Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Koji Yoshimoto Last modified date:2022.06.15

Professor / Deaprtment of Neurosurgery, Graduate School of Medical Sciences / Neurological Institute / Faculty of Medical Sciences


Papers
1. Yusuke Funakoshi, Kosuke Takigawa, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Ryosuke Otsuji, Aki Sako, Tadamasa Yoshitake, Osamu Togao, Akio Hiwatashi, Toru Iwaki, Masahiro Mizoguchi, Koji Yoshimoto, Changes in the Relapse Pattern and Prognosis of Glioblastoma After Approval of First-Line Bevacizumab: A Single-Center Retrospective Study., World neurosurgery, 10.1016/j.wneu.2021.12.075, 159, e479-e487, 2022.03, BACKGROUND: Controversies exist regarding the aggressive recurrence of glioblastoma after bevacizumab treatment. We analyzed the clinical impact of bevacizumab approval in Japan by evaluating the clinical course and relapse pattern in patients with glioblastoma. METHODS: We included 100 patients with IDH-wild-type glioblastoma from September 2006 to February 2018 in our institution. The patients were classified into the pre-bevacizumab (n = 51) and post-bevacizumab (n = 49) groups. Overall, progression-free, deterioration-free, and postprogression survivals were compared. We analyzed the relapse pattern of 72 patients, whose radiographic progressions were evaluated. RESULTS: Significant improvement in progression-free (pre-bevacizumab, 7.5 months; post-bevacizumab, 9.9 months; P = 0.0153) and deterioration-free (pre-bevacizumab, 8.5 months; post-bevacizumab, 13.8 months; P = 0.0046) survivals was seen. These survival prolongations were strongly correlated (r: 0.91, P < 0.0001). The nonenhancing tumor pattern was novel in the post-bevacizumab era (5 of 33). The presence of a nonenhancing tumor did not indicate poor postprogression survival (hazard ratio: 0.82 [0.26-2.62], P = 0.7377). The rate of early focal recurrence was significantly lower (P = 0.0155) in the post-bevacizumab (4 of 33) than in the pre-bevacizumab (18 of 39) era. There was a significant decrease in early focal recurrence after approval of bevacizumab in patients with unresectable tumors (P = 0.0110). The treatment era was significantly correlated with a decreased rate of early focal recurrence (P = 0.0021, univariate analysis; P = 0.0144, multivariate analysis). CONCLUSIONS: Approval of first-line bevacizumab in Japan for unresectable tumors may prevent early progression and clinical deterioration of glioblastoma without worsening the clinical course after relapse..
2. Mari Kirishima, Toshiaki Akahane, Nayuta Higa, Hajime Yonezawa, Hiroyuki Uchida, Ikumi Kitazono, Michiyo Higashi, Koji Yoshimoto, Akihide Tanimoto, Integrated diagnosis of adult-type glioma according to 2021 World Health Organization classification: Analysis of 184 cases using a custom-made next-generation sequencing panel., Pathology international, 10.1111/pin.13197, 72, 3, 207-210, 2022.03.
3. Yutaro Fujii, Ryusuke Hatae, Nobuhiro Hata, Satoshi O Suzuki, Yuhei Sangatsuda, Kosuke Takigawa, Yusuke Funakoshi, Yutaka Fujioka, Daisuke Kuga, Masahiro Mizoguchi, Toru Iwaki, Koji Yoshimoto, A case of ganglioglioma grade 3 with H3 K27M mutation arising in the medial temporal lobe in an elderly patient., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12793, 2022.02, The mutation p.K27M in H3F3A (H3 K27M mutation) is mainly detected in diffuse midline glioma. However, recent studies have demonstrated that H3 K27M mutation could also be observed in a subset of gangliogliomas. Importantly, most H3 K27-mutated ganglioglioma cases also harbor BRAF V600E mutation. Herein, we report a rare case of H3 K27M-mutated ganglioglioma grade 3 without BRAF mutation arising in the medial temporal lobe in an elderly man. A small biopsy specimen was sampled. The pathological diagnosis was diffuse astrocytoma. The tumor progressed gradually during an 18-month follow-up period. Gadolinium enhancement on magnetic resonance imaging was noted 36 months after the biopsy. The patient was referred to a hospital for tumor resection. Histological analysis of resected specimens led to a diagnosis of ganglioglioma grade 3 with H3 K27M mutation. The patient underwent concurrent temozolomide chemotherapy with radiotherapy. Although the patient's condition deteriorated after chemotherapy due to disease progression, he survived for more than 23 months after tumor resection. We present this rare case and discuss the involvement of H3 K27M mutation in ganglioglioma grade 3..
4. 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, Koichi Ichimura, Transcriptome and Methylome Analysis of CNS Germ Cell Tumor Finds its Cell-of-Origin in Embryogenesis and Reveals Shared Similarities with Testicular Counterparts., Neuro-oncology, 10.1093/neuonc/noac021, 2022.02, 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 non-germinomatous 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 non-germinoma/non-seminoma 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..
5. Taiji Hamada, Toshiaki Akahane, Seiya Yokoyama, Nayuta Higa, Mari Kirishima, Kei Matsuo, Michiko Shimokawa, Koji Yoshimoto, Akihide Tanimoto, An oncogenic splice variant of PDGFRα in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors., Scientific reports, 10.1038/s41598-022-05391-9, 12, 1, 1275-1275, 2022.01, Understanding human genome alterations is necessary to optimize genome-based cancer therapeutics. However, some newly discovered mutations remain as variants of unknown significance (VUS). Here, the mutation c.1403A > G in exon 10 of the platelet-derived growth factor receptor-alpha (PDGFRA) gene, a VUS found in adult glioblastoma multiforme (GBM), was introduced in human embryonal kidney 293 T (HEK293T) cells using genome editing to investigate its potential oncogenic functions. Genome editing was performed using CRISPR/Cas9; the proliferation, drug sensitivity, and carcinogenic potential of genome-edited cells were investigated. We also investigated the mechanism underlying the observed phenotypes. Three GBM patients carrying the c.1403A > G mutation were studied to validate the in vitro results. The c.1403A > G mutation led to a splice variant (p.K455_N468delinsN) because of the generation of a 3'-acceptor splice site in exon 10. PDGFRA-mutated HEK293T cells exhibited a higher proliferative activity via PDGFRα and the cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 signaling pathway in a ligand-independent manner. They showed higher sensitivity to multi-kinase, receptor tyrosine kinase, and CDK4/CDK6 inhibitors. Of the three GBM patients studied, two harbored the p.K455_N468delinsN splice variant. The splicing mutation c.1403A > G in PDGFRA is oncogenic in nature. Kinase inhibitors targeting PDGFRα and CDK4/CDK6 signaling should be evaluated for treating GBM patients harboring this mutation..
6. Masanori Sato, Hitoshi Yamahata, Muneyoshi Yasuda, Takaaki Hiwatari, Masanori Yonenaga, Koichi Ishimaru, Osamu Miyanohara, Tetsuro Shimozuru, Koji Yoshimoto, Treatment of rotational/positional vertebral artery occlusion due to degenerative changes in the cervical vertebrae: A case report and review of the literature., Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association, 10.1016/j.jos.2021.12.014, 2022.01.
7. Nobutaka Mukae, Takafumi Shimogawa, Ayumi Sakata, Taira Uehara, Hiroshi Shigeto, Koji Yoshimoto, Takato Morioka, Reflection of the Ictal Electrocorticographic Discharges Confined to the Medial Temporal Lobe to the Scalp-Recorded Electroencephalogram., Clinical EEG and neuroscience, 10.1177/15500594211062702, 15500594211062702-15500594211062702, 2021.11, Objective: Previous reports on the simultaneous recording of electroencephalography (EEG) and electrocorticography (ECoG) have demonstrated that, in patients with temporal lobe epilepsy (TLE), ictal ECoG discharges with an amplitude as high as 1000 μV originating from the medial temporal lobe could not be recorded on EEG. In contrast, ictal EEG discharges were recorded after ictal ECoG discharges propagated to the lateral temporal lobe. Here, we report a case of TLE in which the ictal EEG discharges, corresponding to ictal ECoG discharges confined to the medial temporal lobe, were recorded. Case report: In the present case, ictal EEG discharges were hardly recognized when the amplitude of the ECoG discharges was less than 1500 μV. During the evolution and burst suppression phase, corresponding to highly synchronized ECoG discharges with amplitudes greater than 1500 to 2000 μV, rhythmic negative waves with the same frequency were clearly recorded both on the lateral temporal lobe and scalp. The amplitude of the lateral temporal ECoG was approximately one-tenth of that of the medial temporal ECoG. The amplitude of the scalp EEG was approximately one-tenth of that of the lateral temporal ECoG. Conclusions: Highly synchronized ictal ECoG discharges with high amplitude of greater than 1500 to 2000 μV in the medial temporal lobe could be recorded on the scalp as ictal EEG discharges via volume conduction..
8. Takashi Kawahara, Kazunori Arita, Shingo Fujio, Ryosuke Hanaya, Masamichi Atsuchi, F M Moinuddin, Muhammad Kamil, Tomohisa Okada, Hirofumi Hirano, Naoyuki Kitamura, Naoaki Kanda, Hitoshi Yamahata, Koji Yoshimoto, Dural sac shrinkage signs on magnetic resonance imaging at the thoracic level in spontaneous intracranial hypotension-its clinical significance., Acta neurochirurgica, 10.1007/s00701-021-04933-w, 2021.08, BACKGROUND: Spontaneous intracranial hypotension (SIH) is secondary to a cerebrospinal fluid leak at the spinal level without obvious causative events. Several signs on brain and cervical spine magnetic resonance (MR) imaging (MRI) have been associated with SIH but can be equivocal or negative. This retrospective study sought to identify characteristic SIH signs on thoracic spinal MRI. METHODS: Cranial and spinal MR images of 27 consecutive patients with classic SIH symptoms, who eventually received epidural autologous blood patches (EBPs), were analyzed. RESULTS: The most prevalent findings on T2-weighted MRI at the thoracic level were anterior shift of the spinal cord (96.3%) and dorsal dura mater (81.5%), probably caused by dural sac shrinkage. These dural sac shrinkage signs (DSSS) were frequently accompanied by cerebrospinal fluid collection in the posterior epidural space (77.8%) and a prominent epidural venous plexus (77.8%). These findings disappeared in all six patients who underwent post-EBP spinal MRI. Dural enhancement and brain sagging were minimum or absent on the cranial MR images of seven patients, although DSSS were obvious in these seven patients. For 23 patients with SIH and 28 healthy volunteers, a diagnostic test using thoracic MRI was performed by 13 experts to validate the usefulness of DSSS. The median sensitivity, specificity, positive-predictive value, negative-predictive value, and accuracy of the DSSS were high (range, 0.913-0.931). CONCLUSIONS: Detection of DSSS on thoracic MRI facilitates an SIH diagnosis without the use of invasive imaging modalities. The DSSS were positive even in patients in whom classic cranial MRI signs for SIH were equivocal or minimal..
9. Shingo Fujio, Tareq A Juratli, Tomoko Takajo, Kazunori Arita, Yushi Nagano, Koji Yoshimoto, Naema Nayyar, William T Curry Jr, Maria Martinez-Lage, Daniel P Cahill, Fred G Barker 2nd, Priscilla K Brastianos, Craniopharyngiomas, including Recurrent Cases, Lack TERT Promoter Hotspot Mutations., Neurologia medico-chirurgica, 10.2176/nmc.rc.2020-0339, 61, 6, 385-391, 2021.06, Adamantinomatous craniopharyngiomas (ACP) are characterized by alterations in the CTNNB1 gene while almost all papillary craniopharyngiomas (PCP) harbor a canonical V600E mutation in the BRAF gene. Although other recurrent driver genes have not been described to date in craniopharyngiomas, the heterogeneous clinical course of these tumors might be associated with the acquisition of further genomic alterations. It is well known that telomerase reverse transcriptase (TERT) promoter (TERTp) alterations, including mutations or methylation, upregulate the expression of TERT and increase telomerase activity, promoting tumorigenesis. We investigated whether TERTp mutations or methylation are associated with tumor relapse in a subset of craniopharyngiomas. Samples from 42 patients with histologically confirmed craniopharyngioma were retrieved. We determined TERTp, BRAF, and CTNNB1 hotspot mutations in all samples using targeted sequencing and the TERTp methylation status by methylation-specific polymerase chain reaction (PCR) in 30 samples. While BRAF V600E mutations and CTNNB1 mutations were detected in 12 (28.6%) and 21 patients (50%) in the initial tumors and subsequent recurrences, respectively, none of the patients in our cohort, including those with multiple relapses, harbored a TERTp mutation. Furthermore, TERTp methylation was detected in 14 out of 24 cases (58.3%) with available primary samples; however, no correlation between TERTp methylation with the pathological subtype, genotype, or tumor aggressiveness was detected. These data suggest that elevated telomerase activity via acquisition of TERTp mutations is an infrequent pathway in the tumorigenesis of craniopharyngiomas, regardless of their clinical course..
10. Masahiro Yamamoto, Tomomi Sanomachi, Shuhei Suzuki, Hiroyuki Uchida, Hajime Yonezawa, Nayuta Higa, Tomoko Takajo, Yuki Yamada, Asuka Sugai, Keita Togashi, Shizuka Seino, Masashi Okada, Yukihiko Sonoda, Hirofumi Hirano, Koji Yoshimoto, Chifumi Kitanaka, Roles for hENT1 and dCK in gemcitabine sensitivity and malignancy of meningioma., Neuro-oncology, 10.1093/neuonc/noab015, 23, 6, 945-954, 2021.06, BACKGROUND: High-grade meningiomas are aggressive tumors with high morbidity and mortality rates that frequently recur even after surgery and adjuvant radiotherapy. However, limited information is currently available on the biology of these tumors, and no alternative adjuvant treatment options exist. Although we previously demonstrated that high-grade meningioma cells were highly sensitive to gemcitabine in vitro and in vivo, the underlying molecular mechanisms remain unknown. METHODS: We examined the roles of hENT1 (human equilibrative nucleoside transporter 1) and dCK (deoxycytidine kinase) in the gemcitabine sensitivity and growth of meningioma cells in vitro. Tissue samples from meningiomas (26 WHO grade I and 21 WHO grade II/III meningiomas) were immunohistochemically analyzed for hENT1 and dCK as well as for Ki-67 as a marker of proliferative activity. RESULTS: hENT1 and dCK, which play critical roles in the intracellular transport and activation of gemcitabine, respectively, were responsible for the high gemcitabine sensitivity of high-grade meningioma cells and were strongly expressed in high-grade meningiomas. hENT1 expression was required for the proliferation and survival of high-grade meningioma cells and dCK expression. Furthermore, high hENT1 and dCK expression levels correlated with stronger tumor cell proliferative activity and shorter survival in meningioma patients. CONCLUSIONS: The present results suggest that hENT1 is a key molecular factor influencing the growth capacity and gemcitabine sensitivity of meningioma cells and also that hENT1, together with dCK, may be a viable prognostic marker for meningioma patients as well as a predictive marker of their responses to gemcitabine..
11. Hitoshi Yamahata, Takaaki Hiwatari, Masanori Yonenaga, Masanao Mori, Tadaaki Niiro, Jun Sugata, Tomohisa Okada, Satoshi Yamaguchi, Koji Yoshimoto, CT morphometric analysis of the cervical spinal canal with special reference to the correlation with the vertebral level., Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association, 10.1016/j.jos.2020.04.009, 26, 3, 354-357, 2021.05, BACKGROUND: Narrowness of the spinal canal is associated with the development of cervical myelopathy. While studies have addressed the sagittal diameter of the cervical spinal canal, few evaluated the correlation between the size of the spinal canal and the vertebral level. We addressed this issue. METHODS: Our retrospective study included 102 patients with cranial or spinal disorders. We examined the correlation between the cervical spinal canal diameter (SCD) at C1 to C7 and the inner anteroposterior diameter (IAPD) of the atlas on CT images. RESULTS: At C1, the SCD was largest, at C4 it was smallest. While there was a strong correlation between the IAPD and the SCD at C1 (r = 0.8), the correlation between the size of the atlas and the SCD at C4 to C7 was weak (r = 0.2-0.3). We divided our patients into a normal group (n = 34, SCD ≥ 12 mm at any levels) and a stenosis group (n = 68, SCD < 12 mm at all levels). The mean SCD at C2 to C7 was significantly larger in the normal group. There was no significant difference between the two groups with respect to the IAPD and the SCD at C1. CONCLUSIONS: The size of the subaxial spine does not necessarily affect the size of the atlas. The pathophysiology of spinal canal stenosis should be considered separately at the C1- and the subaxial level..
12. Yusuke Funakoshi, Nobuhiro Hata, Kosuke Takigawa, Hideyuki Arita, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Aki Sako, Toru Umehara, Tadamasa Yoshitake, Osamu Togao, Akio Hiwatashi, Koji Yoshimoto, Toru Iwaki, Masahiro Mizoguchi, Clinical significance of CDKN2A homozygous deletion in combination with methylated MGMT status for IDH-wildtype glioblastoma., Cancer medicine, 10.1002/cam4.3860, 10, 10, 3177-3187, 2021.05, OBJECTIVE: Accumulating evidence from recent molecular diagnostic studies has indicated the prognostic significance of various genetic markers for patients with glioblastoma (GBM). To evaluate the impact of such genetic markers on prognosis, we retrospectively analyzed the outcomes of patients with IDH-wildtype GBM in our institution. In addition, to assess the impact of bevacizumab (BEV) treatment, we compared overall survival (OS) between the pre- and post-BEV eras. METHODS: We analyzed the data of 100 adult patients (over 18 years old) with IDH-wildtype GBM from our database between February 2006 and October 2018. Genetic markers, such as MGMT methylation status, EGFR amplification, CDKN2A homozygous deletion, and clinical factors were analyzed by evaluating the patients' OS. RESULTS: CDKN2A homozygous deletion showed no significant impact on OS in patients with methylated MGMT status (p = 0.5268), whereas among patients with unmethylated MGMT status, there was a significant difference in OS between patients with and without CDKN2A homozygous deletion (median OS: 14.7 and 16.9 months, respectively, p = 0.0129). This difference was more evident in the pre-BEV era (median OS: 10.1 and 15.6 months, respectively, p = 0.0351) but has become nonsignificant in the post-BEV era (median OS: 16.0 and 16.9 months, respectively, p = 0.1010) due to OS improvement in patients with CDKN2A homozygous deletion. However, these findings could not be validated in The Cancer Genome Atlas cohort. CONCLUSIONS: MGMT and CDKN2A status subdivided our cohort into three race-specific groups with different prognoses. Our findings indicate that BEV approval in Japan led to OS improvement exclusively for patients with concurrent unmethylated MGMT status and CDKN2A homozygous deletion..
13. Yusuke Funakoshi, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Kosuke Takigawa, Koji Yoshimoto, Masahiro Mizoguchi, Koji Iihara, Current trend in treatment of glioblastoma in Japan: a national survey using the diagnostic procedure combination database (J-ASPECT study-glioblastoma)., International journal of clinical oncology, 10.1007/s10147-021-01929-5, 2021.05, BACKGROUND: In the treatment for glioblastoma (GBM), treatment modalities, such as bevacizumab (BEV) and carmustine wafers implants have been approved in Japan since 2013. However, it is unclear whether such a trend in treatment complexity can accelerate treatment centralization. The aim of this study was to reveal the current trend in the treatment of GBM in Japan. METHODS: We used diagnostic procedure combination (DPC) database to analyze the data of 1,774 patients from 305 institutions between April 2016 and March 2019. To analyze the situations associated with first-line BEV use during concurrent TMZ (temozolomide)-radiotherapy, we compared TMZ alone and TMZ-BEV groups. RESULTS: Of the 1,774 patients with GBM, tumor removal by craniotomy was performed in 1,572 (88.6%) patients, and stereotactic biopsy was performed in 156 (8.8%) patients. A total of 1,229 (69.3%) patients underwent radiotherapy, and 1,287 (72.5%) patients underwent chemotherapy. TMZ alone was administered to 878 (68.2%) and TMZ combined with BEV in 381 (29.6%) patients. In the TMZ-BEV group, as compared to the TMZ-alone group, the rate of discharge to home was significantly lower (P = 0.0044), and the rate of stereotactic biopsy was significantly higher (P < 0.0001). No significant difference was observed in the distribution of patients between the TMZ alone and TMZ-BEV groups depending on the scale of institution (P = 0.1240). CONCLUSION: First-line BEV administration seems to be selected properly regardless of the institutional scale. This Japan-wide study of GBM treatment revealed that high level and newly introduced treatments have been steadily generalized in Japanese institutions..
14. Masayuki Kanamori, Hirokazu Takami, Shigeru Yamaguchi, Takashi Sasayama, Koji Yoshimoto, Teiji Tominaga, Akihiro Inoue, Naokado Ikeda, Atsushi Kambe, Toshihiro Kumabe, Masahide Matsuda, Shota Tanaka, Manabu Natsumeda, Ken-Ichiro Matsuda, Masahiro Nonaka, Jun Kurihara, Masayoshi Yamaoka, Naoki Kagawa, Naoki Shinojima, Tetsuya Negoto, Yukiko Nakahara, Yoshiki Arakawa, Seiji Hatazaki, Hiroaki Shimizu, Atsuo Yoshino, Hiroshi Abe, Jiro Akimoto, Yu Kawanishi, Tomonari Suzuki, Atsushi Natsume, Motoo Nagane, Yukinori Akiyama, Dai Keino, Tadateru Fukami, Takahiro Tomita, Kohei Kanaya, Tsutomu Tokuyama, Shuichi Izumoto, Mitsutoshi Nakada, Daisuke Kuga, Shohei Yamamoto, Ryogo Anei, Takeo Uzuka, Junya Fukai, Noriyuki Kijima, Keita Terashima, Koichi Ichimura, Ryo Nishikawa, So-called bifocal tumors with diabetes insipidus and negative tumor markers: are they all germinoma?, Neuro-oncology, 10.1093/neuonc/noaa199, 23, 2, 295-303, 2021.02, BACKGROUND: The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed. METHODS: A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan. RESULTS: Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them. CONCLUSION: All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients..
15. Muhammad Kamil, Tatsuki Oyoshi, Soichiro Komasaku, Shinichi Kuroki, Nayuta Higa, Koji Yoshimoto, Fronto-Orbital Advancement and Posterior Cranial Vault Expansion Using Distraction Osteogenesis in Patients With Multiple Craniosynostosis., The Journal of craniofacial surgery, 10.1097/SCS.0000000000007442, 2021.01, ABSTRACT: This study aimed to evaluate the treatment outcomes and the efficiency of techniques of fronto-orbital advancement (FOA) and posterior cranial vault expansion (PCVE) using distraction osteogenesis in patients with multiple craniosynostosis. We assessed the treatment results and outcomes of 8 patients with multiple craniosynostosis at the Kagoshima University Hospital between 2005 and 2019. Each 4 patients underwent FOA and PCVE, respectively, using distraction osteogenesis. The cranial volume and developmental quotient (DQ) were measured at the preoperative period and 1 year after surgery. The mean patient age at surgery was 22 months. The mean preoperative cranial volume was 1027 and 1071 cm3 in the FOA and PCVE groups, respectively. The mean preoperative DQ scores were 74 and 67, respectively. After 1-year of follow-up, the corresponding mean cranial volume became 1108 and 1243 cm3, respectively. The corresponding mean DQ scores also improved to 74 and 81, respectively. The postoperative follow-ups in all cases were uneventful, except for persistent epilepsy in 1 patient. Fronto-orbital advancement and PCVE using distraction osteogenesis might contribute to good outcomes in expanding cranial volume, cosmetic osteogenesis, and infantile development in patients with multiple craniosynostosis. Regarding the cranial volume expansion, especially, PCVE using distraction osteogenesis is more effective than FOA..
