographic and prognostic characteristics of programmed death-ligand 1 expression in high-grade gliomas
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Makoto, Ohno, Shigehisa, Kitano, Kaishi, Satomi, Akihiko, Yoshida, Yasuji, Miyakita, Masamichi, Takahashi, Shunsuke, Yanagisawa, Yukie, Tamura, Koichi, Ichimura, and Yoshitaka, Narita
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Cancer Research ,Lymphocytes, Tumor-Infiltrating ,Neurology ,Oncology ,Tumor Microenvironment ,Humans ,Glioma ,Neurology (clinical) ,Prognosis ,Glioblastoma ,B7-H1 Antigen ,Isocitrate Dehydrogenase - Abstract
Gliomas are characterized by immunosuppressive features. Programmed death-ligand 1 (PD-L1) is overexpressed and plays an important role in the immunosuppressive tumor microenvironments of gliomas. However, the radiographical and prognostic significance of PD-L1 expression remains unclear.Using tissue microarrays, we evaluated PD-L1 expression and the presence of tumor-infiltrating CD4+ and CD8+T cells and CD204+macrophages using immunohistochemical analysis. Contrast enhancement area and fluid-attenuated inversion recovery (FLAIR) hyperintensity area were evaluated by two-dimensional analysis. Kaplan-Meier analysis was performed to evaluate the overall survival time in 44 patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma.We evaluated 71 patients with newly diagnosed high-grade gliomas who were treated between October 1998 and April 2012. PD-L1 expression was observed in 15 patients (21.1%). A significant association of PD-L1 expression with the CD4+ and CD8+ T cell densities, but not with CD204+ macrophage densities, was observed (p = 0.025, p = 0.0098, and p = 0.19, respectively). The FLAIR-to-enhancement ratio was significantly higher in PD-L1+ tumors than in PD-L1- tumors (p = 0.0037). PD-L1 expression did not show a significant association with the median survival time (PD-L1 + vs. PD-L1-: 19.2 vs 14.9 months; p = 0.39).PD-L1 expression was associated with CD4+ and CD8+ T cell infiltration, indicating a significant interplay between PD-L1 and immune cells. The positive correlation of PD-L1 expression with an increased FLAIR-to-enhancement ratio suggested that radiographical characteristics could reflect the immunological status. Our results did not support the prognostic impact of PD-L1 in patients with IDH-wildtype glioblastomas.
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- 2022
6. Clinical utility of comprehensive genomic profiling tests for advanced or metastatic solid tumor in clinical practice
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Hanae Ida, Takafumi Koyama, Takaaki Mizuno, Kuniko Sunami, Takashi Kubo, Kazuki Sudo, Kayoko Tao, Makoto Hirata, Kan Yonemori, Ken Kato, Takuji Okusaka, Yuichiro Ohe, Yoshiyuki Matsui, Naoya Yamazaki, Chitose Ogawa, Akira Kawai, Yoshitaka Narita, Minoru Esaki, and Noboru Yamamoto
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Adult ,Aged, 80 and over ,Cancer Research ,Adolescent ,Neoplasms, Second Primary ,Genomics ,General Medicine ,Middle Aged ,Young Adult ,Oncology ,Child, Preschool ,Neoplasms ,Biomarkers, Tumor ,Humans ,Child ,Aged - Abstract
Previous clinical trials indicate that 10%-25% of patients received genomically matched therapy after comprehensive genomic profiling (CGP) tests. However, the clinical utility of CGP tests has not been assessed in clinical practice. We assessed the clinical utility of CGP tests for advanced or metastatic solid tumor and determined the proportion of patients receiving genomically matched therapy among those with common and non-common cancers. From August 2019 to July 2020, a total of 418 patients had undergone CGP tests, and the results were discussed through the molecular tumor board at our site. The median age of patients was 57 (range: 3-86) years. Colorectal cancer was the most common, with 47 (11%) patients. Actionable genomic alterations (median 3, range: 1-17) were identified in 368 (88.0%) of 418 patients. Druggable genomic alterations were determined in 196 (46.9%) of 418 patients through the molecular tumor board. Genomically matched therapy was administered as the subsequent line of therapy in 51 (12.2%) patients, which is comparable to the proportion we previously reported in a clinical trial (13.4%) (p = 0.6919). The proportion of patients receiving genomically matched therapy was significantly higher among those with common cancers (16.2%) than non-common cancers (9.4%) (p = 0.0365). Genomically matched therapy after the CGP tests was administered to 12.2% of patients, which is similar to the proportion reported in the previous clinical trials. The clinical utility of CGP tests in patients with common cancers greatly exceeded that in patients with non-common cancers.
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- 2022
7. Prognostic factors associated with the transition in treatment methods for brain metastases from colorectal cancer
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Jun Imaizumi, Dai Shida, Narikazu Boku, Hiroshi Igaki, Jun Itami, Yasuji Miyakita, Yoshitaka Narita, Atsuo Takashima, and Yukihide Kanemitsu
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Oncology ,Surgery ,Hematology ,General Medicine - Abstract
Background Treatment of brain metastases (BMs) from colorectal cancer (CRC) has transitioned with the expansion of indications for stereotactic radiotherapy. Our study aimed to assess changes in prognosis and prognostic factors associated with changes in treatment for BMs from CRC. Methods We retrospectively surveyed treatments for and outcomes of BMs from CRC in 208 patients treated during 1997–2018. Patients were divided into two groups according to time of BM diagnosis, i.e., 1997–2013 (“first period”) and 2014–2018 (“second period”). We compared overall survival between the periods and assessed how the transition impacted prognostic factors affecting overall survival, including the following prognostic factors such as Karnofsky performance status (KPS), volume-related factors (BM number and diameter), and BM treatment modalities as covariates. Results Of the 208 patients, 147 were treated in the first period and 61 in the second period. Whole-brain radiotherapy use decreased from 67 to 39% in the second period, and stereotactic radiotherapy use increased from 30 to 62%. Median survival after BM diagnosis improved from 6.1 to 8.5 months (p = 0.0272). Multivariate analysis revealed KPS, control of primary tumor, stereotactic radiotherapy use, and chemotherapy history as independent prognostic factors during the entire observation period. Hazard ratios of KPS, primary tumor control, and stereotactic radiotherapy were higher in the second period, whereas prognostic impact of chemotherapy history before BM diagnosis was similar in both periods. Conclusion Overall survival of patients with BMs from CRC improved since 2014, which can be attributed to advances in chemotherapy and the more widespread use of stereotactic radiotherapy.
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- 2023
8. Clinical application of a highly sensitive digital PCR assay to detect a small fraction of IDH1 R132H-mutant alleles in diffuse gliomas
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Kaishi Satomi, Akihiko Yoshida, Yuko Matsushita, Hirokazu Sugino, Kenji Fujimoto, Mai Honda-Kitahara, Masamichi Takahashi, Makoto Ohno, Yasuji Miyakita, Yoshitaka Narita, Yasushi Yatabe, Junji Shibahara, and Koichi Ichimura
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Cancer Research ,Oncology ,Brain Neoplasms ,Mutation ,Humans ,Glioma ,Neurology (clinical) ,General Medicine ,Polymerase Chain Reaction ,Alleles ,Isocitrate Dehydrogenase - Abstract
The current World Health Organization classification of diffuse astrocytic and oligodendroglial tumors requires the examination of isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations. Conventional analysis tools, including Sanger DNA sequencing or pyrosequencing, fail in detecting these variants of low frequency owing to their limited sensitivity. Digital polymerase chain reaction (dPCR) is a recently developed, highly sensitive, and precise quantitative rare variant assay. This study aimed to establish a robust limit of quantitation of the dPCR assay to detect a small fraction of IDH1 R132H mutation. The dPCR assays with serially diluted IDH1 R132H constructs detected 0.05% or more of mutant IDH1 R132H in samples containing mutant DNA. The measured target/total value of the experiments was proportional to the dilution factors and was almost equal to the actual frequencies of the mutant alleles. Based on the average target/total values, together with a twofold standard deviation of the normal DNA, a limit of quantitation of 0.25% was set to secure a safe margin to judge the mutation status of the IDH1 R132H dPCR assay. In clinical settings, detecting IDH1 R132H using dPCR assays can validate ambiguous immunohistochemistry results even when conventional DNA sequencing cannot detect the mutation and assure diagnostic quality.
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- 2022
9. Transcriptome and methylome analysis of CNS germ cell tumor finds its cell-of-origin in embryogenesis and reveals shared similarities with testicular counterparts
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Hirokazu Takami, Asmaa Elzawahry, Yasin Mamatjan, Shintaro Fukushima, Kohei Fukuoka, Tomonari Suzuki, Takaaki Yanagisawa, Yuko Matsushita, Taishi Nakamura, Kaishi Satomi, Shota Tanaka, Akitake Mukasa, Nobuhito Saito, Masayuki Kanamori, Toshihiro Kumabe, Teiji Tominaga, Keiichi Kobayashi, Motoo Nagane, Toshihiko Iuchi, Kaoru Tamura, Taketoshi Maehara, Kazuhiko Sugiyama, Koji Yoshimoto, Keiichi Sakai, Masahiro Nonaka, Akio Asai, Kiyotaka Yokogami, Hideo Takeshima, Yoshitaka Narita, Soichiro Shibui, Yoichi Nakazato, Natsuko Hama, Yasushi Totoki, Mamoru Kato, Tatsuhiro Shibata, Ryo Nishikawa, Masao Matsutani, and Koichi Ichimura
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Epigenomics ,Male ,Cancer Research ,Embryonic Development ,Neoplasms, Germ Cell and Embryonal ,Seminoma ,Central Nervous System Neoplasms ,Epigenome ,Young Adult ,Oncology ,Testicular Neoplasms ,Mutation ,Basic and Translational Investigations ,Tumor Microenvironment ,Humans ,Neurology (clinical) ,Germinoma ,Child ,Transcriptome - Abstract
Background CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. Methods We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs. Results Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while nongerminomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and nongerminoma/nonseminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance. Conclusions These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.
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- 2023
10. MGMT gene promoter methylation by pyrosequencing method correlates volumetric response and neurological status in IDH wild-type glioblastomas
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Tomohiro Hosoya, Masamichi Takahashi, Mai Honda-Kitahara, Yasuji Miyakita, Makoto Ohno, Shunsuke Yanagisawa, Takaki Omura, Daisuke Kawauchi, Yukie Tamura, Miyu Kikuchi, Tomoyuki Nakano, Akihiko Yoshida, Hiroshi Igaki, Yuko Matsushita, Koichi Ichimura, and Yoshitaka Narita
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Cancer Research ,Neoplasm, Residual ,Brain Neoplasms ,Tumor Suppressor Proteins ,High-Throughput Nucleotide Sequencing ,DNA Methylation ,Prognosis ,O(6)-Methylguanine-DNA Methyltransferase ,DNA Repair Enzymes ,Neurology ,Oncology ,Humans ,Neurology (clinical) ,Glioblastoma ,DNA Modification Methylases ,Retrospective Studies - Abstract
Purpose Although the usefulness of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation analysis for predicting response to chemoradiotherapy and the prognosis of patients with glioblastoma has been widely reported, there is still no consensus regarding how to define MGMT promoter methylation percentage (MGMTpm%) cutoffs by pyrosequencing method. The aim of this study was to determine the optimal cutoff value of MGMT promoter methylation status using volumetric analysis focused on the tumor volume ratio (TVR) measured by MRI. Methods This retrospective study included newly diagnosed IDH wild-type glioblastoma patients with residual tumor after surgery, followed by local radiotherapy with temozolomide. TVR was defined as the tumor volume at 6 months after the initial chemoradiotherapy administration divided by the tumor volume before the start of therapy. The mean MGMTpm% of 16 CpG islands (74–89) was analyzed using pyrosequencing. We statistically analyzed the correlation between MGMTpm%, TVR, and change in Karnofsky performance status. Results The study included 44 patients with residual tumors. Thirteen (92.9%) of 14 patients with MGMTpm% ≥ 23.9% showed 50% or more volumetric response, leading to prolonged survival, and 17 (70.8%) of 24 patients with MGMTpm% Conclusion Evaluation of MGMTpm% by pyrosequencing is important in predicting the volumetric response and prognosis of glioblastoma patients with residual tumors.
