Glioma-initiating cells (GICs) are the source of glioma cells that can self-renew, have pluripotency, and are treatment-resistant, so are the starting point for relapse and eventual death despite ...multimodality therapy. L-methyl-
C methionine PET has observed high accumulation at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. METHODS: We cultured cells in methionine-deprived culture medium for comprehensive analysis. Based on the obtained results, the possible target molecules were chemically inhibited and the respective markers were analyzed.
Methionine depletion markedly decreased proliferation and increased cell death of GICs. Decreased S-adenosyl-methionine, which is synthesized intracellularly by catalyzed by methionine adenosyltransferase using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotency of stem cells, (iii) decreased expression of the core-genes and pluripotent markers of stem cells including FOXM1, SOX2, SOX4, PROM1, and OLIG2, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2, and (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, small nucleolar RNA guiding the pseudouridylation of 28S rRNA, which is essential for translation. In addition, inhibition of cholesterol synthesis with statin resulted in a phenotype similar to that of methionine depletion and decreases in stem cell markers and small nucleolar RNA ACA43. Moreover, suppression of FOXM1 decreased stem cell markers such as SOX4 and PROM1. The gene expression profile for cholesterol production was obtained from the Ivy Glioblastoma Atlas Project database and compared between tumor cells with relatively low methionine levels in areas of pseudopalisading arrangement around necrosis and tumor cells in the infiltrating region, showing that cells in the infiltrating region have higher capacity to produce cholesterol.
Methionine metabolism is closely related with self-renewal, pluripotency, and cell death in GICs through modification of cholesterol biosynthesis, especially in the SREBF2-FOXM1 and ACA43 axis with modification of rRNA.
The increased use of neuroimaging and the aging of society have changed the incidence and proportion of histological types of intracranial tumors in Japan. A population-based epidemiological survey ...has been reported only from Kumamoto Prefecture. We performed a 10-year survey in Miyazaki Prefecture to compare our findings with the incidence rate (IR) of primary intracranial tumors (PIT) reported in the Kumamoto survey. Our study included 1915 new cases of PIT diagnosed in Miyazaki Prefecture between 2007 and 2016. The crude IR was 16.97/100000/year. The most common tumor was meningioma (46.3%), followed by glioma (17.1%), pituitary adenoma (13.1%), schwannoma (8.2%), and malignant lymphoma (3.8%). The age-specific IR of all PITs and of meningiomas, gliomas, pituitary adenomas, schwannomas, lymphomas, and germ cell tumors was similar in both prefectures. To directly compare with the age-adjusted IRs reported in the Kumamoto survey, we calculated the IR for the two prefectures. The age-adjusted IR of primary brain tumors in Miyazaki Prefecture was 14.65/100000/year, which was slightly higher than in the Kumamoto survey (14.09/100000/year between 1989 and 2008). The age-adjusted IR of glioma, schwannoma, and malignant lymphoma showed only a small difference between Miyazaki and Kumamoto. However, the age-adjusted IR of meningiomas was higher in Miyazaki than Kumamoto (6.15- vs. 4.97/100000/year), but the IR of pituitary adenoma was higher in Kumamoto than Miyazaki (2.66- vs. 2.13/100000/year). Although there were some differences between the two surveys, the IR of PIT showed a similar pattern in Kumamoto and Miyazaki, which are neighboring districts on Kyushu Island.
Persistent trigeminal artery (PTA) is the most common persistent carotid-basilar fetal anastomosis and terminates extremely rarely directly in the dominant hemispheric branch of the anterior inferior ...cerebellar artery (AICA). We present a case of a branch of this PTA variant (Saltzman type 3b) demonstrated as the feeding artery of a large posterior petrous meningioma, which was confirmed under direct vision during surgery through the extended retrosigmoid approach. Meticulous dissection from the tumor surface provided early identification of the feeding branch from the PTA and its bifurcation at the attachment of the posterior petrous surface adjacent to the jugular foramen enabled preservation of the terminal cortical branch of the cerebellar hemisphere. Meningioma in the posterior cranial fossa may recruit substantial supply from branches of the PTA terminating in the AICA. This PTA variant should be recognized during surgical resection of posterior fossa neoplasms to prevent ischemic complication of the AICA territory.
We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management.
Data from the Intracranial Germ Cell Tumor Genome ...Analysis (iGCT) Consortium were reviewed. A total of 190 cases were classified as primary germ cell tumors (GCTs) based on central pathological reviews.
All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker positive and 6.1% of non-germinomatous GCTs were marker negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better progression-free survival than those at atypical sites (P = 0.03). A molecular clinical association study revealed frequent mitogen-activated protein kinase (MAPK) pathway mutations in males (51.4% vs 14.3%, P = 0.007), and phosphatidylinositol-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway mutations in basal ganglia cases (P = 0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance.
