Papers - Tanaka Shota

当院で経験したDiffuse midline glioma,H3K27-alteredの臨床的特徴

外間 まどか, 大谷 理浩, 石田 穣治, 梅田 剛志, 井上 陽平, 水田 亮, 井本 良二, 駿河 和城, 劒持 直也, 家護谷 泰仁, 平野 秀一郎, 冨田 祐介, 藤井 謙太郎, 鷲尾 佳奈, 田中 將太

小児の脳神経   49 ( 2 )   209 - 209   2024.4

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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当院で経験したDiffuse midline glioma,H3K27-alteredの臨床的特徴

外間 まどか, 大谷 理浩, 石田 穣治, 梅田 剛志, 井上 陽平, 水田 亮, 井本 良二, 駿河 和城, 劒持 直也, 家護谷 泰仁, 平野 秀一郎, 冨田 祐介, 藤井 謙太郎, 鷲尾 佳奈, 田中 將太

小児の脳神経   49 ( 2 )   209 - 209   2024.4

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial. International journal

Tatsunori Shimoi, Kuniko Sunami, Makoto Tahara, Satoshi Nishiwaki, Shota Tanaka, Eishi Baba, Masashi Kanai, Ichiro Kinoshita, Hidekazu Shirota, Hideyuki Hayashi, Naohiro Nishida, Toshio Kubo, Nobuaki Mamesaya, Yayoi Ando, Natsuko Okita, Taro Shibata, Kenichi Nakamura, Noboru Yamamoto

EClinicalMedicine   69   102447 - 102447   2024.3

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Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2–7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5–12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

DOI： 10.1016/j.eclinm.2024.102447

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Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation. International journal

Sina Neyazi, Erika Yamazawa, Karoline Hack, Shota Tanaka, Genta Nagae, Catena Kresbach, Takayoshi Umeda, Alicia Eckhardt, Kenji Tatsuno, Lara Pohl, Taijun Hana, Michael Bockmayr, Phyo Kim, Mario M Dorostkar, Toshihiro Takami, Denise Obrecht, Keisuke Takai, Abigail K Suwala, Takashi Komori, Shweta Godbole, Annika K Wefers, Ryohei Otani, Julia E Neumann, Fumi Higuchi, Leonille Schweizer, Yuta Nakanishi, Camelia-Maria Monoranu, Hirokazu Takami, Lara Engertsberger, Keisuke Yamada, Viktoria Ruf, Masashi Nomura, Theresa Mohme, Akitake Mukasa, Jochen Herms, Shunsaku Takayanagi, Martin Mynarek, Reiko Matsuura, Katrin Lamszus, Kazuhiko Ishii, Lan Kluwe, Hideaki Imai, Andreas von Deimling, Tsukasa Koike, Martin Benesch, Yoshihiro Kushihara, Matija Snuderl, Shohei Nambu, Stephan Frank, Takaki Omura, Christian Hagel, Kazuha Kugasawa, Viktor F Mautner, Koichi Ichimura, Stefan Rutkowski, Hiroyuki Aburatani, Nobuhito Saito, Ulrich Schüller

Acta neuropathologica   147 ( 1 )   22 - 22   2024.1

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Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class “spinal ependymoma” (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.

DOI： 10.1007/s00401-023-02668-9

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Histopathological, Demographic, and Clinical Signatures of Medulla Oblongata Germ Cell Tumors: A Case Report With the Review of Literature. International journal

Daisuke Sato, Shota Tanaka, Hirokazu Takami, Shunsaku Takayanagi, Yurie Rai, Munetoshi Hinata, Atsuto Katano, Nobuhito Saito