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- 2022
11. Evaluation of the efficacy and safety of TAS0313 in adults with recurrent glioblastoma
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Yoshitaka Narita, Yoshiko Okita, and Yoshiki Arakawa
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Adult ,Epitopes ,Cancer Research ,Oncology ,Brain Neoplasms ,Immunoglobulin G ,Immunology ,Humans ,Immunology and Allergy ,Glioblastoma ,Cancer Vaccines - Abstract
Background TAS0313 is a multi-epitope long peptide vaccine targeting several cancer-associated antigens highly expressed in multiple cancer types, including glioblastoma (GBM). This cohort of a Phase 2 part evaluated the efficacy and safety of TAS0313 in patients with GBM. Methods TAS0313 (27 mg) was administered subcutaneously on Days 1, 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). The secondary endpoints were the disease control rate, progression-free survival (PFS) and 6- and 12-month progression-free survival rates (PFR) and safety. Immunological response was assessed as an exploratory endpoint. Results The best overall response was partial response in 1 patient, and the ORR (95% CI) was 11.1% (0.3–48.2%) in the per-protocol set (n = 9). A further 3 patients achieved stable disease, for a disease control rate (95% CI) of 44.4% (13.7–78.8%). Median (95% CI) PFS was 1.7 (1.3–NE) months and 6- and 12-month PFRs (95% CI) were 22.2% (3.4–51.3%) each. Common (≥ 20% incidence) treatment-related adverse events (AEs) were injection site reactions (n = 8, 80.0%), followed by pyrexia (n = 7, 70.0%), and malaise, injection site erythema and injection site pruritus (n = 2, 20.0% each). There were no grade 4 or 5 treatment-related AEs. No deaths occurred during the study. In some patients, TAS0313 treatment was confirmed to increase cytotoxic T lymphocyte and immunoglobulin G levels compared with baseline. Conclusion TAS0313, a multi-epitope long peptide vaccine, demonstrated promising efficacy and acceptable safety in patients with recurrent GBM. Clinical trial registration JapicCTI-183824 (Date of registration: Jan 11, 2018)
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- 2022
12. Eribulin prolongs survival in an orthotopic xenograft mouse model of malignant meningioma
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Daisuke Kawauchi, Kenkichi Masutomi, Taketoshi Maehara, Hideyuki Arita, Yoshitaka Narita, Arata Tomiyama, Mami Yasukawa, Kenji Fujimoto, Tomoyuki Nakano, Koichi Ichimura, Akihide Kondo, Takamune Achiha, and Masamichi Takahashi
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Cancer Research ,Malignant meningioma ,medicine.medical_treatment ,Brain tumor ,Antineoplastic Agents ,Apoptosis ,Kaplan-Meier Estimate ,Meningioma ,Mice ,chemistry.chemical_compound ,Cell Movement ,Cell Line, Tumor ,Meningeal Neoplasms ,otorhinolaryngologic diseases ,Animals ,Humans ,Medicine ,Telomerase reverse transcriptase ,Viability assay ,Furans ,Promoter Regions, Genetic ,Telomerase ,neoplasms ,Cell Proliferation ,Chemotherapy ,business.industry ,Cell growth ,Cell Cycle Checkpoints ,General Medicine ,Ketones ,medicine.disease ,Xenograft Model Antitumor Assays ,nervous system diseases ,Oncology ,chemistry ,Mutation ,Cancer research ,business ,Eribulin - Abstract
Meningioma is the most common intracranial tumor, with generally favorable patient prognosis. However, patients with malignant meningioma typically experience recurrence, undergo multiple surgical resections, and ultimately have a poor prognosis. Thus far, effective chemotherapy for malignant meningiomas has not been established. We recently reported the efficacy of eribulin (Halaven ®) for glioblastoma with a telomerase reverse transcriptase (TERT) promoter mutation. This study investigated the anti-tumor effect of eribulin against TERT promoter mutation-harboring human malignant meningioma cell lines in vitro and in vivo. Two meningioma cell lines, IOMM-Lee and HKBMM, were used in this study. The strong inhibition of cell proliferation by eribulin via cell cycle arrest was demonstrated through viability assay and flow cytometry. Apoptotic cell death in malignant meningioma cell lines was determined through vital dye assay and immunoblotting. Moreover, a wound healing assay revealed the suppression of tumor cell migration after eribulin exposure. Intraperitoneal administration of eribulin significantly prolonged the survival of orthotopic xenograft mouse models of both malignant meningioma cell lines implanted in the subdural space (p < 0.0001). Immunohistochemistry confirmed apoptosis in brain tumor tissue treated with eribulin. Overall, these results suggest that eribulin is a potential therapeutic agent for malignant meningiomas.
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- 2021
13. Prediction of tissue-of-origin of early stage cancers using serum miRNomes
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Juntaro, Matsuzaki, Ken, Kato, Kenta, Oono, Naoto, Tsuchiya, Kazuki, Sudo, Akihiko, Shimomura, Kenji, Tamura, Sho, Shiino, Takayuki, Kinoshita, Hiroyuki, Daiko, Takeyuki, Wada, Hitoshi, Katai, Hiroki, Ochiai, Yukihide, Kanemitsu, Hiroyuki, Takamaru, Seiichiro, Abe, Yutaka, Saito, Narikazu, Boku, Shunsuke, Kondo, Hideki, Ueno, Takuji, Okusaka, Kazuaki, Shimada, Yuichiro, Ohe, Keisuke, Asakura, Yukihiro, Yoshida, Shun-Ichi, Watanabe, Naofumi, Asano, Akira, Kawai, Makoto, Ohno, Yoshitaka, Narita, Mitsuya, Ishikawa, Tomoyasu, Kato, Hiroyuki, Fujimoto, Shumpei, Niida, Hiromi, Sakamoto, Satoko, Takizawa, Takuya, Akiba, Daisuke, Okanohara, Kouya, Shiraishi, Takashi, Kohno, Fumitaka, Takeshita, Hitoshi, Nakagama, Nobuyuki, Ota, Takahiro, Ochiya, and Hideaki, Takashima
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Cancer Research ,Oncology - Abstract
Background Noninvasive detection of early stage cancers with accurate prediction of tumor tissue-of-origin could improve patient prognosis. Because miRNA profiles differ between organs, circulating miRNomics represent a promising method for early detection of cancers, but this has not been shown conclusively. Methods A serum miRNA profile (miRNomes)–based classifier was evaluated for its ability to discriminate cancer types using advanced machine learning. The training set comprised 7931 serum samples from patients with 13 types of solid cancers and 5013 noncancer samples. The validation set consisted of 1990 cancer and 1256 noncancer samples. The contribution of each miRNA to the cancer-type classification was evaluated, and those with a high contribution were identified. Results Cancer type was predicted with an accuracy of 0.88 (95% confidence interval [CI] = 0.87 to 0.90) in all stages and an accuracy of 0.90 (95% CI = 0.88 to 0.91) in resectable stages (stages 0-II). The F1 score for the discrimination of the 13 cancer types was 0.93. Optimal classification performance was achieved with at least 100 miRNAs that contributed the strongest to accurate prediction of cancer type. Assessment of tissue expression patterns of these miRNAs suggested that miRNAs secreted from the tumor environment could be used to establish cancer type–specific serum miRNomes. Conclusions This study demonstrates that large-scale serum miRNomics in combination with machine learning could lead to the development of a blood-based cancer classification system. Further investigations of the regulating mechanisms of the miRNAs that contributed strongly to accurate prediction of cancer type could pave the way for the clinical use of circulating miRNA diagnostics.
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- 2022
14. Bevacizumab beyond Progression for Newly Diagnosed Glioblastoma (BIOMARK): Phase II Safety, Efficacy and Biomarker Study
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Motoo Nagane, Koichi Ichimura, Ritsuko Onuki, Daichi Narushima, Mai Honda-Kitahara, Kaishi Satomi, Arata Tomiyama, Yasuhito Arai, Tatsuhiro Shibata, Yoshitaka Narita, Takeo Uzuka, Hideo Nakamura, Mitsutoshi Nakada, Yoshiki Arakawa, Takanori Ohnishi, Akitake Mukasa, Shota Tanaka, Toshihiko Wakabayashi, Tomokazu Aoki, Shigeki Aoki, Soichiro Shibui, Masao Matsutani, Keisuke Ishizawa, Hideaki Yokoo, Hiroyoshi Suzuki, Satoshi Morita, Mamoru Kato, and Ryo Nishikawa
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Cancer Research ,Oncology ,bevacizumab ,glioblastoma ,temozolomide ,progression ,biomarker - Abstract
We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, followed by bevacizumab monotherapy, and secondary therapy (BBP: bevacizumab upon progression). Ninety patients received the protocol-defined primary therapy (BBP group, n = 25). Median overall survival (mOS) and median progression-free survival (mPFS) were 25.0 and 14.9 months, respectively. In the BBP group, in which O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors predominated, mOS and mPFS were 5.8 and 1.9 months from BBP initiation and 16.8 and 11.4 months from the initial diagnosis, respectively. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. No unexpected adverse events occurred. Expression profiling using RNA sequencing identified that Cluster 2, which was enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. Cluster 2 was identified as a significantly favorable independent predictor for PFS, along with younger age and methylated MGMT. The novel expression classifier may predict the prognosis of glioblastoma patients treated with bevacizumab.
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- 2022
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15. Surgical site infection caused by Rhizopus caespitosus after metastasectomy for osteosarcoma: First report of infection in humans
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Kazuki Tanimura, Miho Nakajima, Nami Shirakawa, Kayoko Tao, Masanaka Sugiyama, Yuko Watanabe, Ayumu Arakawa, Miyu Kikuchi, Masamichi Takahashi, Yoshitaka Narita, Mika Shiotsuka, Osamu Kobayashi, Satoshi Iwata, Akihiko Yoshida, Masahiro Abe, Satoshi Yamagoe, Yoshitsugu Miyazaki, and Chitose Ogawa
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Oncology ,Pediatrics, Perinatology and Child Health ,Hematology - Published
- 2022
16. Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance
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Takashi Fujii, Daisuke Kawauchi, Eita Uchida, Atsuo Yoshino, Yoshitaka Narita, Nobuyoshi Sasaki, Kojiro Wada, Tatsuya Kobayashi, Masamichi Takahashi, Koichi Ichimura, Arata Tomiyama, Kaishi Satomi, Shun Yamamuro, Akihide Kondo, and Tomoyuki Nakano
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Cancer Research ,Nitrosourea ,nitrosourea ,lomustine ,Mice, Nude ,Salvage therapy ,Antineoplastic Agents ,Methylation ,Histones ,Mice ,chemistry.chemical_compound ,In vivo ,Temozolomide ,medicine ,Animals ,Humans ,U87 ,nimustine ,DNA Modification Methylases ,neoplasms ,Salvage Therapy ,Mice, Inbred BALB C ,Brain Neoplasms ,business.industry ,Tumor Suppressor Proteins ,Nimustine ,glioblastoma ,temozolomide resistance ,Original Articles ,General Medicine ,Lomustine ,Xenograft Model Antitumor Assays ,nervous system diseases ,DNA Repair Enzymes ,Drug Discovery and Delivery ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Apoptosis ,Cancer research ,Female ,Original Article ,Neoplasm Recurrence, Local ,business ,Injections, Intraperitoneal ,medicine.drug - Abstract
Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ‐resistant GBM (TMZ‐R‐GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ‐R‐GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ‐R‐GBM. As a model of TMZ‐R‐GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ‐R‐cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ‐R‐cells after the administration of each drug, the antitumor effects of TMZ against TMZ‐R‐cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ‐R‐cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ‐R‐cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ‐R‐cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ‐R‐GBM., We investigated the antitumor effects of lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents for glioblastomas (GBM), against the model cells of human GBM cases, which gained acquired temozolomide (TMZ) resistance after continuous treatment by TMZ (TMZ‐R‐cells). We discovered that the antitumor effects of TMZ against TMZ‐R‐cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ‐R‐cells as well as parental cells both in vitro and in vivo. In addition, it was also demonstrated that TMZ resistance of TMZ‐R‐cells was regulated at the level of DNA damage response initiation. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against GBM cases with acquired TMZ resistance.