16. Takeo Amemiya, Nobuhiro Hata, Masahiro Mizoguchi, Ryuji Yokokawa, Yoichiro Kawamura, Ryusuke Hatae, Yuhei Sangatsuda, Daisuke Kuga, Yutaka Fujioka, Kosuke Takigawa, Yojiro Akagi, Koji Yoshimoto, Koji Iihara, Takashi Miura, Mesenchymal glioblastoma-induced mature de-novo vessel formation of vascular endothelial cells in a microfluidic device., Molecular biology reports, 10.1007/s11033-020-06061-7, 48, 1, 395-403, 2021.01, High vascularization is a biological characteristic of glioblastoma (GBM); however, an in-vitro experimental model to verify the mechanism and physiological role of vasculogenesis in GBM is not well-established. Recently, we established a self-organizing vasculogenic model using human umbilical vein endothelial cells (HUVECs) co-cultivated with human lung fibroblasts (hLFs). Here, we exploited this system to establish a realistic model of vasculogenesis in GBM. We developed two polydimethylsiloxane (PDMS) devices, a doughnut-hole dish and a 5-lane microfluidic device to observe the contact-independent effects of glioblastoma cells on HUVECs. We tested five patient-derived and five widely used GBM cell lines. Confocal fluorescence microscopy was used to observe the morphological changes in Red Fluorescent Protein (RFP)-HUVECs and fluorescein isothiocyanate (FITC)-dextran perfusion. The genetic and expression properties of GBM cell lines were analyzed. The doughnut-hole dish assay revealed KNS1451 as the only cells to induce HUVEC transformation to vessel-like structures, similar to hLFs. The 5-lane device assay demonstrated that KNS1451 promoted the formation of a vascular network that was fully perfused, revealing the functioning luminal construction. Microarray analysis revealed that KNS1451 is a mesenchymal subtype of GBM. Using a patient-derived mesenchymal GBM cell line, mature de-novo vessel formation could be induced in HUVECs by contact-independent co-culture with GBM in a microfluidic device. These results support the development of a novel in vitro research model and provide novel insights in the neovasculogenic mechanism of GBM and may potentially facilitate the future detection of unknown molecular targets..
17. Masanori Yonenaga, Hitoshi Yamahata, Shingo Fujio, Yushi Nagano, Tomoko Hanada, Satoshi Yamaguchi, Koji Yoshimoto, Navigation-Guided Measurement of the Inferior Limit Through the Endonasal Route to the Craniovertebral Junction., World neurosurgery, 10.1016/j.wneu.2020.08.226, 144, e553-e560, 2020.12, BACKGROUND: The endoscopic endonasal approach (EEA) has been accepted as an alternative option for diseases at the craniovertebral junction. However, the inferior destination through the endoscopic endonasal approach is anatomically higher than that of the transoral approach. Therefore, preoperative assessment of accessibility is mandatory for appropriate selection of indication. Using a navigation system, we examined the inferior limit through the endonasal route and evaluated the relationships between surrounding anatomicl structures and the lowest point. METHODS: This study included patients who underwent endoscopic transsphenoidal surgery for intrasellar lesions at our hospital (N = 23). At the start of surgery, the lowest point (target point [TP]) was marked with a straight probe under guidance of the navigation system. We measured 4 parameters on preoperative computed tomography: nasal length, hard palate length, anterior-posterior diameter of the nasopharynx, and nasopalatine angle. Patients were classified into groups depending on whether the TP was at or above (group A) or below (group B) the hard palatine line. RESULTS: TPs were above the hard palatine line in 15 patients (group A) and below the hard palatine line in 8 patients (group B). No TPs reached the nasopalatine line. Nasal length (P = 0.03) and nasopalatine angle (P = 0.01) were larger in group B than in group A. There were no significant differences in anterior-posterior diameter of the nasopharynx or hard palate length. CONCLUSIONS: The hard palatine line is a reliable parameter for assessing the inferior limit of the endoscopic endonasal approach. Nostril size affects accessibility with surgical instruments..
18. Costansia Bureta, Nayuta Higa, Ryutaro Makino, Tomoko Takajo, Hajime Yonezawa, Hiroyuki Uchida, Koji Yoshimoto, Diffuse Large B-Cell Lymphoma of the Central Nervous System Manifesting with Intratumoral Hemorrhage: A Case Report and Literature Review., World neurosurgery, 10.1016/j.wneu.2020.07.213, 143, 490-494, 2020.11, BACKGROUND: Cases of primary central nervous system lymphoma manifesting with hemorrhage are very rare, with only a few previous studies available. CASE DESCRIPTION: A 49-year-old man presented with occipital headache and visual disturbance for the past 4 months. Computed tomography showed a high-density area involving the left basal ganglia, with surrounding vasogenic edema. Head T2∗-weighted imaging showed a hypointense signaling area. Edematous changes and a midline shift were observed on fluid attenuated inversion recovery magnetic resonance imaging. Radiologic features were highly suggestive of intracerebral hemorrhage. Methylprednisolone pulse therapy improved his symptoms transiently and reduced the size of the lesion. Nonetheless, there was recurrence 1 month later. The patient was referred to our institution; a biopsy was performed, and a diffuse large B-cell lymphoma was diagnosed. After 3 cycles of high-dose methotrexate and whole-brain radiation therapy, his symptoms improved, and there were no signs of recurrence. CONCLUSIONS: We report a very rare case of diffuse large B-cell lymphoma manifested with intratumoral hemorrhage. This case indicates the importance of regular clinical and radiologic follow-up, histopathologic examination, and combined treatment with high-dose methotrexate and whole-brain radiation therapy..
19. Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Mari Kirishima, Taiji Hamada, Kei Matsuo, Shingo Fujio, Tomoko Hanada, Hiroshi Hosoyama, Masanori Yonenaga, Akihisa Sakamoto, Tsubasa Hiraki, Akihide Tanimoto, Koji Yoshimoto, A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas., Cancer science, 10.1111/cas.14597, 111, 10, 3902-3911, 2020.10, Central nervous system tumors are classified based on an integrated diagnosis combining histology and molecular characteristics, including IDH1/2 and H3-K27M mutations, as well as 1p/19q codeletion. Here, we aimed to develop and assess the feasibility of a glioma-tailored 48-gene next-generation sequencing (NGS) panel for integrated glioma diagnosis. We designed a glioma-tailored 48-gene NGS panel for detecting 1p/19q codeletion and mutations in IDH1/2, TP53, PTEN, PDGFRA, NF1, RB1, CDKN2A/B, CDK4, and the TERT promoter (TERTp). We analyzed 106 glioma patients (grade II: 19 cases, grade III: 23 cases, grade IV: 64 cases) using this system. The 1p/19q codeletion was detected precisely in oligodendroglial tumors using our NGS panel. In a cohort of 64 grade Ⅳ gliomas, we identified 56 IDH-wildtype glioblastomas. Within these IDH-wildtype glioblastomas, 33 samples (58.9%) showed a mutation in TERTp. Notably, PDGFRA mutations and their amplification were more commonly seen in TERTp-wildtype glioblastomas (43%) than in TERTp-mutant glioblastomas (6%) (P = .001). Hierarchical molecular classification of IDH-wildtype glioblastomas revealed 3 distinct groups of IDH-wildtype glioblastomas. One major cluster was characterized by mutations in PDGFRA, amplification of CDK4 and PDGFRA, homozygous deletion of CDKN2A/B, and absence of TERTp mutations. This cluster was significantly associated with older age (P = .021), higher Ki-67 score (P = .007), poor prognosis (P = .012), and a periventricular tumor location. We report the development of a glioma-tailored NGS panel for detecting 1p/19q codeletion and driver gene mutations on a single platform. Our panel identified distinct subtypes of IDH- and TERTp-wildtype glioblastomas with frequent PDGFRA alterations..
20. Yuhei Sangatsuda, Fumihito Miura, Hiromitsu Araki, Masahiro Mizoguchi, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae, Yojiro Akagi, Takeo Amemiya, Yutaka Fujioka, Yasuhito Arai, Akihiko Yoshida, Tatsuhiro Shibata, Koji Yoshimoto, Koji Iihara, Takashi Ito, Base-resolution methylomes of gliomas bearing histone H3.3 mutations reveal a G34 mutant-specific signature shared with bone tumors., Scientific reports, 10.1038/s41598-020-73116-x, 10, 1, 16162-16162, 2020.09, Two recurrent mutations, K27M and G34R/V, in H3F3A, encoding non-canonical histone H3.3, are reported in pediatric and young adult gliomas, whereas G34W mutation is prevalent in bone tumors. In contrast to K27M mutation, it remains elusive how G34 mutations affect the epigenome. Here we performed whole-genome bisulfite sequencing of four G34R-mutated gliomas and the G34V-mutated glioma cell line KNS-42 for comparison with gliomas harboring K27M and no mutations in H3F3A and with G34W-mutated bone tumors. G34R-mutated gliomas exhibited lower global methylation levels, similar CpG island (CGI) methylation levels, and compromised hypermethylation of telomere-proximal CGIs, compared to the other two glioma subgroups. Hypermethylated regions specific to G34R-mutated gliomas were enriched for CGIs, including those of OLIG1, OLIG2, and canonical histone genes in the HIST1 cluster. They were notably hypermethylated in osteosarcomas with, but not without, G34W mutation. Independent component analysis revealed that G34 mutation-specific components shared a significant similarity between glioma and osteosarcoma, suggesting that G34 mutations exert characteristic methylomic effects regardless of the tumor tissue-of-origin. CRISPR/Cas9-mediated disruption of G34V-allele in KNS-42 cells led to demethylation of a subset of CGIs hypermethylated in G34R-mutated gliomas. These findings will provide a basis for elucidating epigenomic roles of G34 oncohistone in tumorigenesis..
21. Michelle L Brinkmeier, Hironori Bando, Adriana C Camarano, Shingo Fujio, Koji Yoshimoto, Flávio Sj de Souza, Sally A Camper, Rathke's cleft-like cysts arise from Isl1 deletion in murine pituitary progenitors., The Journal of clinical investigation, 10.1172/JCI136745, 130, 8, 4501-4515, 2020.08, The transcription factor ISL1 is expressed in pituitary gland stem cells and the thyrotrope and gonadotrope lineages. Pituitary-specific Isl1 deletion causes hypopituitarism with increased stem cell apoptosis, reduced differentiation of thyrotropes and gonadotropes, and reduced body size. Conditional Isl1 deletion causes development of multiple Rathke's cleft-like cysts, with 100% penetrance. Foxa1 and Foxj1 are abnormally expressed in the pituitary gland and associated with a ciliogenic gene-expression program in the cysts. We confirmed expression of FOXA1, FOXJ1, and stem cell markers in human Rathke's cleft cyst tissue, but not craniopharyngiomas, which suggests these transcription factors are useful, pathological markers for diagnosis of Rathke's cleft cysts. These studies support a model whereby expression of ISL1 in pituitary progenitors drives differentiation into thyrotropes and gonadotropes and without it, activation of FOXA1 and FOXJ1 permits development of an oral epithelial cell fate with mucinous cysts. This pituitary-specific Isl1 mouse knockout sheds light on the etiology of Rathke's cleft cysts and the role of ISL1 in normal pituitary development..
22. Nayuta Higa, Rivan Dwiutomo, Tatsuki Oyoshi, Shunichi Tanaka, Manoj Bohara, Koji Yoshimoto, A case of developing obstructive hydrocephalus following aqueductal stenosis caused by developmental venous anomalies., Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 10.1007/s00381-019-04489-2, 36, 7, 1549-1555, 2020.07, Developmental venous anomalies (DVAs), previously also known as venous angiomas, are variations of normal trans-medullary veins draining from white and gray matter. DVAs are usually asymptomatic and mostly discovered incidentally on brain imaging. However, some studies have reported symptomatic cases associated with DVAs. In this report, we report an extremely rare case of a 14-month-old boy with obstructive hydrocephalus following aqueductal stenosis caused by developmental venous anomalies. At the age of 14 months, his head circumference exceeded + 2SD significantly. Brain magnetic resonance imaging (MRI) showed triventriculomegaly and dilated collector vein coursing through the Sylvian aqueduct, causing aqueductal stenosis. Endoscopic third ventriculostomy (ETV) was successfully performed. During the procedure, a dilated collector vein was confirmed obstructing the Sylvian aqueduct. Postoperative cine MRI showed good flow signal through the opening and improvement of hydrocephalus was noted. Obstructive hydrocephalus following aqueductal stenosis caused by DVAs is very rare; nonetheless, it can be considered as a causal differential diagnosis for hydrocephalus. Whether ETV should be chosen, as the technique for diversion of cerebrospinal fluid (CSF) flow, remains controversial. This case report showed that ETV was effective and safe..
23. Atsushi Natsume, Kosuke Aoki, Fumiharu Ohka, Sachi Maeda, Masaki Hirano, Alimu Adilijiang, Kazuya Motomura, Minako Sumi, Ryo Nishikawa, Yoshitaka Narita, Yoshihiro Muragaki, Takashi Maruyama, Tamio Ito, Takaaki Beppu, Hideo Nakamura, Takamasa Kayama, Shinya Sato, Motoo Nagane, Kazuhiko Mishima, Yoko Nakasu, Kaoru Kurisu, Fumiyuki Yamasaki, Kazuhiko Sugiyama, Takanori Onishi, Yasuo Iwadate, Mizuhiko Terasaki, Hiroyuki Kobayashi, Akira Matsumura, Eiichi Ishikawa, Hikaru Sasaki, Akitake Mukasa, Takayuki Matsuo, Hirofumi Hirano, Toshihiro Kumabe, Nobusada Shinoura, Naoya Hashimoto, Tomokazu Aoki, Akio Asai, Tatsuya Abe, Atsuo Yoshino, Yoshiki Arakawa, Kenichiro Asano, Koji Yoshimoto, Soichiro Shibui, Yusuke Okuno, Toshihiko Wakabayashi, Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone., Journal of neuro-oncology, 10.1007/s11060-020-03505-9, 148, 1, 17-27, 2020.05, PURPOSE: 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. EXPERIMENTAL: DESIGN: 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. RESULTS: 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. CONCLUSION: 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..
24. Nobuhiro Hata, Masahiro Mizoguchi, Daisuke Kuga, Ryusuke Hatae, Yojiro Akagi, Yuhei Sangatsuda, Takeo Amemiya, Yuhei Michiwaki, Yutaka Fujioka, Kosuke Takigawa, Satoshi O Suzuki, Tadamasa Yoshitake, Osamu Togao, Akio Hiwatashi, Koji Yoshimoto, Koji Iihara, First-line bevacizumab contributes to survival improvement in glioblastoma patients complementary to temozolomide., Journal of neuro-oncology, 10.1007/s11060-019-03339-0, 146, 3, 451-458, 2020.02, INTRODUCTION: First-line bevacizumab (BEV) is now available as a treatment option for glioblastoma patients with severe clinical conditions in Japan. However, the survival benefits remain controversial. To elucidate these potential survival benefits, we retrospectively analyzed survival in glioblastoma patients receiving BEV. METHODS: We analyzed survival in 120 patients with IDH-wild type glioblastoma treated from 2002 to 2018. Overall survival (OS) was assessed in three treatment era subgroups [pre-temozolomide (TMZ), TMZ, and TMZ-BEV], and the correlations of prognostic factors with survival were evaluated. RESULTS: An improvement in survival was observed after BEV approval (median OS in the pre-TMZ, TMZ, and TMZ-BEV eras: 14.6, 14.9, and 22.1 months, respectively). A Cox proportional hazards model identified extent of resection and MGMT methylation status as significant prognostic factors in the TMZ era; however, these factors were not significant in the TMZ-BEV era. In subgroup analyses, patients with MGMT methylation had improved OS after TMZ introduction (pre-TMZ vs. TMZ, 18.5 vs. 28.1 months; P = 0.13), and those without MGMT methylation had significantly increased OS after BEV approval (TMZ vs. TMZ-BEV, 12.2 vs. 16.7 months; P = 0.04). CONCLUSIONS: Our findings imply that optional first-line administration of BEV can overcome the impact of conventional risk factors and prolong survival complementary to TMZ. The patient subgroups benefitting from TMZ and BEV did not seem to overlap, and stratification based on risk factors, including MGMT methylation status, might be effective for selecting patients in whom BEV should be preferentially used as a first-line therapy..
25. Tomoko Hanada;Ryosuke Hanaya;Fauziah Chaira Ummah;Taro Kamisasanuki;Mari Kirishima;Akihide Tanimoto;Kazunori Arita;Koji Yoshimoto, Combined Transcranial-supraorbital and Transconjunctival Approach for Optic Nerve Coloboma with Ophthalmic Dysplasia Associated with Rheumatoid Arthritis., NMC case report journal, 2020.01.
26. Tomoko Hanada, Ryosuke Hanaya, Fauziah Chaira Ummah, Taro Kamisasanuki, Mari Kirishima, Akihide Tanimoto, Kazunori Arita, Koji Yoshimoto, Combined Transcranial-supraorbital and Transconjunctival Approach for Optic Nerve Coloboma with Ophthalmic Dysplasia Associated with Rheumatoid Arthritis., NMC case report journal, 10.2176/nmccrj.cr.2018-0302, 7, 1, 1-4, 2020.01, We report a 59-year-old woman with optic nerve coloboma and ophthalmic dysplasia associated with rheumatoid arthritis. She experienced progressive visual dysfunction over the course of several years and presented with headache and pain in the left eye. Since infancy the visual acuity of her left eye had been compromised and her eyesight worsened gradually until she was blind in the left eye. Macroscopic observation showed a reddish lesion on the sclera thought to be due to rheumatoid arthritis (RA). Magnetic resonance imaging and computed tomography disclosed a well-defined cystic lesion at the left retro-bulbar optic nerve within the optic nerve sheath. We selected the combined transcranial-supraorbital and transconjunctival approach to remove the eyeball after detaching the optic nerve. This technique was successful and the placement of an ocular prosthetic was cosmetically acceptable..
27. Correlation between prognosis of glioblastoma and choline/N-acetyl aspartate ratio in MR spectroscopy.
28. Nayuta Higa, Yoshinari Shinsato, Muhammad Kamil, Takuro Hirano, Tomoko Takajo, Michiko Shimokawa, Kentaro Minami, Masatatsu Yamamoto, Kohichi Kawahara, Hajime Yonezawa, Hirofumi Hirano, Tatsuhiko Furukawa, Koji Yoshimoto, Kazunori Arita, Formin-like 1 (FMNL1) Is Associated with Glioblastoma Multiforme Mesenchymal Subtype and Independently Predicts Poor Prognosis., International journal of molecular sciences, 10.3390/ijms20246355, 20, 24, 2019.12, Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is characterized by rapid proliferation, aggressive migration, and invasion into normal brain tissue. Formin proteins have been implicated in these processes. However, the role of formin-like 1 (FMNL1) in cancer remains unclear. We studied FMNL1 expression in glioblastoma samples using immunohistochemistry. We sought to analyze the correlation between FMNL1 expression, clinicopathologic variables, and patient survival. Migration and invasion assays were used to verify the effect of FMNL1 on glioblastoma cell lines. Microarray data were downloaded from The Cancer Genome Atlas and analyzed using gene set enrichment analysis (GSEA). FMNL1 was an independent predictor of poor prognosis in a cohort of 217 glioblastoma multiforme cases (p < 0.001). FMNL1 expression was significantly higher in the mesenchymal subtype. FMNL1 upregulation and downregulation were associated with mesenchymal and proneural markers in the GSEA, respectively. These data highlight the important role of FMNL1 in the neural-to-mesenchymal transition. Conversely, FMNL1 downregulation suppressed glioblastoma multiforme cell migration and invasion via DIAPH1 and GOLGA2, respectively. FMNL1 downregulation also suppressed actin fiber assembly, induced morphological changes, and diminished filamentous actin. FMNL1 is a promising therapeutic target and a useful biomarker for GBM progression..
29. Yuhei Michiwaki, Nobuhiro Hata, Masahiro Mizoguchi, Akio Hiwatashi, Daisuke Kuga, Ryusuke Hatae, Yojiro Akagi, Takeo Amemiya, Yutaka Fujioka, Osamu Togao, Satoshi O Suzuki, Koji Yoshimoto, Toru Iwaki, Koji Iihara, Relevance of calcification and contrast enhancement pattern for molecular diagnosis and survival prediction of gliomas based on the 2016 World Health Organization Classification., Clinical neurology and neurosurgery, 10.1016/j.clineuro.2019.105556, 187, 105556-105556, 2019.12, OBJECTIVES: The significance of conventional neuroimaging features for predicting molecular diagnosis and patient survival based on the updated World Health Organization (WHO) classification remains uncertain. We assessed the relevance of neuroimaging features (ring enhancement [RE], non-ring enhancement [non-RE], overall gadolinium enhancement [GdE], and intratumoral calcification [IC]) for molecular diagnosis and survival in glioma patients. PATIENTS AND METHODS: We evaluated 234 glioma patients according to the updated WHO classification. Isocitrate dehydrogenase (IDH), H3F3A, BRAF hotspot mutations, TERT promotor mutation, and chromosome 1p/19q co-deletion were examined. RE, non-RE, GdE, and IC were evaluated as significant neuroimaging findings. Kaplan-Meier analyses were performed to evaluate overall survival (OS) and the correlations of prognostic factors were evaluated by log-rank tests. Univariate and multivariate analyses were performed to detect prognostic factors for OS. RESULTS: A total of 207 patients were eligible. In 110 patients presenting RE, 102 (93%) were glioblastoma (GBM), IDH-wild type. In 97 patients without RE, presence of GdE or IC were not significantly different between IDH-mutant and -wild type tumors, whereas presence of GdE was a significant indicator of higher WHO grades. IC was the only significant finding for 1p/19q co-deleted tumors. TERT promoter mutation was observed in 7/17 patients with diffuse astrocytic glioma, IDH-wild type; recently-defined as "molecular GBM." IC, RE, and GdE were observed with lower prevalence in molecular GBMs. While presence of RE, GdE, and absence of IC were significant factors of OS in overall cohort, presence of GdE was not significant in OS in cases without RE, and IDH-mutant tumors. IC was a significant predictor of favorable OS in cases without RE and IDH-wild type tumors. Multivariate analysis also validated these findings. CONCLUSION: GdE alone is not a significant predictor of IDH mutation status, but the pattern of enhancement is a significant predictor with RE demonstrating high sensitivity and specificity for GBM, IDH-wild type. Predicting "molecular GBM" by conventional neuroimaging is difficult. Moreover, GdE is not a significant factor of survival analyzed with pattern of enhancement or molecular stratifications. IC is an important radiographic finding for predicting molecular diagnosis and survival in glioma patients..
30. Masanori Sato, Shingo Fujio, Tomoko Takajo, Kiyohisa Kamimura, Tsubasa Hiraki, Hitoshi Yamahata, Kazunori Arita, Koji Yoshimoto, Large Intraosseous Schwannoma in Petrous Apex Presenting with Intratumoral Hemorrhage., World neurosurgery, 10.1016/j.wneu.2019.07.179, 131, 53-57, 2019.11, BACKGROUND: Intracranial schwannomas are rarely confined to the skull. We here report a large schwannoma localized in the petrous apex that presented with intratumoral hemorrhage. CASE DESCRIPTION: A 35-year-old woman with mild hearing disturbance and ear fullness underwent computed tomography scan and magnetic resonance imaging, which demonstrated a tumor accompanied with intratumoral hematoma in the right petrous apex. Bone marrow was totally destroyed, but the bone cortex was relatively preserved. Pathologic specimen showed that the tumor was composed of proliferation of elongated neoplastic cells and positive for S-100 protein. It showed a nuclear palisading pattern, compatible with schwannoma. The lack of any cranial nerve signs and relative preservation of canals through which cranial nerves pass suggested the neurilemma cells surrounded vessels or mismigrated fetal neurilemma cells in the petrous apex as origin of the tumor. Benign nature of the tumor and total disappearance of the symptoms, supposedly due to the spontaneous absorption of the hematoma, made the patient choose a wait-and-watch approach. Magnetic resonance imaging studied 7 years after the diagnosis showed significant decrease of the tumor volume and disappearance of the hematoma. CONCLUSIONS: Although it is a large intraosseous schwannoma in the petrous apex, it has a benign nature, its size is reduced due to the hematoma absorption, and the patient is asymptomatic. We observed the patients for 7 years after the diagnosis..
