Abstract Background Early seizures after craniotomy are significant perioperative events that can be detrimental to patients. Although the preventive effects of antiseizure drugs on seizures after craniotomies have not been demonstrated and the use of antiseizure drugs to prevent seizures after craniotomy is not recommended by official guidelines, many clinicians prescribe these drugs to prevent seizures after craniotomies. The current discrepancy between the guideline recommendations and actual clinical practice is problematic.This multi-center, randomized clinical trial was designed to investigate the preventive effects of perampanel on early seizures after craniotomy. Method This multi-center, open-label, randomized clinical trial will be conducted at five hospitals in Nagoya, Japan between February 2024 and December 2026. A total of 142 seizure-naive patients with supratentorial brain tumors will be recruited. The participants will be randomly assigned to the treatment and control groups (1:1). Participants in the treatment group will receive 2 mg of perampanel for 2 days before surgery and 28 days postoperatively. The participants in the control group will not take antiseizure drugs. The primary outcome is the incidence of seizures within 28 days after craniotomy. Secondary outcomes are length of hospital stay, length of intensive care unit stay, and postoperative complications. Discussion Considering the discrepancy between the guidelines and the clinical use of antiseizure drugs for the control of early seizures after craniotomy, there is an urgent need for new evidence. This is the first multi-center, randomized clinical trial to investigate the preventive effect of perampanel on early seizures after craniotomy. The results of this trial have important implications for the current, unsubstantiated, perioperative use of antiseizure drugs. Trial registration Japan Registry of Clinical Trials approved and registered this trial n 9th April 2024. Approved number is jRCTs041230117. Japan Registry of Clinical Trials is an approved member of the Primary Registry Network of the World Health Organization’s International Clinical Trials Registry Platform.
Although the risk of developing malignant lymphoma is higher in patients with rheumatoid arthritis (RA) than in the general population, primary central nervous system lymphoma (PCNSL) in patients with RA is extremely rare. In recent years, there has been concern that biological disease-modifying antirheumatic drugs (bDMARDs), widely administered to patients with RA, might increase the risk of cancer development. The authors report the first case of PCNSL in a patient with RA receiving the bDMARD tocilizumab.A 70-year-old man who was diagnosed with RA in 2010 was treated with low-dose methotrexate (MTX) from 2010 to 2015. Tocilizumab was commenced in 2012. In 2018, he developed gait disturbances, and gadolinium-enhanced magnetic resonance imaging showed multiple contrast-enhanced lesions in the basal ganglia and brain stem. Stereotactic brain biopsy led to the diagnosis of diffuse large B-cell lymphoma, and finally PCNSL was diagnosed. He was treated with five courses of MTX 3.5 g/m2, and his disease has been in remission for 34 months.Low-dose MTX and bDMARDs are associated with the concern of increased cancer risk in patients with RA. Because tocilizumab has been in use for a relatively short time, further accumulation of cases and careful follow-up are necessary.
Abstract Although high-dose methotrexate (HD-MTX)-based chemotherapy, such as rituximab, HD-MTX, procarbazine and vincristine (R-MPV) regimen, has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), predictive factors for response to R-MPV have not yet been investigated. Then, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R-MPV. 47 and 21 patients with PCNSL treated with R-MPV and HD-MTX respectively were included, and correlation of their MYD88 and CD79B status with prognosis was analyzed. R-MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5-year progression-free and overall survival rates, respectively). Among the 47 patients, 36 harbored MYD88 L265P or CD79B Y196 mutations. While the MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (P < 0.05). However, the association of the CD79B Y196 mutation with a better prognosis was not observed in the HD-MTX cohort, which indicated that the CD79B Y196 mutation was a predictive marker for a favorable response to R-MPV. Furthermore, we established an all-in-one rapid genotyping system for these genetic mutations. This system enabled the detection of these genetic mutations in a small amount of biopsy samples within 90 min. In conclusion, we revealed that the CD79B Y196 mutation is associated with a good response to R-MPV, and the rapid and accurate genotyping system for MYD88 L265P and CD79B Y196 mutations that we developed in this study will enable reliable rapid molecular diagnosis and early prediction of response to R-MPV, which might help to determine the best treatment strategy for PCNSL.
