Multicenter Study

. 2024 Jul 27;12(1):120.

doi: 10.1186/s40478-024-01808-w.

Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort

Nobuhide Hayashi^{1

2

3}, Junya Fukai^{4

5}, Hirokazu Nakatogawa^{6

7

8}, Hiroshi Kawaji^{6

8}, Ema Yoshioka^{6

9}, Yoshinori Kodama^{6

10}, Kosuke Nakajo^{6

11}, Takehiro Uda^{6

11}, Kentaro Naito^{6

11}, Noriyuki Kijima^{6

12}, Yoshiko Okita^{6

12}, Naoki Kagawa^{6

12}, Yoshinobu Takahashi^{6

13}, Naoya Hashimoto^{6

13}, Hideyuki Arita^{6

14}, Koji Takano^{6

14}, Daisuke Sakamoto^{6

15}, Tomoko Iida^{6

15}, Yoshiki Arakawa^{6

16}, Takeshi Kawauchi^{6

17}, Yukihiko Sonoda^{6

18}, Yuta Mitobe^{6

18}, Kenichi Ishibashi^{6

19}, Masahide Matsuda^{6

20}, Takamune Achiha^{6

21}, Takahiro Tomita^{6

22}, Masahiro Nonaka^{6

23}, Keijiro Hara^{6

24}, Noriyoshi Takebe^{6

25}, Takashi Tsuzuki^{6

26}, Yoshikazu Nakajima^{6

26

27}, Shiro Ohue^{6

28}, Nobuyuki Nakajima^{6

29}, Akira Watanabe^{6

30}, Akihiro Inoue^{6

31}, Masao Umegaki^{6

32}, Daisuke Kanematsu^{6

9}, Asako Katsuma^{6

33}, Miho Sumida^{6

33}, Tomoko Shofuda^{6

34}, Masayuki Mano^{6

35}, Manabu Kinoshita^{6

14

36}, Kanji Mori^{6

37}, Naoyuki Nakao^{6

38}, Yonehiro Kanemura^{6

9

33

39}

Affiliations

¹ Department of Neurosurgery, Wakayama Rosai Hospital, Kinomoto 93-1, Wakayama City, Wakayama, 640-8505, Japan. nbh-hayashi@wakayamah.johas.go.jp.
² Kansai Molecular Diagnosis Network for CNS Tumors, Osaka City, Osaka, 540-0006, Japan. nbh-hayashi@wakayamah.johas.go.jp.
³ Department of Neurological Surgery, School of Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama City, Wakayama, 641-8510, Japan. nbh-hayashi@wakayamah.johas.go.jp.
⁴ Kansai Molecular Diagnosis Network for CNS Tumors, Osaka City, Osaka, 540-0006, Japan. junfukai@wakayama-med.ac.jp.
⁵ Department of Neurological Surgery, School of Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama City, Wakayama, 641-8510, Japan. junfukai@wakayama-med.ac.jp.
⁶ Kansai Molecular Diagnosis Network for CNS Tumors, Osaka City, Osaka, 540-0006, Japan.
⁷ Department of Pediatric Neurosurgery, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, 430-8558, Japan.
⁸ Department of Neurosurgery, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, 430-8558, Japan.
⁹ Division of Molecular Medicine, Department of Biomedical Research and Innovation, Institute for Clinical Research, NHO Osaka National Hospital, Osaka City, Osaka, 540-0006, Japan.
¹⁰ Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka City, Osaka, 541-8567, Japan.
¹¹ Department of Neurosurgery, Osaka Metropolitan University Graduate School of Medicine, Osaka City, Osaka, 545-8585, Japan.
¹² Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
¹³ Department of Neurosurgery, School of Medical Science, Kyoto Prefectural University Graduate, Kyoto City, Kyoto, 602-8566, Japan.
¹⁴ Department of Neurosurgery, Osaka International Cancer Institute, Osaka City, Osaka, 541-8567, Japan.
¹⁵ Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan.
¹⁶ Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto City, Kyoto, 606-8507, Japan.
¹⁷ Department of Neurosurgery, Osaka Red Cross Hospital, Osaka City, Osaka, 543-8555, Japan.
¹⁸ Department of Neurosurgery, Faculty of Medicine, Yamagata University, Yamagata City, Yamagata, 990-8560, Japan.
¹⁹ Department of Neurosurgery, Osaka City General Hospital, Osaka City, Osaka, 534-0021, Japan.
²⁰ Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
²¹ Department of Neurosurgery, Kansai Rosai Hospital, Amagasaki, Hyogo, 660-8511, Japan.
²² Department of Neurosurgery, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama City, Toyama, 930-0194, Japan.
²³ Department of Neurosurgery, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.
²⁴ Department of Neurosurgery, Tokushima University Graduate School of Biomedical Sciences, Tokushima City, Tokushima, 770-8501, Japan.
²⁵ Department of Neurosurgery, Medical Research Institute, Tazuke Kofukai Foundation, Kitano Hospital, Osaka City, Osaka, 530-8480, Japan.
²⁶ Department of Neurosurgery, Sakai City Medical Center, Sakai, Osaka, 593-8304, Japan.
²⁷ Department of Neurosurgery, Kobe Tokushukai Hospital, Kobe, Hyogo, 655-0017, Japan.
²⁸ Department of Neurosurgery, Ehime Prefectural Central Hospital, Matsuyama, Ehime, 790-0024, Japan.
²⁹ Department of Neurosurgery, Tokyo Medical University, Tokyo, 160-0023, Japan.
³⁰ Department of Neurosurgery, Kindai University Nara Hospital, Ikoma, Nara, 630-0293, Japan.
³¹ Department of Neurosurgery, Ehime University School of Medicine, Toon, Ehime, 791-0295, Japan.
³² Department of Neurosurgery, Suita Municipal Hospital, Suita, Osaka, 564-8567, Japan.
³³ Division of Regenerative Medicine, Department of Biomedical Research and Innovation, Institute for Clinical Research, NHO Osaka National Hospital, Osaka City, Osaka, 540-0006, Japan.
³⁴ Division of Stem Cell Research, Department of Biomedical Research and Innovation, Institute for Clinical Research, NHO Osaka National Hospital, Osaka City, Osaka, 540-0006, Japan.
³⁵ Department of Central Laboratory and Surgical Pathology, NHO Osaka National Hospital, Osaka City, Osaka, 540-0006, Japan.
³⁶ Department of Neurosurgery, Asahikawa Medical University, Asahikawa, Hokkaido, 078-8510, Japan.
³⁷ Department of Neurosurgery, Yao Municipal Hospital, Yao, Osaka, 581-0069, Japan.
³⁸ Department of Neurological Surgery, School of Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama City, Wakayama, 641-8510, Japan.
³⁹ Department of Neurosurgery, NHO Osaka National Hospital, Osaka City, Osaka, 540-0006, Japan.