31. Hitoshi Yamahata, Satoshi Yamaguchi, Toshiya Osanai, Masaaki Takeda, Takafumi Mitsuhara, Masanao Mori, Shunichi Tanaka, Masanori Yonenaga, Akira Taguchi, Yosuke Watanabe, Masaru Abiko, Toshitaka Seki, Toru Sasamori, Kazunori Arita, Koji Yoshimoto, Cauda Equina Occupation Ratio as a New Imaging Parameter for the Evaluation of Spinal Dural Arteriovenous Fistulae., World neurosurgery, 10.1016/j.wneu.2019.07.069, 130, e1020-e1027, 2019.10, BACKGROUND: Because spinal dural arteriovenous fistulae (SDAVF) are rare and their clinical presentation is nonspecific, they are often overlooked during diagnostic evaluations. Typical magnetic resonance imaging (MRI) findings are intramedullary T2-weighted signal hyperintensity and perimedullary flow voids. There are few reports on the characteristic signs of the cauda equina. We assessed the significance of a new imaging parameter, the cauda equina occupation ratio (CEOR), for the evaluation of SDAVF. METHODS: We retrospectively analyzed the clinical charts and radiological findings of 20 SDAVF patients treated at our institutions. We evaluated sagittal T2-weighted MRI scans and assessed the CEOR, the occupation ratio of the cauda equina compared to the sagittal diameter of the corresponding lumbar spinal canal. The controls were 21 age- and sex-matched subjects. RESULTS: Of the 20 SDAVF, 10 were at the thoracic and 10 at the lumbar spine. There was no significant difference between the preoperative CEOR and the spinal level of the fistulae or the neurological signs. On preoperative MRI scans, the mean CEOR was 56.0 ± 7.8; postoperatively, it was 37.1 ± 7.4 (P = 0.000). The preoperative CEOR was significantly larger in SDAVF patients than in the controls (P = 0.000); postoperatively, it was smaller than in the controls (P = 0.14). CONCLUSIONS: The preoperative CEOR was larger in patients with SDAVF than in the controls. It normalized after successful occlusion of the fistula. Our findings indicate that the CEOR is a useful parameter for the pre- and postoperative evaluation of SDAVF..
32. Shingo Fujio, Tomoko Takajo, Yasuyuki Kinoshita, Ryosuke Hanaya, Hiroshi Arimura, Jun Sugata, Sei Sugata, Manoj Bohara, Tsubasa Hiraki, Koji Yoshimoto, Kazunori Arita, Sellar Xanthogranuloma: A Quest Based on Nine Cases Assessed with an Anterior Pituitary Provocation Test., World neurosurgery, 10.1016/j.wneu.2019.06.021, 130, e150-e159, 2019.10, BACKGROUND: Xanthogranuloma is a chronic inflammatory mass characterized by cholesterol crystal deposition, which is rarely seen in the sellar region. The objective of this study is to identify the clinical features and cause of sellar xanthogranulomas. METHODS: We retrospectively analyzed manifestation, radiographic, and endocrinologic presentation in 9 patients (7 women and 2 men) whom we had previously treated. RESULTS: The patients were between 26 and 73 years of age (median, 56 years). The chief symptoms were visual symptoms in 3, polyuria in 3, headache in 4, and tiredness in 4 patients. Perimetry found visual field deficit in 6 patients. Anterior pituitary provocation tests disclosed impairment of ≥1 hormone in all patients: growth hormone in 8 patients and adrenocorticotropic hormone-cortisol axis in 8 patients. The lesions were suprasellar in 2 patients, intrasellar in 2 patients, and intrasuprasellar region in 5 patients. Three of the lesions were solid and 6 were single cystic to multicystic. Very low intensity area on T2-weighted magnetic resonance imaging was observed in 4 lesions. Postcontrast study performed in 7 lesions showed enhancement in solid parts or cyst walls. Surgical decompression improved visual disturbance in half of the patients but rarely improved hormonal deficits. Follow-up (median, 47 months) found no recurrence of the lesion. In addition to these 9 cases, we found 2 xanthogranulomatous lesions pathologically associated with ciliated epithelia, which also presented with severe hypopituitarism. CONCLUSIONS: Xanthogranuloma seems to be the last stage of the chronic inflammation affecting Rathke cleft cyst or craniopharyngioma presenting with severe anterior pituitary insufficiency..
33. Shingo Fujio, Tareq A Juratli, Kazunori Arita, Hirofumi Hirano, Yushi Nagano, Tomoko Takajo, Koji Yoshimoto, Ivanna V Bihun, Alexander B Kaplan, Naema Nayyar, Alexandria L Fink, Mia S Bertalan, Shilpa S Tummala, William T Curry Jr, Pamela S Jones, Maria Martinez-Lage, Daniel P Cahill, Fred G Barker, Priscilla K Brastianos, A Clinical Rule for Preoperative Prediction of BRAF Mutation Status in Craniopharyngiomas., Neurosurgery, 10.1093/neuros/nyy569, 85, 2, 204-210, 2019.08, BACKGROUND: Papillary craniopharyngiomas are characterized by BRAFV600E mutations. Targeted therapy can elicit a dramatic radiographic regression of these tumors. Therefore, prediction of BRAF mutation status before definitive surgery could enable neoadjuvant treatment strategies. OBJECTIVE: To establish preoperative prediction criteria to identify patients with a BRAF mutant craniopharyngioma. METHODS: Sixty-four patients with craniopharyngioma were included in this study. We determined BRAF mutation status by targeted sequencing. After scoring interobserver variability between presurgical clinical data and radiographic features, we established a diagnostic rule for BRAF mutation in our discovery cohort. We then validated the rule in an independent cohort. RESULTS: The BRAFV600E mutation was detected in 12 of 42 patients in the discovery cohort. There were no patients under age 18 with BRAF mutation. Calcification was rare in tumors with BRAF mutation (P < .001), and 92% of them were supradiaphragmatic in location. Combining these 3 features-older than 18 years, absence of calcification, and supradiaphragmatic tumor location-we established a rule for predicting BRAF mutation. In cases where all 3 criteria were fulfilled, the sensitivity and specificity for the presence of BRAF mutation were 83% and 93%, respectively. In the validation cohort (n = 22), the sensitivity was 100% and specificity was 89%. CONCLUSION: We propose predictive criteria for a BRAF mutation in craniopharyngioma using preoperative clinical and radiographic data. This rule may be useful in identifying patients who could potentially benefit from neoadjuvant BRAFV600E-targeted systemic therapies..
34. Jun Sugata, Tessei Ueda, Natsuko Tanoue, Kazuho Hirahara, Kiyohisa Kamimura, Kazunori Arita, Koji Yoshimoto, A midline prepontine cyst: Serial magnetic resonance imaging over 20 years shows very slow growth after its rapid shrinkage., The neuroradiology journal, 10.1177/1971400918821085, 32, 2, 98-102, 2019.04, An otherwise healthy 22-month-old boy suffered high fever, irritability, nausea, dysphagia, dysarthria and right hemiparesis. Magnetic resonance imaging showed a cystic mass, 15 mm in diameter, with surrounding oedema in the base of the lower pons. The symptoms subsided in about 10 days after onset, followed by a rapid decrease of the cyst size to 5 mm. Thereafter, the patient's psychomotor growth has been normal. Annual follow-up magnetic resonance imaging scans showed very gradual enlargement of the cyst located on the ventral surface of the pontomedullary junction, reaching 16 mm in diameter in 21 years after onset. It was hyperintense on T1-weighted and isointense on T2-weighted magnetic resonance imaging. No haemosiderin deposition or gadolinium enhancement was seen. This is a rare report of a two decade longitudinal follow-up of a midline prepontine cyst showing asymptomatic and very slow growth. The possible nature of the cyst includes neurenteric, dermoid and epidermoid cyst..
35. Muhammad Kamil, Yoshinari Shinsato, Nayuta Higa, Takuro Hirano, Masashi Idogawa, Tomoko Takajo, Kentaro Minami, Michiko Shimokawa, Masatatsu Yamamoto, Kohichi Kawahara, Hajime Yonezawa, Hirofumi Hirano, Tatsuhiko Furukawa, Koji Yoshimoto, Kazunori Arita, High filamin-C expression predicts enhanced invasiveness and poor outcome in glioblastoma multiforme., British journal of cancer, 10.1038/s41416-019-0413-x, 120, 8, 819-826, 2019.04, BACKGROUND: Glioblastoma multiforme (GBM), the most common brain malignancy in adults, is generally aggressive and incurable, even with multiple treatment modalities and agents. Filamins (FLNs) are a group of actin-binding proteins that regulate the actin cytoskeleton in cells. However, the role of FLNs in malignancies-particularly in GBM-is unclear. METHODS: The relation between FLNC expression and overall survival in GBM was evaluated by the Kaplan-Meier analysis using GBM patients from the Kagoshima University Hospital (n = 90) and data from the Cancer Genome Atlas (TCGA) (n = 153). To assess FLNC function in GBM, cell migration and invasion were examined with Transwell and Matrigel invasion assays using FLNC-overexpressing U251MG and LN299 GBM cells, and ShRNA-mediated FLNC knocked-down KNS81 and U87MG cells. The gelatin zymography assay was used to estimate matrix metalloproteinase (MMP) 2 activity. RESULTS: In silico analysis of GBM patient data from TCGA and immunohistochemical analyses of clinical GBM specimens revealed that increased FLNC expression was associated with poor patient prognosis. FLNC overexpression in GBM cell lines was positively correlated with enhanced invasiveness, but not migration, and was accompanied by upregulation of MMP2. CONCLUSIONS: FLNC is a potential therapeutic target and biomarker for GBM progression..
36. Hitoshi Yamahata, Jun Sugata, Masanao Mori, Tadaaki Niiro, Masanori Yonenaga, Satoshi Yamaguchi, Takaaki Hiwatari, Tomohisa Okada, Kazunori Arita, Koji Yoshimoto, Measurement of Cervical Sagittal Alignment Parameters on X-Ray Films of Adults without Severe Spinal Deformity Whose Shoulder Hides the Lower Cervical Column., World neurosurgery, 10.1016/j.wneu.2018.09.051, 121, e147-e153-e153, 2019.01, OBJECTIVE: The Cobb angle between the lower endplate of C2 and C7 (C2L-C7L angle) is a traditional parameter used for the assessment of the cervical alignment. However, when the lower cervical column is masked by the shoulder, measurements are difficult. In the present study, we inspected 191 X-ray films, measured the Cobb angle between C2L and the endplates at the several levels of the lower cervical column, and assessed their usefulness of such measurements for the determination of cervical sagittal alignment. METHODS: We obtained X-ray films on 191 patients ranging in age from 20 to 93 years. The Cobb angle between C2L and the C7 upper (C7U), the C6 lower (C6L), the C6 upper (C6U), and the C5 lower endplate (C5L) was measured and compared with the C2L-C7L angle. RESULTS: C7L was identified in 116 of 191 patients (60.7%). Except for C2L-C7U angle (P = 0.55), the difference in the mean between C2L-C7L angle and the angle between C2L and the other endplates was statistically significant (P < 0.05). There was a very strong correlation between C2L-C7L angle and C2L-C7U angle (r = 0.99), C2L-C6L angle (r = 0.96), C2L-C6U angle (r = 0.94), and C2L-C5L angle (r = 0.86). CONCLUSIONS: To measure the C2L-C7L angle on unclear X-ray films, C7U can be substituted for C7L. Our measurement data for the C6 and C5 endplates were statistically different; however, the correlation between the C2L-C7L angle and C2L-C6U angle, C2L-C6L angle or C2L-C5L angle was very strong. In patients with unclear lower vertebral bodies, cervical sagittal alignment can be predicted by using adjacent endplates..
37. Osamu Togao;Akio Hiwatashi;Makoto Obara;Koji Yamashita;Daichi Momosaka;Ataru Nishimura;Koichi Arimura;Nobuhiro Hata;Koji Yoshimoto;Koji Iihara;Marc Van Cauteren;Hiroshi Honda, 4D ASL-based MR angiography for visualization of distal arteries and leptomeningeal collateral vessels in moyamoya disease: a comparison of techniques., European radiology, 2018.11.
38. Osamu Togao, Akio Hiwatashi, Makoto Obara, Koji Yamashita, Daichi Momosaka, Ataru Nishimura, Koichi Arimura, Nobuhiro Hata, Koji Yoshimoto, Koji Iihara, Marc Van Cauteren, Hiroshi Honda, 4D ASL-based MR angiography for visualization of distal arteries and leptomeningeal collateral vessels in moyamoya disease: a comparison of techniques., European radiology, 10.1007/s00330-018-5462-7, 28, 11, 4871-4881, 2018.11, OBJECTIVES: To evaluate the performance of four-dimensional pseudo-continuous arterial spin labeling (4D-pCASL)-based angiography using CENTRA-keyhole and view sharing (4D-PACK) in the visualization of flow dynamics in distal cerebral arteries and leptomeningeal anastomosis (LMA) collaterals in moyamoya disease in comparison with contrast inherent inflow-enhanced multiphase angiography (CINEMA), with reference to digital subtraction angiography (DSA). METHODS: Thirty-two cerebral hemispheres from 19 patients with moyamoya disease (mean age, 29.7 ± 19.6 years; five males, 14 females) underwent both 4D-MR angiography and DSA. Qualitative evaluations included the visualization of anterograde middle cerebral artery (MCA) flow and retrograde flow via LMA collaterals with reference to DSA. Quantitative evaluations included assessments of the contrast-to-noise ratio (CNR) on these vessels. The linear mixed-effect model was used to compare the 4D-PACK and CINEMA methods. RESULTS: The vessel visualization scores were significantly higher with 4D-PACK than with CINEMA in the visualization of anterograde flow for both Observer 1 (CINEMA, 3.53 ± 1.39; 4D-PACK, 4.53 ± 0.80; p < 0.0001) and Observer 2 (CINEMA, 3.50±1.39; 4D-PACK, 4.31 ± 0.86; p = 0.0009). The scores were higher with 4D-PACK than with CINEMA in the visualization of retrograde flow for both Observer 1 (CINEMA, 3.44 ± 1.05; 4D-PACK, 4.47 ± 0.88; p < 0.0001) and Observer 2 (CINEMA, 3.19 ± 1.20; 4D-PACK, 4.38 ± 0.91; p < 0.0001). The maximum CNR in the anterograde flow was higher in 4D-PACK (40.1 ± 16.1, p = 0.0001) than in CINEMA (27.0 ± 16.6). The maximum CNR in the retrograde flow was higher in 4D-PACK (36.1 ± 10.0, p < 0.0001) than in CINEMA (15.4 ± 8.0). CONCLUSIONS: The 4D-PACK provided better visualization and higher CNRs in distal cerebral arteries and LMA collaterals compared with CINEMA in patients with this disease. KEY POINTS: • The 4D-PACK enables good visualization of distal cerebral arteries in moyamoya disease. • The 4D-PACK enables direct visualization of leptomeningeal collateral vessels in moyamoya disease. • Vessel visualization by 4D-PACK can be useful in assessing cerebral hemodynamics..
39. Yuhei Sangatsuda;Nobuhiro Hata;Satoshi O Suzuki;Yojiro Akagi;Ryusuke Hatae;Daisuke Kuga;Koji Yoshimoto;Seiya Momosaki;Toru Iwaki;Koji Iihara, An elderly case of malignant small cell glioma with hemorrhage coexistent with a calcified pilocytic astrocytoma component in the cerebellar hemisphere., Neuropathology : official journal of the Japanese Society of Neuropathology, 2018.10.
40. Yuhei Sangatsuda, Nobuhiro Hata, Satoshi O Suzuki, Yojiro Akagi, Ryusuke Hatae, Daisuke Kuga, Koji Yoshimoto, Seiya Momosaki, Toru Iwaki, Koji Iihara, An elderly case of malignant small cell glioma with hemorrhage coexistent with a calcified pilocytic astrocytoma component in the cerebellar hemisphere., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12478, 38, 5, 493-497, 2018.10, Pilocytic astrocytoma is a less aggressive form of glial tumor that commonly occurs in the pediatric population, and its malignant transformation is extremely rare. Here, we report an elderly case of malignant small cell glioma with hemorrhage coexistent with a calcified pilocytic astrocytoma component. An 80-year-old male was found to have a right cerebellar non-enhanced tumor with hematoma adjoining a calcified nodule. The lesion was surgically removed, and a histological examination verified that the tumor was a malignant small cell glioma with hemorrhagic change and the calcified nodule showed features of pilocytic astrocytoma. Genetic analyses revealed no glioma-relevant genetic alterations such as IDH and BRAF mutations. Although calcification is generally observed in slowly growing gliomas, the aggressive clinical course of calcified cerebellar pilocytic astrocytoma has been previously reported. Our extremely rare case shows that careful follow-up is necessary even for calcified pilocytic astrocytomas..
41. Kazufumi Kikuchi, Akio Hiwatashi, Osamu Togao, Koji Yamashita, Ryotaro Kamei, Koji Yoshimoto, Koji Iihara, Satoshi O Suzuki, Toru Iwaki, Yuriko Suzuki, Hiroshi Honda, Arterial spin-labeling is useful for the diagnosis of residual or recurrent meningiomas., European radiology, 10.1007/s00330-018-5404-4, 28, 10, 4334-4342, 2018.10, OBJECTIVES: ASL is useful in evaluating tumour blood flow and in detecting hypervascular tumours. The purpose of this study was to assess the additive value of ASL to non-contrast and contrast-enhanced (NC/CE)-T1WI for diagnosing residual or recurrent meningiomas. METHODS: This retrospective study included 25 postoperative patients (20 women, 5 men; median age, 65 [32-85] years) with and 25 gender- and age-matched postoperative patients without residual or recurrent meningiomas. ASL was performed using a pseudocontinuous method. Seven independent observers (two radiology residents, two general radiologists and three neuroradiologists) participated in two reading sessions consisting of only NC/CE-T1WI (first session) or NC/CE-T1WI with ASL (second session). We evaluated the sensitivity and diagnostic performance for the detection of residual or recurrent meningiomas. The diagnostic performance was assessed using a figure of merit (FOM) calculated via jackknife free-response receiver-operating characteristics. Statistical analysis was performed with paired t tests, with a significance level of p < .05. RESULTS: The sensitivities were as follows (NC/CE-T1WI vs. NC/CE-T1WI with ASL): residents (62.1% vs. 70.7%), general radiologists (75.9% vs. 87.9%), neuroradiologists (97.7% vs. 100%) and all observers (81.3% vs. 88.2%). The FOMs were as follows (NC/CE-T1WI vs. NC/CE-T1WI with ASL): residents (0.76 vs. 0.83), general radiologists (0.83 vs. 0.93), neuroradiologists (0.95 vs. 0.99) and all observers (0.86 vs. 0.93). The addition of ASL significantly improved the diagnostic parameters for all observers except neuroradiologists (p <. 05). CONCLUSIONS: ASL improved the detection rate of residual or recurrent meningiomas on NC/CE-T1WI among both radiology residents and general radiologists. KEY POINTS: • ASL improved diagnostic performance for residual/recurrent meningioma compare to NC/CE-T1WI alone. • Diagnostic sensitivity was increased after adding ASL compared with NC/CE-T1WI. • FOM was increased after adding ASL compared with NC/CE-T1WI..
42. Shunya Tanaka, Tsutomu Hitotsumatsu, Yasuo Sugita, Katsuya Ishido, Osamu Ito, Ryusuke Hatae, Yojiro Akagi, Koji Yoshimoto, Koji Iihara, Gliosarcoma arising from oligodendroglioma (Oligosarcoma): A case report with genetic analyses., Pathology international, 10.1111/pin.12723, 68, 10, 567-573, 2018.10, Gliosarcomas are a type of bimorphic tumor composed of glial and sarcomatous elements, and are considered to be a variant of glioblastoma, WHO grade IV. To date, only rare cases of gliosarcoma with oligodendroglial components (oligosarcoma) have been reported. We report a case of oligosarcoma consisting of gliosarcoma arising from recurrent oligodendroglioma. A 53-year-old man, who had undergone a gross total resection of oligodendroglioma (WHO grade II) 11 years earlier, presented with a local tumor recurrence. The patient underwent a second gross total resection, whereupon a histopathological examination further revealed residual features of classical oligodendroglioma, and newly-developed sarcomatous characteristics. Both the primary and recurrent tumors showed 1p/19q co-deletion and mutation of the isocitrate dehydrogenase 1 (IDH1) gene, consistent with being oligodendroglial in nature. Loss of heterozygosity (LOH) of chromosome 1p/19q and IDH1 mutation have seldom been analyzed in previous reports of oligosarcomas. We report a rare case study supported by the results of genetic analyses. Our analyses have revealed that the sarcomatous component represents a metaplastic change occurring in the oligodendroglial element..
43. Wakabayashi T, Natsume A, Mizusawa J, Katayama H, Fukuda H, Sumi M, Nishikawa R, Narita Y, Muragaki Y, Maruyama T, Ito T, Beppu T, Nakamura H, Kayama T, Sato S, Nagane M, Mishima K, Nakasu Y, Kurisu K, Yamasaki F, Sugiyama K, Onishi T, Iwadate Y, Terasaki M, Kobayashi H, Matsumura A, Ishikawa E, Sasaki H, Mukasa A, Matsuo T, Hirano H, Kumabe T, Shinoura N, Hashimoto N, Aoki T, Asai A, Abe T, Yoshino A, Arakawa Y, Asano K, Yoshimoto K, Shibui S, Members of Japan Clinical, Oncology Group, Brain Tumor, Study Group, JCOG-BTSG, JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonβ plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma., J Neurooncol., 10.1007/s11060-018-2831-7, 138, 3, 627-636, 2018.07.
44. Daisuke Kuga;Nobuhiro Hata;Yojiro Akagi;Takeo Amemiya;Yuhei Sangatsuda;Ryusuke Hatae;Koji Yoshimoto;Masahiro Mizoguchi;Koji Iihara, The Effectiveness of Salvage Treatments for Recurrent Lesions of Oligodendrogliomas Previously Treated with Upfront Chemotherapy., 2018.06.
45. Daisuke Kuga, Nobuhiro Hata, Yojiro Akagi, Takeo Amemiya, Yuhei Sangatsuda, Ryusuke Hatae, Koji Yoshimoto, Masahiro Mizoguchi, Koji Iihara, The Effectiveness of Salvage Treatments for Recurrent Lesions of Oligodendrogliomas Previously Treated with Upfront Chemotherapy., World neurosurgery, 10.1016/j.wneu.2018.03.069, 114, e735-e742-e742, 2018.06, BACKGROUND: We previously reported a favorable outcome in a case series of patients with oligodendrogliomas treated with upfront chemotherapy; however, their progression-free survival (PFS) was relatively short considering their long-term overall survival (OS). This suggests that salvage treatments after progression were effective. However, the clinical impact of salvage treatments on outcomes of patients with recurrent oligodendrogliomas has not been precisely investigated. METHODS: Our case series included 28 patients with newly diagnosed isocitrate dehydrogenase-mutant and 1p/19q-codeleted oligodendroglial tumors treated with upfront procarbazine, nimustine, and vincristine. Clinical outcomes and patterns of recurrence were reviewed retrospectively. RESULTS: The median follow-up period of enrolled patients was 90.2 months. Disease progression occurred in 15 patients (53.6%), whereas the cancer appeared as local relapse alone in 14 (93.3%) patients. Salvage treatments were performed for all local relapses; thereafter, most of the subsequent progressions also appeared as resectable local relapses. The 5-year PFS and OS rates from the first progression were 30.3% and 92.9%, respectively. These relatively short PFS and favorable OS indicated the effectiveness of salvage treatment even after multiple progression. Thus far, 9 (60%) of 15 patients are deterioration-free with locally controlled lesions or complete remission; however, clinical deterioration was observed in 6 patients, and 4 of them experienced dissemination. CONCLUSIONS: In isocitrate dehydrogenase-mutant and 1p/19q-codeleted oligodendrogliomas, most of the tumors that demonstrated early progression appeared as local, nonlethal lesions, which have been well-controlled by salvage treatments. A precise diagnosis of oligodendrogliomas using molecular parameters is crucial to receive the best benefit from salvage treatment..
46. Osamu Togao, Akio Hiwatashi, Koji Yamashita, Kazufumi Kikuchi, Daichi Momosaka, Koji Yoshimoto, Daisuke Kuga, Masahiro Mizoguchi, Satoshi O Suzuki, Toru Iwaki, Marc Van Cauteren, Koji Iihara, Hiroshi Honda, Measurement of the perfusion fraction in brain tumors with intravoxel incoherent motion MR imaging: validation with histopathological vascular density in meningiomas., The British journal of radiology, 10.1259/bjr.20170912, 91, 1085, 20170912-20170912, 2018.05, OBJECTIVE: To evaluate the quantification performance of the perfusion fraction (f) measured with intravoxel incoherent motion (IVIM) MR imaging in a comparison with the histological vascular density in meningiomas. METHODS: 29 consecutive patients with meningioma (59.0 ± 16.8 years old, 8 males and 21 females) who underwent a subsequent surgical resection were examined with both IVIM imaging and a histopathological analysis. IVIM imaging was conducted using a single-shot SE-EPI sequence with 13 b-factors (0, 10, 20, 30, 50, 80, 100, 200, 300, 400, 600, 800, 1000 s mm-2) at 3T. The perfusion fraction (f) was calculated by fitting the IVIM bi-exponential model. The 90-percentile f-value in the tumor region-of-interest (ROI) was defined as the maximum f-value (f-max). Histopathological vascular density (%Vessel) was measured on CD31-immunostainted histopathological specimens. The correlation and agreement between the f-values and %Vessel was assessed. RESULTS: The f-max (15.5 ± 5.5%) showed excellent agreement [intraclass correlation coefficient (ICC) = 0.754] and a significant correlation (r = 0.69, p < 0.0001) with the %Vessel (12.9 ± 9.4%) of the tumors. The Bland-Altman plot analysis showed excellent agreement between the f-max and %Vessel (bias, -2.6%; 95% limits of agreement, from -16.0 to 10.8%). The f-max was not significantly different among the histological subtypes of meningioma. CONCLUSION: An excellent agreement and a significant correlation were observed between the f-values and %Vessel. The f-value can be used as a noninvasive quantitative imaging measure to directly assess the vascular volume fraction in brain tumors. Advances in knowledge: The f-value measured by IVIM imaging showed a significant correlation and an excellent agreement with the histological vascular density in the meningiomas. The f-value can be used as a noninvasive and quantitative imaging measure to directly assess the volume fraction of capillaries in brain tumors..