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- 2021
17. Safety and efficacy of depatuxizumab mafodotin in Japanese patients with malignant glioma: A nonrandomized, phase 1/2 trial
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Keisuke Ueki, Masayuki Kanamori, Hao Xiong, Yasuko Nishimura, Motoo Nagane, Yoshihiro Muragaki, Masakazu Yamada, Yoshitaka Narita, Kazuhiko Mishima, Masahide Matsuda, Katsunori Asai, Shota Kasai, Toshihiro Kumabe, Naoki Kagawa, Isao Date, Hiroyuki Kobayashi, Jun-ichiro Kuroda, Christopher Ocampo, and Takaaki Beppu
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,temozolomide ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Drug Therapy ,Japan ,Clinical Research ,Glioma ,Internal medicine ,medicine ,Clinical endpoint ,Anti–epidermal growth factor receptor therapy ,Humans ,depatuxizumab mafodotin ,Adverse effect ,Aged ,Chemotherapy ,Temozolomide ,business.industry ,Brain Neoplasms ,Incidence (epidemiology) ,Gene Amplification ,General Medicine ,Original Articles ,malignant glioma ,Chemoradiotherapy ,Middle Aged ,medicine.disease ,Survival Analysis ,ErbB Receptors ,Treatment Outcome ,Oncology ,Concomitant ,Original Article ,Female ,Neoplasm Grading ,business ,medicine.drug ,recurrent glioblastoma - Abstract
INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux‐M), as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second‐line arms, patients with EGFR‐amplified recurrent WHO grade III/IV glioma received Depatux‐M plus chemotherapy (temozolomide) or Depatux‐M alone regardless of EGFR status. In first‐line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux‐M plus chemoradiotherapy. The study was halted following lack of survival benefit with first‐line Depatux‐M in the global trial INTELLANCE‐1. The primary endpoint was 6‐month progression‐free survival (PFS) in patients with EGFR‐amplified tumors receiving second‐line Depatux‐M plus chemotherapy. Common nonocular treatment‐emergent adverse events (TEAEs) with both second‐line and first‐line Depatux‐M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second‐line Depatux‐M plus chemotherapy and all patients receiving second‐line Depatux‐M alone or first‐line Depatux‐M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6‐month PFS estimate was 25.6% (95% confidence interval [CI] 11.4‒42.6), and median PFS was 2.1 months (95% CI 1.9‒3.9) with second‐line Depatux‐M plus chemotherapy in the EGFR‐amplified subgroup. This study showed acceptable safety profile of Depatux‐M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263)., INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin, as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in Japanese patients with World Health Organization grade III/IV glioma. The results of this trial demonstrate an acceptable safety profile of depatuxizumab mafodotin, with ocular side effects being the most common adverse events that were mostly reversible. Second‐line depatuxizumab mafodotin in combination with temozolomide resulted in a 6‐month progression‐free survival estimate of 25.6% (95% confidence interval 11.4‒42.6) in patients with EGFR‐amplified tumors and showed encouraging antitumor activity in this subgroup of patients (NCT02590263).
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- 2021
18. Liquid biopsy of cerebrospinal fluid for MYD88 L265P mutation is useful for diagnosis of central nervous system lymphoma
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Yoshiaki Shiokawa, Takaki Omura, Saki Shimizu, Koichi Ichimura, Motoo Nagane, Akihide Kondo, Kuniaki Saito, Yoshitaka Narita, Yuko Matushita, Keiichi Kobayashi, Nobuyoshi Sasaki, Yoshiko Nakano, and Yuki Yamagishi
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Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Stereotactic biopsy ,Lymphoma ,medicine.medical_treatment ,medicine.disease_cause ,Polymerase Chain Reaction ,Sensitivity and Specificity ,cerebrospinal fluid ,Central Nervous System Neoplasms ,Cerebrospinal fluid ,Clinical Research ,Humans ,Medicine ,Digital polymerase chain reaction ,central nervous system lymphoma ,Liquid biopsy ,Allele ,Aged ,Aged, 80 and over ,Chemotherapy ,Mutation ,liquid biopsy ,medicine.diagnostic_test ,digital PCR ,business.industry ,High-Throughput Nucleotide Sequencing ,Original Articles ,DNA, Neoplasm ,General Medicine ,Middle Aged ,medicine.disease ,Oncology ,Myeloid Differentiation Factor 88 ,Original Article ,Female ,MYD88 ,business ,Cell-Free Nucleic Acids - Abstract
The current standard of diagnosing central nervous system (CNS) lymphoma is stereotactic biopsy, however the procedure has a risk of surgical complication. Liquid biopsy of the CSF is a less invasive, non‐surgical method that can be used for diagnosing CNS lymphoma. In this study, we established a clinically applicable protocol for determining mutations in MYD88 in the CSF of patients with CNS lymphoma. CSF was collected prior to the start of chemotherapy from 42 patients with CNS lymphoma and matched tumor specimens. Mutations in MYD88 in 33 tumor samples were identified using pyrosequencing. Using 10 ng each of cellular DNA and cell‐free DNA (cfDNA) extracted from the CSF, the MYD88 L265P mutation was detected using digital PCR. The conditions to judge mutation were rigorously determined. The median Target/Total value of cases with MYD88 mutations in the tumors was 5.1% in cellular DNA and 22.0% in cfDNA. The criteria to judge mutation were then determined, with a Target/Total value of 0.25% as the cutoff. When MYD88 mutations were determined based on these criteria, the sensitivity and specificity were 92.2% and 100%, respectively, with cellular DNA; and the sensitivity and specificity were 100% with cfDNA. Therefore, the DNA yield, mutated allele fraction, and accuracy were significantly higher in cfDNA compared with that in cellular DNA. Taken together, this study highlights the importance of detecting the MYD88 L265P mutation in cfDNA of the CSF for diagnosing CNS lymphoma using digital PCR, a highly accurate and clinically applicable method., Development of a liquid biopsy for less invasive diagnosis of CNS lymphoma is in progress. In this study, the conditions for detecting the MYD88 L265P mutation by digital PCR were set, and extremely high accuracy was confirmed. This method is fully clinically feasible.
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- 2021
19. Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study
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Mitsutoshi Nakada, Naoki Kagawa, Manabu Natsumeda, Shota Tanaka, Yukihiko Sonoda, Yasuo Iwadate, Tomokazu Aoki, Nobuhiro Hata, Hironobu Minami, Yuki Hirata, Shigeru Yamaguchi, Yoshiki Arakawa, Satoshi Suehiro, Kazuhiko Sugiyama, Toshihiko Wakabayashi, Yoichi Nakazato, Shunsuke Hagihara, Jun-ichiro Kuroda, Yoshitaka Narita, Yoshihiro Muragaki, Motoo Nagane, Ryo Nishikawa, and Eiichi Ishikawa
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Oncology ,medicine.medical_specialty ,Gliosarcoma ,Bevacizumab ,Phases of clinical research ,Japan ,Internal medicine ,Glioma ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Clinical endpoint ,Humans ,Programmed cell death ,Temozolomide ,business.industry ,Bayesian approach ,Bayes Theorem ,Hematology ,General Medicine ,medicine.disease ,Clinical Trial ,Confidence interval ,Phase II ,Nivolumab ,Surgery ,Original Article ,Neoplasm Recurrence, Local ,business ,Glioblastoma ,medicine.drug - Abstract
Background An open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence glioblastoma. Methods Patients with first recurrence of histologically confirmed World Health Organization Grade IV glioma, after treatment with temozolomide and radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression (Response Assessment in Neuro-Oncology criteria) or toxicity. Primary endpoint was 1-year overall survival rate assessed by Bayesian approach. The prespecified efficacy criterion was that the Bayesian posterior probability threshold for exceeding the 1-year overall survival of bevacizumab (34.5%) from the Japanese phase 2 study (JO22506) would be 93%. Results Of the 50 enrolled patients, 44 (88.0%) had recurrent malignant glioma (glioblastoma, gliosarcoma), and of these, 26 (59.1%) had at least one measurable lesion at baseline. The Bayesian posterior mean 1-year overall survival (90% Bayesian credible intervals) with nivolumab was 54.4% (42.27–66.21), and the Bayesian posterior probability of exceeding the threshold of the 1-year overall survival rate of bevacizumab (34.5%) was 99.7%. Median (90% confidence interval) overall and progression-free survival was 13.1 (10.4–17.7) and 1.5 (1.4–1.5) months, respectively. One partial response was observed (objective response rate 1/26 evaluable patients [3.8%]). Treatment-related adverse event rates were 14.0% for Grade 3–4 and 2.0% for Grade 5; most adverse events resolved and were manageable. Conclusions The 1-year overall survival with nivolumab monotherapy in Japanese patients with glioblastoma met the prespecified efficacy criterion. The safety profile of nivolumab was consistent with that observed in other tumor types. Clinical Trial Registration JapicCTI-152967.
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- 2021
20. Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C
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Kazuhiko Mishima, Ryo Nishikawa, Yoshitaka Narita, Junki Mizusawa, Minako Sumi, Tomoyuki Koga, Nobuyoshi Sasaki, Manabu Kinoshita, Motoo Nagane, Yoshiki Arakawa, Koji Yoshimoto, Ichiyo Shibahara, Naoki Shinojima, Kenichiro Asano, Takao Tsurubuchi, Hikaru Sasaki, Akio Asai, Takashi Sasayama, Yasutomo Momii, Atsushi Sasaki, Shigeo Nakamura, Masaru Kojima, Jun-ichi Tamaru, Kazuhiro Tsuchiya, Miho Gomyo, Kayoko Abe, Manabu Natsumeda, Fumiyuki Yamasaki, Hiroshi Katayama, and Haruhiko Fukuda
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
Background The goal was to determine whether the addition of temozolomide (TMZ) to the standard treatment of high-dose methotrexate (HD-MTX) and whole-brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL) improves survival. Methods An open-label, randomized, phase III trial was conducted in Japan, enrolling immunocompetent patients aged 20–70 years with histologically confirmed, newly diagnosed PCNSL. After administration of HD-MTX, patients were randomly assigned to receive WBRT (30 Gy) ± 10 Gy boost (arm A) or WBRT ± boost with concomitant and maintenance TMZ for 2 years (arm B). The primary endpoint was overall survival (OS). Results Between September 29, 2014 and October 15, 2018, 134 patients were enrolled, of whom 122 were randomly assigned and analyzed. At the planned interim analysis, 2-year OS was 86.8% (95% confidence interval [CI]: 72.5–94.0%) in arm A and 71.4% (56.0–82.2%) in arm B. The hazard ratio was 2.18 (95% CI: 0.95–4.98), with the predicted probability of showing the superiority of arm B at the final analysis estimated to be 1.3%. The study was terminated early due to futility. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was measured in 115 tumors, and it was neither prognostic nor predictive of TMZ response. Conclusions This study failed to demonstrate the benefit of concomitant and maintenance TMZ in newly diagnosed PCNSL.
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- 2022
21. Effect of adjuvant radiotherapy after subtotal resection for WHO grade I meningioma: a propensity score matching analysis of the Brain Tumor Registry of Japan
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Soichi Oya, Hirofumi Nakatomi, Nao Ichihara, Yukinori Akiyama, Masahiko Wanibuchi, Yoshitaka Narita, Fusao Ikawa, and Nobuhiro Mikuni
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Cancer Research ,medicine.medical_specialty ,Brain tumor ,Urology ,Subgroup analysis ,World Health Organization ,Skull Base Neoplasms ,Meningioma ,03 medical and health sciences ,0302 clinical medicine ,Japan ,Interquartile range ,Meningeal Neoplasms ,otorhinolaryngologic diseases ,medicine ,Humans ,Registries ,Propensity Score ,Retrospective Studies ,Brain Neoplasms ,Proportional hazards model ,business.industry ,Therapeutic effect ,Hazard ratio ,medicine.disease ,Treatment Outcome ,Neurology ,Oncology ,030220 oncology & carcinogenesis ,Propensity score matching ,Radiotherapy, Adjuvant ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
This study aimed to improve the understanding of the role of adjuvant radiotherapy (AR) after subtotal resection (STR) of World Health Organization (WHO) grade I meningiomas. We retrospectively reviewed the Brain Tumor Registry of Japan database. Among 7341 patients diagnosed with intracranial meningioma during 2001–2008, we identified 406 patients with WHO grade I meningioma treated with STR as initial treatment. Data on progression-free survival (PFS) were assessed for their relevance to clinical factors including age, sex, tumor location and size, presence of preoperative symptoms, and AR. AR was administered for 73 patients (18.0%). Regrowth occurred in 90 cases (22.2%) during the median follow-up period of 6.0 years (interquartile range, 2.7–7.7 years). Multivariate Cox regression analysis of the entire cohort showed that no AR was associated with significantly shorter PFS (hazard ratio [HR] 2.52, 95% confidence interval [CI] 1.33–5.42, p = 0.004). The therapeutic effect of AR was confirmed for skull base, but not non-skull base, meningiomas (p = 0.003 and 0.69, respectively). Propensity score matching analysis balanced the influence of confounding factors to generate AR+ and AR− cohorts of 73 patients each. PFS was significantly longer in the AR+ cohort than in the AR− cohort (HR 3.46, 95% CI 1.53–8.59, p = 0.003). Subgroup analysis demonstrated the favorable effect of AR only for skull base meningiomas. Our study revealed that AR improves tumor control after STR in WHO grade I meningiomas. However, this beneficial effect might be limited to skull base meningiomas.