PMID: 39061104
PMCID: PMC11282756
DOI: 10.1186/s40478-024-01808-w

Multicenter Study

Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort

Nobuhide Hayashi et al. Acta Neuropathol Commun. 2024.

. 2024 Jul 27;12(1):120.

doi: 10.1186/s40478-024-01808-w.

Authors

Affiliations

¹ Department of Neurosurgery, Wakayama Rosai Hospital, Kinomoto 93-1, Wakayama City, Wakayama, 640-8505, Japan. nbh-hayashi@wakayamah.johas.go.jp.
² Kansai Molecular Diagnosis Network for CNS Tumors, Osaka City, Osaka, 540-0006, Japan. nbh-hayashi@wakayamah.johas.go.jp.
³ Department of Neurological Surgery, School of Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama City, Wakayama, 641-8510, Japan. nbh-hayashi@wakayamah.johas.go.jp.
⁴ Kansai Molecular Diagnosis Network for CNS Tumors, Osaka City, Osaka, 540-0006, Japan. junfukai@wakayama-med.ac.jp.
⁵ Department of Neurological Surgery, School of Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama City, Wakayama, 641-8510, Japan. junfukai@wakayama-med.ac.jp.
⁶ Kansai Molecular Diagnosis Network for CNS Tumors, Osaka City, Osaka, 540-0006, Japan.
⁷ Department of Pediatric Neurosurgery, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, 430-8558, Japan.
⁸ Department of Neurosurgery, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, 430-8558, Japan.
⁹ Division of Molecular Medicine, Department of Biomedical Research and Innovation, Institute for Clinical Research, NHO Osaka National Hospital, Osaka City, Osaka, 540-0006, Japan.
¹⁰ Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka City, Osaka, 541-8567, Japan.
¹¹ Department of Neurosurgery, Osaka Metropolitan University Graduate School of Medicine, Osaka City, Osaka, 545-8585, Japan.
¹² Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
¹³ Department of Neurosurgery, School of Medical Science, Kyoto Prefectural University Graduate, Kyoto City, Kyoto, 602-8566, Japan.
¹⁴ Department of Neurosurgery, Osaka International Cancer Institute, Osaka City, Osaka, 541-8567, Japan.
¹⁵ Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan.
¹⁶ Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto City, Kyoto, 606-8507, Japan.
¹⁷ Department of Neurosurgery, Osaka Red Cross Hospital, Osaka City, Osaka, 543-8555, Japan.
¹⁸ Department of Neurosurgery, Faculty of Medicine, Yamagata University, Yamagata City, Yamagata, 990-8560, Japan.
¹⁹ Department of Neurosurgery, Osaka City General Hospital, Osaka City, Osaka, 534-0021, Japan.
²⁰ Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
²¹ Department of Neurosurgery, Kansai Rosai Hospital, Amagasaki, Hyogo, 660-8511, Japan.
²² Department of Neurosurgery, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama City, Toyama, 930-0194, Japan.
²³ Department of Neurosurgery, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.
²⁴ Department of Neurosurgery, Tokushima University Graduate School of Biomedical Sciences, Tokushima City, Tokushima, 770-8501, Japan.
²⁵ Department of Neurosurgery, Medical Research Institute, Tazuke Kofukai Foundation, Kitano Hospital, Osaka City, Osaka, 530-8480, Japan.
²⁶ Department of Neurosurgery, Sakai City Medical Center, Sakai, Osaka, 593-8304, Japan.
²⁷ Department of Neurosurgery, Kobe Tokushukai Hospital, Kobe, Hyogo, 655-0017, Japan.
²⁸ Department of Neurosurgery, Ehime Prefectural Central Hospital, Matsuyama, Ehime, 790-0024, Japan.
²⁹ Department of Neurosurgery, Tokyo Medical University, Tokyo, 160-0023, Japan.
³⁰ Department of Neurosurgery, Kindai University Nara Hospital, Ikoma, Nara, 630-0293, Japan.