47. Tomohiro Okuda;Nobuhiro Hata;Satoshi O Suzuki;Koji Yoshimoto;Koichi Arimura;Takeo Amemiya;Yojiro Akagi;Daisuke Kuga;Utako Oba;Yuhki Koga;Shouichi Ohga;Toru Iwaki;Koji Iihara, Pediatric ganglioglioma with an H3 K27M mutation arising from the cervical spinal cord., Neuropathology : official journal of the Japanese Society of Neuropathology, 2018.04.
48. Tomohiro Okuda, Nobuhiro Hata, Satoshi O Suzuki, Koji Yoshimoto, Koichi Arimura, Takeo Amemiya, Yojiro Akagi, Daisuke Kuga, Utako Oba, Yuhki Koga, Shouichi Ohga, Toru Iwaki, Koji Iihara, Pediatric ganglioglioma with an H3 K27M mutation arising from the cervical spinal cord., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12471, 38, 4, 422-427, 2018.04, The 2016 edition of the World Health Organization Classification of Tumors of the Central Nervous System introduced "diffuse midline glioma H3 K27M mutant" as a new diagnostic entity. These tumors predominately affect pediatric patients and arise from midline structures such as the brainstem, thalamus and spinal cord. Here, we report a rare patient with spinal ganglioglioma carrying an H3 K27M mutation. A 10-year-old boy presented with an intramedullary tumor in the cervical spinal cord. The lesion was partially removed and histologically diagnosed as ganglioglioma. After the remnant tumor grew within 3 months after surgery, the patient underwent radiotherapy. Genetic analyses revealed an H3F3A K27M mutation but no other genetic alterations such as IDH and BRAF mutations. This case may point to pathological heterogeneity in gliomas with H3 K27M mutations..
49. Yojiro Akagi, Koji Yoshimoto, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae, Takeo Amemiya, Yuhei Sangatsuda, Satoshi O Suzuki, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara, Reclassification of 400 consecutive glioma cases based on the revised 2016WHO classification., Brain tumor pathology, 10.1007/s10014-018-0313-4, 35, 2, 81-89, 2018.04, In this study, we reclassified 400 consecutive glioma cases including pediatric cases, using the revised 2016 WHO classification with samples collected from the Kyushu University Brain Tumor Bank. The IDH1/2, H3F3A, key genetic markers in the 2016 classification, were analyzed using high-resolution melting, with DNA extracted from frozen tissues. The 1p/19q codeletions were evaluated using a microsatellite-based loss of heterozygosity analysis, with 18 markers, to detect loss of the entire chromosome arm. In the integrated diagnosis, 29 oligodendroglioma cases and 28 anaplastic oligodendroglioma cases were diagnosed as "IDH-mutant and 1p/19q-codeleted," while 2 oligodendroglioma cases and 5 anaplastic oligodendroglioma cases were diagnosed as not otherwise specified (NOS). These "NOS" cases were either IDH-mutants or 1p/19q-codeleted, although characteristic oligodendroglial features were evident histologically. Better overall survival of patients with oligodendroglioma correlated with the molecular characteristic of "IDH-mutant and 1p/19q-codeleted," rather than the WHO grade. Eleven "glioblastoma, IDH-wild-type" cases were classified as "1p/19q-codeleted", however, chromosome 10 loss was also detected in 10 out of 11 cases. The 2016 WHO criteria for glioma classification leads to better diagnosis of patients. However, there are technical pitfalls and problems to be solved in the molecular analysis of routine diagnostics..
50. Ryota Kurogi;Akira Nakamizo;Satoshi O Suzuki;Masahiro Mizoguchi;Koji Yoshimoto;Toshiyuki Amano;Takeo Amemiya;So Takagishi;Koji Iihara, Inhibition of glioblastoma cell invasion by hsa-miR-145-5p and hsa-miR-31-5p co-overexpression in human mesenchymal stem cells., Journal of neurosurgery, 2018.03.
51. Ryota Kurogi, Akira Nakamizo, Satoshi O Suzuki, Masahiro Mizoguchi, Koji Yoshimoto, Toshiyuki Amano, Takeo Amemiya, So Takagishi, Koji Iihara, Inhibition of glioblastoma cell invasion by hsa-miR-145-5p and hsa-miR-31-5p co-overexpression in human mesenchymal stem cells., Journal of neurosurgery, 10.3171/2017.8.JNS1788, 130, 1, 44-55, 2018.03, OBJECTIVE: Human bone marrow–derived mesenchymal stem cells (hMSCs) show tropism for brain tumors and may
be a useful vehicle for drug or gene delivery to malignant gliomas. Recently, some microRNAs (miRNAs) have been shown to suppress the invasiveness of malignant gliomas. METHODS: To test their potential to become vehicles for the delivery of miRNA to malignant gliomas, hMSCs were
engineered so that hMSC secretion of miRNAs that inhibit glioma cell invasion was enabled without altering the hMSC tropism for glioma cells. RESULTS: In coculture, hMSCs cotransfected with hsa-miR-145-5p and -31-5p miRNAs showed markedly reduced
invasion by U87 glioma cells in a contact-dependent manner both in vitro and ex vivo, with invasion of hMSCs cotransfected with these 2 miRNAs by the U87 cells reduced to 60.7% compared with control cells. According to a Matrigel invasion assay, the tropism of the hMSCs for U87 cells was not affected. In glioma cell lines U251 and LN229, hMSCs exhibited tropism in vivo, and invasion of hMSCs cotransfected with hsa-miR-145-5p and -31-5p was also significantly less than that of control cells. When U87 cells were coimplanted into the striatum of organotypic rat brain slices with hMSCs cotransfected with hsa-miR-145 and -31-5p, the relative invasive area decreased by 37.1%; interestingly, these U87 cells showed a change to a rounded morphology that was apparent at the invasion front. Whole-genome microarray analysis of the expression levels of 58,341 genes revealed that the co-overexpression of hsa-miR-145-5p and -31-5p
downregulated FSCN1 expression in U87 cells. CONCLUSIONS: This study demonstrates that miRNA overexpression in hMSCs can alter the function of glioma cells
via contact-dependent transfer. Co-overexpression of multiple miRNAs may be a useful and novel therapeutic strategy. The study results suggest that hMSCs can be applied as a delivery vehicle for miRNAs..
52. Osamu Togao;Akio Hiwatashi;Makoto Obara;Koji Yamashita;Kazufumi Kikuchi;Ryotaro Kamei;Ataru Nishimura;Koichi Arimura;Koji Yoshimoto;Koji Iihara;Marc Van Cauteren;Hiroshi Honda, Acceleration-selective Arterial Spin-labeling MR Angiography Used to Visualize Distal Cerebral Arteries and Collateral Vessels in Moyamoya Disease., Radiology, 2018.02.
53. Koji Yoshimoto;Ryusuke Hatae;Satoshi O Suzuki;Nobuhiro Hata;Daisuke Kuga;Yojiro Akagi;Takeo Amemiya;Yuhei Sangatsuda;Nobutaka Mukae;Masahiro Mizoguchi;Toru Iwaki;Koji Iihara, High-resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas., Neuropathology : official journal of the Japanese Society of Neuropathology, 2018.02.
54. Osamu Togao, Akio Hiwatashi, Makoto Obara, Koji Yamashita, Kazufumi Kikuchi, Ryotaro Kamei, Ataru Nishimura, Koichi Arimura, Koji Yoshimoto, Koji Iihara, Marc Van Cauteren, Hiroshi Honda, Acceleration-selective Arterial Spin-labeling MR Angiography Used to Visualize Distal Cerebral Arteries and Collateral Vessels in Moyamoya Disease., Radiology, 10.1148/radiol.2017162279, 286, 2, 611-621, 2018.02, Purpose To evaluate and compare the performance of acceleration-selective arterial spin labeling (AccASL) magnetic resonance (MR) angiography in the visualization of cerebral arteries and collateral vessels in patients with Moyamoya disease with that of time-of-flight (TOF) MR angiography, with digital subtraction angiography (DSA) as the reference standard. Materials and Methods Thirty-six cerebral hemispheres from 22 patients with Moyamoya disease underwent TOF and AccASL MR angiography and DSA. Qualitative evaluations included imaging of the terminal internal carotid artery (ICA), distal middle cerebral arteries (MCAs), Moyamoya vessels, and leptomeningeal anastomosis (LMA) collaterals with reference to DSA. Quantitative evaluations included assessment of contrast-to-noise ratio (CNR) and number of vessels in MCA branches. The linear mixed-effect model was used to compare the two methods. Results Mean scores for qualitative evaluation were significantly higher with AccASL angiography than with TOF angiography for imaging distal MCAs (3.9 ± 0.3 [standard deviation] vs 2.9 ± 1.1; P < .001), Moyamoya vessels (3.6 ± 0.6 vs 2.7 ± 0.9, P < .001), and LMA collaterals (3.8 ± 0.6 vs 1.8 ± 0.7, P < .001). Scores for steno-occlusive degree around the terminal ICAs were better with TOF angiography than with AccASL angiography (2.6 ± 0.5 vs 2.4 ± 0.6, P = .023). CNRs in the M4 segment were significantly higher with AccASL angiography (11.9 ± 12.9, P < .001) than with TOF angiography (4.1 ± 7.9). The number of vessels was significantly higher with AccASL angiography (18.3 ± 5.0, P < .001) than with TOF angiography (8.9 ± 4.9). The increase in the number of vessels from TOF angiography to AccASL angiography was greater in patients with severe ICA steno-occlusion (late ICA stage group, 11.4 ± 4.5; early ICA stage group, 6.8 ± 4.0; P = .007) and well-developed leptomeningeal anastomosis (mildly developed LMA group, 7.1 ± 4.3; well-developed LMA group, 11.3 ± 4.5; P = .011). Conclusion AccASL MR angiography enables better visualization of distal cerebral arteries and collateral vessels in patients with Moyamoya disease than does TOF MR angiography, while TOF MR angiography enables better visualization of stenosis of proximal arteries. Both methods work in a mutually beneficial manner in the assessment of cerebral arteries. © RSNA, 2017 Online supplemental material is available for this article..
55. Koji Yoshimoto, Ryusuke Hatae, Satoshi O Suzuki, Nobuhiro Hata, Daisuke Kuga, Yojiro Akagi, Takeo Amemiya, Yuhei Sangatsuda, Nobutaka Mukae, Masahiro Mizoguchi, Toru Iwaki, Koji Iihara, High-resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12408, 38, 1, 3-10, 2018.02, Craniopharyngioma consists of adamantinomatous and papillary subtypes. Recent genetic analysis has demonstrated that the two subtypes are different, not only in clinicopathological features, but also in molecular oncogenesis. Papillary craniopharyngioma (pCP) is characterized by a BRAF mutation, the V600E (Val 600 Glu) mutation. Adamantinomatous craniopharyngioma (aCP) can be distinguished by frequent β-catenin gene (CTNNB1) mutations. Although these genetic alterations can be a diagnostic molecular marker, the precise frequency of these mutations in clinical specimens remains unknown. In this study, we first evaluated BRAF V600E and CTNNB1 mutations in four and 14 cases of pCP and aCP, respectively, using high-resolution melting analysis followed by Sanger sequencing. The results showed that 100% (4/4) of pCP cases had BRAF V600E mutations, while 78% (11/14) of the aCP cases had CTNNB1 mutations, with these genetic alterations being subtype-specific and mutually exclusive. Second, we evaluated BRAF V600E and CTNNB1 mutations by immunohistochemical analysis (IHC). All pCP cases showed positive cytoplasmic staining with the BRAF V600E-mutant antibody (VE-1), whereas 86% (12/14) of aCP cases showed positive cytoplasmic and nuclear staining for CTNNB1, suggesting a CTNNB1 mutation. Only one case of wild-type CTNNB1 on the DNA analysis showed immunopositivity on IHC. We did not detect a coexistence of BRAF V600E and CTNNB1 mutations in any single tumor, which indicated that these genetic alterations were mutually exclusive. We also report our modified IHC protocol for VE-1 staining, and present the possibility that BRAF V600E mutations can be used as a diagnostic marker of pCP in the differentiation of Rathke cleft cyst with squamous metaplasia..
56. Kazufumi Kikuchi, Akio Hiwatashi, Osamu Togao, Koji Yamashita, Koji Yoshimoto, Masahiro Mizoguchi, Satoshi O Suzuki, Toru Iwaki, Yuriko Suzuki, Hiroshi Honda, Correlation between arterial spin-labeling perfusion and histopathological vascular density of pediatric intracranial tumors., Journal of neuro-oncology, 10.1007/s11060-017-2604-8, 135, 3, 561-569, 2017.12, Traditional MRI methods for estimation of blood flow in brain tumors require high-flow injection of contrast agents through large-bore intravenous access, which limits their pediatric utility. In contrast, arterial spin-labeling (ASL) can be used without contrast media. This study aimed to evaluate the relationship between tumor blood flow (TBF) measured by ASL and histopathological vascular density in pediatric brain tumors. Nineteen consecutive children were evaluated (10 boys, 9 girls; median age: 6 years; 8 high-grade and 11 low-grade tumors). ASL was performed with a pseudocontinuous labeling time of 1650 ms and post-labeling delay of 1525 ms. The maximal absolute (aTBF) and relative (rTBF) tumor blood flows were measured. To evaluate the relative vascular area (%Vessel), the total stained vascular area was divided by the whole tissue area. Spearman's rank-order correlation, the Mann-Whitney U test, and receiver operating characteristic analysis were used for statistical analysis. The absolute and relative TBF rates were 4.9-92.9 mL/100 g/min and 0.17-3.59 mL/100 g/min, respectively. The %Vessel was 0.6-30.2%. The %Vessel showed a significant positive correlation with TBF (aTBF: r = 0.87, P < 0.0001; rTBF: r = 0.89, P < 0.0001). The TBF rate of high-grade tumors was significantly higher than that of low-grade tumors (aTBF: P = 0.0050, rTBF: P = 0.0036). The rTBF had the best diagnostic performance (area under the curve: 0.89). ASL perfusion imaging without contrast material can be used for accurate evaluation of histopathological vascular density and may be helpful for tumor grading in children..
57. Kenji Miki, Koichi Arimura, Ataru Nishimura, Koji Yoshimoto, Tetsuro Sayama, Koji Iihara, Revascularization Operation for Moyamoya Disease with Concurrent von Willebrand Disease., World neurosurgery, 10.1016/j.wneu.2017.08.141, 108, 991.e17-991.e21, 2017.12, BACKGROUND: Although extracranial-intracranial (EC-IC) bypass is an effective treatment strategy for symptomatic moyamoya disease, surgeons need to be cautious regarding the possibility of postoperative hemorrhagic complications in patients with a concurrent coagulation disorder. Here, we describe a case of EC-IC bypass for moyamoya disease concurrent with von Willebrand disease type 1. CASE DESCRIPTION: Following perioperative replacement of the von Willebrand factor, the patient showed an uneventful and uncomplicated clinical course. CONCLUSION: This is the first reported case of EC-IC bypass being performed for moyamoya disease in a patient with concurrent von Willebrand disease. We emphasize the importance of appropriate management with replacement of the von Willebrand factor during the perioperative period to avoid hemorrhagic complications..
58. Kenji Miki, Koji Yoshimoto, Ataru Nishimura, Satoshi O Suzuki, Akio Hiwatashi, Koji Iihara, A Case of Ecchordosis Physaliphora in the Prepontine Cistern: A Rare Entity in the Differential Diagnosis of an Epidermoid Cyst., World neurosurgery, 10.1016/j.wneu.2017.06.003, 105, 1033.e11-1033.e14, 2017.09, BACKGROUND: Ecchordosis physaliphora (EP) is a benign notochordal remnant that is usually asymptomatic. We report a case of a symptomatic large EP mimicking an epidermoid cyst. CASE DESCRIPTION: A 44-year-old woman presented with right facial dysesthesia. Brain magnetic resonance imaging showed a mass with a diameter of 3.2 cm that was hypointense on T1-weighted imaging, hyperintense on T2-weighted imaging, isointense to hyperintense on diffusion-weighted imaging, and hyperintense on apparent diffusion coefficient map (1.2-1.6 × 10-3 mm2/second). There was no apparent contrast enhancement. Differential diagnoses included epidermoid cyst, dermoid cyst, EP, chordoma, chondrosarcoma, neurenteric cyst, and arachnoid cyst. Clinicopathologic examination revealed that the mass was an EP. CONCLUSIONS: EP in the prepontine cistern should be considered in the differential diagnosis of epidermoid cyst..
59. Daichi Momosaka, Osamu Togao, Akio Hiwatashi, Koji Yamashita, Koji Yoshimoto, Megumu Mori, Toru Iwaki, Hiroshi Honda, Spindle cell/sclerosing rhabdomyosarcoma with intracranial invasion without destroying the bone of the skull base: a case report and literature review., Acta radiologica open, 10.1177/2058460117727316, 6, 8, 2058460117727316-2058460117727316, 2017.08, Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) is a new subtype of rhabdomyosarcoma included in the World Health Organization soft tissue and bone tumor classification in 2013. Despite the increasing number of reported cases of ssRMS, the imaging characteristics of ssRMS are not established. Herein, we present the case of an elderly Japanese woman with ssRMS of the masticator space with intracranial invasion without destruction of the adjacent bone. Attention should be paid to the presence of intracranial infiltration that may indicate a worse prognosis. Tumor growth without bone destruction could be a key finding to differentiate ssRMSs from conventional subtypes of rhabdomyosarcoma..
60. Koji Yoshimoto, Ryusuke Hatae, Yuhei Sangatsuda, Satoshi O Suzuki, Nobuhiro Hata, Yojiro Akagi, Daisuke Kuga, Murata Hideki, Koji Yamashita, Osamu Togao, Akio Hiwatashi, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara, Prevalence and clinicopathological features of H3.3 G34-mutant high-grade gliomas: a retrospective study of 411 consecutive glioma cases in a single institution., Brain tumor pathology, 10.1007/s10014-017-0287-7, 34, 3, 103-112, 2017.07, A recurrent glycine-to-arginine/valine alteration at codon 34 (G34R/V) within H3F3A, a gene that encodes the replication-independent histone variant H3.3, reportedly occurs exclusively in pediatric glioblastomas. However, the clinicopathological and biological significances of this mutation have not been completely elucidated; especially, no such data exist for tumor samples from Japanese patients. We analyzed 411 consecutive glioma cases representing patients of all ages. Our results demonstrated that 14 patients (3.4%) harbored H3F3A mutations, of which four had G34R mutations and 10 had K27M mutations. G34R-mutant tumors were located in the parietal region in two patients and the basal ganglia in one patient. One patient showed multi-lobular extension similar to the pattern observed in gliomatosis cerebri. Regarding neuroradiological features, intratumoral calcification was evident in two cases and all cases showed no or scarce contrast enhancement on MRI. Histopathologically, the four G34R-mutant cases included three glioblastomas and one astroblastoma. We have also investigated alterations in histone methylation including H3K27me3, H3K9me3, and H3K4me3 in G34R-mutant samples by immunohistochemistry. These results indicate that G34R-mutant tumors are likely to show extensive infiltration and alterations in global histone trimethylation might also play an important role in G34R mutant tumors..
61. Ryusuke Hatae, Nobuhiro Hata, Satoshi O Suzuki, Koji Yoshimoto, Daisuke Kuga, Hideki Murata, Yojiro Akagi, Yuhei Sangatsuda, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara, A comprehensive analysis identifies BRAF hotspot mutations associated with gliomas with peculiar epithelial morphology., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12347, 37, 3, 191-199, 2017.06, Brain tumors harbor various BRAF alterations, the vast majority of which are the BRAF kinase-activating V600E mutation. BRAF mutations are most frequently detected in certain subtypes of low-grade glioma, such as pilocytic astrocytoma (PA), pleomorphic xanthoastrocytoma (PXA), ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNT). However, it is unclear whether gliomas harboring BRAF mutations can be invariably regarded as these glioma subtypes or their derivatives. To address this question, we analyzed 274 gliomas in our institutional case series. We performed high-resolution melting analyses and subsequent direct Sanger sequencing on DNA isolated from snap-frozen tumor tissues. As expected, BRAF mutations were detected in the aforementioned low-grade gliomas: in 4/27 PAs, 2/3 PXAs, 4/8 GGs, and 1/6 DNTs. In addition to these gliomas, 1/2 astroblastomas (ABs) and 2/122 glioblastomas (GBs) harbored BRAF mutations. Pathological investigation of the two GBs revealed that one was a GB displaying epithelial features that presumably arose from a precedent GG, whereas the other GB, which harbored a rare G596 A mutation, showed marked epithelial features, including astroblastic rosettes. Our results indicate that in addition to being present in established BRAF-associated gliomas, BRAF mutations might be associated with epithelial features in high-grade gliomas, including sheet-like arrangement of polygonal tumor cells with a plump cytoplasm and astroblastic rosettes, and thus could potentially serve as a genetic marker for these features..
62. Nobuhiro Hata, Ryusuke Hatae, Koji Yoshimoto, Hideki Murata, Daisuke Kuga, Yojiro Akagi, Yuhei Sangatsuda, Satoshi O Suzuki, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara, Insular primary glioblastomas with IDH mutations: Clinical and biological specificities., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12362, 37, 3, 200-206, 2017.06, Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower-grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations. The median overall survival of these five patients was 29 months (range: 4 to >40 months), which is considered good prognoses. Clinical and radiographic characteristics were distinct from IDH-wildtype (IDH-wt) pGBMs. IDH-mutant (IDH-mut) tumors consistently involved insular lesions and were subdivided into: (i) the two cases of elderly patients with long clinical histories and features implying multistep tumor development; and (ii) the three cases of younger patients with diffusely swelling insular tumors, slight contrast enhancement and no necrosis. Genetic and expression analyses of IDH-mut pGBMs were similar to those of sGBMs, suggesting that they are indeed distinct from their IDH-wt counterparts. TERT promoter mutation, a genetic marker of oligodendroglial derivation, was detected in one long-surviving case, but genetic alterations in the astrocyte-sGBM pathway were generally prevalent in IDH-mut pGBMs. Our results present a unique phenotype of IDH-mut pGBMs arising from insular cortex region, the molecular backgrounds of which are similar to sGBMs..
63. Shintaro Fukushima, Satoshi Yamashita, Hisato Kobayashi, Hirokazu Takami, Kohei Fukuoka, Taishi Nakamura, Kai Yamasaki, Yuko Matsushita, Hiromi Nakamura, Yasushi Totoki, Mamoru Kato, Tomonari Suzuki, Kazuhiko Mishima, Takaaki Yanagisawa, Akitake Mukasa, Nobuhito Saito, Masayuki Kanamori, Toshihiro Kumabe, Teiji Tominaga, Motoo Nagane, Toshihiko Iuchi, Koji Yoshimoto, Masahiro Mizoguchi, Kaoru Tamura, Keiichi Sakai, Kazuhiko Sugiyama, Mitsutoshi Nakada, Kiyotaka Yokogami, Hideo Takeshima, Yonehiro Kanemura, Masahide Matsuda, Akira Matsumura, Kazuhiko Kurozumi, Keisuke Ueki, Masahiro Nonaka, Akio Asai, Nobutaka Kawahara, Yuichi Hirose, Tatusya Takayama, Yoichi Nakazato, Yoshitaka Narita, Tatsuhiro Shibata, Masao Matsutani, Toshikazu Ushijima, Ryo Nishikawa, Koichi Ichimura, Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas, ACTA NEUROPATHOLOGICA, 10.1007/s00401-017-1673-2, 133, 3, 445-462, 2017.03, Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 14 in Japan. The World Health Organization classification recognizes several subtypes of iGCTs, which are conventionally subclassified into pure germinoma or non-germinomatous GCTs. Recent exhaustive genomic studies showed that mutations of the genes involved in the MAPK and/or PI3K pathways are common in iGCTs; however, the mechanisms of how different subtypes develop, often as a mixed-GCT, are unknown. To elucidate the pathogenesis of iGCTs, we investigated 61 GCTs of various subtypes by genome-wide DNA methylation profiling. We showed that pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other iGCTs subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. Unlike PGC, however, hypomethylation extends to long interspersed nuclear element retrotransposons. Histologically and epigenetically distinct microdissected components of mixed-GCTs shared identical somatic mutations in the MAPK or PI3K pathways, indicating that they developed from a common ancestral cell..