Cureus   16 ( 1 )   e51861   2024.1

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The medulla oblongata is one of the rarest sites of occurrence for germ cell tumors (GCTs) of the central nervous system. As there is scant data regarding epidemiology, clinical presentations, optimal intervention, and long-term prognosis, we aimed to delineate the features of this rare entity by presenting our representative case and performing a quantitative review of the literature. A 24-year-old woman presented to our department with vertigo and swallowing difficulties. Magnetic resonance imaging revealed a homogenously enhanced exophytic lesion arising from the medulla oblongata and extending to the fourth ventricle. Surgical resection was performed and a histological diagnosis of pure germinoma was made. The patient underwent chemotherapy and whole-ventricular irradiation. No recurrence has been experienced for 4 months after the surgery. According to the literature, the prognosis of GCTs at the medulla oblongata seems no worse than those at typical sites. Striking features including occurrence at an older age, female preponderance, and a predominance of germinoma were noteworthy. The pattern of local recurrence suggests extensive radiation coverage is not a prerequisite. Special attention is needed for cardiac and respiratory functions as the main factors eliciting mortality.

DOI： 10.7759/cureus.51861

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Pineal Parenchymal Tumors

Yosuke Kitagawa, Patrick Y. Wen, Shota Tanaka

Textbook of Uncommon Cancer: Fifth Edition   939 - 948   2024.1

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Pineal parenchymal tumors (PPTs) are a wide spectrum of pineal gland tumors (pineocytoma, PPT of intermediate differentiation, and pineoblastoma) and have a variety of differential diagnoses including germ cell tumors and astrocytomas. Accurate histological diagnosis is crucial for optimization of treatments. Pineocytoma, a benign PPT (WHO grade 1), can potentially be cured by complete resection, for which a surgical approach along the cerebellar tentorium is preferred. In contrast, pineoblastoma, a malignant PPT (grade 4), requires aggressive adjuvant treatments with craniospinal irradiation and chemotherapy, usually cisplatin based. PPT of intermediate differentiation is generally treated similarly to pineoblastoma.

DOI： 10.1002/9781119196235.ch66

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Glioblastoma with high O6-methyl-guanine DNA methyltransferase expression are more immunologically active than tumors with low MGMT expression. International journal

Yoshihiro Kushihara, Shota Tanaka, Yukari Kobayashi, Koji Nagaoka, Miyu Kikuchi, Takahide Nejo, Erika Yamazawa, Shohei Nambu, Kazuha Kugasawa, Hirokazu Takami, Shunsaku Takayanagi, Nobuhito Saito, Kazuhiro Kakimi

Frontiers in immunology   15   1328375 - 1328375   2024

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BACKGROUND: Glioblastoma (GBM) is a highly lethal brain tumor. The effectiveness of temozolomide (TMZ) treatment in GBM is linked to the methylation status of O6-methyl-guanine DNA methyltransferase (MGMT) promoter. Patients with unmethylated MGMT promoter have limited treatment options available. Consequently, there is a pressing need for alternative therapeutic strategies for such patients. METHODS: Data, including transcriptomic and clinical information, as well as information on MGMT promoter methylation status in primary GBM, were obtained from The Cancer Genome Atlas (TCGA) (n=121) and Chinese Glioma Genome Atlas (CGGA) (n=83) datasets. Samples were categorized into high and low MGMT expression groups, MGMT-high (MGMT-H) and MGMT-low (MGMT-L) tumors. A comprehensive transcriptome analysis was conducted to explore the tumor-immune microenvironment. Furthermore, we integrated transcriptome data from 13 GBM patients operated at our institution with findings from tumor-infiltrating lymphocyte (TIL) cultures, specifically investigating their response to autologous tumors. RESULTS: Gene signatures associated with various immune cells, including CD8 T cells, helper T cells, B cells, and macrophages, were noted in MGMT-H tumors. Pathway analysis confirmed the enrichment of immune cell-related pathways. Additionally, biological processes involved in the activation of monocytes and lymphocytes were observed in MGMT-H tumors. Furthermore, TIL culture experiments showed a greater presence of tumor-reactive T cells in MGMT-H tumors compared to MGMT-L tumors. These findings suggest that MGMT-H tumors has a potential for enhanced immune response against tumors mediated by CD8 T cells. CONCLUSION: Our study provides novel insights into the immune cell composition of MGMT-H tumors, which is characterized by the infiltration of type 1 helper T cells and activated B cells, and also the presence of tumor-reactive T cells evidenced by TIL culture. These findings contribute to a better understanding of the immune response in MGMT-H tumors, emphasizing their potential for immunotherapy. Further studies are warranted to investigate on the mechanisms of MGMT expression and antitumor immunity.