There are no accurate mass screening methods for early detection of central nervous system (CNS) tumors. Recently, liquid biopsy has received a lot of attention for less-invasive cancer screening. Unlike other cancers, CNS tumors require efforts to find biomarkers due to the blood–brain barrier, which restricts molecular exchange between the parenchyma and blood. Additionally, because a satisfactory way to collect urinary biomarkers is lacking, urine-based liquid biopsy has not been fully investigated despite the fact that it has some advantages compared to blood or cerebrospinal fluid-based biopsy. Here, we have developed a mass-producible and sterilizable nanowire-based device that can extract urinary microRNAs efficiently. Urinary microRNAs from patients with CNS tumors (n = 119) and noncancer individuals (n = 100) were analyzed using a microarray to yield comprehensive microRNA expression profiles. To clarify the origin of urinary microRNAs of patients with CNS tumors, glioblastoma organoids were generated. Glioblastoma organoid-derived differentially expressed microRNAs (DEMs) included 73.4% of the DEMs in urine of patients with parental tumors but included only 3.9% of those in urine of noncancer individuals, which suggested that many CNS tumor-derived microRNAs could be identified in urine directly. We constructed the diagnostic model based on the expression of the selected microRNAs and found that it was able to differentiate patients and noncancer individuals at a sensitivity and specificity of 100 and 97%, respectively, in an independent dataset. Our findings demonstrate that urinary microRNAs extracted with the nanowire device offer a well-fitted strategy for mass screening of CNS tumors.
Abstract Meningioma is the most frequently occurring intracranial neoplasms in adults. Tumor removal surgery and radiotherapy were the widely accepted standard treatment for meningioma. Most meningioma cases were cured by extended total removal. However, some tumors develop in locations less amenable to resection, resulting in tumor recurrence after incomplete tumor removal followed by radiotherapy. Although several comprehensive studies have revealed frequently found molecular alterations of meningiomas, effective treatment reagents targeting specific molecular alterations have not been identified yet because of limited number of representative research models such as tumor cell lines or animal models of meningiomas. Recently developed 3D culture technologies have led to the development of novel cancer models, termed organoid models, due to their quite high efficiency of establishment. In this study, we established primary organoid culture methods using malignant meningioma cell lines (e.g. HKBMM and IOMM-Lee) and patient-derived meningioma tissues. Using this novel method, we have been able to establish six organoid models (four WHO grade I meningiomas, one WHO grade III one and one solitary fibrous tumor (SFT)) using tumor tissues derived from six consecutive patients with 100% success rate. Histological analyses, whole exome sequencing and copy number analyses revealed that these organoids exhibited consistent histological features and molecular profiling with those of parental tumors. Using public database, we identified upregulated FOXM1 was correlated with increased tumor proliferation. Over-expression of FOXM1 in benign meningioma organoids increased organoid proliferation, while depletion of FOXM1 in malignant ones decreased their proliferation. We revealed that novel organoid model for meningioma enable to shed light on the tumor biology of meningioma.
Abstract BACKGROUND Diffuse hemispheric gliomas, H3 G34-mutant (DHGs-G34m) are newly recognized pediatric-type diffuse high-grade gliomas. We describe detail imaging features of seven cases of DHGs-G34m and consider about progression pattern of DHGs-G34m. RESULTS H3 G34R or H3 G34V was detected by sanger sequencing in all tumors. Mean age of onset was 16.5 years (range: 10-26). Tumors were located on frontal (2), parietal (2), temporal lobe (1) and insular cortex (1), respectively. In one case, gliomatosis cerebri-like multiple lesions involving the cortex and basal ganglia occurred. Magnetic resonance imaging showed T2/FLAIR high lesions with poor contrast enhancement in all cases. All tumors harbored restriction of diffusion. Cystic component and hemorrhage were observed in five and three cases, respectively. Six patients underwent preoperative positron emission tomography. Strong accumulation of methionine and partial accumulation of FDG in all cases. All tumors harbored T2/FLAIR high lesions in the deep white matter, most of which showed methionine accumulation. All patients underwent surgery (total resection in one case, partial resection in five cases, and biopsy in one case) followed by radiation chemotherapy. The mean progression free survival was 9.9 months (range: 1.6-33.1 months). All tumors harbored diffuse infiltration along the white matter, which was temporarily reduced by bevacizumab, but eventually invaded into cerebral peduncle via pyramidal tract and into contralateral brain via corpus callosum or anterior commissure in six cases. Extensive infiltration of tumor cells into the contralateral brain and brain stem was confirmed histopathologically in the autopsy brain of one case. The mean overall survival was 21.6 months (range: 8.9-48.3 months). CONCLUSION DHGs-G34m showed deep white matter infiltration from the time of initial onset, which made gross total resection difficult. Residual lesions extensively infiltrated along the white matter and eventually invaded the brainstem and contralateral brain, leading to death.