64. Osamu Togao, Akio Hiwatashi, Koji Yamashita, Kazufumi Kikuchi, Jochen Keupp, Koji Yoshimoto, Daisuke Kuga, Masami Yoneyama, Satoshi O Suzuki, Toru Iwaki, Masaya Takahashi, Koji Iihara, Hiroshi Honda, Grading diffuse gliomas without intense contrast enhancement by amide proton transfer MR imaging: comparisons with diffusion- and perfusion-weighted imaging., European radiology, 10.1007/s00330-016-4328-0, 27, 2, 578-588, 2017.02, OBJECTIVES: To investigate whether amide proton transfer (APT) MR imaging can differentiate high-grade gliomas (HGGs) from low-grade gliomas (LGGs) among gliomas without intense contrast enhancement (CE). METHODS: This retrospective study evaluated 34 patients (22 males, 12 females; age 36.0 ± 11.3 years) including 20 with LGGs and 14 with HGGs, all scanned on a 3T MR scanner. Only tumours without intense CE were included. Two neuroradiologists independently performed histogram analyses to measure the 90th-percentile (APT90) and mean (APTmean) of the tumours' APT signals. The apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were also measured. The parameters were compared between the groups with Student's t-test. Diagnostic performance was evaluated with receiver operating characteristic (ROC) analysis. RESULTS: The APT90 (2.80 ± 0.59 % in LGGs, 3.72 ± 0.89 in HGGs, P = 0.001) and APTmean (1.87 ± 0.49 % in LGGs, 2.70 ± 0.58 in HGGs, P = 0.0001) were significantly larger in the HGGs compared to the LGGs. The ADC and rCBV values were not significantly different between the groups. Both the APT90 and APTmean showed medium diagnostic performance in this discrimination. CONCLUSIONS: APT imaging is useful in discriminating HGGs from LGGs among diffuse gliomas without intense CE. KEY POINTS: • Amide proton transfer (APT) imaging helps in grading non-enhancing gliomas • High-grade gliomas showed higher APT signal than low-grade gliomas • APT imaging showed better diagnostic performance than diffusion- and perfusion-weighted imaging..
65. Koji Yoshimoto, Mukae Nobutaka, Daisuke Kuga, Daisuke Inoue, Makoto Hashizume, Koji Iihara, Dual optical channel three-dimensional neuroendoscopy: Clinical application as an assistive technique in endoscopic endonasal surgery, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management, 10.1016/j.inat.2016.08.001, 6, 45-50, 2016.12, Three-dimensional (3D) high-definition endoscopy is an innovative technical advancement that helps surgeons gain precise depth perception and spatial recognition during endoscopic surgery. Here, we describe a new dual optical channel 3D neuroendoscopic technique and its clinical application. We performed endoscopic endonasal surgery on 88 patients using 3D and two-dimensional (2D) endoscopes in conjunction. We evaluated the usefulness of stereoscopic images acquired by dual optical channel 3D endoscopy during endoscopic surgery and compared the image resolution between dual optical channel 3D endoscopy and 2D endoscopy. Additionally, we compared the stereoscopic images acquired by dual optical channel and Visionsense 3D endoscopy in three cases. Combination surgery using 3D and 2D endoscopy was found to be safe. Stereoscopic images were useful in several surgical steps, especially in recognition of complex bony structures, bone drilling, and suprasellar manipulation. The magnitude of binocular disparity was greater in dual optical channel 3D endoscopy than in Visionsense 3D endoscopy. Stereoscopic images acquired by dual optical channel 3D neuroendoscopy were of adequate quality and were useful for endoscopic endonasal surgery. In consideration of its lower image resolution compared to that of 2D high-definition endoscopy, dual optical channel 3D neuroendoscopy can be applied as an assistive technique in endoscopic endonasal surgery. The magnitude of binocular disparity is one of the key factors to be considered for evaluation of the clinical significance of 3D endoscopy..
66. Koji Yoshimoto, Akiko Kada, Daisuke Kuga, Ryusuke Hatae, Hideki Murata, Yojiro Akagi, Kunihiro Nishimura, Ryota Kurogi, Ataru Nishimura, Nobuhiro Hata, Masahiro Mizoguchi, Tetsuro Sayama, Koji Iihara, Current Trends and Healthcare Resource Usage in the Hospital Treatment of Primary Malignant Brain Tumor in Japan: A National Survey Using the Diagnostic Procedure Combination Database (J-ASPECT Study-Brain Tumor)., Neurologia medico-chirurgica, 10.2176/nmc.oa.2016-0172, 56, 11, 664-673, 2016.11, We conducted this study to clarify the current trends and healthcare resource usage in the treatment of inpatients with primary malignant brain tumors. The Diagnostic Procedure Combination (DPC) data of all inpatients treated between 2013 and 2014 in the 370 core and branch hospitals enrolled in the Japanese Neurosurgical Society training program were collected. DPC is a discharge abstract and administrative claims database of inpatients. We assessed 6,142 primary, malignant brain tumor patients. Patient information, diagnostic information, treatment procedure, and healthcare resource usage were analyzed. Chemotherapy was the most frequent treatment (27% of cases), followed by surgery (13%) and surgery + chemo-radiotherapy (11%). Temozolomide (TMZ), the most frequently used chemotherapeutic drug, was administered to 1,236 patients. Concomitant TMZ and radiotherapy was administered to 816 patients, and was performed according to the Stupp regimen in many cases. The mean length of hospital stay (LOS) was 16 days, and the mean medical cost was 1,077,690 yen. The average medical cost of TMZ-only treatment was 1,138,620 yen whilst it was 4,424,300 yen in concomitant TMZ patients. The LOS was significantly shorter in high-volume than in low-volume hospitals, and the medical cost was higher in hospitals treating 21-50 patients compared to those treating 1-10 patients. However, the direct medical cost of TMZ treatment was the same across different volume hospitals. This is the first report of current trends and healthcare resource usage in the treatment of primary malignant brain tumor inpatients in the TMZ era in Japan..
67. Koji Yamashita, Akio Hiwatashi, Osamu Togao, Kazufumi Kikuchi, Yoshiyuki Kitamura, Masahiro Mizoguchi, Koji Yoshimoto, Daisuke Kuga, Satoshi O Suzuki, Shingo Baba, Takuro Isoda, Toru Iwaki, Koji Iihara, Hiroshi Honda, Diagnostic utility of intravoxel incoherent motion mr imaging in differentiating primary central nervous system lymphoma from glioblastoma multiforme., Journal of magnetic resonance imaging : JMRI, 10.1002/jmri.25261, 44, 5, 1256-1261, 2016.11, PURPOSE: To evaluate the diagnostic performance of intravoxel incoherent motion (IVIM) MR imaging and 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma multiforme (GBM). MATERIALS AND METHODS: Fifty patients, 17 with PCNSL and 33 with GBM, were retrospectively studied. From the 3 Tesla IVIM data, the perfusion fraction (f) and diffusion coefficient (D) were obtained. In addition, the maximum standard uptake value (SUVmax ) was obtained from the FDG-PET data. Each of the three parameters was compared between PCNSL and GBM using Mann-Whitney U-test. The performance in discriminating between PCNSL and GBM was evaluated using receiver-operating characteristics analysis and area-under-the-curve (AUC) values for the three parameters. RESULTS: The fmax and Dmin values were significantly higher in GBM than in PCNSL (P < 0.01 and P < 0.0001, respectively). In addition, the SUVmax value was significantly lower in GBM than in PCNSL (P < 0.0005). The AUC values for fmax , Dmin , and SUVmax were 0.756, 0.905, and 0.857, respectively. The combination of the fmax and Dmin increased the diagnostic performance (AUC = 0.936) of fmax (P < 0.05), but this value was not significantly different from the values for Dmin (P = 0.30). CONCLUSION: IVIM-MR imaging noninvasively provides useful quantitative information in distinguishing between PCNSL and GBM. J. Magn. Reson. Imaging 2016;44:1256-1261..
68. Hideyuki Arita, Kai Yamasaki, Taishi Nakamura, Mitsuaki Shirahata, Keiichi Kobayashi, Kaoru Tamura, Junya Fukai, Yuzo Terakawa, Kanji Mori, Hideo Nakamura, Koji Yoshimoto, Yonehiro Kanemura, Akitake Mukasa, Motoo Nagane, Keisuke Ueki, Takashi Komori, Ryo Nishikawa, Yoshitaka Narita, Koichi Ichimura, TERT PROMOTER MUTATION IS A POOR PROGNOSTIC MARKER FOR GBMS AND INTERACTS WITH MGMT METHYLATION STATUS, NEURO-ONCOLOGY, 18, 108-108, 2016.11.
69. Hideyuki Arita, Kai Yamasaki, Yuko Matsushita, Taishi Nakamura, Asanao Shimokawa, Hirokazu Takami, Shota Tanaka, Akitake Mukasa, Mitsuaki Shirahata, Saki Shimizu, Kaori Suzuki, Kuniaki Saito, Keiichi Kobayashi, Fumi Higuchi, Takeo Uzuka, Ryohei Otani, Kaoru Tamura, Kazutaka Sumita, Makoto Ohno, Yasuji Miyakita, Naoki Kagawa, Naoya Hashimoto, Ryusuke Hatae, Koji Yoshimoto, Naoki Shinojima, Hideo Nakamura, Yonehiro Kanemura, Yoshiko Okita, Manabu Kinoshita, Kenichi Ishibashi, Tomoko Shofuda, Yoshinori Kodama, Kanji Mori, Yusuke Tomogane, Junya Fukai, Koji Fujita, Yuzo Terakawa, Naohiro Tsuyuguchi, Shusuke Moriuchi, Masahiro Nonaka, Hiroyoshi Suzuki, Makoto Shibuya, Taketoshi Maehara, Nobuhito Saito, Motoo Nagane, Nobutaka Kawahara, Keisuke Ueki, Toshiki Yoshimine, Etsuo Miyaoka, Ryo Nishikawa, Takashi Komori, Yoshitaka Narita, Koichi Ichimura, A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas., Acta neuropathologica communications, 10.1186/s40478-016-0351-2, 4, 1, 79-79, 2016.08, The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients' treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas..
70. Akio Hiwatashi, Osamu Togao, Koji Yamashita, Kazufumi Kikuchi, Koji Yoshimoto, Masahiro Mizoguchi, Satoshi O Suzuki, Takashi Yoshiura, Hiroshi Honda, Evaluation of glioblastomas and lymphomas with whole-brain CT perfusion: Comparison between a delay-invariant singular-value decomposition algorithm and a Patlak plot., Journal of neuroradiology = Journal de neuroradiologie, 10.1016/j.neurad.2016.01.147, 43, 4, 266-72, 2016.07, OBJECTIVE: Correction of contrast leakage is recommended when enhancing lesions during perfusion analysis. The purpose of this study was to assess the diagnostic performance of computed tomography perfusion (CTP) with a delay-invariant singular-value decomposition algorithm (SVD+) and a Patlak plot in differentiating glioblastomas from lymphomas. MATERIALS AND METHODS: This prospective study included 17 adult patients (12 men and 5 women) with pathologically proven glioblastomas (n=10) and lymphomas (n=7). CTP data were analyzed using SVD+ and a Patlak plot. The relative tumor blood volume and flow compared to contralateral normal-appearing gray matter (rCBV and rCBF derived from SVD+, and rBV and rFlow derived from the Patlak plot) were used to differentiate between glioblastomas and lymphomas. The Mann-Whitney U test and receiver operating characteristic (ROC) analyses were used for statistical analysis. RESULTS: Glioblastomas showed significantly higher rFlow (3.05±0.49, mean±standard deviation) than lymphomas (1.56±0.53; P<0.05). There were no statistically significant differences between glioblastomas and lymphomas in rBV (2.52±1.57 vs. 1.03±0.51; P>0.05), rCBF (1.38±0.41 vs. 1.29±0.47; P>0.05), or rCBV (1.78±0.47 vs. 1.87±0.66; P>0.05). ROC analysis showed the best diagnostic performance with rFlow (Az=0.871), followed by rBV (Az=0.771), rCBF (Az=0.614), and rCBV (Az=0.529). CONCLUSION: CTP analysis with a Patlak plot was helpful in differentiating between glioblastomas and lymphomas, but CTP analysis with SVD+ was not..
71. Koji Yoshimoto, MR Imaging-Based Analysis of Glioblastoma Multiforme: Estimation of IDH1 Mutation Status, 2016.06.
72. Hideki Murata, Koji Yoshimoto, Detection of proneural/mesenchymal marker xpression in glioblastoma: temporospatial dynamics and association with chromatin-modifying gene expression, J Neurooncol. 2015;125(1):33-41. , 2016.06.
73. Koji Yoshimoto, Dual optical channel three-dimensional neuroendoscopy: Clinical application as an assistive technique in endoscopic endonasal surgery, 6, 45-50, 2016.06.
74. Koichi Ichimura, Shintaro Fukushima, Yasushi Totoki, Yuko Matsushita, Ayaka Otsuka, Arata Tomiyama, Tohru Niwa, Hirokazu Takami, Taishi Nakamura, Tomonari Suzuki, Kohei Fukuoka, Takaaki Yanagisawa, Kazuhiko Mishima, Yoichi Nakazato, Fumie Hosoda, Yoshitaka Narita, Soichiro Shibui, Akihiko Yoshida, Akitake Mukasa, Nobuhito Saito, Toshihiro Kumabe, Masayuki Kanamori, Teiji Tominaga, Keiichi Kobayashi, Saki Shimizu, Motoo Nagane, Toshihiko Iuchi, Masahiro Mizoguchi, Koji Yoshimoto, Kaoru Tamura, Taketoshi Maehara, Kazuhiko Sugiyama, Mitsutoshi Nakada, Keiichi Sakai, Yonehiro Kanemura, Masahiro Nonaka, Akio Asai, Kiyotaka Yokogami, Hideo Takeshima, Nobutaka Kawahara, Tatsuya Takayama, Masahiro Yao, Mamoru Kato, Hiromi Nakamura, Natsuko Hama, Ryuichi Sakai, Toshikazu Ushijima, Masao Matsutani, Tatsuhiro Shibata, Ryo Nishikawa, Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy., Acta neuropathologica, 10.1007/s00401-016-1557-x, 131, 6, 889-901, 2016.06, Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in MTOR (6.5 %), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs..
75. Osamu Togao, Akio Hiwatashi, Koji Yamashita, Kazufumi Kikuchi, Masahiro Mizoguchi, Koji Yoshimoto, Satoshi O Suzuki, Toru Iwaki, Makoto Obara, Marc Van Cauteren, Hiroshi Honda, Differentiation of high-grade and low-grade diffuse gliomas by intravoxel incoherent motion MR imaging., Neuro-oncology, 10.1093/neuonc/nov147, 18, 1, 132-41, 2016.01, BACKGROUND: Our aim was to assess the diagnostic performance of intravoxel incoherent motion (IVIM) MR imaging for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). METHODS: Forty-five patients with diffuse glioma (age 50.9 ± 20.4 y; 26 males, 19 females) were assessed with IVIM imaging using 13 b-values (0-1000 s/mm(2)) at 3T. The perfusion fraction (f), true diffusion coefficient (D), and pseudo-diffusion coefficient (D*) were calculated by fitting the bi-exponential model. The apparent diffusion coefficient (ADC) was obtained with 2 b-values (0 and 1000 s/mm(2)). Relative cerebral blood volume was measured by the dynamic susceptibility contrast method. Two observers independently measured D, ADC, D*, and f, and these measurements were compared between the LGG group (n = 16) and the HGG group (n = 29). RESULTS: Both D (1.26 ± 0.37 mm(2)/s in LGG, 0.94 ± 0.19 mm(2)/s in HGG; P < .001) and ADC (1.28 ± 0.35 mm(2)/s in LGG, 1.03 ± 0.19 mm(2)/s in HGG; P < .01) were lower in the HGG group. D was lower than ADC in the LGG (P < .05) and HGG groups (P < .0001). D* was not different between the groups. The f-values were significantly larger in HGG (17.5 ± 6.3%) than in LGG (5.8 ± 3.8%; P < .0001) and correlated with relative cerebral blood volume (r = 0.85; P < .0001). Receiver operating characteristic analyses showed areas under curve of 0.95 with f, 0.78 with D, 0.73 with ADC, and 0.60 with D*. CONCLUSION: IVIM imaging is useful in differentiating HGGs from LGGs..
76. K. Yamashita, A. Hiwatashi, O. Togao, K. Kikuchi, R. Hatae, K. Yoshimoto, M. Mizoguchi, S. O. Suzuki, T. Yoshiura, H. Honda, MR Imaging-Based Analysis of Glioblastoma Multiforme: Estimation of IDH1 Mutation Status, AMERICAN JOURNAL OF NEURORADIOLOGY, 10.3174/ajnr.A4491, 37, 1, 58-65, 2016.01, BACKGROUND AND PURPOSE: Glioblastoma multiforme is highly aggressive and the most common type of primary malignant brain tumor in adults. Imaging biomarkers may provide prognostic information for patients with this condition. Patients with glioma with isocitrate dehydrogenase 1 (IDH1) mutations have a better clinical outcome than those without such mutations. Our purpose was to investigate whether the IDH1 mutation status in glioblastoma multiforme can be predicted by using MR imaging.
MATERIALS AND METHODS: We retrospectively studied 55 patients with glioblastoma multiforme with wild type IDH1 and 11 patients with mutant IDH1. Absolute tumor blood flow and relative tumor blood flow within the enhancing portion of each tumor were measured by using arterial spin-labeling data. In addition, the maximum necrosis area, the percentage of cross-sectional necrosis area inside the enhancing lesions, and the minimum and mean apparent diffusion coefficients were obtained from contrast-enhanced T1-weighted images and diffusion-weighted imaging data. Each of the 6 parameters was compared between patients with wild type IDH1 and mutant IDH1 by using the Mann-Whitney U test. The performance in discriminating between the 2 entities was evaluated by using receiver operating characteristic analysis.
RESULTS: Absolute tumor blood flow, relative tumor blood flow, necrosis area, and percentage of cross-sectional necrosis area inside the enhancing lesion were significantly higher in patients with wild type IDH1 than in those with mutant IDH1 (P < .05 each). In contrast, no significant difference was found in the ADC(minimum) and ADC(mean). The area under the curve for absolute tumor blood flow, relative tumor blood flow, percentage of cross-sectional necrosis area inside the enhancing lesion, and necrosis area were 0.850, 0.873, 0.739, and 0.772, respectively.
CONCLUSIONS: Tumor blood flow and necrosis area calculated from MR imaging are useful for predicting the IDH1 mutation status..
77. Hideki Murata, Koji Yoshimoto, Ryusuke Hatae, Yojiro Akagi, Masahiro Mizoguchi, Nobuhiro Hata, Daisuke Kuga, Akira Nakamizo, Toshiyuki Amano, Tetsuro Sayama, Koji Iihara, Detection of proneural/mesenchymal marker expression in glioblastoma: temporospatial dynamics and association with chromatin-modifying gene expression., Journal of neuro-oncology, 10.1007/s11060-015-1886-y, 125, 1, 33-41, 2015.10, Proneural and mesenchymal are two subtypes of glioblastoma identified by gene expression profiling. In this study, the primary aim was to detect markers to develop a clinically applicable method for distinguishing proneural and mesenchymal glioblastoma. The secondary aims were to investigate the temporospatial dynamics of these markers and to explore the association between these markers and the expression of chromatin-modifying genes. One hundred thirty-three glioma samples (grade II: 14 samples, grade III: 18, grade IV: 101) were analyzed. We quantified the expression of 6 signature genes associated with proneural and mesenchymal glioblastoma by quantitative reverse transcription-polymerase chain reaction. We assigned proneural (PN) and mesenchymal (MES) scores based on the average of the 6 markers and calculated a predominant metagene (P-M) score by subtracting the MES from the PN score. We used these scores to analyze correlations with malignant transformation, tumor recurrence, tumor heterogeneity, chromatin-modifying gene expression, and HDAC7 expression. The MES score positively correlated with tumor grade, whereas the PN score did not. The P-M score was able to distinguish the proneural and mesenchymal subtypes. It was decreased in cases of tumor recurrence and malignant transformation and showed variability within a tumor, suggesting intratumoral heterogeneity. The PN score correlated with the expression of multiple histone-modifying genes, whereas the MES score was associated only with HDAC7 expression. Thus, we demonstrated a simple and straightforward method of quantifying proneural/mesenchymal markers in glioblastoma. Of note, HDAC7 expression might be a novel therapeutic target in glioblastoma treatment..
78. Nobuhiro Hata, Satoshi O Suzuki, Hideki Murata, Ryusuke Hatae, Yojiro Akagi, Yuhei Sangatsuda, Toshiyuki Amano, Koji Yoshimoto, Tomoko Tahira, Masahiro Mizoguchi, Genetic analysis of a case of glioblastoma with oligodendroglial component arising during the progression of diffuse astrocytoma., Pathology oncology research : POR, 10.1007/s12253-014-9850-2, 21, 3, 839-43, 2015.07, The most recent definition of glioblastoma with oligodendroglioma component (GBMO) assigned clinical significance to the observation of oligodendroglial foci within glioblastomas. However, the pathological mechanism of its histogenesis has not yet been determined. We report the genetic analysis of a GBMO case that evolved from an astrocyte lineage. A 37-year-old male underwent a third craniotomy for the removal of recurrent lesions of a secondary glioblastoma originating from a previous diffuse astrocytoma. The lesion in the right frontal lobe contained oligodendroglial foci within a glioblastoma background, while the remaining lesions showed only classic glioblastoma histology. Genetic analyses revealed distal 10q loss of heterozygosity (LOH) occurring de novo in the oligodendroglial tissue, as well as 10p, 17p LOH, and isocitrate dehydrogenase-1 gene (IDH1) mutations inherited from the previous lesions. The final recurrent glioblastoma underwent LOH on almost the entire of chromosome 10. Based on these results, the importance of an oligodendroglial component in glioblastomas may be limited..
79. Akira Maekawa, Kenichi Kohashi, Yuichi Yamada, Akira Nakamizo, Koji Yoshimoto, Masahiro Mizoguchi, Toru Iwaki, Yoshinao Oda, A case of intracranial solitary fibrous tumor/hemangiopericytoma with dedifferentiated component., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12181, 35, 3, 260-5, 2015.06, We report the case of a 51-year-old Japanese man with an intracranial dedifferentiated solitary fibrous tumor/hemangiopericytoma (SFT/HPC) identified morphologically and immunohistochemically, comprised of a typical SFT/HPC with a high-grade pleomorphic component. NAB2-STAT6 fusion transcripts were detected by reverse transcriptase polymerase chain reaction in both the conventional and high-grade components. The tumor cells in both components showed the nuclear expression of STAT6 protein, indicating the diagnostic value of these examinations. Intracranial dedifferentiated SFT/HPC is a very rare but important differential diagnosis in intracranial pleomorphic tumors..