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- 2021
22. Outcomes of salvage fractionated re-irradiation combined with bevacizumab for recurrent high-grade gliomas that progressed after bevacizumab treatment**
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Hajime Yonezawa, Yoshitaka Narita, Satoshi Shima, Yukie Tamura, Masamichi Takahashi, Yuko Matsushita, Hiroshi Igaki, Yasuji Miyakita, Koichi Ichimura, and Makoto Ohno
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Angiogenesis Inhibitors ,Gastroenterology ,Re-Irradiation ,Young Adult ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Glioma ,Internal medicine ,Brainstem glioma ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Aged ,Aged, 80 and over ,Salvage Therapy ,Leukopenia ,Proteinuria ,Brain Neoplasms ,business.industry ,Standard treatment ,Not Otherwise Specified ,General Medicine ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Survival Analysis ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,Neoplasm Recurrence, Local ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug ,Anaplastic astrocytoma - Abstract
Background There is no standard treatment for patients with recurrent high-grade gliomas who progress after bevacizumab treatment. We evaluated the outcomes of re-irradiation combined with bevacizumab for patients refractory to bevacizumab. Methods Between January 2015 and September 2019, patients with progression after bevacizumab treatment were treated with re-irradiation combined with bevacizumab (25 Gy in five fractions). Results Fourteen patients [glioblastoma, isocitrate dehydrogenase (IDH) wild type (N = 6), glioblastoma, IDH mutant (N = 4), anaplastic astrocytoma, IDH wild type (N = 1), anaplastic astrocytoma, IDH mutant (N = 1), glioblastoma, not otherwise specified (N = 1) and radiologically diagnosed brainstem glioma (N = 1)] were included in this study. The median survival and progression-free survival times after re-irradiation combined with bevacizumab were 6.1 and 3.8 months, respectively. The 6-month survival and progression-free survival rates were 54.5 and 15.7%, respectively. Patients with a Karnofsky performance status of ≥70 tended to have longer median survival time (9.3 vs. 5.4 months, respectively; P = 0.058) and had a significantly longer median progression-free survival time (4.2 vs. 3.7 months, respectively; P = 0.046) than those with a Karnofsky performance status of Conclusions Re-irradiation combined with bevacizumab for patients with recurrent high-grade gliomas who progress after bevacizumab treatment was feasible. Re-irradiation combined with bevacizumab is a potential treatment option, especially for patients with a Karnofsky performance status of ≥70.
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- 2021
23. Evidence-based recommendations on categories for extent of resection in diffuse glioma
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Martin J. van den Bent, Yoshitaka Narita, Michael Weller, Michael A. Vogelbaum, Daniel P. Cahill, Mitchel S. Berger, Lorenzo Bello, Philipp Karschnia, Joerg-Christian Tonn, University of Zurich, and Tonn, Joerg-Christian
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0301 basic medicine ,Surgical resection ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Evidence-based practice ,610 Medicine & health ,Extent of resection ,Neurosurgical Procedures ,03 medical and health sciences ,Diffuse Glioma ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Terminology as Topic ,Humans ,Medicine ,1306 Cancer Research ,Evidence-Based Medicine ,Brain Neoplasms ,business.industry ,Subtotal Resection ,Glioma ,medicine.disease ,Magnetic Resonance Imaging ,10040 Clinic for Neurology ,Clinical trial ,Treatment Outcome ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Near total resection ,2730 Oncology ,Radiology ,Neoplasm Grading ,business ,Glioblastoma - Abstract
Surgical resection represents the standard of care in diffuse glioma, and more extensive tumour resection appears to be associated with favourable outcome. Up to now, terminology to describe extent of resection has been inconsistently applied across clinical trials which hampers comparative analysis of cohorts between different studies. Based on a comprehensive literature review, we developed evidence-based expert recommendations on categories for extent of resection. Recommendations are formulated for the categories ‘biopsy’, ‘partial resection’, ‘subtotal resection’, ‘near total resection’, ‘complete resection’ and ‘supramaximal resection’. Definitions rest on reduction of contrast- and non–contrast-enhancing tumour in glioblastoma, and on reduction of T2/FLAIR-hyperintense tumour in gliomas WHO grade 2 or 3. Both relative reduction of tumour volume (in percentage) as a measurement of surgical efficacy and absolute residual tumour volume (in cm3) as a measurement of remaining tumour burden are incorporated into the categories for extent of resection. Class of evidence for the proposed categories ranges from class IIB to IV. Limitations of the suggested categories are discussed. The proposed categories on extent of resection offer a framework to standardize nomenclature based on previous studies, and will need to be evaluated in prospective, molecularly well-defined cohorts. Our categories may eventually help as a stratification factor for future clinical trials.
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- 2021
24. ET-7 EVALUATION OF HYPOXIA-TARGETING RADIOPHARMACEUTICAL64CU-ATSM FOR PET MONITORING WITH LOCAL THERAPY IN HIGH-GRADE GLIOMA MODEL
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Yukie Yoshii, Fukiko Hihara, Hiroki Matsumoto, Chika Igarashi, Tomoko Tachibana, Mitsuhiro Shinada, Zhang Ming-Rong, Akito Oshima, Hidemitsu Sato, Yoshitaka Narita, Hiroaki Kurihara, Tetsuya Yamamoto, Tatsuya Higashi, and Kensuke Tateishi
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Oncology ,Surgery ,Neurology (clinical) - Abstract
World Health Organization (WHO)-defined central nervous system (CNS) grade 4 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, despite aggressive surgical resection, and new therapeutic approaches are required for local tumor control. 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 radiopharmaceutical 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM). We examined the safety and therapeutic potential of 64Cu-ATSM PETx for HGG patient-derived xenograft (PDX) tumors, which recapitulated the parent tumor phenotype of high expression of hypoxia-inducible factor-1α and BNIP3, biomarkers of tissue hypoxia. Biodistribution, dosimetry, and toxicity studies of 64Cu-ATSM local administration 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 WHO CNS grade 4 HGGs.
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- 2022
25. ACT-13 DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA: A FIRST-IN-HUMAN, PHASE 1 STUDY
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Arakawa Yoshiki, David Reardon, Yoshitaka Narita, Samuel Goldlust, George Anstass, Dragana McMullen, Edward Dow, Masataka Seki, Yudai Furuta, Gregory Song, and Howard Colman
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Background The brain's cells are fully dependent on their own de novo biosynthesis of cholesterol as the blood-brain barrier prevents its uptake from the circulation. In normal glial cells, proper regulation of cholesterol synthesis depends on its cell density and is turned off when the cell density exceeds a certain level. On the other hand, gliomas maintain high levels of cholesterol synthesis to support abnormal growth under any condition. Upregulation of cholesterol synthesis genes is associated with decreased survival in patients with glioblastoma (GBM). Therefore, gliomas are potentially sensitive to cholesterol synthesis inhibition. DSP-0390 is an investigational small molecule inhibitor of EBP, an enzyme in one of the last steps of cholesterol biosynthesis. By inhibiting de novo cholesterol synthesis, cytotoxicity can be induced more selectively against hyperproliferative GBM cells. DSP-0390 has shown significant antitumor activity in orthotopic xenograft GBM models (data on file). Methods DSP-0390 will be evaluated in a phase 1 study in patients with recurrent high-grade glioma (NCT05023551). Key eligibility criteria: age ≥18 years; KPS score ≥70%; and adequate organ and hematologic function. Patients must not have multifocal disease, leptomeningeal metastasis, extracranial metastasis. In Dose Escalation, 21-30 patients with World Health Organization (WHO) grade III or IV malignant glioma who progressed after ≥1 prior therapy will be enrolled. Dose escalation will be guided by a Bayesian Logistic Regression Model until identification of the maximum tolerated dose or recommended dose for expansion. Dose Expansion will enroll approximately 20-40 patients with WHO grade IV GBM who progressed after primary therapy and have measurable disease. Study endpoints include safety (treatment-emergent adverse events [AEs], serious AEs, and dose-limiting toxicities), efficacy (6-month progression-free survival [PFS], objective response, PFS, duration of response, and 12-month overall survival), pharmacokinetics (PK), and pharmacodynamic biomarkers. This study is currently recruiting in the United States and Japan.
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- 2022
26. MET-10 A SINGLE CENTER RETROSPECTIVE ANALYSIS OF AWAKE CRANIOTOMY FOR METASTATIC BRAIN TUMOR
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Shunsuke Yanagisawa, Makoto Ohno, Masamichi Takahashi, Takayasu Mukai, Yuki Kawaguhci, Takuro Sakurai, Mami Oki, Aiko Matsuoka, Yasuji Miyakita, and Yoshitaka Narita
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Background/purpose Recent advances in cancer treatment provide surgical indication chances of metastatic brain tumors, and awake craniotomy for them is increasing. However, a small number of hospitals can perform awake craniotomy by limitation of hospital capacity. Here we show a single center retrospective analysis of awake craniotomy for metastatic brain tumor. Materials and Methods we analyzed consecutive 35 cases from January 2016 to January 2022 in our hospital. Rehabilitation staff evaluated them before surgery and after within a week. Result Patients characteristic were as follows. Mean and median age 57.0 (16-81) and median 62 respectively. Left side tumor were 31(88.6%). Frontal lobe was 26(74.3%), temporal lobe 5(14.3%), parietal lobe 3(8.6%), occipital lobe 1. Origin of cancer was lung 17(48.6%), gastrointestinal lesion 5(14.3%), breast 4(11.4%), soft tissues 3(8.6%), radiation necrosis 4(11.4%), uterus and malignant melanoma 1 respectively. KPS was 100-90 18(51.4%), KPS 80 6(8.6%) and KPS70 11(31.4%). Gross total removal was 30, partial removal was 5. MMSE of before and after surgery was mean 27.1 and median 29. Trail Making Test (TMT) of 24 cases test showed improvement in 11 (45.8%) cases. Median OS was 18.8 months (95%CI: 11.2-526). Discussion/conclusion We selected most awake craniotomy on left frontal lobe and each evaluating scales showed no deterioration. Awake craniotomy for metastatic brain tumor is effective procedure for saving function.
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- 2022
27. PEDT-18 PHASE I/II TRIAL OF OP-10 (ONC201) IN JAPANESE PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE MIDLINE GLIOMA
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Keiko Okada, Yoshitaka Narita, Yuhki Koga, Ryo Nishikawa, Katsuyoshi Koh, Atsushi Manabe, Keita Terashima, Kazunari Miyairi, Fumi Taguchi, and Junichi Hara
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Background Diffuse midline glioma (DMG) occurs mainly in the brain stem and most of patients have the mutation of histone (H3K27M). The prognosis is poor, and median overall survival (OS) is less than 12 months. OP-10 (ONC201) have antagonistic activity against dopamine D2 ha and to activate ClpP, a mitochondrial protease, leading tumor cells to apoptosis. We conducted a multicenter, single-arm, open-label phase I/II study of OP-10 in Japan. Methods A 3 + 3 design was used to determine the recommended dose of OP-10 for nine patients with recurrent or refractory glioma in the phase-I trial. Patients with recurrent or refractory DMG in the phase-II trial orally received OP-10 once weekly until discontinuation because of progression or adverse events. The efficacy and safety of OP-10 were evaluated in the phase-II part. The tumor objective response rate (ORR), the primary endpoint of the phase-II trial, was assessed through a blinded, independent central review according to RANO-LGG criteria. Results A total of 9 (age: 24-72 years) and 31 (age: 4-39 years) patients were administered in the phase-I and phase-II trials, respectively. Although the lower limit of the 90% confidence interval for ORR did not exceed the pre-specified threshold (5%), nine of 31 patients showed tumor regression on T2/FLAIR images. In the phase-II trial, the median OS was 28.4 weeks, and the OS rate at 6 months was 54.8%. Adverse events of grade ≥ 3 were reported in five of 31 (16.1%) patients in the phase-II part, with death of disease, hyperuricemia, malaise, pyrexia, alanine transaminase elevation, and aspartate transaminase elevation. Conclusion The results of this study suggested that OP-10 might be efficacious in some patients with recurrent or refractory DMG, without major safety concerns.