Abstract INTRODUCTION The usefulness of methionine PET examination in diagnosing brain tumors is widely recognized, and it is a frequently used examination method for distinguishing primary tumors from non-neoplastic lesions and recurrent lesions from radiation necrosis. In addition, during surgery, it has the property of being taken up by actively dividing tumor cells, which is useful for identifying the extent of resection. Method: Methionine PET examination was performed in 228 consecutive cases in our department from January 2021 to April 2023, and medical records and genetic analysis data were retrospectively analyzed. RESULTS Of the 228 cases, 146 cases provided useful data for clinical practice, such as the diagnosis of tumors and the differentiation of recurrent tumors from necrosis. On the other hand, there were 9 cases in which the pathological diagnosis of the resected specimen was “tumor” despite the lack of significant methionine accumulation. The details were astrocytoma, cavernous hemangioma, spinal ependymoma, etc. On the other hand, 26 cases were finally diagnosed as “non-neoplastic disease”. Of these, 13 cases had methionine accumulation. The details of the cases that were finally diagnosed as “non-neoplastic disease” were multiple sclerosis, cerebral infarction, dural arteriovenous fistula, inflammatory disease, etc. There were 12 cases in which a diagnosis of “neoplastic disease” was not revealed after methionine PET examination, and the patient was continuously observed. None of these 12 cases had an acute or malignant course. CONCLUSION Although methionine PET is considered useful for diagnosing neoplastic disease, there are cases in which there is no uptake, especially in astrocytoma, and a certain number of cases in which uptake was observed even in non-neoplastic diseases, so caution is required. In addition, in terms of treatment, it is possible to aim to improve surgical accuracy by integrating methionine PET images with intraoperative MRI and intraoperative molecular analysis techniques, and we report an example of this.
Abstract Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene. Central nervous system tumors, such as choroid plexus tumors, medulloblastomas, and diffuse gliomas, are frequently found in patients with LFS. Although molecular profiles of diffuse gliomas that develop in pediatric patients with LFS have been elucidated, those in adults are limited. Recently, diffuse gliomas have been divided into pediatric- and adult-type gliomas, based on their distinct molecular profiles. In the present study, we investigated the molecular profiles of high-grade gliomas in three adults with LFS. These tumors revealed characteristic histopathological findings of high-grade glioma or glioblastoma and harbored wild-type IDH1/2 according to whole exome sequencing (WES). However, these tumors did not exhibit the key molecular alterations of glioblastoma, IDH-wildtype such as TERT promoter mutation, EGFR amplification, or chromosome 7 gain and 10 loss. Although WES revealed no other characteristic gene mutations or copy number alterations in high-grade gliomas, such as those in histone H3 genes, PDGFRA amplification was found in all three cases together with uniparental disomy of chromosome 17p, where the TP53 gene is located. DNA methylation analyses revealed that all tumors exhibited DNA methylation profiles similar to those of pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3-/IDH-wt), RTK1 subtype. These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS.
Abstract Since 2020, tirabrutinib which is a Bruton’s tyrosine kinase (BTK) inhibitor has been available for recurrent or refractory PCNSL cases. The number of studies reporting efficiency and adverse effect of tirabrutinib treatment for recurrent or refractory PCNSL has been limited yet. In this study, we investigated clinical course of eight refractory or recurrent PCNSL cases treated with tirabrutinib in our institute. Eight PCNSL cases treated with tirabrutinib included four recurrent cases and four refractory cases. Five cases obtained CR or PR after 26.8 days administration of tirabrutinib and other two cases also exhibited obvious improvement of clinical symptoms after 23.5 days administration of tirabrutinib. Among three cases exhibiting intraocular lesions, two cases revealed improvement of visual dysfunction and the other case obtained SD status of intraocular lesion. The most frequently found adverse effect was the skin rash. CTCAE grade 2 (n=2) or 3 (n=2) rash was found after mean 16 days or 94 days of tirabrutinib administration, respectively. Two cases with grade 3 rash could start taking the low-dose tirabrutinib after improvement of rash. Althouth one case experienced shingles, no other case experienced serious adverse effects. Although adverse effect of rash was frequently found, we could obtain high response rate of tirabrutinib treatment for recurrent or refractory PCNSL cases. We need to establish quantitative assessment method for analysis of treatment response of tirabrutinib for intraocular lesions.