80. Megumu Mori, Toru Chiba, Akira Nakamizo, Ryuichi Kumashiro, Masaharu Murata, Tomohiko Akahoshi, Morimasa Tomikawa, Yuichiro Kikkawa, Koji Yoshimoto, Masahiro Mizoguchi, Tomio Sasaki, Makoto Hashizume, Intraoperative visualization of cerebral oxygenation using hyperspectral image data: a two-dimensional mapping method., International journal of computer assisted radiology and surgery, 10.1007/s11548-014-0989-9, 9, 6, 1059-72, 2014.11, PURPOSE: Superficial temporal artery (STA)-middle cerebral artery (MCA) bypass is an important technique for cerebrovascular reconstruction. Intraoperative hemodynamic imaging is needed to perform cerebrovascular reconstruction safely and effectively. Optical intrinsic signal (OIS) imaging is commonly used for assessing cerebral hemodynamics in experimental studies, because it can provide high-resolution mapping images. However, OIS is not used clinically due to algorithm, instrumentation and spectral resolution limitations. We tested the feasibility of a hyperspectral camera (HSC) for assessment of cortical hemodynamics with spectral imaging of the cerebral cortex in rats and in vivo humans. METHODS: A hyperspectral camera (HSC) was tested in a rat model of cerebral ischemia (middle cerebral artery occlusion) and during human revascularization surgery (STA-MCA anastomosis). Changes in cortical oxygen saturation were derived from spectral imaging data (400-800 nm) collected by exposing the cortex to Xenon light. Reflected light was sampled using the HSC. The system was then tested intraoperatively during superficial temporal artery to middle cerebral artery anastomosis procedures. Comparison with single-photon emission computed tomography (SPECT) imaging data was done. RESULTS: During middle cerebral artery occlusion in rats, the HSC technique showed a significant decrease in cortical oxygen saturation in the ischemic hemisphere. In clinical cases, the cortical oxygen saturation was increased after STA-MCA anastomosis, which agreed with the SPECT imaging data. CONCLUSION: Continuous collection of imaging spectroscopic data is feasible and may provide reliable quantification of the hemodynamic responses in the brain. The HSC system may be useful for monitoring intraoperative changes in cortical surface hemodynamics during revascularization procedures in humans..
81. Tomihiro Wakamiya, Satoshi O Suzuki, Hideomi Hamasaki, HIroyuki Honada, Masahiro Mizoguchi, Koji Yoshimoto, Toru Iwaki, Elevated expression of fatty acid synthase and nuclear localization of carnitine palmitoyltransferase 1C are common among human gliomas, Neuropathology, 34, 5, 465-474, 2014.10.
82. Tomihiro Wakamiya, Satoshi O Suzuki, Hideomi Hamasaki, Hiroyuki Honda, Masahiro Mizoguchi, Koji Yoshimoto, Toru Iwaki, Elevated expression of fatty acid synthase and nuclear localization of carnitine palmitoyltransferase 1C are common among human gliomas., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12132, 34, 5, 465-74, 2014.10, Fatty acid synthase (FASN) and carnitine palmitoyltransferase 1C (CPT1C), a brain-specific isoform of the CPT1 family, are upregulated in certain types of cancers, including gliomas. Acetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis, and its phosphorylated form inhibits lipid synthesis. We examined the expression and subcellular localization of these fatty acid metabolism-related molecules in human gliomas. We performed immunostaining of two glioma cell lines (U373MG and U87MG) and 41 surgical specimens of diffuse gliomas with various histological grades (21 with the isocitrate dehydrogenase 1(IDH1) R132H mutation and 20 without the mutation). In the cultured glioma cells, CPT1C and phosphorylated ACC (p-ACC) were mainly localized to the nuclei, whereas FASN localized to the cytoplasm. In the surgical specimens, most glioma tissues showed nuclear staining for CPT1C and p-ACC, and cytoplasmic staining for FASN, regardless of the genetic status of IDH1 and the histological grade. Therefore, elevated cytoplasmic expression of FASN and nuclear localization of CPT1C are common among human diffuse gliomas, which may be regulated by the differential phosphorylation status of ACC in the cellular compartment..
83. Osamu Togao, Takashi Yoshiura, Jochen Keupp, Akio Hiwatashi, Koji Yamashita, Kazufumi Kikuchi, Yuriko Suzuki, Satoshi O Suzuki, Toru Iwaki, Nobuhiro Hata, Masahiro Mizoguchi, Koji Yoshimoto, Koji Sagiyama, Masaya Takahashi, Hiroshi Honda, Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades., Neuro-oncology, 10.1093/neuonc/not158, 16, 3, 441-8, 2014.03, BACKGROUND: Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. We prospectively assessed the usefulness of APT imaging in predicting the histological grade of adult diffuse gliomas. METHODS: Thirty-six consecutive patients with histopathologically proven diffuse glioma (48.1 ± 14.7 y old, 16 males and 20 females) were included in the study. APT MRI was conducted on a 3T clinical scanner and was obtained with 2 s saturation at 25 saturation frequency offsets ω = -6 to +6 ppm (step 0.5 ppm). δB0 maps were acquired separately for a point-by-point δB0 correction. APT signal intensity (SI) was defined as magnetization transfer asymmetry at 3.5 ppm: magnetization transfer ratio (MTR)asym = (S[-3.5 ppm] - S[+3.5 ppm])/S0. Regions of interest were carefully placed by 2 neuroradiologists in solid parts within brain tumors. The APT SI was compared with World Health Organization grade, Ki-67 labeling index (LI), and cell density. RESULTS: The mean APT SI values were 2.1 ± 0.4% in grade II gliomas (n = 8), 3.2 ± 0.9% in grade III gliomas (n = 10), and 4.1 ± 1.0% in grade IV gliomas (n = 18). Significant differences in APT intensity were observed between grades II and III (P < .05) and grades III and IV (P < .05), as well as between grades II and IV (P < .001). There were positive correlations between APT SI and Ki-67 LI (P = .01, R = 0.43) and between APT SI and cell density (P < .05, R = 0.38). The gliomas with microscopic necrosis showed higher APT SI than those without necrosis (P < .001). CONCLUSIONS: APT imaging can predict the histopathological grades of adult diffuse gliomas..
84. Masahiro Mizoguchi, Nobuhiro Hata, Satoshi O Suzuki, Yutaka Fujioka, Hideki Murata, Toshiyuki Amano, Akira Nakamizo, Koji Yoshimoto, Toru Iwaki, Tomio Sasaki, Pediatric glioblastoma with oligodendroglioma component: aggressive clinical phenotype with distinct molecular characteristics., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12029, 33, 6, 652-7, 2013.12, The 2007 World Health Organization classification defined a new variant of glioblastoma (GBM) containing oligodendroglioma foci as GBM with an oligodendroglioma component (GBMO), which shows a favorable clinical outcome compared with "classic" GBM. However, all of the reported cases of GBMO have been adult cases, with no previous reports of pediatric cases. In this report, we demonstrated molecular characteristics of a pediatric GBMO case, showing aggressive clinical behavior with 8-month overall survival. The case showed neither isocitrate dehydrogenase 1/2 genes (IDH1/2) mutation nor 1p/19q co-deletion, a hallmark of oligodendroglioal tumors. In addition, microsatellite instability, leading to the putative mechanism of temozolomide (TMZ) resistance, was frequently detected. Molecular genetic analysis may provide critical prognostic and therapeutic insights, especially for the pediatric glioma containing oligodendroglioma components..
85. Daisuke Inoue, Koji Yoshimoto, Munenori Uemura, Masaki Yoshida, Kenoki Ohuchida, Hajime Kenmotsu, Morimasa Tomikawa, Tomio Sasaki, Makoto Hashizume, Three-dimensional high-definition neuroendoscopic surgery: a controlled comparative laboratory study with two-dimensional endoscopy and clinical application., Journal of neurological surgery. Part A, Central European neurosurgery, 10.1055/s-0033-1345100, 74, 6, 357-65, 2013.11, BACKGROUND: The purpose of this research was to investigate the usefulness of three-dimensional (3D) endoscopy compared with two-dimensional (2D) endoscopy in neuroendoscopic surgeries in a comparative study and to test the clinical applications. METHODS: Forty-three examinees were divided into three groups according to their endoscopic experience: novice, beginner, or expert. Examinees performed three separate tasks using 3D and 2D endoscopy. A recently developed 3D high-definition (HD) neuroendoscope, 4.7 mm in diameter (Shinko Optical Co., Ltd., Tokyo, Japan) was used. In one of the three tasks, we developed a full-sized skull model of acrylic-based plastic using a 3D printer and a patient's thin slice computed tomography data, and evaluated the execution time and total path length of the tip of the pointer using an optical tracking system. Sixteen patients underwent endoscopic transnasal transsphenoidal pituitary surgery using both 3D and 2D endoscopy. RESULTS: Horizontal motion was evaluated using task 1, and anteroposterior motion was evaluated with task 3. Execution time and total path length in task 3 using the 3D system in both novice and beginner groups were significantly shorter than with the 2D system (p < 0.05), although no significant difference between 2D and 3D systems in task 1 was seen. In both the novice and beginner groups, the 3D system was better for depth perception than horizontal motion. No difference was seen in the expert group in this regard. The 3D HD endoscope was used for the pituitary surgery and was found very useful to identify the spatial relationship of carotid arteries and bony structures. CONCLUSIONS: The use of a 3D neuroendoscope improved depth perception and task performance. Our results suggest that 3D endoscopes could shorten the learning curve of young neurosurgeons and play an important role in both general surgery and neurosurgery..
86. Koji Yoshimoto, Yukie Araki, Toshiyuki Amano, Kenichi Matsumoto, Akira Nakamizo, Tomio Sasaki, Clinical features and pathophysiological mechanism of the hemianoptic complication after the occipital transtentorial approach., Clinical neurology and neurosurgery, 10.1016/j.clineuro.2012.11.024, 115, 8, 1250-6, 2013.08, OBJECTIVE: To obtain detailed insight into neuro-ophthalmological characteristics and pathophysiology of hemianoptic complications after occipital transtentorial surgery. METHODS: We reviewed the cases of 14 patients surgically treated by the occipital transtentorial approach. Treated lesions included 6 posterior third ventricle tumors, including pineal and tectal lesions, 3 falco-tentorial meningiomas, and 5 superior cerebellar lesions. The surgeries were performed by the unilateral occipital transtentorial approach with patients in the prone position. RESULTS: Visual functions were preoperatively normal in all patients. After surgery, 11 patients (79%) showed hemianoptic complications detected by a confrontation test in the immediate postoperative period. The condition began to improve in the early postoperative days. The visual field recovered completely in 6 patients within 10 days, 2 patients recovered within 3 months, and 3 patients complained of permanent visual field defects. Optometric neuro-ophthalmic evaluation in the early postoperative period failed to detect complete homonymous hemianopsia, but homonymous inferior quadrantanopia and scotomatous defects were observed in 6 patients. These visual field defects were permanent in 3 patients. Postoperative MRI showed no morphological abnormality except these three patients. Atrophic change of the occipital lobe with preservation of striate cortex was associated with persistent visual field defects in two patients. Cerebral blood flow evaluation by single photon emission computed tomography suggested that temporary local hyperperfusion of the retracted occipital region when visual field defect was present. CONCLUSION: Hemianoptic visual field defects can recover via inferior quadrantanopia or scotomatous defect. All of these defects are attributable to injury to the optic radiation as well to the occipital lobe. Hyperperfusion of the retracted occipital region may underlie the pathophysiology of hemianoptic complications after the occipital transtentorial approach..
87. Koji Yoshimoto, Akira Nakamizo, Tomio Sasaki, Surgical techniques for the dissection of encased perforators in giant clinoidal meningiomas., Acta neurochirurgica, 10.1007/s00701-013-1750-9, 155, 8, 1409-12, 2013.08, BACKGROUND: Surgical treatment of giant clinoidal meningiomas remains a challenging task for neurosurgeons. Here, we present details of the surgical techniques for the dissection of encased perforators. METHODS: The dissection of encased perforators is summarized as follows: (1) split the tumor above the encased arteries and perforators; (2) find the entrance and exit points of the perforators, and estimate the running course of the perforators within the tumor; (3) dissect and expose the perforators along the estimated line. CONCLUSIONS: The surgical techniques described in this article will aid in achieving maximum tumor resection while preserving encased perforators..
88. Koji Yoshimoto, The transventricular preforniceal approach for exophytic chiasmatic/hypothalamic astrocytomas extending into the anterior third ventricle, ACTA NEUROCHIRURGICA, 10.1007/s00701-013-1642-z, 155, 4, 727-732, 2013.04.
89. Toshiyuki Amano, Satoshi O Suzuki, Masahiro Mizoguchi, Koji Yoshimoto, Akira Nakamizo, Hideki Murata, Toru Iwaki, Tomio Sasaki, Fibrotic nodule arising from the cerebellopontine angle., Brain tumor pathology, 10.1007/s10014-012-0105-1, 30, 2, 122-7, 2013.04, The authors present an extremely rare case of a fibrotic nodule arising from the cerebellopontine (CP) angle. A 57-year-old male had suffered from hearing disturbance and tinnitus for several years. Computed tomography revealed a high-density mass in the left CP angle with little enhancement after intravenous administration of contrast media. Magnetic resonance imaging (MRI) showed a very hypointense mass on T2-weighted imaging. T1-weighted MRI with gadolinium revealed very faint, delayed enhancement of the tumor. The patient underwent surgical resection of the tumor. Histopathologically the lesion comprised entirely fibrotic tissue consisting of thick collagenous fibers and sclerosing blood vessels with a few intervening viable cells with, partly, the immunophenotype of arachnoid cells. Intracranial fibrotic nodules are extremely rare. This tumor, however, had some radiological features similar to those of other, more common, tumors for example meningiomas or solitary fibrous tumors; it was, therefore, difficult to distinguish it from the others. It is believed that intracranial fibrotic nodules usually have benign, non-neoplastic characteristics, although their natural history is not yet fully understood. It is, therefore, necessary to be able to perform a differential diagnosis that will distinguish this rare condition from other intracranial fibrous neoplasms that occasionally have malignant features..
90. Koji Yoshimoto, Tadahisa Shono, Koichiro Matsukado, Tomio Sasaki, The transventricular preforniceal approach for exophytic chiasmatic/hypothalamic astrocytomas extending into the anterior third ventricle., Acta neurochirurgica, 10.1007/s00701-013-1642-z, 155, 4, 727-32, 2013.04, BACKGROUND: Surgical treatment of large exophytic chiasmatic/hypothalamic astrocytomas extending into the anterior third ventricle remains a challenging task for neurosurgeons. In particular, when the tumor extends from the chiasmatic region upward to the foramen of Monro, damage to the fornix and other neurovascular structures is a major concern. OBJECTIVE: To describe the technique used in the transventricular preforniceal surgical approach to remove the superior and superoposterior part of the tumor in the third ventricle for treatment of exophytic chiasmatic/hypothalamic astrocytoma. METHODS: The transventricular preforniceal approach was used in two cases of exophytic chiasmatic/hypothalamic astrocytoma. The approach is summarized in 4 procedures: 1) exposure of the anterior horn of the lateral ventricle by the transcallosal approach, 2) identification of the foramen of Monro and the fornix, 3) incision of the septum pellucidum or the wall of the lateral ventricle, in front of the columns of the fornix, and 4) removal of the tumor through the space between the anterior commissure and the columns of the fornix. RESULTS: Because the tumor compressed the foramen of Monro posteriorly and stretched the space between the anterior commissure and the columns of the fornix, the posterosuperior part of the tumor in the third ventricle was successfully removed through the surgical corridor in front of the columns of the fornix. In both cases, tumors were successfully removed using this approach without damaging the fornix and the anterior commissure. Residual tumor was removed using an anterior interhemispheric translamina terminalis approach in a two-stage surgery. CONCLUSIONS: The transventricular preforniceal approach can be applied for removing the superior part of exophytic chiasmatic/hypothalamic astrocytomas, because the space between the anterior commissure and the fornix is stretched by the tumor, providing an appropriate surgical corridor..
91. A Case of Left Basal Ganglia Lesion presented with Right Hemiparesis.
92. D. Inoue, B. Cho, M. Mori, Y. Kikkawa, T. Amano, A. Nakamizo, K. Yoshimoto, M. Mizoguchi, M. Tomikawa, J. Hong, M. Hashizume, T. Sasaki, Preliminary Study on the Clinical Application of Augmented Reality Neuronavigation, JOURNAL OF NEUROLOGICAL SURGERY PART A-CENTRAL EUROPEAN NEUROSURGERY, 10.1055/s-0032-1333415, 74, 2, 71-76, 2013.03, Objective To develop an augmented reality (AR) neuronavigation system with Web cameras and examine its clinical utility.
Methods The utility of the system was evaluated in three patients with brain tumors. One patient had a glioblastoma and two patients had convexity meningiomas. Our navigation system comprised the open-source software 3D Slicer (Brigham and Women's Hospital, Boston, Massachusetts, USA), the infrared optical tracking sensor Polaris (Northern Digital Inc., Waterloo, Canada), and Web cameras. We prepared two different types of Web cameras: a handheld type and a headband type. Optical markers were attached to each Web camera. We used this system for skin incision planning before the operation, during craniotomy, and after dural incision.
Results We were able to overlay these images in all cases. In Case 1, accuracy could not be evaluated because the tumor was not on the surface, though it was generally suitable for the outline of the external ear and the skin. In Cases 2 and 3, the augmented reality error was similar to 2 to 3 mm.
Conclusion AR technology was examined with Web cameras in neurosurgical operations. Our results suggest that this technology is clinically useful in neurosurgical procedures, particularly for brain tumors close to the brain surface..
93. [Cranioplasty following decompressive craniectomy in children: clinical pitfalls]..
94. Koji Yamashita, Takashi Yoshiura, Akio Hiwatashi, Osamu Togao, Koji Yoshimoto, Satoshi O Suzuki, Koichiro Abe, Kazufumi Kikuchi, Yasuhiro Maruoka, Masahiro Mizoguchi, Toru Iwaki, Hiroshi Honda, Differentiating primary CNS lymphoma from glioblastoma multiforme: assessment using arterial spin labeling, diffusion-weighted imaging, and ¹⁸F-fluorodeoxyglucose positron emission tomography., Neuroradiology, 10.1007/s00234-012-1089-6, 55, 2, 135-43, 2013.02, INTRODUCTION: Our purpose was to evaluate the diagnostic performance of arterial spin labeling (ASL) perfusion imaging, diffusion-weighted imaging (DWI), and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating primary central nervous system lymphomas (PCNSLs) from glioblastoma multiformes (GBMs). METHODS: Fifty-six patients including 19 with PCNSL and 37 with GBM were retrospectively studied. From the ASL data, an absolute tumor blood flow (aTBF) and a relative tumor blood flow (rTBF) were obtained within the enhancing portion of each tumor. In addition, the minimum apparent diffusion coefficient (ADCmin) and the maximum standard uptake value (SUVmax) were obtained from DWI and FDG-PET data, respectively. Each of the four parameters was compared between PCNSLs and GBMs using Kruskal-Wallis test. The performance in discriminating between PCNSLs and GBMs was evaluated using the receiver-operating characteristics analysis. Area-under-the-curve (AUC) values were compared among the four parameters using a nonparametric method. RESULTS: The aTBF, rTBF, and ADCmin were significantly higher in GBMs (mean aTBF ± SD = 91.6 ± 56.0 mL/100 g/min, mean rTBF ± SD = 2.61 ± 1.61, mean ADCmin ± SD = 0.78 ± 0.19 × 10(-3) mm(2)/s) than in PCNSLs (mean aTBF ± SD = 37.3 ± 10.5 mL/100 g/min, mean rTBF ± SD = 1.24 ± 0.37, mean ADCmin ± SD = 0.61 ± 0.13 × 10(-3) mm(2)/s) (p < 0.005, respectively). In addition, SUVmax was significantly lower in GBMs (mean ± SD = 13.1 ± 6.34) than in PCNSLs (mean ± SD = 22.5 ± 7.83) (p < 0.005). The AUC for aTBF (0.888) was higher than those for rTBF (0.810), ADCmin (0.768), and SUVmax (0.848), although their difference was not statistically significant. CONCLUSION: ASL perfusion imaging is useful for differentiating PCNSLs from GBMs as well as DWI and FDG-PET..
95. Akira Nakamizo, Toshiyuki Amano, Masahiro Mizoguchi, Koji Yoshimoto, Tomio Sasaki, Dorsal location of the cochlear nerve on vestibular schwannoma: preoperative evaluation, frequency, and functional outcome., Neurosurgical review, 10.1007/s10143-012-0400-7, 36, 1, 39-43, 2013.01, The cochlear nerve is most commonly located on the caudoventral portion of the capsule of vestibular schwannomas and rarely on the dorsal portion. In such a condition, total removal of the tumor without cochlear nerve dysfunction is extremely difficult. The purpose of our study was to identify the frequency of this anatomical condition and the status of postoperative cochlear nerve function; we also discuss the preoperative radiological findings. The study involved 114 patients with unilateral vestibular schwannomas operated on via a retrosigmoid (lateral suboccipital) approach. Locations of the cochlear nerve on the tumor capsule were ventral, dorsal, caudal, and rostral. Ventral and dorsal locations were further subdivided into rostral, middle, and caudal third of the tumor capsule. The postoperative cochlear nerve function and preoperative magnetic resonance (MR) findings were reviewed retrospectively. In 56 patients that had useful preoperative hearing, useful hearing was retained in 50.0% (28 of 56) of patients after surgery. The cochlear nerve was located on the dorsal portion of the tumor capsule in four patients (3.5%), and useful hearing was preserved in only one of these patients (25%) in whom the tumor had been partially resected. This tumor-nerve anatomical relationship was identified in all tumors of <2 cm at preoperative MR cisternography. MR cisternography has the potential to identify the tumor-nerve anatomical relationship, especially in small-sized tumors that usually require therapeutic intervention that ensures hearing preservation. Hence, careful evaluation of the preoperative MR cisternography is important in deciding the therapeutic indications..
96. Masahiro Mizoguchi, Koji Yoshimoto, Tomio Sasaki, Glioma of the Central Nervous System Surveillance Counterpoint: Japan, Patient Surveillance After Cancer Treatment, 10.1007/978-1-60327-969-7_106, 521-523, 2013.01.
97. Koji Yoshimoto, Clinical features and pathophysiological mechanism of the hemianoptic complication after the occipital transtentorial approach, Clin Neurol Neurosurg, 10.1016/j.clineuro.2012.11.024, 2012.12.
98. Koji Yoshimoto, Associations between microRNA expression and mesenchymal marker gene expression in glioblastoma, NEURO-ONCOLOGY, 10.1093/neuonc/nos145, 14, 9, 1153-1162, 2012.09.
99. Xinlong Ma, Koji Yoshimoto, Yaulei Guan, Nobuhiro Hata, Masahiro Mizoguchi, Noriaki Sagata, Hideki Murata, Daisuke Kuga, Toshiyuki Amano, Akira Nakamizo, Tomio Sasaki, Associations between microRNA expression and mesenchymal marker gene expression in glioblastoma., Neuro-oncology, 10.1093/neuonc/nos145, 14, 9, 1153-62, 2012.09, The subclassification of glioblastoma (GBM) into clinically relevant subtypes using microRNA (miRNA)- and messenger RNA (mRNA)-based integrated analysis has been attempted. Because miRNAs regulate multiple gene-signaling pathways, understanding miRNA-mRNA interactions is a prerequisite for understanding glioma biology. However, such associations have not been thoroughly examined using high-throughput integrated analysis. To identify significant miRNA-mRNA correlations, we selected and quantified signature miRNAs and mRNAs in 82 gliomas (grade II: 14, III: 16, IV: 52) using real-time reverse-transcriptase polymerase chain reaction. Quantitative expression data were integrated into a single analysis platform that evaluated the expression relationship between miRNAs and mRNAs. The 21 miRNAs include miR-15b, -21, -34a, -105, -124a, -128a, -135b, -184, -196a-b, -200a-c, -203, -302a-d, -363, -367, and -504. In addition, we examined 23 genes, including proneural markers (DLL3, BCAN, and OLIG2), mesenchymal markers (YKL-40, CD44, and Vimentin), cancer stem cell-related markers, and receptor tyrosine kinase genes. Primary GBM was characterized exclusively by upregulation of mesenchymal markers, whereas secondary GBM was characterized by significant downregulation of mesenchymal markers, miR-21, and -34a, and by upregulation of proneural markers and miR-504. Statistical analysis showed that expression of miR-128a, -504, -124a, and -184 each negatively correlated with the expression of mesenchymal markers in GBM. Our functional analysis of miR-128a and -504 as inhibitors demonstrated that suppression of miR-128a and -504 increased the expression of mesenchymal markers in glioblastoma cell lines. Mesenchymal signaling in GBM may be negatively regulated by miR-128a and -504..