DOI： 10.3389/fimmu.2024.1328375

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Treatment of Tenosynovial Giant Cell Tumor of the Cervical Spine with Postoperative Anti-RANKL Antibody (Denosumab) Administration

Yuichi Hirata, Takayuki Nagase, Susumu Sasada, Yoshiyuki Ayada, Hayato Miyake, Chiaki Sugahara, Hidetaka Yamamoto, Yoshinao Oda, Takao Yasuhara, Shota Tanaka

Acta Medica Okayama   78 ( 6 )   469 - 474   2024

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Tenosynovial giant cell tumor (TGCT) is a fibrous histiocytic tumor originating in the synovial membrane. While cervical TGCT may not be considered a common diagnosis preoperatively because it is relatively rare, it has a high recurrence rate and should be considered. Total resection is preferable, but it can be challenging due to the risk of damaging the vertebral artery. Denosumab has shown effectiveness as a postoperative treatment for osteolytic bone lesion. Denosumab administration coupled with close follow-up might offer an effective postoperative treatment option for unresectable TGCT with bone invasion.

DOI： 10.18926/AMO/67877

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Nasal immature teratoma in an elderly patient: Clinicopathological and epigenetic analogies with central nervous system counterparts, alongside genomic divergences International journal

Shintaro Inoue, Hirokazu Takami, Shota Tanaka, Masashi Nomura, Shunsaku Takayanagi, Yuki Saito, Shu Kikuta, Kenji Kondo, Reiko Matsuura, Masako Ikemura, Sho Yamazawa, Masao Matsutani, Ryo Nishikawa, Yuko Matsushita, Koichi Ichimura, Nobuhito Saito

Neuropathology   2024

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Germ cell tumors (GCTs) are categorized as gonadal or extra-gonadal, based on the origin. Extra-gonadal GCTs predominantly manifest within the central nervous system (CNS), mediastinum, retroperitoneum, and sacrococcygeal region. These malignancies are most frequently diagnosed in the pediatric, adolescent, and young adult demographics. Incidences of GCT within the nasal cavity are notably scarce, with only six cases documented. This report details the case of a 70-year-old man who presented with a left nasal mass ultimately diagnosed as immature teratoma. A remarkable aspect of this case was the detection of SMARCA4 (BRG1) loss through immunohistochemical analysis. In addition, methylation profiling aligned this case with CNS GCTs, specifically those classified as non-germinomatous GCTs. This molecular characterization informed a tailored therapeutic strategy incorporating carboplatin and etoposide, alongside localized irradiation. This individualized treatment regimen achieved favorable outcomes, with the patient remaining recurrence free for over three years. This highlights the need for precise therapeutic approaches in the management of extragonadal GCTs, particularly those arising in atypical anatomical locations. The present case accentuates the significance of thorough diagnostic evaluations and customized treatment plans for rare GCT presentations. Further empirical and clinical investigations are warranted to enhance our understanding of and refine therapeutic protocols for such exceptional cases.