³¹ Department of Neurosurgery, Ehime University School of Medicine, Toon, Ehime, 791-0295, Japan.
³² Department of Neurosurgery, Suita Municipal Hospital, Suita, Osaka, 564-8567, Japan.
³³ Division of Regenerative Medicine, Department of Biomedical Research and Innovation, Institute for Clinical Research, NHO Osaka National Hospital, Osaka City, Osaka, 540-0006, Japan.
³⁴ Division of Stem Cell Research, Department of Biomedical Research and Innovation, Institute for Clinical Research, NHO Osaka National Hospital, Osaka City, Osaka, 540-0006, Japan.
³⁵ Department of Central Laboratory and Surgical Pathology, NHO Osaka National Hospital, Osaka City, Osaka, 540-0006, Japan.
³⁶ Department of Neurosurgery, Asahikawa Medical University, Asahikawa, Hokkaido, 078-8510, Japan.
³⁷ Department of Neurosurgery, Yao Municipal Hospital, Yao, Osaka, 581-0069, Japan.
³⁸ Department of Neurological Surgery, School of Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama City, Wakayama, 641-8510, Japan.
³⁹ Department of Neurosurgery, NHO Osaka National Hospital, Osaka City, Osaka, 540-0006, Japan.

PMID: 39061104
PMCID: PMC11282756
DOI: 10.1186/s40478-024-01808-w

Erratum in

Correction: Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort.
Hayashi N, Fukai J, Nakatogawa H, Kawaji H, Yoshioka E, Kodama Y, Nakajo K, Uda T, Naito K, Kijima N, Okita Y, Kagawa N, Takahashi Y, Hashimoto N, Arita H, Takano K, Sakamoto D, Iida T, Arakawa Y, Kawauchi T, Sonoda Y, Mitobe Y, Ishibashi K, Matsuda M, Achiha T, Tomita T, Nonaka M, Hara K, Takebe N, Tsuzuki T, Nakajima Y, Ohue S, Nakajima N, Watanabe A, Inoue A, Umegaki M, Kanematsu D, Katsuma A, Sumida M, Shofuda T, Mano M, Kinoshita M, Mori K, Nakao N, Kanemura Y. Hayashi N, et al. Acta Neuropathol Commun. 2024 Oct 1;12(1):155. doi: 10.1186/s40478-024-01863-3. Acta Neuropathol Commun. 2024. PMID: 39354603 Free PMC article. No abstract available.

Abstract

This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma. We retrospectively analyzed 93 patients with diffuse midline glioma (47 thalamus, 24 brainstem, 12 spinal cord and 10 other midline locations) treated at 24 affiliated hospitals in the Kansai Molecular Diagnosis Network for CNS Tumors. Considering the term "midline" areas, which had been confused in previous reports, we classified four midline locations based on previous reports and anatomical findings. Clinical and molecular characteristics of the study cohort included: age 4-78 years, female sex (41%), lower-grade histology (56%), preoperative Karnofsky performance status (KPS) scores ≥ 80 (49%), resection (36%), adjuvant radiation plus chemotherapy (83%), temozolomide therapy (76%), bevacizumab therapy (42%), HIST1H3B p.K27M mutation (2%), TERT promoter mutation (3%), MGMT promoter methylation (9%), BRAF p.V600E mutation (1%), FGFR1 mutation (14%) and EGFR mutation (3%). Median progression-free and overall survival time was 9.9 ± 1.0 (7.9-11.9, 95% CI) and 16.6 ± 1.4 (13.9-19.3, 95% CI) months, respectively. Female sex, preoperative KPS score ≥ 80, adjuvant radiation + temozolomide and radiation ≥ 50 Gy were associated with favorable prognosis. Female sex and preoperative KPS score ≥ 80 were identified as independent good prognostic factors. This study demonstrated the current state of clinical practice for patients with diffuse midline glioma and molecular analyses of diffuse midline glioma in real-world settings. Further investigation in a larger population would contribute to better understanding of the pathology of diffuse midline glioma.