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- 2022
28. BT-4 PROGNOSIS OF HISTOLOGICALLY DIAGNOSED GRADE 2-3 IDH-WILD TYPE DIFFUSE GLIOMAS TREATED WITH RADIATION AND TEMOZOLOMIDE
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Hideyuki Arita, Shunsaku Takayangi, Shota Tanaka, Taishi Nakamura, Mitsuaki Shirahata, Kaoru Tamura, Takeo Uduka, Motoo Nagane, Yoshitaka Narita, and Koichi Ichimura
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Although adult diffuse gliomas, IDH-wildtype, histologically diagnosed as grade 2-3 have been regarded as clinically equivalents with glioblastomas, the prognosis of this population has scarcely been discussed with further consideration of treatment backgrounds. This retrospective study aimed to investigate the prognosis of adult patients with IDH-wildtype diffuse gliomas histologically diagnosed as WHO grade 2-3 using a cohort with homogenous treatment background. A total of 214 IDH-wildtype cases were extracted from the collected data of the previous study investigating the prognostic significance of molecular markers (Arita, Acta Neuropathol Commun 2016). The inclusion criteria were as follows: supratentorial tumor, pretreatment Karnofsky Performance status of 70 or higher, wildtype-H3.3 status, chemoradiation therapy with temozolomide after the initial surgery. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier methods. The histological diagnosis in this study was made based on the WHO 2016 classification, and the histological criteria is compatible with the current classification (CNS WHO5).The mean age was 62.8, 59.8 and 60.2 years in grade 2 (n=8), 3 (n=45) and 4 (n=161) case, respectively. The higher ratio of biopsy cases was associated lower grades (50% in grade 2, 22% in grade 3 and 9% in grade 4 cases). Grade 2-3 cases showed short survival (OS 24.7 months and PFS 9.7months) despite the intensive treatment of chemoradiation at the time of diagnosis. In details, OS was 41.5, 23.1 and 17.8 months in grade 2, 3 and 4 cases, respectively. PFS was 12.6, 9.7 and 8.2 months in grade 2, 3 and 4 cases, respectively. Our results revealed that IDH-wildtype grade 2-3 cases showed dismal prognosis even after the chemoradiation at the time of diagnosis. Further development of treatments is needed in this population as well as glioblastomas, IDH-wildtype.
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- 2022
29. ACT-2 JCOG0911A2 AND ESTABLISHING AN INFRASTRUCTURE FOR RADIOLOGICAL STUDIES FOR JCOG BRAIN TUMOR STUDY GROUP CLINICAL TRIALS
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Manabu Kinoshita, Keita Sasaki, Atsushi Natsume, Toshihiko Wakabayashi, Yoshiki Arakawa, and Yoshitaka Narita
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Background Radiological information is indispensable to understanding the pathology and correctly assessing the treatment response of malignant brain tumors. Clinical trials conducted outside of Japan have vigorously collected and investigated radiological images of the enrolled patients and published many significant findings, such as the RANO criteria. The authors initiated the JCOG0911A2 study, which is an ancillary analysis of JCOG0911, and established an infrastructure for collecting and analyzing raw radiological images of patients enrolled in clinical trials conducted by the JCOG brain tumor study group. JCOG0911A2 study design and infrastructure for radiological image storage: JCOG0911A2 aims to collect all radiological images related to the JCOG0911 study, conduct radiomics analysis, and complete general radiological research. Among 122 registered patients, 2532 series from 118 cases accounting for 237 GB of data were collected as of June 28, 2022. All collected data were anonymized and stored in Osirix MD with triple data backup. JCOG0911A2's treatment response assessment will be performed according to the RANO criteria. Thus, the authors developed a script in MATLAB that enables semi-automatic treatment response assessment according to the investigators' annotations on Osirix MD. Data Management The abovementioned “semi-automatic treatment response assessment script” was not necessary until up to a collection of 30 cases. However, manual management became impossible as more case data arrived, and establishing a sophisticated and systematic data management system was inevitable. The data management system developed for JCOG0911A2 is also used with minor modifications for the ongoing JCOG study. Conclusion JCOG0911A2 study established a reliable infrastructure capable of handling radiological images from patients enrolled in JCOG brain tumor study group clinical trials.
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- 2022
30. RTID-03. DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA: A FIRST-IN-HUMAN, PHASE 1 STUDY
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David A Reardon, Yoshitaka Narita, Yoshiki Arakawa, Samuel Goldlust, George Anstass, Dragana McMullen, Edward Dow, Masataka Seki, Yudai Furuta, Gregory Song, and Howard Colman
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
The brain's cells are dependent on their own biosynthesis of cholesterol as the blood-brain barrier prevents uptake from the circulation. In normal glial cells, regulation of cholesterol synthesis depends on cell density and is turned off when density exceeds a certain level. Gliomas maintain high levels of cholesterol synthesis genes to support abnormal growth. Upregulation of cholesterol synthesis genes is associated with decreased survival in patients with glioblastoma (GBM). Therefore, gliomas are potentially sensitive to cholesterol synthesis inhibition. DSP-0390, an investigational small molecule, inhibits EBP, an enzyme in one of the last, crucial steps of cholesterol biosynthesis. By inhibiting cholesterol synthesis, cytotoxicity can be induced selectively against hyperproliferative GBM cells. DSP-0390 has shown significant antitumor activity in orthotopic xenograft models of human GBM (data on file).DSP-0390 will be evaluated in a phase 1 study in patients with recurrent, high-grade glioma (NCT05023551). Key eligibility criteria: age >18 years; Karnofsky Performance Status score >70%; adequate renal, hepatic, and hematologic function. Patients must not have multifocal disease, leptomeningeal metastasis or extracranial metastasis, abnormal electrocardiograms, or significant cardiovascular disease. In Dose Escalation, 21-30 patients with World Health Organization (WHO) grade III or IV malignant glioma who progressed after >1 prior therapy will be enrolled. Dose level enrollment will be guided by a Bayesian Logistic Regression Model until identification of the maximum tolerated dose or recommended dose for expansion. Dose Expansion for clinical activity will enroll approximately 20-40 patients with WHO grade IV GBM who progressed after primary therapy and have measurable disease. Patients will receive oral DSP-0390 once daily. Study endpoints include safety (treatment-emergent adverse events [AEs], serious AEs, and dose-limiting toxicities), efficacy (6-month progression-free survival [PFS], objective response, PFS, duration of response, and 12-month overall survival), pharmacokinetics (PK), and pharmacodynamic biomarkers. This study is currently recruiting in the United States and Japan.
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- 2022
31. Clinical Application of Comprehensive Genomic Profiling Tests for Diffuse Gliomas
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Takaki Omura, Masamichi Takahashi, Makoto Ohno, Yasuji Miyakita, Shunsuke Yanagisawa, Yukie Tamura, Miyu Kikuchi, Daisuke Kawauchi, Tomoyuki Nakano, Tomohiro Hosoya, Hiroshi Igaki, Kaishi Satomi, Akihiko Yoshida, Kuniko Sunami, Makoto Hirata, Tatsunori Shimoi, Kazuki Sudo, Hitomi S. Okuma, Kan Yonemori, Hiromichi Suzuki, Koichi Ichimura, and Yoshitaka Narita
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Cancer Research ,Oncology ,glioma ,genomic profiling test ,clinical actionability ,germline mutations ,neoplasms - Abstract
Next-generation sequencing-based comprehensive genomic profiling test (CGPT) enables clinicians and patients to access promising molecularly targeted therapeutic agents. Approximately 10% of patients who undergo CGPT receive an appropriate agent. However, its coverage of glioma patients is seldom reported. The aim of this study was to reveal the comprehensive results of CGPT in glioma patients in our institution, especially the clinical actionability. We analyzed the genomic aberrations, tumor mutation burden scores, and microsatellite instability status. The Molecular Tumor Board (MTB) individually recommended a therapeutic agent and suggested further confirmation of germline mutations after considering the results. The results of 65/104 patients with glioma who underwent CGPTs were reviewed by MTB. Among them, 12 (18.5%) could access at least one therapeutic agent, and 5 (7.7%) were suspected of germline mutations. A total of 49 patients with IDH-wildtype glioblastoma showed frequent genomic aberrations in the following genes: TERT promoter (67%), CDKN2A (57%), CDKN2B (51%), MTAP (41%), TP53 (35%), EGFR (31%), PTEN (31%), NF1 (18%), BRAF (12%), PDGFRA (12%), CDK4 (10%), and PIK3CA (10%). Since glioma patients currently have very limited standard treatment options and a high recurrence rate, CGPT might be a facilitative tool for glioma patients in terms of clinical actionability and diagnostic value.
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- 2022
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32. Abstract 1506: Decoding multi-omics genetic profiling reveals heterogeneity in adult pan-gliomas
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Takuma Nakashima, Yusuke Funakoshi, Atsuhito Uneda, Yuriko Sugihara, Shohei Nambu, Manabu Kinoshita, Yoshiki Arakawa, Shota Tanaka, Joji Ishida, Ryuta Saito, Ryosuke Hanaya, Koji Yoshimoto, Yoshitaka Narita, and Hiromichi Suzuki
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Cancer Research ,Oncology - Abstract
Adult-type diffuse gliomas (Glioblastoma (GBM), Astrocytoma, Oligodendroglioma) are the most common malignant brain tumor in adults with dismal prognoses. Recent large-scale genomic studies have established molecular classification of glioma based on coding mutations and copy number variations. However, whole-genome landscape and multi-omics profiles of gliomas are not well analyzed. To understand the multi-omics genetic landscape of gliomas, we performed deep whole-genome sequencing (≥ ×120 coverage) of 357 cases with adult-type diffuse gliomas (162 GBMs, 96 astrocytomas, 99 oligodendrogliomas) along with EPIC DNA methylation profiling. RNA-seq, whole-genome bisulfate sequencing, and assay for transposase-accessible chromatin with sequencing (ATAC-seq) were performed on 349, 40, and 40 of these tumors, respectively. Deep WGS delineated a fine view of clonal architecture demonstrating mutational order during tumor initiation of each glioma. Mutational signature varies between clonal and subclonal mutations, supporting a model that tumors acquire genetic alterations by distinct mechanisms based on their developmental stage. Structural variants (SVs) are more frequently detected in higher malignant gliomas. While a complex SV is rare in Astrocytoma and Oligodendroglioma (35% of samples), a large proportion of GBM cases (85%) have complex SV with ≥ 10 breakpoints, which involves multiple different chromosomes including driver genes. CDKN2A homozygous deletions and focal CDK4 amplifications are often induced by complex SVs in GBM. These results suggest that complex SVs could play a pivotal role in the initiation and progression of GBM. Integrative analysis of transcriptomic and epigenomic profiles by similarity network fusion (SNF) identifies homogenous clusters in each glioma where those clusters are associated with mutational and SV signatures, suggesting that specific cell states may have distinct sensitivities to mutational processes. In oligodendrogliomas, the SNF classification detected a cluster with poor prognosis which has an enrichment of stem cell-like signature by CIBERSORTx deconvolution analysis. ATAC-seq demonstrated distinct features of genome-wide chromatin accessibility in each glioma which may reflect the difference of cell of the origin. Most of the focally amplified genes have open chromatin status suggesting that tumors take advantage of not only gene duplication but also a transcriptional activity to activate driver genes. Our integrated analysis uncovers molecular mechanisms of gliomas which will help to understand glioma-genesis. Citation Format: Takuma Nakashima, Yusuke Funakoshi, Atsuhito Uneda, Yuriko Sugihara, Shohei Nambu, Manabu Kinoshita, Yoshiki Arakawa, Shota Tanaka, Joji Ishida, Ryuta Saito, Ryosuke Hanaya, Koji Yoshimoto, Yoshitaka Narita, Hiromichi Suzuki. Decoding multi-omics genetic profiling reveals heterogeneity in adult pan-gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1506.