DOI： 10.1111/neup.13008

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Tectal glioma: clinical, radiological, and pathological features, and the importance of molecular analysis

Ryoji Imoto, Yoshihiro Otani, Kentaro Fujii, Joji Ishida, Shuichiro Hirano, Naoya Kemmotsu, Yasuki Suruga, Ryo Mizuta, Yasuhito Kegoya, Yohei Inoue, Tsuyoshi Umeda, Madoka Hokama, Kana Washio, Hiroyuki Yanai, Shota Tanaka, Kaishi Satomi, Koichi Ichimura, Isao Date

Brain Tumor Pathology   2024

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Tectal glioma (TG) is a rare lower grade glioma (LrGG) that occurs in the tectum, mainly affecting children. TG shares pathological similarities with pilocytic astrocytoma (PA), but recent genetic analyses have revealed distinct features, such as alterations in KRAS and BRAF. We conducted a retrospective review of cases clinically diagnosed as TG and treated at our institute between January 2005 and March 2023. Six cases were identified and the median age was 30.5 years. Four patients underwent biopsy and two patients underwent tumor resection. Histological diagnoses included three cases of PA, one case of astrocytoma, and two cases of high-grade glioma. The integrated diagnosis, according to the fifth edition of the World Health Organization Classification of Tumours of the central nervous system, included two cases of PA and one case each of diffuse high-grade glioma; diffuse midline glioma H3 K27-altered; glioblastoma; and circumscribed astrocytic glioma. Among the three patients who underwent molecular evaluation, two had KRAS mutation and one had H3-3A K27M mutation. Our results demonstrate the diverse histological and molecular characteristics of TG distinct from other LrGGs. Given the heterogeneous pathological background and the risk of pathological progression in TG, we emphasize the importance of comprehensive diagnosis, including molecular evaluation.

DOI： 10.1007/s10014-024-00494-9

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Characteristics and outcomes of subarachnoid hemorrhage from vertebral artery dissection: A comparative study with other non-traumatic etiologies. International journal

Shu Oshita, Tetsuya Yumoto, Shunta Jinno, Ippei Matsuo, Takashi Hongo, Hiromichi Naito, Masafumi Hiramatsu, Jun Haruma, Kenji Sugiu, Shota Tanaka, Atsunori Nakao

Acute medicine & surgery   11 ( 1 )   e70031   2024

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AIM: Vertebral artery dissection (VAD) is a rare cause of non-traumatic subarachnoid hemorrhage (SAH) with significant clinical implications. This study compared the clinical characteristics and outcomes of SAH from intracranial VAD rupture to those from other etiologies, primarily aneurysmal rupture. METHODS: This single-center retrospective cohort study at Okayama University Hospital included patients with non-traumatic SAH diagnosed between 2019 and 2023. Patients were categorized into "VAD rupture" and "other etiologies" groups. The main outcome was clinical presentation and symptoms. Additional outcomes included ICU mortality, in-hospital mortality, and unfavorable outcomes at discharge and 6 months, defined as a modified Rankin Scale score of 3-6. RESULTS: A total of 66 patients were included, with 14 in the VAD rupture group and 52 in the other etiologies group. The VAD rupture group was younger (median age 49 vs. 64 years, p = 0.003) and had a higher incidence of out-of-hospital cardiac arrest (42.9% vs. 9.6%, p = 0.011). Preceding headache was more common in the VAD rupture group (78.6% vs. 11.5%, p < 0.001), with a median duration of 36 h before presentation. ICU and in-hospital mortality was higher in the VAD rupture group (both 50.0% vs. 19.3%, p = 0.019). No significant differences were found in unfavorable neurological outcomes at hospital discharge and 6 months. CONCLUSIONS: VAD-related SAH often presents with prodromal headaches, severe symptoms like out-of-hospital cardiac arrest, and higher ICU and in-hospital mortality than other SAH causes, though long-term outcomes are similar. Larger, prospective studies are needed to refine interventions.