The in-depth findings of this study regarding clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.
Craniopharyngiomas remain surgically challenging because of the strong adhesion to vital neurovascular structures. We propose a system for the selection of surgical approaches based on the optic ...recess (OR) displacement pattern to facilitate surgical planning and obtain optimum visual and endocrinologic outcomes.
Craniopharyngiomas were divided into 3 types based on the OR displacement pattern: superior, anterior, and involvement types. Selected surgical approaches and patient outcome were retrospectively reviewed according to these classifications. Visual and endocrinologic outcomes were compared among the groups.
This study included 26 patients with primary craniopharyngiomas who underwent surgery at our institution, classified into 11 anterior, 11 superior, and 4 involvement types. The extended endoscopic endonasal approach provided excellent exposure inferodorsal aspect of the chiasm for manipulation of the dissection plane in the anterior and superior types with midline location. A unilateral subfrontal approach was required for tumor of the superior type with lateral extension. An interhemispheric translamina terminalis approach could provide safe dissection under direct vision of strong adhesion at the superior aspect of the chiasm in the involvement type. Visual and endocrinologic outcomes were better in the involvement type compared with the superior and anterior types. Visual outcome was significantly correlated with preoperative visual function.
Craniopharyngiomas with the involvement type are indicated for the translamina terminalis approach to achieve the best visual and endocrinologic outcome. Our classification of the OR displacement pattern is useful to select the optimal surgical approach for craniopharyngiomas more accurately and concisely, especially in cases with third ventricular extension.
Hepatocyte growth factor activator inhibitor type 2 (HAI‐2), encoded by the SPINT2 gene, is a membrane‐anchored protein that inhibits proteases involved in the activation of hepatocyte growth factor ...(HGF), a ligand of MET receptor. Epigenetic silencing of the SPINT2 gene has been reported in a human glioblastoma cell line (U87) and glioblastoma‐derived cancer stem cells. However, the incidence of SPINT2 methylation in tumor tissues obtained from glioma patients is unknown. In this study, we analyzed the methylation status of the SPINT2 gene of eight human glioblastoma cell lines and surgically resected glioma tissues of different grades (II, III, and IV) by bisulfite sequence analysis and methylation‐specific PCR. Most glioblastoma lines (7/8) showed methylation of the SPINT2 gene with a significantly reduced level of SPINT2mRNA compared to cultured astrocytes and normal brain tissues. However, all glioblastoma lines expressed mRNA for HGF activator (HGFAC), a target protease of HAI‐2/SPINT2. Forced expression of SPINT2 reduced MET phosphorylation of U87 glioblastoma cells both in vitro and in intracranial xenografts in nude mice. Methylation‐specific PCR analysis of the resected glioma tissues indicated notable methylation of the SPINT2 gene in 33.3% (2/6), 71.4% (10/14), and 74.3% (26/35) of grade II, III, and IV gliomas, respectively. Analysis of RNA sequencing data in a public database indicated an increased HGFAC/SPINT2 expression ratio in high‐grade compared to low‐grade gliomas (P = .01). In summary, aberrant methylation of the SPINT2 gene is frequently observed in high‐grade gliomas and might confer MET signaling in the glioma cells.
The SPINT2 gene was aberrantly methylated in high‐grade gliomas. Forced expression of SPINT2 in glioblastoma cells suppressed MET phosphorylation.
Abstract
BACKGROUND
Microvascular decompression (MVD) is the most effective procedure for the long-term management of trigeminal neuralgia (TGN). However, retrospective and single-center studies are ...inherently biased, and there are currently no prospective, multicenter studies.
OBJECTIVE
To evaluate the short- and long-term outcomes and complications in patients with TGN who underwent MVD at specialized Japanese institutions.
METHODS
We enrolled patients with TGN who underwent MVD between April 2012 and March 2015. We recorded their facial pain grade and complications at 7 d (short term), 1 yr (mid-term), and 3 yr (long term) postoperatively.
RESULTS
There were 166 patients, comprising 60 men and 106 women (mean age 62.7 yr). Furthermore, 105 patients were aged over 60 yr. We conducted neuromonitoring in 84.3% of the cases. The complete pain relief, mortality, and complication rates at the short-term follow-up were 78.9%, 0%, and 16.3%, respectively. Overall, 155 patients (93.4%) completed the long-term follow-up, with the complete pain relief and complication rates of 80.0% and 5.2%, respectively.
CONCLUSION
In the hands of experienced neurosurgeons, MVD for TGN can achieve high long-term curative effects. In addition, complications are uncommon and usually transient. Our results indicate that MVD is an effective and safe treatment for patients with TGN, including elderly patients.