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- 2023
33. The first-in-human phase I study of a brain penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas
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Atsushi Natsume, Yoshiki Arakawa, Yoshitaka Narita, Kazuhiko Sugiyama, Nobuhiro Hata, Yoshihiro Muragaki, Naoki Shinojima, Toshihiro Kumabe, Ryuta Saito, Kazuya Motomura, Yohei Mineharu, Yasuji Miyakita, Fumiyuki Yamasaki, Yuko Matsushita, Koichi Ichimura, Kazumi Ito, Masaya Tachibana, Yasuyuki Kakurai, Naoko Okamoto, Takashi Asahi, Soichiro Nishijima, Tomoyuki Yamaguchi, Hiroshi Tsubouchi, Hideo Nakamura, and Ryo Nishikawa
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
Background Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001. Methods This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method. Results The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples. Conclusions DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).
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- 2022
34. Highly sensitive detection of TERT promoter mutations in recurrent glioblastomas using digital PCR
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Mai Kitahara, Yasuji Miyakita, Akira Matsumura, Koichi Ichimura, Masamichi Takahashi, Yoshitaka Narita, Shunichiro Miki, Masahide Matsuda, Eiichi Ishikawa, Yuko Matsushita, Makoto Ohno, Kaishi Satomi, and Akihiko Yoshida
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Cancer Research ,Pathology ,medicine.medical_specialty ,DNA Mutational Analysis ,Population ,Biology ,Polymerase Chain Reaction ,Sensitivity and Specificity ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,medicine ,Humans ,Digital polymerase chain reaction ,Telomerase reverse transcriptase ,Promoter Regions, Genetic ,education ,Telomerase ,Sanger sequencing ,education.field_of_study ,Tumor microenvironment ,Brain Neoplasms ,General Medicine ,medicine.disease ,Isocitrate Dehydrogenase ,nervous system diseases ,Isocitrate dehydrogenase ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,symbols ,Cancer research ,Pyrosequencing ,Neurology (clinical) ,Oligodendroglioma ,Neoplasm Recurrence, Local ,Glioblastoma ,030217 neurology & neurosurgery - Abstract
Telomerase reverse transcriptase promoter (TERTp) hotspot mutations are the most frequent mutations in primary glioblastomas (GBM). Previous studies have shown that the combination of TERTp and isocitrate dehydrogenase (IDH) status may serve as a useful diagnostic marker for oligodendroglioma and glioblastoma. In oligodendrogliomas, TERTp and IDH mutations, along with the 1p/19q codeletion, usually coexist and are likely to be founder mutations. However, in contrast to oligodendroglioma, the role of the TERTp status in GBM remains obscure. Here, we used Sanger sequencing, pyrosequencing, and digital PCR (dPCR) to examine the TERTp status in 15 pairs of frozen tissue samples from primary and recurrent IDH wild-type GBM, all of which were operated in a single institute. We showed that the TERTp status was stable between primary and recurrent GBM but this consistency was only detected by dPCR. The results suggest that dPCR is a powerful, highly sensitive tool to detect TERTp mutations, especially in a mixed cell population (e.g., a recurrent GBM tissue) where earlier treatment may have grossly altered the tumor microenvironment.
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- 2020
35. Phase I/II study of tirabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma
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Hajime Yonezawa, Kazuhiko Mishima, Noriko Fukuhara, Katsunori Asai, Motoo Nagane, Junsaku Kitagawa, Yoshiki Arakawa, Ryo Nishikawa, Naoki Shinojima, Yoshitaka Narita, Kazuhiko Sugiyama, Yasuhito Terui, and Arata Aoi
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Central Nervous System ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,Clinical Investigations ,Neutropenia ,Gastroenterology ,Tyrosine-kinase inhibitor ,Central Nervous System Neoplasms ,Refractory ,Bruton’s tyrosine kinase ,Internal medicine ,medicine ,Bruton's tyrosine kinase ,AcademicSubjects/MED00300 ,Humans ,Erythema multiforme ,Protein Kinase Inhibitors ,CARD11 ,Leukopenia ,biology ,primary central nervous system lymphoma ,business.industry ,Lymphoma, Non-Hodgkin ,Primary central nervous system lymphoma ,Imidazoles ,medicine.disease ,tirabrutinib ,Pyrimidines ,Treatment Outcome ,Oncology ,Tolerability ,biology.protein ,AcademicSubjects/MED00310 ,Neurology (clinical) ,medicine.symptom ,MYD88 ,business - Abstract
BackgroundThe safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL).MethodsPatients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II.ResultsForty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types.ConclusionThese data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL.Trial registrationJapicCTI-173646.
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- 2020
36. Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone
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Kazuhiko Mishima, Atsushi Natsume, Yasuo Iwadate, Takanori Onishi, Toshihiko Wakabayashi, Tomokazu Aoki, Kazuhiko Sugiyama, Tamio Ito, Eiichi Ishikawa, Yusuke Okuno, Yoshitaka Narita, Toshihiro Kumabe, Takaaki Beppu, Ryo Nishikawa, Koji Yoshimoto, Masaki Hirano, Kenichiro Asano, Kaoru Kurisu, Kazuya Motomura, Hideo Nakamura, Yoshiki Arakawa, Nobusada Shinoura, Minako Sumi, Kosuke Aoki, Shinya Sato, Fumiyuki Yamasaki, Akio Asai, Tatsuya Abe, Soichiro Shibui, Motoo Nagane, Hiroyuki Kobayashi, Takayuki Matsuo, Akitake Mukasa, Hikaru Sasaki, Yoshihiro Muragaki, Atsuo Yoshino, Akira Matsumura, Fumiharu Ohka, Yoko Nakasu, Sachi Maeda, Mizuhiko Terasaki, Hirofumi Hirano, Alimu Adilijiang, Takamasa Kayama, Naoya Hashimoto, and Takashi Maruyama
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Methyltransferase ,Antineoplastic Agents ,Deep sequencing ,Young Adult ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Internal medicine ,Temozolomide ,Humans ,Medicine ,Telomerase reverse transcriptase ,DNA Modification Methylases ,Telomerase ,Aged ,Sanger sequencing ,Performance status ,Brain Neoplasms ,business.industry ,Tumor Suppressor Proteins ,Hazard ratio ,Microsatellite instability ,Interferon-beta ,Middle Aged ,medicine.disease ,Isocitrate Dehydrogenase ,DNA Repair Enzymes ,Treatment Outcome ,Neurology ,030220 oncology & carcinogenesis ,symbols ,Female ,Neurology (clinical) ,Glioblastoma ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonβ (IFNβ) plus temozolomide (TMZ) with that of TMZ alone. Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations. Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30–0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21–0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22–2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNβ + Radiotherapy (RT) group were found. This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNβ addition were identified.
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- 2020
37. Validation study of the Japanese version of MD Anderson Symptom Inventory for Brain Tumor module
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Shota Tanaka, Masamichi Takahashi, Yoshitaka Narita, Kiyoko Kamibeppu, Akitake Mukasa, Tito R. Mendoza, Charles S. Cleeland, Iori Sato, Shunsaku Takayanagi, Nobuhito Saito, and Terri Armstrong
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Psychometrics ,Concurrent validity ,Severity of Illness Index ,Correlation ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Japan ,Cronbach's alpha ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Reliability (statistics) ,Aged ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,Performance status ,Brain Neoplasms ,business.industry ,Reproducibility of Results ,General Medicine ,Middle Aged ,Distress ,Cross-Sectional Studies ,Oncology ,Convergent validity ,030220 oncology & carcinogenesis ,Physical therapy ,Original Article ,Female ,Patient-reported outcome ,business - Abstract
Objective The MD Anderson Symptom Inventory for Brain Tumor (MDASI-BT) module is a widely used instrument for measuring symptom burden and interference of daily activities in brain tumor patients. This study aims to develop and validate its Japanese version (MDASI-BT-Japanese). Methods Following forward and backward translation of the original MDASI-BT into Japanese, understandability and feasibility were assessed by cognitive debriefing. Subsequently, patients with brain tumors were asked to fill out MDASI-BT-Japanese and European Quality of Life-5 Dimensions (EQ-5D). Feasibility, reliability and validity of MDASI-BT-Japanese were assessed. Results Cognitive debriefing confirmed overall ease of completion and good understandability. The study population composed of 140 patients with brain tumors (most commonly gliomas). The mean symptom severity score and mean interference score were 1.9 ± 1.7 and 2.8 ± 2.7, respectively. The top items included distress and drowsiness for symptom severity and general activity and work for interference. The median time required was 4 minutes (range, 0.5–30), and missing values were seen in 1%. Internal consistency was proven by excellent Cronbach’s coefficient alpha (0.94 for symptom severity, 0.92 for interference). Test–retest reliability was assessed with acceptable intra-class correlation coefficient (mean, 0.76). Correlation efficient ranged between 0.7 and 0.9 for convergent validity. Known-group validity was confirmed by significantly different mean symptom severity score and mean interference score among patients with different performance status. As evidence of concurrent validity, MDASI-BT-Japanese correlated with EQ-5D in the hypothesized magnitude and direction. Conclusions The newly developed MDASI-BT-Japanese has demonstrated feasibility, reliability and validity in evaluation of clinical benefit in Japanese-speaking brain tumor patients.
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- 2020
38. Assessment of Therapeutic Outcome and Role of Reirradiation in Patients With Radiation-induced Glioma
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Makoto Ohno, Yasuji Miyakita, Masamichi Takahashi, Shunsuke Yanagisawa, Yukie Tamura, Daisuke Kawauchi, Miyu Kikuchi, Hiroshi Igaki, Akihiko Yoshida, Kaishi Satomi, Yuko Matsushita, Koichi Ichimura, and Yoshitaka Narita
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Oncology ,Brain Neoplasms ,Humans ,Radiology, Nuclear Medicine and imaging ,Glioma ,Astrocytoma ,Glioblastoma ,Isocitrate Dehydrogenase ,Re-Irradiation ,Retrospective Studies - Abstract
Background We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG). Methods We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan’s criteria for RIG in our database during 2001–2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing. Results The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9–30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemotherapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy. Conclusions RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Determining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma.
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- 2021
39. Recommended first-line management of brain metastases from melanoma: A multicenter survey of clinical practice
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Paola Anna Jablonska, Chin Heng Fong, Timothy Kruser, Jessica Weiss, Zhihui Amy Liu, Hirokazu Takami, Yoshitaka Narita, Fabio Ynoe de Moraes, Archya Dasgupta, Choo Khoon Ong, James C.H. Yang, Jih Hsiang Lee, Nicholas Pavlakis, Paul Kongkham, Marcus Butler, and David B. Shultz
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Proto-Oncogene Proteins B-raf ,Oncology ,Brain Neoplasms ,Surveys and Questionnaires ,Mutation ,Humans ,Radiology, Nuclear Medicine and imaging ,Hematology ,Melanoma ,Protein Kinase Inhibitors - Abstract
Radiotherapy (RT) and surgery (Sx) are effective in treating brain metastases. However, immune checkpoint inhibitors (ICI) have shown activity against asymptomatic melanoma brain metastases (MBM). BRAF/MEK inhibitors can be used to treat BRAF V600 mutation positive (BRAF+) MBM.We conducted an international survey among experts from medical oncology (MO), clinical oncology (CO), radiation oncology (RO), and neurosurgery (NS) about treatment recommendations for patients with asymptomatic BRAF+ or BRAF mutation negative (BRAF-) MBM. Eighteen specific clinical scenarios were presented and a total of 267 responses were collected. Answers were grouped and compared using Fisher's exact test.In most MBM scenarios, survey respondents, regardless of specialty, favored RT in addition to systemic therapy. However, for patients with BRAF+ MBM, MO and CO were significantly more likely than RO and NS to recommend BRAF/MEK inhibitors alone, without the addition of RT, including the majority of MO (51%) for patients with 1-3 MBM, all2 cm. Likewise, for BRAF- MBM, MO and CO more commonly recommended single or dual agent ICI only and dual agent ICI therapy alone was the most common recommendation from MO or CO for MBM2 cm. When at least 1 of 3 MBM (BRAF+ or BRAF-) was2 cm, upfront Sx was recommended by all groups with the exception that MO and RO recommended RT for BRAF- MBM.In most clinical settings involving asymptomatic MBM, experts recommended RT in addition to systemic therapy. However, recommendations varied significantly according to specialty, with MO and CO more commonly recommending dual systemic therapy alone for up to 9 BRAF- MBM2 cm.