DOI： 10.1002/ams2.70031

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Distinct patterns of copy number alterations may predict poor outcome in central nervous system germ cell tumors

Hirokazu Takami, Kaishi Satomi, Kohei Fukuoka, Taishi Nakamura, Shota Tanaka, Akitake Mukasa, Nobuhito Saito, Tomonari Suzuki, Takaaki Yanagisawa, Kazuhiko Sugiyama, Masayuki Kanamori, Toshihiro Kumabe, Teiji Tominaga, Kaoru Tamura, Taketoshi Maehara, Masahiro Nonaka, Akio Asai, Kiyotaka Yokogami, Hideo Takeshima, Toshihiko Iuchi, Keiichi Kobayashi, Koji Yoshimoto, Keiichi Sakai, Yoichi Nakazato, Masao Matsutani, Motoo Nagane, Ryo Nishikawa, Koichi Ichimura

Scientific Reports   13 ( 1 )   2023.12

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.

DOI： 10.1038/s41598-023-42842-3

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Other Link： https://www.nature.com/articles/s41598-023-42842-3

Long-term survival after cordectomy in a case of spinal cord diffuse midline glioma, H3K27-altered: illustrative case

Daisuke Sato, Hirokazu Takami, Shota Tanaka, Shunsaku Takayanagi, Masako Ikemura, Nobuhito Saito

Journal of Neurosurgery: Case Lessons   6 ( 25 )   2023.12

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BACKGROUND Spinal cord diffuse midline glioma, H3K27-altered, is an extremely rare entity with a poor prognosis. However, its optimal treatment remains poorly defined. Although cordectomy was introduced in the early 20th century, its efficacy has been questioned and shrouded behind the scenes. OBSERVATIONS A 76-year-old male with recent-onset paraparesis of the lower extremities and paresthesia presented to our outpatient clinic. Magnetic resonance imaging revealed an intra-axial spinal cord tumor extending from T12 to L2. The patient underwent laminectomy and partial tumor resection, and the surgical specimen was histologically diagnosed as a diffuse midline glioma, H3K27-altered. Although standard chemoradiotherapy was implemented, the patient experienced local tumor recurrence 2 years later and underwent cordectomy at T9. The patient was alive at the 4-year follow-up after cordectomy without tumor recurrence. According to the literature, patients with lesions in the lower thoracic cord below T8 achieveda longer survival than those with lesions in the upper thoracic cord above T5. LESSONS Cordectomy benefits selected cases of high-grade spinal cord gliomas. Maximal prevention of cerebrospinal fluid dissemination by tumor cells is indisputably important, and tumors located below the lower thoracic spine may be the key to success in establishing a long-term prognosis after cordectomy.

DOI： 10.3171/CASE23296

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Intraventricular central neurocytoma molecularly defined as extraventricular neurocytoma: a case representing the discrepancy between clinicopathological and molecular classifications

Daisuke Sato, Hirokazu Takami, Shunsaku Takayanagi, Masako Ikemura, Reiko Matsuura, Shota Tanaka, Nobuhito Saito

Brain Tumor Pathology   40 ( 4 )   230 - 234   2023.10

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Central neurocytoma (CN) is classically defined by its intraventricular location, neuronal/neurocytic differentiation, and histological resemblance to oligodendroglioma. Extraventricular neurocytoma (EVN) shares similar histological features with CN, while it distributes any site without contact with the ventricular system. CN and EVN have distinct methylation landscapes, and EVN has a signature fusion gene, FGFR1-TACC1. These characteristics distinguish between CN and EVN. A 30-year-old female underwent craniotomy and resection of a left intraventricular tumor at our institution. The histopathology demonstrated the classical findings of CN. Adjuvant irradiation with 60 Gy followed. No recurrence has been recorded for 25 years postoperatively. RNA sequencing revealed FGFR1-TACC1 fusion and methylation profile was discrepant with CN but compatible with EVN. We experienced a case of anatomically and histologically proven CN in the lateral ventricle. However, the FGFR1-TACC1 fusion gene and methylation profiling suggested the molecular diagnosis of EVN. The representative case was an "intraventricular" neurocytoma displaying molecular features of an "extraventricular" neurocytoma. Clinicopathological and molecular definitions have collided in our case and raised questions about the current definition of CN and EVN.