100. Koji Yamashita, Takashi Yoshiura, Akio Hiwatashi, Osamu Togao, Koji Yoshimoto, Satoshi O Suzuki, Kazufumi Kikuchi, Masahiro Mizoguchi, Toru Iwaki, Hiroshi Honda, Arterial spin labeling of hemangioblastoma: differentiation from metastatic brain tumors based on quantitative blood flow measurement., Neuroradiology, 10.1007/s00234-011-0977-5, 54, 8, 809-13, 2012.08, INTRODUCTION: Hemangioblastoma and metastatic tumors are the major differential diagnoses for the posterior fossa tumors in adults. Our purpose was to evaluate the efficacy of ASL in differentiating hemangioblastomas from metastatic brain tumors. METHODS: A total of 19 patients including 5 with a hemangioblastomas and 14 with metastatic tumors (7 from lung cancer, 4 from breast cancer, 1 from RCC, 1 from gastric cancer, and 1 from unknown origin) were enrolled in this study. ASL was performed using a pulsed ASL method at a 3-T unit. aTBF was measured as a mean absolute blood flow value within a region of interest drawn in the tumor. In addition, rTBF was obtained by normalizing the aTBF by a blood flow measured in the normal-appearing cortical gray matter. The aTBF and rTBF values were compared between hemangioblastomas and metastatic tumors using Student's t test. RESULTS: Both the aTBF and rTBF values were significantly higher in hemangioblastomas (mean aTBF ± SD = 437 ± 274 mL/100 g/min, mean rTBF ± SD = 7.96 ± 3.12) in comparison with metastatic brain tumors (mean aTBF ± SD = 125 ± 134 mL/100 g/min, mean rTBF ± SD = 2.98 ± 3.91; p < 0.05, respectively). However, a metastasis from RCC showed very high aTBF (559 mL/100 g/min) and rTBF (16.2). CONCLUSION: Our results demonstrated that ASL provides useful information to differentiate between hemangioblastomas and metastatic brain tumors. Metastasis from RCC may mimic hemangioblastoma on ASL blood flow measurement..
101. Masahiro Mizoguchi, Koji Yoshimoto, Xinlong Ma, Yanlei Guan, Nobuhiro Hata, Toshiyuki Amano, Akira Nakamizo, Satoshi O Suzuki, Toru Iwaki, Tomio Sasaki, Molecular characteristics of glioblastoma with 1p/19q co-deletion., Brain tumor pathology, 10.1007/s10014-012-0107-z, 29, 3, 148-53, 2012.07, Recent developments in molecular analysis have revealed genetic alterations in human gliomas. Loss of heterozygosity (LOH) is a critical molecular marker for classification of human glioma, and is useful for predicting outcome. Our previous LOH study identified a small subgroup of glioblastoma (GBM), with 1p/19q co-deletion, with a favorable clinical outcome. In this study, we investigated molecular pathological features of eight GBM with 1p/19q co-deletion compared with "classic" GBM and anaplastic oligodendroglioma (AO). We estimated EGFR gene amplification, EGFRvIII expression, CDKN2A (p16) homozygous deletion, and isocitrate dehydrogenase 1/2 (IDH1/2) gene mutations. We also conducted an analysis of the expression of proneural genes (DLL3, OLIG2, SOX2). On histopathological review, only one GBM was diagnosed as glioblastoma with oligodendroglioma component (GBMO). Loss of chromosomes 10 and 17p is common, and neither IDH1/2 mutations nor EGFRvIII expression were detected in GBM with 1p/19q co-deletion. The expression profile revealed high expression of the OLIG2 gene in this subgroup. High expression of proneural gene OLIG2 without EGFRvIII expression may be associated with a favorable clinical outcome; however, IDH1/2 gene status and the extent of LOH regions may indicate that this small subgroup of GBM is a distinct genetic subgroup from oligodendroglial tumors..
102. Akira Nakamizo, Koji Yoshimoto, Toshiyuki Amano, Masahiro Mizoguchi, Tomio Sasaki, Crocodile tears syndrome after vestibular schwannoma surgery., Journal of neurosurgery, 10.3171/2011.12.JNS111859, 116, 5, 1121-5, 2012.05, OBJECT: Crocodile tears syndrome (CTS) is a lacrimal hypersecretion disorder characterized by excessive tearing with gustatory stimulation while eating, drinking, or smelling food. Surgeons tend to overlook CTS after vestibular schwannoma (VS) surgery because its symptoms are less obvious compared with facial paralysis. The authors aim to elucidate the precise incidence and the detailed natural course of CTS after VS surgery. METHODS: This study included 128 consecutive patients with unilateral VSs resected via a retrosigmoid, lateral suboccipital approach. Clinical information on the patients was obtained by retrospective chart review. The presence of, time of onset of, and recovery of patients from CTS were obtained from the chart or evaluated from the most recent outpatient visit. RESULTS: A total of 14 patients (10.9%) developed CTS. Motor function of the facial nerve at discharge was statistically related to the occurrence of CTS (p < 0.001). The odds ratio of House-Brackmann Grade 4 compared with Grade 1 was 86.4 (p < 0.001). A bimodal distribution of CTS onset was observed, with a mean onset of 6.1 ± 4.0 months after resection. The CTS improved in 10 patients (71%) at various intervals, whereas CTS resolved in only 7 patients (50%) at a mean interval of 10.9 ± 7.9 months. The mean interval to recovery in the early-onset group was 9.7 ± 7.9 months, and it was 18 months in the late-onset group; the mean is given ± SD throughout. CONCLUSIONS: The occurrence of CTS following VS surgery was more common than expected; however, a surgical procedure intended to protect the functioning of the facial nerve appears to be conducive to reduction of the occurrence of CTS. To reduce the distress caused by CTS, all patients should be given sufficient information and provide their informed consent prior to surgery..
103. Akira Nakamizo, Satoshi O Suzuki, Takafumi Shimogawa, Toshiyuki Amano, Masahiro Mizoguchi, Koji Yoshimoto, Tomio Sasaki, Concurrent spinal nerve root schwannoma and meningioma mimicking single-component schwannoma., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/j.1440-1789.2011.01239.x, 32, 2, 190-5, 2012.04, We present a first case of concurrent tumors consisting of schwannoma and meningioma arising at the same spinal level in a patient without neurofibromatosis. A 49-year-old man without clinical evidence of neurofibromatosis presented with a 5-month history of right neck pain. MRI demonstrated an extradural tumor involving the right-sided C2 nerve root with a small intradural component. T1- and T2-weighted and contrast-enhanced MRI could not differentiate the intradural tumor as different from the extradural tumor. Total removal of the tumors was performed. No contiguity of the extradural tumor with the intradural tumor was seen. The intradural tumor attached strongly to the dura mater around the C2 nerve root exits. Intraoperative pathological diagnosis confirmed the extradural tumor as schwannoma and the intradural tumor as meningioma. We therefore thoroughly coagulated the dura mater adjacent to the intradural tumor and resected the dura mater around the nerve root exits together with the tumor. Pathological examination revealed that the resection edge of the extradural component consisted of a spinal nerve with thickened epineurium and was free of neoplastic cells. No schwannoma component was evident in the intradural tumor. No obvious transition thus existed between the extra- and intradural tumors. Distinguishing these tumors prior to surgery is critical for determining an optimal surgical plan, as schwannoma and meningioma require different surgical procedures. We therefore recommend a careful review of preoperative imaging with the possibility of concurrent tumors in mind..
104. Tomio Sasaki, Koji Yoshimoto, Suzuki O. Satoshi, Vestibular schwannoma (vs) surgery: Histological considerations and operative results, Tumors of the Central Nervous System, Volume 7: Meningiomas and Schwannomas, 10.1007/978-94-007-2894-3_35, 325-334, 2012.01, In vestibular schwannoma (VS) surgery, understanding of the tumor capsules and nerve-tumor interface is very important to achieve extensive tumor removal while preserving facial and cochlear nerve function. We here demonstrate that tumor capsules of VS consist of thin perineurium of the vestibular nerve and remaining vestibular nerve fibers based on our histological examinations. Also, we show our operative concept of “subcapsular” or “subperineurial” dissection to preserve cranial nerve functions. In this procedure, we place the cleavage plane between the tumor capsules and the tumor parenchyma, which enables us to perform nearly total removal of the tumor by tracing this cleavage plane. Finally, we present our surgical outcomes based on this histological consideration, and conclude that we could increase the possibilities of preserving facial and cochlear nerve functions by performing “subcapsular” or “subperineurial” dissection..
105. Yamashita K, Yoshiura T, Hiwatashi A, Togao O, Yoshimoto K, Suzuki SO, Kikuchi K, Mizoguchi M, Iwaki T, Honda H, Arterial spin labeling of hemangioblastoma:differentiation from metastatic brain tumors based on quantitative blood flow measurement, Neuroradiology, 2011.11.
106. Yoshimoto K, Ma X, Guan Y, Mizoguchi M, Nakamizo A, Amano T, Hata N, Kuga D,Sasaki T, Expression of stem cell marker and receptor kinase genes in glioblastoma tissue quantified by real-time RT-PCR, Brain Tumor Pahology, 28, 4, 291-6, 2011.10.
107. Koji Yoshimoto, Xinlong Ma, Yaulei Guan, Masahiro Mizoguchi, Akira Nakamizo, Toshiyuki Amano, Nobuhiro Hata, Daisuke Kuga, Tomio Sasaki, Expression of stem cell marker and receptor kinase genes in glioblastoma tissue quantified by real-time RT-PCR., Brain tumor pathology, 10.1007/s10014-011-0046-0, 28, 4, 291-6, 2011.10, Glioblastoma is dependent on a specific signaling pathway to maintain its tumor phenotype. The receptor tyrosine kinase (RTK) family mediates the multiple oncogenic growth factor receptor signaling and contributes to the pathogenesis of glioblastoma. Recently, many studies have shown that the expression of stem cell marker in glioblastoma tissue has prognostic significance, which indicates that the quantification of stem cell markers and RTK genes yields biological information about glioblastoma. In this study, we quantified RNA expression levels of stem cell markers [CD133, Nestin, BMI-1, maternal embryonic leucine zipper kinase (MELK), and Notch1-4] as well as RTKs (EGFR, ErbB4, VEGFR1-3, FGFR1, -2, PDGFRΑ, and PDGFRΒ) in 42 clinical samples of glioblastoma by the real-time RT-PCR method. We demonstrated that the expression of MELK is exclusively upregulated in glioblastoma tissue. Notch receptor expression is moderately upregulated and is correlated with that of VEGFR2, VEGFR3, and PDGFRβ. Unsupervised clustering identified one unique sample group that showed high expression of most of the genes analyzed. Our results suggest that quantification of these stem cell markers and RTK genes can stratify patients based on the expression profile, which might provide insight into the glioma biology in each cluster..
108. Masahiro Mizoguchi, Daisuke Kuga, Yanlei Guan, Nobuhiro Hata, Akira Nakamizo, Koji Yoshimoto, Tomio Sasaki, Erratum: Loss of heterozygosity analysis in malignant gliomas (Brain Tumor Pathol DOI: 10.1007/s10014-011-0038-0), Brain Tumor Pathology, 10.1007/s10014-011-0049-x, 28, 3, 197, 2011.07.
109. Hashiguchi K, Morioka T, Yoshida F, Yoshimoto K, Shono T, Natori Y, Nagata S, Sasaki T, Feasibility of intraoperative motor-evoked potential monitoring for skull base tumors with a high risk of postoperative motor deterioration, Acta Neurochir (Wien), 153, 6, 1191-200, 2011.06.
110. Mizoguchi M, Kuga D, Guan Y, Hata N, Nakamizo A, Yoshimoto K, Sasaki T, Loss of heterozygosity analysis in malignant gliomas, Brain Tumor Pathology, 28, 3, 191-6, 2011.06.
111. Sasaki T, Hashiguchi K, Yoshimoto K, Nakamizo A, Mizoguchi M, Worldwide academic contributions of Japanese neurosurgeons, Neurol Med Chir (Tokyo), 51, 6, 405-14, 2011.06.
112. Kimiaki Hashiguchi, Takato Morioka, Fumiaki Yoshida, Koji Yoshimoto, Tadahisa Shono, Yoshihiro Natori, Shinji Nagata, Tomio Sasaki, Feasibility of intraoperative motor-evoked potential monitoring for skull base tumors with a high risk of postoperative motor deterioration., Acta neurochirurgica, 10.1007/s00701-011-1006-5, 153, 6, 1191-200, 2011.06, OBJECTIVE: To establish the validity and utility of motor-evoked potential (MEPs) monitoring for skull base tumor resection, we explored the relationship between MEP monitoring results and postoperative motor function. METHODS: MEPs were successfully monitored during 76 operations in 68 patients with a high risk of motor morbidity. MEP monitoring data were correlated with perioperative clinical motor function. RESULTS: MEPs remained stable in 56 operations (73.7%), and no postoperative motor deterioration was observed. Transient or permanent deterioration of MEPs (<50% of the initial amplitude before surgery) occurred in 20 operations (26.3%). This deterioration was reversible after intervention in seven cases (9.2%). Irreversible deterioration in MEPs was seen in 13 cases (17.1%). In five cases, the final amplitude was greater than 10%. Two of these patients experienced transient loss of MEPs and moderate to severe hemiparesis. Both patients showed full recovery within 6 months after the operation. The other three patients experienced no postoperative worsening of motor function. The final MEP amplitude was less than 10% in the other eight patients, including five with permanent MEP loss. All of these patients experienced severe postoperative motor dysfunction. Recovery of motor function was worse in most participants in this group compared with those in the other groups. CONCLUSION: Intraoperative MEP monitoring is a valid indicator of pyramidal tract pathway function for skull base tumor surgery..
113. Nakamizo A, Akagi Y, Amano T, Suzuki SO, Otsuka R, Abe Y, Yoshimoto K, Iwaki T, Sasaki T, Donor-derived adult T-cell leukaemia, Lancet, 2011.03.
114. Akira Nakamizo, Yojiro Akagi, Toshiyuki Amano, Satoshi O Suzuki, Rie Otsuka, Yasunobu Abe, Koji Yoshimoto, Toru Iwaki, Tomio Sasaki, Donor-derived adult T-cell leukaemia., Lancet (London, England), 10.1016/S0140-6736(11)60315-2, 377, 9771, 1124-1124, 2011.03.
115. Torisu R, Suzuki SO, Masui K, Yoshimoto K, Mizoguchi M, Hashizume M, Canoll P, Goldman JE, Sasaki T, Iwaki T, Persistent roles of signal transduction of platelet-derived growth factor B in genesis, growth, and anaplastic transformation of gliomas in an in-vivo serial transplantation model, Brain Tumor Pathology, 2011.02.
116. Araki Y, Mizoguchi M, Yoshimoto K, Shono T, Amano T, Nakamizo A, Suzuki SO, Iwaki T, Sasaki T, Quantitative digital assessment of MGMT immunohistochemical expression in glioblastoma tissue, Brain Tumor Pathology, 2011.02.
117. Rina Torisu, Satoshi O Suzuki, Kenta Masui, Koji Yoshimoto, Masahiro Mizoguchi, Makoto Hashizume, Peter Canoll, James E Goldman, Tomio Sasaki, Toru Iwaki, Persistent roles of signal transduction of platelet-derived growth factor B in genesis, growth, and anaplastic transformation of gliomas in an in-vivo serial transplantation model., Brain tumor pathology, 10.1007/s10014-010-0006-0, 28, 1, 33-42, 2011.02, We previously reported that retrovirally transduced platelet-derived growth factor-B (PDGFB) in glial progenitors of the rat cerebral white matter, subventricular zone, or brain stem induced malignant brain tumors closely resembling human glioblastoma (GBM). While human GBMs may progress over the period of several months to a few years, prospective, long-term in-vivo observation of histological changes of the tumor tissues is not feasible in these models, because the animals undergo rapid tumor progression and mortality within approximately 1 month. We thus performed successive, long-term in-vivo transplantation of the PDGFB-induced tumor cells into the rat cerebrum. Primary retroviral transduction of PDGFB in the glial progenitors of the rat basal ganglia induced malignant glioma resembling human GBM or anaplastic oligodendroglioma (AOL) consisting of relatively monomorphous tumor cells expressing markers for the oligodendrocyte lineage. In the course of long-term successive transplantation, tumor cells presented pleomorphism as well as focal GFAP expression. This suggests that secondary chromosomal aberration and dysregulation of gene expression following accelerated cell cycle by PDGFB stimulation would induce morphological and immunophenotypic changes in tumor cells. Furthermore, while the primary tumors contained only a minor fraction of proviral GFP-expressing or hemagglutinin-expressing cells, most tumor cells came to express these proviral genes in the course of serial transplantation suggesting a persistent role of PDGFB-expressing cells in maintenance and growth of the tumors. This model would be useful for investigation of the long-term effects of PDGFB stimulation in glioma tissues on anaplastic evolution..
118. Yukie Araki, Masahiro Mizoguchi, Koji Yoshimoto, Tadahisa Shono, Toshiyuki Amano, Akira Nakamizo, Satoshi O Suzuki, Toru Iwaki, Tomio Sasaki, Quantitative digital assessment of MGMT immunohistochemical expression in glioblastoma tissue., Brain tumor pathology, 10.1007/s10014-010-0004-2, 28, 1, 25-31, 2011.02, Recent reports have suggested an important clinical role for hypermethylation of the O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter in patients with glioblastomas. Whether MGMT protein expression is correlated with promoter hypermethylation and patient outcomes, however, has not been elucidated. Here we describe a quantitative digital method for assessment of MGMT-specific immunostaining, and analyze the relationship between expression levels and methylation status of the MGMT promoter. We investigated 46 tumors from patients who received a diagnosis of glioblastoma or gliosarcoma. Immunohistochemistry with anti-MGMT antibody and methylation-specific PCR using bisulfite-modified tumor DNA were performed. The digital assessment method used image-analysis software to determine a digital MGMT staining index, and the results were compared with those obtained via conventional visual assessments. The digital staining index clearly correlated with the methylation status of MGMT promoter. In addition, the index correlated with our observational results when nuclear and cytoplasmic staining were assessed in three different fields. Our digital assessment method enabled us to assess uncertain immunopositive samples objectively and quantitatively, which is an important consideration when examining heterogeneous cellular staining. We expect that this method will be useful for assessment of heterogeneous staining with any antibodies..
119. Shirakawa Y, Yoshiura T, Hiwatashi A, Yamashita K, Kamano H, Shioyama Y, Abe K, Amano T, Nakamizo A, Yoshimoto K, Honda H, Torisu R, Suzuki S, Honda H, Pseudoprogression following concurrent temozolomide and radiotherapy in a patient with glioblastoma: findings on functional imaging techniques, Fukuoka Igaku Zasshi, 2010.12.
120. Yuko Shirakawa, Takashi Yoshiura, Akio Hiwatashi, Koji Yamashita, Hironori Kamano, Yoshiyuki Shioyama, Kouichiro Abe, Toshiyuki Amano, Akira Nakamizo, Koji Yoshimoto, Hiroyuki Honda, Rina Torisu, Satoshi Suzuki, Hiroshi Honda, Pseudoprogression following concurrent temozolomide and radiotherapy in a patient with glioblastoma: findings on functional imaging techniques., Fukuoka igaku zasshi = Hukuoka acta medica, 10.15017/19675, 101, 12, 257-64, 2010.12, Concurrent temozolomide (TMZ) and radiotherapy became the new standard of care for patients diagnosed with glioblastoma multiforme (GBM). Recently, there has been an increasing awareness of progressive and enhancing lesions on MR images immediately after treatment. These lesions may be a treatment effect, so-called pseudoprogression. We experienced one case pathologically and clinically diagnosed as pseudoprogression. The lesion showed a high apparent diffusion coefficient on diffusion-weighted imaging, low blood volume on perfusion imaging, and low uptake of 18F-fluorodeoxyglucose on positron emission tomography. The lesion was pathologically diagnosed as pseudoprogression after additional surgical resection..
121. Guan Y, Mizoguchi M, Yoshimoto K, Hata N, Shono T, Suzuki SO, Araki Y, Kuga D, Nakamizo A, Amano T, Ma X, Hayashi K, Sasaki T, MiRNA-196 is upregulated in glioblastoma but not in anaplastic astrocytoma and has prognostic significance., Clinical Cancer Research, 2010.08.
122. Yanlei Guan, Masahiro Mizoguchi, Koji Yoshimoto, Nobuhiro Hata, Tadahisa Shono, Satoshi O Suzuki, Yukie Araki, Daisuke Kuga, Akira Nakamizo, Toshiyuki Amano, Xinlong Ma, Kenshi Hayashi, Tomio Sasaki, MiRNA-196 is upregulated in glioblastoma but not in anaplastic astrocytoma and has prognostic significance., Clinical cancer research : an official journal of the American Association for Cancer Research, 10.1158/1078-0432.CCR-10-0207, 16, 16, 4289-97, 2010.08, PURPOSE: MicroRNAs (miRNA) are short noncoding RNAs that can play critical roles in diverse biological processes. They are implicated in tumorigenesis and function both as tumor suppressors and as oncogenes. The clinical significance of miRNA expression profiles in malignant gliomas remains unclear. EXPERIMENTAL DESIGN: In this study, we examined the expression levels of 365 mature human miRNAs in 12 malignant gliomas, including 8 glioblastomas and 4 anaplastic astrocytomas, using TaqMan real-time quantitative PCR arrays. A validation study was done to corroborate a subset of the results, including expression levels of miR-196a, -196b, -21, and -15b, by analyzing 92 malignant gliomas by conventional real-time PCR. We modeled the relationship between the expression levels of these miRNAs and the survival rate of 39 glioblastoma patients by Kaplan-Meier method and multivariate analysis. RESULTS: Expression profiles in glioblastomas and anaplastic astrocytomas suggested that 16 miRNAs were candidate markers associated with the malignant progression of gliomas. Among them, miR-196a showed the most significant difference (P = 0.0038), with miR-196b also having a high significance (P = 0.0371). Both miRNAs showed increased expression levels in glioblastomas relative to both anaplastic astrocytomas and normal brains in the validation study. Furthermore, patients with high miR-196 expression levels showed significantly poorer survival by the Kaplan-Meier method (P = 0.0073). Multivariate analysis showed that miR-196 expression levels were an independent predictor of overall survival in all 39 glioblastoma patients (P = 0.021; hazard ratio, 2.81). CONCLUSIONS: Our results suggest that miR-196 may play a role in the malignant progression of gliomas and may be a prognostic predictor in glioblastomas..
123. Shono T, Mizoguchi M, Yoshimoto K, Amano T, Natori Y, Sasaki T, Clinical course of abducens nerve palsy associated with skull base tumours, Acta Neurochir (Wien), 2009.07.
124. T. Shono, M. Mizoguchi, K. Yoshimoto, T. Amano, Y. Natori, T. Sasaki, Clinical course of abducens nerve palsy associated with skull base tumours, ACTA NEUROCHIRURGICA, 10.1007/s00701-009-0312-7, 151, 7, 733-738, 2009.07, The clinical course of abducens nerve palsy associated with skull base tumour is rarely reported. In this study, we examined the post-operative course of abducens nerve palsies associated with various skull base tumours.
Between January 2003 and December 2006, 240 patients with various skull base tumours underwent surgery at Kyushu University Hospital. Among them, nine patients presented with abducens nerve palsies (ten nerves) following surgery. The conditions included two pituitary adenomas, two trigeminal schwannomas and five meningiomas. We evaluated the function of the abducens nerves in these patients on admission, at discharge, and periodically in the outpatient clinic.
Four of the abducens nerve palsies already existed prior to surgery, and six of them developed post-operatively. In the four patients with pituitary adenomas and trigeminal schwannomas, all nerves were anatomically preserved and showed complete recovery of function within 6 months after surgery. In contrast, only two of the six palsies in patients with skull base meningiomas showed complete recovery. In three patients with petro-clival meningiomas, the abducens nerves were completely transected during surgery, and one was reconstructed using fibrin glue. This patient remarkably recovered from the abducens nerve palsy within 2 years.
The abducens nerve palsies in pituitary adenomas and trigeminal schwannomas showed a better clinical course compared to those in skull base meningiomas. The abducens nerve palsies that occur with skull base meningiomas are less likely to recover. Nevertheless, it is important to preserve the nerves and to perform surgical repair if the nerve is transected..
125. Kuga D, Mizoguchi M, Guan Y, Hata N, Yoshimoto K, Shono T, Suzuki SO, Kukita Y, Tahira T, Nagata S, Sasaki T, Hayashi K, Prevalence of copy-number neutral LOH in glioblastomas revealed by genomewide analysis of laser-microdissected tissues, Neuro-Oncology, 10 (6):995-1003, 2008.12.