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- 2021
40. RBIO-03. INITIAL RESULT OF DEVELOP ROBUST DEEP LEARNING MODEL FOR DETECTING GENOMIC STATUS IN GLIOMAS AGAINST IMAGE DIFFERENCES AMONG FACILITIES
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Satoshi Takahashi, Masamichi Takahashi, Manabu Kinoshita, Mototaka Miyake, Jun Sese, Kazuma Kobayashi, Koichi Ichimura, Yoshitaka Narita, Ryuji Hamamoto, and Consortium of Molecular Diagnosis of glioma
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Cancer Research ,Telomerase ,Catabolism ,Computational biology ,Biology ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,medicine.disease ,Genome ,Tissue Degeneration ,Isocitrate dehydrogenase ,Oncology ,Glioma ,Mutation (genetic algorithm) ,medicine ,Neurology (clinical) ,Gene - Abstract
BACKGROUND The importance of detecting the genomic status of gliomas is increasingly recognized and IDH (isocitrate dehydrogenase) mutation and TERT (telomerase reverse transcriptase) promoter mutation have a significant impact on treatment decisions. Noninvasive prediction of these genomic statuses in gliomas is a challenging problem; however, a deep learning model using magnetic resonance imaging (MRI) can be a solution. The image differences among facilities causing performance degradation, called domain shift, have also been reported in other tasks such as brain tumor segmentation. We investigated whether a deep learning model could predict the gene status, and if so, to what extent it would be affected by domain shift. METHOD We used the Multimodal Brain Tumor Segmentation Challenge (BraTS) data and the Japanese cohort (JC) dataset consisted of brain tumor images collected from 544 patients in 10 facilities in Japan. We focused on IDH mutation and TERT promoter mutation. The deep learning models to predict the statuses of these genes were trained by the BraTS dataset or the training portion of the JC dataset, and the test portion of the JC dataset evaluated the accuracy of the models. RESULTS The IDH mutation predicting model trained by the BraTS dataset showed 80.0% accuracy for the validation portion of the BraTS dataset; however, only 67.3% for the test portion of the JC dataset. The TERT promoter mutation predicting model trained by the training portion of the JC dataset showed only 49% accuracy for the test portion of the JC dataset. CONCLUSION IDH mutation can be predicted by deep learning models using MRI, but the performance degeneration by domain shift was significant. On the other hand, TERT promoter mutation could not be predicted accurately enough by current deep learning techniques. In both mutations, further studies are needed.
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- 2021
41. The Clinical Characteristics and Outcomes of Incidentally Discovered Glioblastoma
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Miyu Kikuchi, Yoshitaka Narita, Daisuke Kawauchi, Koichi Ichimura, Yukie Tamura, Makoto Ohno, Shunsuke Yanagisawa, Masamichi Takahashi, Mai Honda-Kitahara, and Yasuji Miyakita
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Oncology ,Cancer Research ,Incidental Findings ,medicine.medical_specialty ,Brain Neoplasms ,Kaplan-Meier Estimate ,Prognosis ,medicine.disease ,Radiography ,Treatment Outcome ,Neurology ,Internal medicine ,medicine ,Humans ,Neurology (clinical) ,Glioblastoma - Abstract
Objective With an increase in the number of imaging examinations and the development of imaging technology, a small number of glioblastomas (GBMs) are identified by incidental radiological images. These incidentally discovered glioblastomas (iGBMs) are rare, and their clinical features are not well understood. Here, we investigated the clinical characteristics and outcomes of iGBM. Methods Data of newly diagnosed iGBM patients who were treated at our institution between August 2005 and October 2019 were reviewed. An iGBM was defined as a GBM without a focal sign, discovered on radiological images obtained for reasons unrelated to the tumor. Kaplan-Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS). Results Of 234 patients with newly diagnosed GBM, four (1.7%) were classified as having iGBM. Health screening was the most common reason for tumor discovery (75.0%). The preoperative Karnofsky performance status score was 100 in three patients. Tumors were found on the right side in three cases. The mean volume of preoperative enhanced tumor lesion was 16.8 cm3. The median duration from confirmation of an enhanced lesion to surgery was 13.5 days. In all cases, either total (100%) or subtotal (95–99%) resections were achieved. The median PFS and OS were 11.5 and 20.0 months, respectively. Conclusions The iGBMs were often small and in the right non-eloquent area, and the patients had good performance status. We found that timely therapeutic intervention provided iGBM patients with favorable outcomes. This report suggests that early detection of GBM may lead to a better prognosis.
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- 2021
42. RT-8 POST-IRRADIATION COURSE OF GLIOMAS OF THALAMUS AND BRAINSTEM
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Shimizu Yuri, Yoshitaka Narita, Koichi Ichimura, Yasuji Miyakita, Makoto Ohno, Masamichi Takahashi, Syunsuke Yanagisawa, Satoshi Shima, Kanako Kojima, Tairo Kashihara, Kana Takahashi, Koji Inaba, Jyun Itami, and Hiroshi Igaki
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Objective We retrospectively reviewed the post-irradiation course of cases treated with radiotherapy for the gliomas involving thalamus or brainstem. Methods Thirty-seven gliomas involving thalamus or brainstem treated with radiotherapy from 2007 to 2021 in our hospital were included. Median age was 47 (19-79) years, and KPS at the start of irradiation was 80% or less in 26 cases. Tumor localization was thalamus only/brainstem only/both thalamus and brainstem for 20/9/8 cases. Two cases did not undergo biopsy, and the others underwent surgery before irradiation. Two cases underwent partial excision of the lesion near the thalamus, 6 cases underwent partial excision from other than the thalamus-brainstem, and 27 cases underwent biopsy only. The pathological diagnosis based on the WHO classification at the time of surgery was glioblastoma (GBM) in 8 cases, high-grade glioma other than glioblastoma (HGG) in 23 cases (including 9 cases of diffuse midline glioma K27M), and low-grade glioma (LGG) in 6 cases. Results Median observation period was 16(2-66) months. Median PFS/median OS/5-year OS rate were 13 months/25 months/20% in all 37 cases. Median PFS was 66/18/7 months for LGG/ HGG/ GBM, and 5-year OS was 75/16/15%. Symptomatic cerebral edema associated with tumor growth was observed in one GBM 9 months after irradiation. In HGG, 7/23 cases underwent the VP shunting before irradiation, and one case who underwent ventriculostomy before irradiation had a VP shunting created for worsening hydrocephalus 3 months after irradiation. In one case of GBM, a VP shunt was created immediately after surgery. Conclusions Compared to the past reports of gliomas, it was suggested that the localization in thalamic brainstem was a factor for a worse prognosis in HGG.
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- 2022
43. COT-8 DEVELOPMENT OF TARGETED GENE PANEL FOR RAPID MOLECULAR DIAGNOSIS OF BRAIN TUMORS
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Takuma Nakashima, Yusuke Funakoshi, Atsuhito Uneda, Shohei Nambu, Mai Kitahara, Shunsuke Yanagisawa, Makoto Ohno, Masamichi Takahashi, Yasuji Miyakita, Yoshitaka Narita, and Hiromichi Suzuki
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Background Brain tumors are diagnosed based on pathological and genetic features defined by WHO classification. Although targeted gene panels are clinically available, most of them do not cover all the necessary genes for the diagnosis of brain tumors. Moreover, broad copy number analysis, which the current WHO classification requires, usually lacks in the gene panel. Another problem is that those panels demand a high burden of time and cost, which disturbs rapid diagnosis and broad application. To overcome those problems, we developed a rapid and cost-effective workflow of molecular diagnosis for brain tumors. Methods Our panel contains 109 genes of which 68 are necessary for fundamental molecular diagnosis and 41 are other common driver genes. To detect copy number changes and structural variants, which generate a fused gene, additional probes are placed on common SNPs and introns containing common breakpoints. MGMT methylation status is examined at the same time using bisulfite-converted DNA amplification. Sequencing data is analyzed using a supercomputer. Results The analysis time is within 4 days: 2 days for library preparation, 1 day for sequencing, and 12 hours for analysis. Detected driver alterations were validated by whole genome sequencing data. MGMT methylation status was correlated between the results of our workflow and pyrosequencing. Conclusions We have developed a rapid comprehensive molecular analysis workflow that detects genetic alterations and MGMT methylation. Our method allows a cost-effective molecular diagnosis with high accuracy, which would improve molecular diagnosis for brain tumors.
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- 2022
44. PEDT-10 PHASE II TRIAL OF PATHOLOGY-BASED THREE-GROUP TREATMENT STRATIFICATION FOR PATIENTS WITH CNS GERM CELL TUMORS: A LONG-TERM FOLLOW-UP STUDY
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Hirokazu Takami, Tomonari Suzuki, Kazuhiko Takabatake, Takamitsu Fujimaki, Michinari Okamoto, Shigeru Yamaguchi, Masayuki Kanamori, Kenichiro Matsuda, Yukihiko Sonoda, Manabu Natsumeda, Junya Ichinose, Mitsutoshi Nakada, Ai Muroi, Eiichi Ishikawa, Masamichi Takahashi, Yoshitaka Narita, Fumi Higuchi, Masahiro Shin, Yohei Mineharu, Yoshiki Arakawa, Naoki Kagawa, Shinji Kawabata, Masahiko Wanibuchi, Takeshi Takayasu, Fumiyuki Yamasaki, Kentaro Fujii, Joji Ishida, Isao Date, Keisuke MIyake, Hiroshi Fujioka, Daisuke Kuga, Shinji Yamashita, Hideo Takeshima, Naoki Shinojima, Akitake Mukasa, Shota Tanaka, Akio Asai, Ryo Nishikawa, and Masao Matsutani
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Background Phase II clinical trial funded by Ministry of Health, Labour and Welfare from 1995 to 2003 evaluated efficacy of pathology-based three-group treatment stratification for CNS germ cell tumors (GCTs). We here present long-term follow-up results. Methods Total 228 cases were registered. Germinoma was treated with carboplatin+etoposide (CARE) and extended-local irradiation, local irradiation was added for intermediate-prognosis-group, and poor-prognosis-group was treated with ifosfamide+cisplatin+etoposide (ICE) and whole-brain or craniospinal irradiation. Results Mean/median ages at diagnosis were 16.8/16 years and female-to-male ratio was 40-188. Registry included 123 germinomas, 76 intermediate-prognosis-group cases (including 38 germinoma with STGC), 28 poor-prognosis-group cases and 1 mature teratoma. Median 222-months follow-up was conducted, and 56 recurrences and 39 deaths were recorded. 10 and 20-year recurrence-free survival (RFS) for germinoma, intermediate and poor-prognosis-groups were 84/79%, 83/76% and 59/59%, respectively, and overall survival (OS) for each were 97/91%, 92/85% and 57/53%, respectively. Prognosis for germinoma with or without STGC was the same. Basal ganglia germinoma showed significantly shorter RFS but OS was not different from other locations. Median age at death was 24 years, and ages were significantly different depending on causes, such as disease-related (14 years on average) and complications (29 years). OS after recurrence at 5/10/20 years were 64/62/48%.Hormonal supplementation was seen in 82% for neurohypophyseal cases and antidiuretic hormone supplementation was most frequent (82%). Among available cases, 20-out-of-155 cases showed neoplastic/vascular complications, among which cavernous malformation was the most (n=9). Median period until complication presentation was 235 months, and the rate at 20 years was 11%. Conclusions Germinoma and intermediate-prognosis-group cases showed long-term survival for approximately 90%, while more intensive treatment would be necessitated for poor-prognosis-group. Long-term survivors often required hormonal supplementation, and increasing frequency of treatment-related complications was observed. There is no end of outpatient follow-up for CNS GCT patients.