DOI： 10.1007/s10014-023-00469-2

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PTPN11 variant may be a prognostic indicator of IDH-wildtype glioblastoma in a comprehensive genomic profiling cohort International journal

Ryohei Otani, Masachika Ikegami, Ryoji Yamada, Hirohisa Yajima, Shinji Kawamura, Sakura Shimizu, Shota Tanaka, Shunsaku Takayanagi, Hirokazu Takami, Tatsuro Yamaguchi

Journal of Neuro-Oncology   164 ( 1 )   221 - 229   2023.8

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PURPOSE: Glioblastoma (GBM) is the most common type of primary malignant brain tumor and has a poor prognosis. Identifying novel targets and stratification strategies is urgently needed to improve patient survival. The present study aimed to identify clinically relevant genomic alterations in IDH-wildtype GBM using data from comprehensive genomic profiling (CGP) assays performed nationwide in Japan. METHODS: The CGP assay results of 392 IDH-wildtype GBM cases performed between October 2019 and February 2023 obtained from the Center for Cancer Genomics and Advanced Therapeutics were retrospectively analyzed. RESULTS: The median patient age was 52.5 years, and 207 patients (53%) were male. In the 286 patients for whom survival information was available, a protein-tyrosine phosphatase non-receptor type 11 (PTPN11) variant detected in 20 patients (6.8%) was extracted as the gene associated with significantly shorter overall survival (p = 0.002). Multivariate analysis demonstrated that the PTPN11 variant and poor performance status were independent prognostic indicators. In contrast, no prognostic impact was observed in the cohort in The Cancer Genome Atlas data. The discrepancy in the prognostic impact of the PTPN11 variant from these two pools might have resulted from differences in the biases affecting the survival of patients who underwent a CGP assay, including left-truncation and right-censored bias. However, survival simulation done to adjust for these biases showed that the prognostic impact of the PTPN11 variant was also significant. CONCLUSIONS: The PTPN11 variant was a negative prognostic indicator of IDH-wildtype GBM in the patient cohort with the CGP assay.

DOI： 10.1007/s11060-023-04411-6

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Brain Metastasis Mimicking Glioma on Imaging Appearance During Tyrosine Kinase Inhibitor Administration: A Case Series and Literature Review. International journal

Yurie Rai, Hirokazu Takami, Kei Kawaguchi, Shunsaku Takayanagi, Shota Tanaka, Yoichi Yasunaga, Nobuhito Saito

Cureus   15 ( 8 )   e43591   2023.8

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OBJECTIVE: Preoperative imaging diagnosis is critical to planning treatment strategies; however, it is occasionally challenging and sometimes misleading. The effects of molecularly targeted therapies on imaging appearances remain uncharted. We investigated the imaging characteristics of brain metastasis during tyrosine kinase inhibitor (TKI) administration. METHODS: We analyzed the 12 cases of brain metastasis from lung cancer in our institute, including a case of a 49-year-old woman under gefitinib. Additionally, we reviewed the cases of brain metastasis from lung cancer with gefitinib treatment in the literature. RESULTS: A woman during five-year gefitinib treatment for postoperative recurrence of lung adenocarcinoma was found to have a cerebellar tumoral lesion incidentally on magnetic resonance imaging (MRI). This lesion did not harbor any peritumoral edema, along with appearing hypometabolic on fluorodeoxyglucose (FDG) positron emission tomography (PET). This appearance was inconsistent with a typical metastatic appearance, and high-grade glioma was instead highly suspected, leading to a decision to proceed to gross total tumor resection. The pathological diagnosis, however, was brain metastasis from lung cancer. The other 11 cases without TKI treatment showed peritumoral edema on MRI and higher accumulation of FDG on PET. The two cases of brain metastasis with gefitinib in the literature showed no peritumoral edema on MRI. CONCLUSION: TKIs like gefitinib can affect tumor biology, leading to a loss of typical imaging findings such as peritumoral brain edema and hyper-metabolism. As preoperative imaging diagnosis guides us in surgical planning, including biopsy or resection, ongoing treatment information should be fully integrated into imaging interpretation.