Graphical Abstract
Graphical Abstract
Advances in cancer treatment have improved the survival of patients with cancer, with a concomitant increase in the proportion of patients with metastatic brain tumors (MBTs). In this study, we used ...cancer registries established in Japan after 2016 and available patient data by organ in order to conduct an accurate epidemiological study. To the best of our knowledge, this is the first study to report on the detailed epidemiological data on MBT at the prefectural level in Japan using the Miyazaki Brain Tumor Database and Miyazaki Cancer Registry. This study included 425 new cases of MBTs diagnosed in Miyazaki Prefecture from 2007 to 2016. As per our findings, the most frequent primary tumor in Miyazaki Prefecture was found to be in the lung (49.4%), followed by colon/rectum/anus (9.4%) and breast (8.5%). Among patients with MBTs, 59.1% were males, a number closely similar to that of Japan, as shown in the Japanese Brain Tumor Registry (55.5%). The median age at diagnosis was 68 and 63 years in Miyazaki Prefecture and Japan, respectively. Although more patients were symptomatic in Miyazaki Prefecture than in Japan (88.5% vs. 15.5%), fewer patients opted for surgery (33.6% vs. 61.9%), probably because of their advanced age at diagnosis. As per the findings of this study, the annual incidence rate of new MBTs (i.e., ratio of the number of new cancer registrations to that of new MBT patients in Miyazaki Prefecture) was at 0.41%. The number of tumor sites in MBTs was independent of the total number of cancers per organ. Considering the expansion of cancer registries worldwide, including those on brain tumors, further epidemiological analysis of MBTs is deemed warranted.
Abstract
Background
We conducted a phase III trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)-A24+ recurrent glioblastoma to develop a new treatment modality.
Methods
...We randomly assigned 88 recurrent glioblastoma patients to receive PPV (n = 58) or the placebo (n = 30) at a 2-to-1 ratio. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebos were injected 1×/week for 12 weeks.
Results
Our trial met neither the primary (overall survival OS) nor secondary endpoints. Unfavorable factors for OS of 58 PPV patients compared with 30 placebo patients were SART2-93 peptide selection (n = 13 vs 8, hazard ratio HR: 15.9), ≥70 years old (4 vs 4, 7.87), >70 kg body weight (10 vs 7, 4.11), and performance status (PS)3 (8 vs 2, 2.82), respectively. Consequently, the median OS for PPV patients without SART2-93 selection plus one of these 3 favorable factors (<70 y old, ≤70 kg, or PS0–2) was significantly longer than that for the corresponding placebo patients (HR: 0.49, 0.44, and 0.51), respectively. Preexisting immunity against both all 12 warehouse peptides besides SART2-93 and the other cytotoxic T lymphocyte epitope peptides was significantly depressed in the patients with SART2-93 selection (n = 21) compared with that of the patients without SART2-93 selection (n = 67). Biomarkers correlative for favorable OS of the PPV patients were a lower percentage of CD11b+CD14+HLA-DRlow immunosuppressive monocytes and a higher percentage of CD4+CD45RA− activated T cells, the intermediate levels of chemokine C-C ligand 2 (CCL2), vascular endothelial growth factor, interleukin (IL)-6, IL-17, or haptoglobin, respectively.
Conclusion
This phase III trial met neither the primary nor secondary endpoints.
Abstract
BACKGROUND
Microvascular decompression (MVD) is the most effective procedure for hemifacial spasm (HFS). MVD results from nonspecialized or low-volume institutes are not always reliable. ...Most studies on MVD for HFS are retrospective and single centered; to the best of our knowledge, no prospective, multicenter studies exist.
OBJECTIVE
To evaluate short- and long-term outcomes and complications in patients who underwent MVD for HFS in specialized Japanese institutions, in this multicenter, prospective, cohort study.
METHODS
Included patients had undergone MVD for HFS in study centers between April 2012 and March 2015. Patients’ postoperative grade of involuntary movements and complications were recorded postoperatively at 7 d (short-term) and at 1 (mid-term) and 3 (long-term) yr.
RESULTS
A total of 486 patients (150 men, 336 women; mean age 53.9 yr with 181 patients over 60 yr) were enrolled during the study period. Neuromonitoring was used in 96.3% of the cases. The complete cure rate of symptom relief, mortality rate, and complication rate at short-term follow-up were 70.6%, 0%, and 15%, respectively. The long-term follow-up was completed by 463 patients (95.3%); the complete cure rate of symptom relief and complication rate were 87.1% and 3.0%, respectively.
CONCLUSION
Our study revealed that under expert guidance and intraoperative neuromonitoring, the long-term curative effect rate of MVD for HFS is high, while complications are uncommon and usually transient. Our results indicate that MVD is an effective and safe treatment for patients with HFS, including elderly patients.
Graphical Abstract
Graphical Abstract
PDF