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- 2022
45. ACT-19 A REPORT OF PHASE I PART OF PHASE I/II STUDY OF MAINTENANCE THERAPY WITH METFORMIN AND TEMOZOLOMIDE FOR GLIOBLASTOMA
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Makoto Ohno, Chifumi Kitanaka, Yasuji Miyakita, Shota Tanaka, Masamichi Takahashi, Shunsuke Yanagisawa, Yukihiko Sonoda, Kenichiro Matsuda, Kazuhiko Mishima, Tomonari Suzuki, Mitsuaki Shirahara, Eiichi Ishikawa, Ken Ohashi, Motoo Nagane, and Yoshitaka Narita
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Background Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. One strategy for overcoming resistance is developing a new therapy targeting the cancer stem/initiating cells. We have shown that the antidiabetic drug metformin (MF) can induce differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. We conducted a phase I/II study to examine the clinical effect of MF combined with standard maintenance temozolomide (TMZ). Here, we report the result of phase I part and the current status of phase II part. Patients and Methods Patients between 20 and 74 years of age with supratentorial GBM histologically diagnosed according to the World Health Organization 2016 classification were eligible. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first 6 weeks after MF initiation. Results Between February 2021 and January 2022, the first three patients were treated with 1,500 mg/day MF and the next four patients were treated with 2,250 mg/day MF, which is the maximum dose approved in Japan. The median age of the patients was 41 years. Three tumors (42.9 %) were IDH1/2 mutants and 4 (57.1 %) were IDH1/2 wild-types. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, which were observed in three patients. All of them were manageable, with grade 1 or 2. Only one grade 3 seizure was reported, which was likely related to the tumor. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up. Conclusion MF dose of up to 2,250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to phase II study with 2,250 mg/day MF.
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- 2022
46. GEN-8 COMPREHENSIVE WHOLE GENOME SEQUENCING ANALYSIS ELUCIDATES STRUCTURAL VARIANTS IN MEDULLOBLASTOMA
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Yusuke Funakoshi, Takuma Nakashima, Atsuhito Uneda, Koji Yoshimoto, Yoshitaka Narita, and Hiromichi Suzuki
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Introduction Medulloblastoma is the most common malignant pediatric brain tumor with a poor prognosis. International collaborative efforts for sequencing the genomes of medulloblastomas have delineated the landscape of coding mutations. However, little is yet known about structural variants (SVs). Here, we analyzed whole-genome sequencing (WGS) data of medulloblastoma to reveal the comprehensive genetic aberrations, including SVs. Methods We collected and analyzed publically available WGS data of 432 cases with medulloblastoma from MAGIC consortium, ICGC, and St Jude cloud. Results The median coverage is 36.4x with no difference among cohorts. The median number of SV per case is 1.0 (WNT), 5.0 (SHH), 6.0 (Group 3), and 5.0 (Group 4), respectively. SHH medulloblastoma with TP53 mutation has significantly a greater number of SVs (77.0/sample), suggesting that genome instability by TP53 mutations gives rise to SVs. At least one SV involved in already known driver genes in 10.9% of the SHH cases, supporting a model where SV could lead to tumor initiation. Since some of those SVs are caused by copy-neutral translocation, detecting those alterations is challenging by other than WGS. Complex SVs involving TERT focal amplification are identified in 11.5% of the SHHα subtype which usually does not have TERT promoter mutation. Although TERT promoter mutation is enriched predominantly in the SHHδ subtype, overexpression of TERT may be necessary for tumor maintenance in some of the SHHα cases. Unbalanced amplifications are commonly observed in known drive genes such as PPM1D, CCND2, and PVT1 where a part of exons are exclusively amplified, implying that functionally important regions are selectively altered by SVs which could promote tumor development. Conclusions SV affects not just copy number changes but also the structure of the genome, where breakpoints exist based on gene function and regulations. SVs along with genetic mutations contribute to medulloblastoma pathogenesis.
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- 2022
47. COT-18 DATABASE STUDY ON TRENDS IN MEDICAL EXAMINATIONS OF PATIENTS WITH MALIGNANT BRAIN TUMORS
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Yuko Hirose, Daisuke Fukui, Nanae Sunahara, Yoshitaka Narita, and Yuzo Horibuchi
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Background and Purpose Glioblastoma is the most is the poorest prognosis tumor of all carcinomas. Various factors contribute to deterioration for glioblastoma such as age, KPS, and surgical removal level. The most important factors for poor prognosis are that half of patients with glioblastoma have a KPS ≤ 70 at the start of treatment because glioblastoma progresses rapidly. There have been no comprehensive reports on the trends in visits and time to initiation of treatment for patients with glioblastoma. We analyzed the actual clinical course of malignant brain tumor patients using the receipt database with the aim of raising awareness of prompt diagnosis and treatment. Methods Because this study included patient-visit transitions, we utilized receipt data from JMDC Inc., which can be tracked through changes of medical facilities. We analyzed for data for the period January 1, 2005, to March 31, 2022. Results and Discussion The study included 493 patients with malignant neoplasms of brain, aged 18 years or older, who underwent surgery and received radiation or temozolomide. The medical departments that visited for the first time before surgery were general internal medicine, neurosurgery, followed by ophthalmologist, orthopedics, and otolaryngology. The period from the date of the first visit to surgery was 21 days for neurosurgery and 46 days for general internal medicine. The mean time from MRI to surgery was 11 days when surgery was performed at the MRI site, and 22 days when the patient was referred to another hospital after MRI. This study clarified the actual situation when patients with malignant brain tumors visit a department besides neurosurgery. In order to facilitate prompt diagnosis and treatment, it is necessary to raise awareness of the disease among the departments where patients are likely to visit for the first time.
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- 2022
48. GEN-10 WHOLE GENOME LANDSCAPE OF GLIOBLASTOMA, IDH-WILD TYPE
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Takuma Nakashima, Yusuke Funakoshi, Atsuhito Uneda, Shohei Nambu, Shota Tanaka, Joji Ishida, Ryuta Saito, Ryosuke Hanaya, Koji Yoshimoto, Yoshitaka Narita, and Hiromichi Suzuki
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Introduction: Glioblastoma, IDH-wild type (GBM) is the most common malignant brain tumor with a dismal prognosis. Although its coding region is well-analyzed, little is yet known about the landscape of whole-genome in GBM. Here, we analyzed whole-genome sequencing data from large cohorts to completely uncover the genetic aberrations in GBM. Methods: We analyzed 281 whole-genome sequencing data of patients with GBM, of which 152 cases are from our cohort with deep coverage (×120) and 129 cases are from a public database. Results: The median numbers of somatic mutations and structural variants (SVs) per case are 3.0/Mb and 62.5, respectively. While a complex SV is rare in other malignant brain tumors such as IDH-mutant glioma (35% of samples), a large proportion of GBM cases (85%) have complex SV with ≥10 breakpoints. CDKN2A/B homozygous deletions (HDs) are usually comprised of a simple deletion in IDH-mutant glioma whereas about a quarter of CDKN2A/B HDs in GBM are induced by complex SVs. In addition, 30.5% of extrachromosomal DNA (ecDNA) involves multiple chromosomes. Taken together, complex SVs could play a key role in the initiation and progression of GBM. Our deep WGS enables us to delineate a fine view of clonal architecture, where mutational signature varies between clonal and subclonal mutations. The majority of clonal mutations consist of the clock-like signature, whereas subclonal mutations have a relatively low proportion of the clock-like signature. Instead, several other signatures including the APOBEC signature significantly increase in subclones, presuming that various mutational processes along with the clock-like signature contribute to the GBM pathogenesis in its progression phase. Conclusions: GBM evolves through exploiting complex structural variants involving multiple driver genes and the accumulation of genetic mutations caused by distinct mechanisms depending on its developmental stage.
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- 2022
49. NQPC-1 INSIGHTS FROM PREOPERATIVE FATIGUE ASSESSMENT IN GLIOMA PATIENTS
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Takuro Sakurai, Toshihisa Nakashima, Mayumi Horikawa, Yoichi Shimizu, Naoko Inamura, Ai Sumiyoshi, Aiko Matsuoka, Mami Oki, Noriko Watanabe, Yusuke Okita, Shota Yokota, Risa Abe, Kaneyuki Ichikawa, Yasuji Miyakita, Masamichi Takahashi, Makoto Ohno, Shunsuke Yanagisawa, Akira Kawai, and Yoshitaka Narita
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Introduction Glioma is a rare type of tumor, and the research on fatigue and QOL in glioma patients is limited. Research from other countries has reported patients with intense fatigue in the preoperative stage, but no similar studies could be found in Japan. In the present study, we report a retrospective investigation of fatigue assessment performed during preoperative rehabilitation evaluation. Participants and Methods Participants were 90 patients admitted to the hospital for glioma surgery between January 2016 and December 2020 who underwent five specific preoperative evaluations: KPS, MMSE, Motor-Functional Independence Measure (Motor FIM), Cancer Fatigue Scale (CFS), and grip strength. Participants were divided into a CFS-High(CFS-H) group (CFS>19 points) and a CFS-Low (CFS-L) group (CFS Results Participants were 90 patients with high-grade glioma. Fifty-seven were men, and the median age was 45 (15-81). Thirty-three participants (37%) had intense fatigue before surgery (CFS-H group: 33 participants, CFS-L group: 57 participants). In the CFS-H group and CFS-L group respectively, age was 46.5/44 (p=0.36), MMSE was 24 points/29 points (p=0.00255), Motor FIM was 89 points/91 points (p=0.0383), and grip strength was 22.2kg/25.5kg (p=0.194). Discussion The present study suggests that some Japanese high-grade glioma patients also experience intense fatigue before surgery. Compared to patients with low fatigue, those with high fatigue were suggested to have significant declines in cognitive function and ADL.
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- 2022
50. PEDT-12 NATIONWIDE LANDSCAPE OF GENOMIC ANALYSIS OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
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Yuko Watanabe, Masamichi Takahashi, Takafumi Koyama, Kuniko Sunami, Takashi Kubo, Hourin Cho, Makoto Hirata, Kayoko Tao, Kazuki Sudo, Shinji Kohsaka, Shunsuke Yanagisawa, Makoto Ohno, Yasuji Miyakita, Noboru Yamamoto, and Yoshitaka Narita
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Background and Purpose In Japan, cancer-gene profiling (CGP) tests, such as the OncoGuide NCC Oncopanel System, FoundationOne CDx Cancer Genome Profile (F-one), and FoundationOne Liquid CDx Cancer Genome Profile, are covered by insurance and clinically applied to promote cancer genomic medicine. Information from CGP tests is managed at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and shared with clinicians after discussions at the Expert Panel (EP). We provide an overview of the registered pediatric CNS tumors. Methods We extracted and analyzed CNS/brain data from the C-CAT registry from June 2019 to June 2022 for ages 0–19 years. Variables such as age, gender, histopathological diagnosis, CGP test type, ECOG Performance Status (PS), registration status, genetic abnormalities, and treatments were analyzed. Results Among 1133 patients of all ages with CNS tumors, 361 (31.9%) were aged 0–19 years; Of the 918 patients aged 0-19 years with any type of cancer, those with CNS tumors accounted for 34.2%; 188 patients were aged under 10 years, 173 patients were teenagers, 174 patients were males, 187 patients were females; PS was 0 in 47.9% of patients. The most common histopathological diagnoses were medulloblastoma, diffuse midline glioma and glioblastoma. Genetic abnormalities included TP53 mutations in 85 cases, H3F3A mutations in 38 cases, STK11 mutations in 36 cases, BRAF mutations in 33 cases, BRAF-KIAA1549 fusions in 24 cases, and TMB high in 16 cases. Seventy-six patients (21.1%) were offered treatment options in the EP, and 26 patients (7.2%) received the recommended treatment, including two in physician-initiated trials, four in company trials, eleven in treatments within insurance coverage, and eleven in others. Discussion This is the first report of genetic analysis of pediatric CNS tumors on a nationwide scale. Pediatric CNS tumors have a large number of registered cases; thus, drug development for them is urgently needed.
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- 2022
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