DOI： 10.7759/cureus.43591

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CHD5 gene variant predicts leptomeningeal metastasis after surgical resection of brain metastases of breast cancer International journal

Ryohei Otani, Daichi Sadato, Ryoji Yamada, Hirohisa Yajima, Shinji Kawamura, Sakura Shimizu, Shota Tanaka, Shunsaku Takayanagi, Hirokazu Takami, Tatsuro Yamaguchi

Journal of Neuro-Oncology   163 ( 3 )   657 - 662   2023.7

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PURPOSE: Leptomeningeal metastasis (LM) is a complication of surgery for brain metastasis and is a risk factor of poor prognosis. The risk of LM is particularly high after surgery for a breast cancer metastasis to the brain. If the risk of LM after surgical resection for a brain metastasis were predictable, appropriate adjuvant therapy could be administered to individual patients to improve their prognosis. The present study aimed to reveal the genetic characteristics of brain metastases as means of predicting LM in breast cancer patients. METHODS: Ten patients with brain metastases of breast cancer presented LM after surgical resection were analyzed by whole-exome sequencing. RESULTS: A chromodomain-helicase-DNA-binding protein 5 (CHD5) gene alteration was detected in nine cases (90%), including a nonsynonymous variant in four cases and copy number deletion in five cases. CHD5 protein expression was lost in nine cases and had decreased in one case. The frequency of CHD5 gene alteration in brain metastases with LM was significantly higher than in primary breast cancer (2.3%) or in brain metastases of breast cancer (0%) (p < 0.0001). CONCLUSIONS: These results suggested that the CHD5 gene alteration was associated with LM after surgical resection of breast cancer brain metastases. Searching for the gene alteration might predict the LM risk after surgical resection.

DOI： 10.1007/s11060-023-04381-9

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Lymphoproliferative disorder during temozolomide therapy; a representative case of a formidable complication and management challenges. International journal

Daisuke Sato, Hirokazu Takami, Shunsaku Takayanagi, Kazuki Taoka, Mariko Tanaka, Reiko Matsuura, Shota Tanaka, Nobuhito Saito

BMC neurology   23 ( 1 )   224 - 224   2023.6

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Lymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described. CASE PRESENTATION: A patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and "other iatrogenic immunodeficiency-associated lymphoproliferative disorder" (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD. CONCLUSIONS: This is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

DOI： 10.1186/s12883-023-03274-8

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脳腫瘍のメチル化診断 中枢神経胚細胞腫におけるコピー数異常と予後との相関

高見 浩数, 里見 介史, 福岡 講平, 中村 大志, 田中 將太, 武笠 晃丈, 齊藤 延人, 鈴木 智成, 柳澤 隆昭, 杉山 一彦, 金森 政之, 隈部 俊宏, 冨永 悌二, 田村 郁, 前原 健寿, 埜中 正博, 淺井 昭雄, 横上 聖貴, 竹島 秀雄, 井内 俊彦, 小林 啓一, 吉本 幸司, 酒井 圭一, 中里 洋一, 松谷 雅生, 永根 基雄, 西川 亮, 市村 幸一

Brain Tumor Pathology   40 ( Suppl. )   063 - 063   2023.5

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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IDH野生型低悪性度星細胞腫の臨床・病理学的特徴と治療の変遷 46症例の解析

高柳 俊作, 田中 將太, 高見 浩数, 池村 雅子, 齊藤 延人

Brain Tumor Pathology   40 ( Suppl. )   099 - 099   2023.5

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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