Keywords: Clinical characteristic; Diffuse midline glioma; H3 K27-altered; Midline location; Molecular feature; Prognostic factor; Survival.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest in association with this paper.

Figures

**Fig. 1**
Flowchart of patient selection

**Fig. 2**
a Schematic illustration of tumor locations and each number. Thalamus: 47, Brainstem: 24, Spinal cord: 12, Others: 10. b Distribution of patients’ age and sex. There are 26 cases (≤ 18 years) (28%), 60 cases (64%) (19–69 years) and 7 cases (≥ 70 years) (8%)

**Fig. 3**
Tile panel demonstrating clinical and molecular characteristics of histone H3 K27-mutant diffuse midline glioma patients in Kansai Network (n = 93)

**Fig. 4**
Kaplan–Meier survival curves according to tumor locations. a Median progression-free survival of the cohort (n = 77) was 9.9 ± 1.0 (7.9–11.9, 95% CI) months. Thalamus (n = 43), 9.8 months; Brainstem (n = 18), 11.0 months; Spinal cord (n = 9), 9.1 months; Others (n = 7), 8.7 months. b Median overall survival (mOS) of the cohort (n = 87) was 16.6 ± 1.4 (13.9–19.3, 95% CI) months. Thalamus (n = 43), 19.2 months; Brainstem (n = 22), 12.4 months; Spinal cord (n = 12), 16.0 months; Others (n = 10), 12.0 months

**Fig. 5**
Kaplan–Meier survival curves according to clinical factors: age (a), sex (b), preoperative KPS score (c), extent of surgical resection (d) adjuvant treatment (e) and radiation dose (f) in the study cohort

**Fig. 6**
Kaplan–Meier survival curves according to molecular factors: *TERT* (a), *MGMT* (b), *TP53* (c), *BRAF* (d), *FGFR1* (e) and *EGFR* (f) in the study cohort

See this image and copyright information in PMC

Cited by

Characteristics and outcomes of diffuse non-midline gliomas with H3F3A gene mutation in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort study.
Nakatogawa H, Fukai J, Kawaji H, Hayashi N, Yoshioka E, Kodama Y, Nakajo K, Uda T, Arakawa Y, Takada S, Kijima N, Ishibashi K, Okuda T, Sonoda Y, Ohue S, Arita H, Matsuda M, Fukami T, Tomita T, Inoue A, Achiha T, Kashiwagi H, Kanematsu D, Katsuma A, Sumida M, Shofuda T, Mano M, Kinoshita M, Mori K, Inenaga C, Kanemura Y. Nakatogawa H, et al. Acta Neuropathol Commun. 2025 Apr 16;13(1):77. doi: 10.1186/s40478-025-01989-y. Acta Neuropathol Commun. 2025. PMID: 40241149 Free PMC article.
Correction: Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort.
Hayashi N, Fukai J, Nakatogawa H, Kawaji H, Yoshioka E, Kodama Y, Nakajo K, Uda T, Naito K, Kijima N, Okita Y, Kagawa N, Takahashi Y, Hashimoto N, Arita H, Takano K, Sakamoto D, Iida T, Arakawa Y, Kawauchi T, Sonoda Y, Mitobe Y, Ishibashi K, Matsuda M, Achiha T, Tomita T, Nonaka M, Hara K, Takebe N, Tsuzuki T, Nakajima Y, Ohue S, Nakajima N, Watanabe A, Inoue A, Umegaki M, Kanematsu D, Katsuma A, Sumida M, Shofuda T, Mano M, Kinoshita M, Mori K, Nakao N, Kanemura Y. Hayashi N, et al. Acta Neuropathol Commun. 2024 Oct 1;12(1):155. doi: 10.1186/s40478-024-01863-3. Acta Neuropathol Commun. 2024. PMID: 39354603 Free PMC article. No abstract available.
The Clinical and Molecular Landscape of Rosette-Forming Glioneuronal Tumors.
Yang Z, Zhang X. Yang Z, et al. Biomedicines. 2024 Oct 12;12(10):2325. doi: 10.3390/biomedicines12102325. Biomedicines. 2024. PMID: 39457636 Free PMC article. Review.

References

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Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort

Affiliations

Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

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Cited by

References

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Erratum in

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