126. Daisuke Kuga, Masahiro Mizoguchi, Yanlei Guan, Nobuhiro Hata, Koji Yoshimoto, Tadahisa Shono, Satoshi O Suzuki, Yoji Kukita, Tomoko Tahira, Shinji Nagata, Tomio Sasaki, Kenshi Hayashi, Prevalence of copy-number neutral LOH in glioblastomas revealed by genomewide analysis of laser-microdissected tissues., Neuro-oncology, 10.1215/15228517-2008-064, 10, 6, 995-1003, 2008.12, We have employed a laser-capture microdissection technique and single-nucleotide polymorphism arrays to characterize genomic alterations associated with the development of glioblastoma multiforme (GBM). Combined analysis of loss of heterozygosity (LOH) and copy number revealed that more than half (56.3%) of the 254 identified LOH loci showed no copy-number alteration, indicating the presence of copy-number neutral LOH (cnLOH). Furthermore, we found a GBM case that showed cnLOH in 18 of the 22 autosomes. These results were confirmed by quantitative real-time PCR, microsatellite analysis, and fluorescence in situ hybridization. The high rate of cnLOH suggests that epigenetic abnormalities of many genes are involved in the development and progression of GBMs..
127. Guan Y, Hata N, Kuga D, Yoshimoto K, Mizoguchi M, Shono T, Suzuki SO, Tahira T, Kukita Y, Higasa K, Yokoyama N, Nagata S, Iwaki T, Sasaki T, Hayashi K, Allelic losses of chromosome 1p36 in meningioma tissues detected by improved quantitative single strand conformation polymorphism analysis, International Journal of Cancer, 122: 1820-1826, 2008.04.
128. Landon J. Inge, Sigrid A. Rajasekaran, Koji Yoshimoto, Paul S. Mischel, William McBride, Elliot Landaw, Ayyappan K. Rajasekaran, Evidence for a potential tumor suppressor role for the Na,K-ATPase beta(1)-subunit, HISTOLOGY AND HISTOPATHOLOGY, 23, 4, 459-467, 2008.04, The Na,K-ATPase, consisting of two essential subunits (alpha, beta), plays a critical role in the regulation of ion homeostasis in mammalian cells. Recent studies indicate that reduced expression of the beta(1) isoform (NaK-beta(1)) is commonly observed in carcinoma and is associated with events involved in cancer progression. In this study, we present evidence that repletion of NaK-beta(1) in Moloney sarcoma virus-transformed Madin-Darby canine kidney cells (MSVMDCK), a highly tumorigenic cell line, inhibits anchorage independent growth and suppresses tumor formation in immunocompromised mice. Additionally, using an in vitro cell-cell aggregation assay, we showed that cell aggregates of NaK-beta(1) subunit expressing MSVMDCK cells have reduced extracellular regulated kinase (ERK) 1/2 activity compared with parental MSV-MDCK cells. Finally, using immunohistochemistry and fully quantitative image analysis approaches, we showed that the levels of phosphorylated ERK 1/2 are inversely correlated to the NaK-beta(1) levels in the tumors. These findings reveal for the first time that NaK-beta(1) has a potential tumor-suppressor function in epithelial cells..
129. Yanlei Guan, Nobuhiro Hata, Daisuke Kuga, Koji Yoshimoto, Masahiro Mizoguchi, Tadahisa Shono, Satoshi O Suzuki, Tomoko Tahira, Yoji Kukita, Koichiro Higasa, Nobuhiko Yokoyama, Shinji Nagata, Toru Iwaki, Tomio Sasaki, Kenshi Hayashi, Narrowing of the regions of allelic losses of chromosome 1p36 in meningioma tissues by an improved SSCP analysis., International journal of cancer, 10.1002/ijc.23297, 122, 8, 1820-6, 2008.04, Mapping loss of heterozygosity (LOH) regions in the genomes of tumor tissues is a practical approach for identifying genes whose loss is related to tumorigenesis. Conventional LOH analyses using microsatellite or single nucleotide polymorphism (SNP) markers require the simultaneous examination of tumor- and matched normal-DNA. Here, we improved the previously developed SNP-based LOH assay using single strand conformation polymorphism (SSCP) analysis, so that LOH in tumor samples heavily contaminated with normal DNA can now be precisely estimated, even when matched normal DNA is not available. We demonstrate the reliability of the improved SSCP-based LOH detection method, called the LOH estimation by quantitative SSCP analysis using averaged control (LOQUS-AC), by comparing the results with those of the previous "LOH estimated by quantitative SSCP assay" (LOQUS) method. Using the LOQUS-AC assay, LOH was detected at a high consistency (98.1%) with the previous LOQUS method. We then applied this new method to characterize LOH profiles in 130 meningiomas, using 68 SNPs (i.e., a mean inter-SNP interval of 441 kbp) that are evenly distributed throughout chromosome 1p36. Benign, atypical and anaplastic meningiomas exhibited 1p36 LOH at frequencies of 48.39, 84.62 and 100.00%, respectively, using LOQUS-AC. Subsequently, we detected a candidate common LOH region on 1p36.11 that might harbor tumor suppressor genes related to malignant progression of meningioma..
130. Yoshimoto K, Dang J, Zhu S, Nathanson D, Huang T, Dumont R, Seligson D, Yong WH, Xiong Z, Rao N, Winther H, Chakravarti A, Bigner D, Mellinghoff IK, Horvath S, Cavenee WK, Cloughesy TF, Mischel PS:, Detection of EGFRvIII in routinely processed glioblastoma clinical samples, Clinical Cancer Research, 14(2): 488-493, 2008.01.
131. Cloughesty TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL, Antitumor activity of rapamycin in patients with recurrent PTEN-deficient glioblastoma, Plos Medicine, 5(1): 139-151, 2008.01.
132. Tim F. Cloughesy, Koji Yoshimoto, Phioanh Nghiemphu, Kevin Brown, Julie Dang, Shaojun Zhu, Teli Hsueh, Yinan Chen, Wei Wang, David Youngkin, Linda Liau, Neil Martin, Don Becker, Marvin Bergsneider, Albert Lai, Richard Green, Tom Oglesby, Michael Koleto, Jeff Trent, Steve Horvath, Paul S. Mischel, Ingo K. Mellinghoff, Charles L. Sawyers, Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-Deficient glioblastoma, PLOS MEDICINE, 10.1371/journal.pmed.0050008, 5, 1, 139-151, 2008.01, Background There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population.
Methods and Findings Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin ( mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells ( measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation ( measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p=0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test).
Conclusions Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development..
133. Koji Yoshimoto, Julie Dang, Shaojun Zhu, David Nathanson, Tiffany Huang, Rebecca Dumont, David B. Seligson, William H. Yong, Zhenggang Xiong, Nagesh Rao, Henrik Winther, Arnab Chakravarti, Darell D. Bigner, Ingo K. Mellinghoff, Steve Horvath, Webster K. Cavenee, Timothy F. Cloughesy, Paul S. Mischel, Development of a real-time RT-PCR assay for detecting EGFRvIII in glioblastoma samples, CLINICAL CANCER RESEARCH, 10.1158/1078-0432.CCR-07-1966, 14, 2, 488-493, 2008.01, Purpose: Epidermal growth factor receptor variant III (EGFRvIII) is an oncogenic, constitutively active mutant form of the EGFR that is commonly expressed in glioblastoma and is also detected in a number of epithelial cancers. EGFRvIII presents a unique antigenic target for anti-EGFRvIII vaccines and it has been shown to modulate response to EGFR kinase inhibitor therapy. Thus, detection in clinical samples may be warranted. Existing patents preclude the use of anti-EGFRvIII antibodies for clinical detection. Further, frozen tissue is not routinely available, particularly for patients treated in the community. Thus, detection of EGFRvIII in formalin-fixed paraffin-embedded (FFPE) clinical samples is a major challenge.
Experimental Design: We developed a real-time reverse transcription-PCR (RT-PCR) assay for detecting EGFRvIII in FFPE samples and analyzed 59 FFPE glioblastoma clinical samples with paired frozen tissue from the same surgical resection. We assessed EGFRvIII protein expression by immunohistochemistry using two distinct specific anti-EGFRvIII antibodies and examined EGFR gene amplification by fluorescence in situ hybridization.
Results: The FFPE RT-PCR assay detected EGFRvIII in 16 of 59 (27%) samples, exclusively in cases with EGFR amplification, consistent with the expected frequency of this alteration. The FFPE RT-PCR assay was more sensitive and specific for detecting EGFRvIII than either of the two antibodies alone, or in combination, with a sensitivity of 93% (95% confidence interval, 0.78-1.00) and a specificity of 98% (95% confidence interval, 0.93-1.00).
Conclusion: This assay will facilitate accurate assessment of EGFRvIII in clinical samples and may aid in the development of strategies for stratifying patients for EGFRvIII-directed therapies..
134. Jeffrey C. Lee, Igor Vivanco, Rameen Beroukhim, Julie H. Y. Huang, Whei L. Feng, Ralph M. DeBiasi, Koji Yoshimoto, Jennifer C. King, Phioanh Nghiemphu, Yuki Yuza, Qing Xu, Heidi Greulich, Roman K. Thomas, J. Guillermo Paez, Timothy C. Peck, David J. Linhart, Karen A. Glatt, Gad Getz, Robert Onofrio, Liuda Ziaugra, Ross L. Levine, Stacey Gabriel, Tomohiro Kawaguchi, Keith O'Neill, Haumith Khan, Linda M. Liau, Stanley F. Nelson, P. Nagesh Rao, Paul Mischel, Russell O. Pieper, Tim Cloughesy, Daniel J. Leahy, William R. Sellers, Charles L. Sawyers, Matthew Meyerson, Ingo K. Mellinghoff, Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain, PLOS MEDICINE, 10.1371/journal.pmed.0030485, 3, 12, 2264-2273, 2006.12, Background Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy.
Methods and Findings Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors.
Conclusions Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma..
135. Nobuhiro Hata, Tadahisa Shono, Koji Yoshimoto, Masahiro Mizoguchi, Tadao Kawamura, Shinji Nagata, Kenichi Matsumoto, Kenshi Hayashi, Toru Iwaki, Tomio Sasaki, An astroblastoma case associated with loss of heterozygosity on chromosome 9p., Journal of neuro-oncology, 10.1007/s11060-006-9157-6, 80, 1, 69-73, 2006.10, The tumorigenesis of astroblastomas has not yet been elucidated on the basis of histopathological studies, and genetic studies may be useful for obtaining additional information regarding the tumorigenesis of these tumors. Here, we report an astroblastoma case in which a genetic analysis was performed. A 16-year-old female with a progressive headache was found to have a demarcated cystic tumor with a mural nodule in the right parietal lobe. Total removal of the tumor was achieved and a histological examination verified that the tumor was an astroblastoma. A genetic analysis using microsatellite markers revealed loss of heterozygosity (LOH) on chromosome 9p. The postoperative course was uneventful and, to date, she has been followed up for 2 years with no signs of recurrence. This is the first reported case of an astroblastoma in which LOH was detected on 9p. Based on this result, the tumorigenesis of astroblastomas is discussed..
136. Cho-Lea Tso, Peter Shintaku, James Chen, Qinghai Liu, Jason Liu, Zugen Chen, Koji Yoshimoto, Paul S. Mischel, Timothy F. Cloughesy, Linda M. Liau, Stanley F. Nelson, Primary glioblastomas express mesenchymal stem-like properties, MOLECULAR CANCER RESEARCH, 10.1158/1541-7786.MCR-06-0005, 4, 9, 607-619, 2006.09, Glioblastoma is the most common and aggressive primary brain cancer. Recent isolation and characterization of brain tumor-initiating cells supports the concept that transformed neural stem cells may seed glioblastoma. We previously identified a wide array of mesenchymal tissue transcripts overexpressed in a broad set of primary glioblastoma (de novo) tumors but not in secondary glioblastoma (derived from lower-grade) tumors, low-grade astrocytomas, or normal brain tissues. Here, we extend this observation and show that a subset of primary glioblastoma tumors and their derived tumor lines express cellular and molecular markers that are associated with mesenchymal stem cells (MSC) and that glioblastoma cell cultures can be induced to differentiate into multiple mesenchymal lineage-like cell types. These findings suggest either that a subset of primary glioblastomas derive from transformed stem cells containing MSC-like properties and retain partial phenotypic aspects of a MSC nature in tumors or that glioblastomas activate a series of genes that result in mesenchymal properties of the cancer cells to effect sustained tumor growth and malignant progression..
137. Nobuhiro Hata, Koji Yoshimoto, Nobuhiko Yokoyama, Masahiro Mizoguchi, Tadahisa Shono, Yanlei Guan, Tomoko Tahira, Yoji Kukita, Koichiro Higasa, Shinji Nagata, Toru Iwaki, Tomio Sasaki, Kenshi Hayashi, Allelic losses of chromosome 10 in glioma tissues detected by quantitative single-strand conformation polymorphism analysis., Clinical chemistry, 10.1373/clinchem.2005.060954, 52, 3, 370-8, 2006.03, BACKGROUND: Detection of loss of heterozygosity (LOH) in clinical tissue samples is frequently difficult because samples are usually contaminated with noncancerous cells or because tumor cells in single tissues have genetic heterogeneity, and the precision of available techniques is insufficient for reliable analysis in such materials. We hypothesized that single-strand conformation polymorphism (SSCP) analysis can precisely quantify the gene dosage in mixed samples and is suitable for detection of LOH in clinical tissue samples. METHODS: We assessed the accuracy of a fluorescent SSCP method for the quantification of single-nucleotide polymorphism (SNP) alleles, using DNAs that were composed of cancerous DNA mixed with noncancerous DNA at various ratios. We applied this method to precisely characterize LOH in glioma tissue samples, using 96 SNPs that were evenly distributed throughout chromosome 10. RESULTS: LOH could be detected even in the cancerous DNA heavily contaminated (up to 80%) with noncancerous DNA. Using this method, we obtained LOH profiles of 56 gliomas with resolution at the SNP level (i.e., 1.5-Mbp interval). Anaplastic astrocytomas exhibited both 10p and 10q LOH, whereas diffuse astrocytomas frequently (63% of the cases) exhibited loss of 10p alone. We also found a possible new LOH region (around 10p13) in gliomas. CONCLUSIONS: The present method is effective for precise mapping of LOH region in surgically obtained tumor tissues and could be applicable to the genetic diagnosis of cancers other than gliomas..
138. CL Tso, WA Freije, A Day, ZG Chen, B Merriman, A Perlina, Y Lee, EQ Dia, K Yoshimoto, PS Mischel, LM Liau, TF Cloughesy, SF Nelson, Distinct transcription profiles of primary and secondary glioblastoma subgroups, CANCER RESEARCH, 10.1158/0008-5472.CAN-05-0077, 66, 1, 159-167, 2006.01, Glioblastomas are invasive and aggressive tumors of the brain, generally considered to arise from glial cells. A subset of these cancers develops from lower-grade gliomas and can thus be clinically classified as "secondary," whereas some glioblastomas occur with no prior evidence of a lower-grade tumor and can be clinically classified as "primary." Substantial genetic differences between these groups of glioblastomas have been identified previously. We used large-scale expression analyses to identify glioblastoma-associated genes (GAG) that are associated with a more malignant phenotype via comparison with lower-grade astrocytomas. We have further defined gene expression differences that distinguish primary and secondary glioblastomas. GAGs distinct. to primary or secondary tumors provided information on the heterogeneous properties and apparently distinct oncogenic mechanisms of these tumors. Secondary GAGs primarily include mitotic cell cycle components, suggesting the loss of function in prominent cell cycle regulators, whereas primary GAGs highlight. genes typical of a stromal response, suggesting the importance of extracellular signaling. Immunohistochemical staining of glioblastoma tissue arrays confirmed expression differences. These data highlight that the development of gene pathway-targeted therapies may need to be specifically tailored to each subtype of glioblastoma..
139. IK Mellinghoff, MY Wang, Vivanco, I, DA Haas-Kogan, SJ Zhu, EQ Dia, KV Lu, K Yoshimoto, JHY Huang, DJ Chute, BL Riggs, S Horvath, LM Liau, WK Cavenee, PN Rao, R Beroukhim, TC Peck, JC Lee, WR Sellers, D Stokoe, M Prados, TF Cloughesy, CL Sawyers, PS Mischel, Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors, NEW ENGLAND JOURNAL OF MEDICINE, 10.1056/NEJMoa051918, 353, 19, 2012-2024, 2005.12, BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown.
METHODS: We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro.
RESULTS: Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib.
CONCLUSIONS: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors..
140. KV Lu, KA Jong, GY Kim, J Singh, EQ Dia, K Yoshimoto, MY Wang, TF Cloughesy, SF Nelson, PS Mischel, Differential induction of glioblastoma migration and growth by two forms of pleiotrophin, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1074/jbc.M502614200, 280, 29, 26953-26964, 2005.07, Glioblastoma is the most common malignant brain tumor of adults and one of the most lethal cancers. The secreted growth factor pleiotrophin (PTN) promotes glioblastoma migration and proliferation, initiating its oncogenic activities through two cell surface receptors, the protein tyrosine phosphatase receptor zeta (PTPRZ1) and the anaplastic lymphoma kinase (ALK), respectively. Here, we report on the presence and purification of two naturally occurring forms of PTN ( 18 and 15 kDa) that differentially promote glioblastoma migration and proliferation. Using a panel of glioblastoma cell lines, including low passage patient-derived cultures, we demonstrate that PTN15 promotes glioblastoma proliferation in an ALK-dependent fashion, whereas immobilized PTN18 promotes haptotactic migration of glioblastoma cells in a PTPRZ1-dependent fashion. Mass spectrometric analysis indicated that PTN15 differs from PTN18 by processing of 12 C-terminal amino acids. To demonstrate clinical relevance, we show that PTN15, PTN18, and PTPRZ1 are significantly overexpressed in glioblastoma relative to normal brain at both mRNA and protein levels using microarray, Western blot, and tissue microarray analyses on human tumors. These results indicate that the PTN18-PTPRZ1 and the PTN15-ALK signaling pathways represent potentially important therapeutic targets for glioblastoma invasion and growth..
141. Yoshimoto K. Iwaki T. Inamura T. Fukui M, Tahira T, Hayashi K., Multiplexed analysis of post-PCR fluorescence-labeled microsatellite alleles and statistical evaluation of their imbalance in brain tumors, Japan journal of cancer research, 93, 3, 284-290, 2002.12.
142. Akira Nakamizo, Takanori Inamura, Kiyonobu Ikezaki, Koji Yoshimoto, Satoshi Inoha, Masahiro Mizoguchi, Toshiyuki Amano, Masashi Fukui, Enhanced apoptosis in pilocytic astrocytoma: a comparative study of apoptosis and proliferation in astrocytic tumors., Journal of neuro-oncology, 10.1023/A:1015705305540, 57, 2, 105-14, 2002.04, Both cell proliferation and cell death occur simultaneously in tumor tissue, and extent of tumor growth reflects the net balance of these events. We correlated cell proliferation, spontaneous cell death, and alterations in tumor suppressor proteins with one another and with survival of patients with primary astrocytic tumors. In 39 astrocytic tumor specimens (6 pilocytic astrocytomas, 14 fibrillary astrocytomas, 9 anaplastic astrocytomas, and 10 glioblastomas), we determined the MIB-1 labeling index, the apoptotic ratio according to nick end labeling with morphologic confirmation, the p53 labeling index, and the presence of p53 or PTEN mutations. MIB- I labeling indices of pilocytic astrocytomas, fibrillary astrocytomas, anaplastic astrocytomas, and glioblastomas were 0.30+/-0.32; 1.84+/-1.87; 19.3+/-6.42; and 28.0+/-14.5 (mean +/- SD), respectively. Corresponding apoptotic ratios were 17.9+/-5.16; 3.96+/-3.57; 1.18+/-0.93; and 2.11+/-1.60 (mean +/- SD). The apoptotic ratio in pilocytic astrocytomas was significantly higher than in other astrocytic tumors (fibrillary astrocytomas, p < 0.05; anaplastic astrocytomas and glioblastomas, p < 0.01). MIB-1 showed a significant negative correlation with apoptosis (p < 0.01). MIB- I and apoptosis showed significant negative and positive correlations with patient survival (p < 0.01). Mutations of p53 and PTEN show no correlation with survival and apoptotic ratio. The apoptotic ratio can clearly distinguish pilocytic astrocytomas from other tumors, and this biological feature may reflect less aggressive growth of pilocytic astrocytomas..
143. Koji Yoshimoto, Toru Iwaki, Takanori Inamura, Masashi Fukui, Tomoko Tahira, Kenshi Hayashi, Multiplexed analysis of post-PCR fluorescence-labeled microsatellite alleles and statistical evaluation of their imbalance in brain tumors., Japanese journal of cancer research : Gann, 93, 3, 284-90, 2002.03, Detection of the loss of chromosomal regions in cancerous tissues has diagnostic and prognostic relevance, and the development of a reliable and cost-effective technique for this is clinically important. Here we present an efficient technique for quantitative detection of microsatellite alleles, using a post-PCR fluorescence-labeling procedure and multiplexed analysis. We also present a new statistical method for the interpretation of the data that permits reliable and sensitive evaluation of the allelic status of sampled DNA. A high-resolution analysis of allelic imbalance on chromosomes 1p, 10 and 19q in 28 glioma samples of various types using this method revealed that allelic imbalances are more frequent than have been reported, suggesting the diagnostic value of this method in examining the genetic profiles of gliomas..
144. K Yoshimoto, Takeshita, I, T Inoue, T Yamaguchi, M Ohta, K Matsumoto, Multi-level disruption of the spinal nerve root sleeves in spontaneous spinal cerebrospinal fluid leakage - Two case reports, NEUROLOGIA MEDICO-CHIRURGICA, 10.2176/nmc.41.154, 41, 3, 154-159, 2001.03, A 37-year-old male and an 18-year-old male presented with spontaneous spinal cerebrospinal fluid (CSF) leakage from multiple nerve root sleeves. Both patients suffered abrupt onset of intense headache followed by nausea, dizziness, and one patient with and one without positional headache. Radioisotope spinal cisternography of both patients revealed that the CSF leaks were not localized in a special zone but distributed to multiple spinal nerve root sleeves, Magnetic resonance (MR) myelography suggested that the spinal CSF column was fully expanded to the root sleeves. The extraspinal nerve bundles demonstrated numerous high intensity spots. Both patients were treated conservatively, and their symptoms resolved within one month. Repeat radioisotope cisternography and MR myelography confirmed the spine was normal after recovery. We suggest that spreading disruption of the arachnoid membrane occurs at the nerve root sleeves due to CSF overflow into the spinal canal..
145. T Inamura, S Nishio, Y Miyagi, K Kamikaseda, K Ueda, M Fukui, K Yoshimoto, Primary choroid plexus carcinoma producing carbohydrate antigen 19-9, CLINICAL NEUROPATHOLOGY, 19, 6, 268-272, 2000.11, An autopsy case of primary choroid plexus adenocarcinoma arising in a 40-year-old female, who was associated with a high serum level of a carbohydrate antigen 19-9 (CA19-9), is herein presented. After a subtotal removal of a tumor in the left lateral ventricle, the serum level of CA19-9 decreased rapidly, and immunohistochemical examinations of tumor tissue specimens obtained at surgery revealed intense reactivity for CA19-9. The present case may be the first example in which a primary choroid plexus carcinoma was shown to produce CA19-9..
146. S Nishio, Takeshita, I, K Yoshimoto, T Yamaguchi, Granular cell tumor of the pituitary stalk, CLINICAL NEUROLOGY AND NEUROSURGERY, 10.1016/S0303-8467(98)00017-1, 100, 2, 144-147, 1998.06, A 52-year-old woman, who had been treated for Parkinson disease for 2 years, was found to have a suprasellar granular cell tumor. The clinical and pathological features, as well as some of the nosologic problems of this rare tumor of the neurohypophysis are briefly discussed. (C) 1998 Elsevier Science B.V. All rights reserved..
147. K Yoshimoto, S Nishio, S Suzuki, M Fukui, K Hasuo, Movable oil in the brain: Intracranial ruptured dermoid tumors - Case illustration, JOURNAL OF NEUROSURGERY, 86, 4, 734-734, 1997.04.
148. Koji Yoshimoto, Current Trends and Healthcare Resource Usage in the Hospital Treatment of Primary Malignant Brain Tumor in Japan: A National Survey Using the Diagnostic Procedure Combination Database (J-ASPECT Study-Brain Tumor), NEUROLOGIA MEDICO-CHIRURGICA, 10.2176/nmc.oa.2016-0172, 56, 11, 664-673.