Comprehensive Molecular Genetic Analysis in Glioma Patients by Next Generation Sequencing

Background@#Glioma is caused by multiple genomic alterations. The evolving classification of glio-mas emphasizes the significance of molecular testing. Next generation sequencing (NGS) offers the assessment of parallel combinations of multiple genetic alterations and identifying actionable mutations that guide treatment. This study comprehensively analyzed glioma patients using multi-gene NGS panels, providing powerful insights to inform diagnostic classification and targeted therapies. @*Methods@#We conducted a targeted panel-based NGS analysis on formalin-fixed and paraffin-embedded nucleic acids extracted from a total of 147 glioma patients. These samples underwent amplicon capture-based library preparation and sequenced using the Oncomine Comprehensive Assay platform. The resulting sequencing data were then analyzed using the bioinformatics tools. @*Results@#A total of 301 mutations, were found in 132 out of 147 tumors (89.8%). These muta-tions were in 68 different genes. In 62 tumor samples (42.2%), copy number variations (CNVs) with gene amplifications occurred in 25 genes. Moreover, 25 tumor samples (17.0%) showed gene fusions in 6 genes and intragenic deletion in a gene. Our analysis identified actionable targets in several genes, including 11 with mutations, 8 with CNVs, and 3 with gene fusions and intragenic deletion. These findings could impact FDA-approved therapies, NCCN guideline-based treatments, and clinical trials. @*Conclusion@#We analyzed precisely diagnosing the classification of gliomas, detailing the frequency and co-occurrence of genetic alterations and identifying genetic alterations with potential therapeutic targets by NGS-based molecular analysis. The high-throughput NGS analysis is an efficient and powerful tool to comprehensively support molecular testing in neurooncology.

Single-center study on clinicopathological and typical molecular pathologic features of metastatic brain tumor

Background@#The metastatic brain tumor is the most common brain tumor. The aim of this study was to demonstrate the clinicopathological and molecular pathologic features of brain metastases (BM). @*Methods@#A total of 269 patients were diagnosed with BM through surgical resection at Seoul St. Mary’s Hospital from January 2010 to March 2020. We reviewed the clinicopathological features and molecular status of primary and metastatic brain tissues using immunohistochemistry and molecular pathology results. @*Results@#Among 269 patients, 139 males and 130 females were included. The median age of primary tumor was 58 years (range, 13 to 87 years) and 86 patients (32.0%) had BM at initial presentation. Median BM free interval was 28.0 months (range, 1 to 286 months). The most frequent primary site was lung 46.5% (125/269), and followed by breast 15.6% (42/269), colorectum 10.0% (27/269). Epidermal growth factor receptor (EGFR) mutation was found in 50.8% (32/63) and 58.0% (40/69) of lung primary and BM, respectively. In both breast primary and breast cancer with BM, luminal B was the most frequent subtype at 37.9% (11/29) and 42.9% (18/42), respectively, followed by human epidermal growth factor receptor 2 with 31.0% (9/29) and 33.3% (14/42). Triple-negative was 20.7% (6/29) and 16.7% (7/42), and luminal A was 10.3% (3/29) and 7.1% (3/42) of breast primary and BM, respectively. In colorectal primary and colorectal cancer with BM, KRAS mutation was found in 76.9% (10/13) and 66.7% (2/3), respectively. @*Conclusions@#We report the clinicopathological and molecular pathologic features of BM that can provide useful information for understanding the pathogenesis of metastasis and for clinical trials based on the tumor’s molecular pathology.

Cytomegalovirus-Specific Immunotherapy for Glioblastoma Treatments

Over the last two decades, numerous studies have investigated the presence of human cytomegalovirus (CMV) within glioblastoma or gliomas; however, the results are severely conflicting. While a few researchers have suggested the potential benefits of cytotoxic T lymphocyte or dendritic cell-based vaccines for recurrent or newly diagnosed glioblastoma patients, several studies did not at all agree with the existence of CMV in glioblastoma cells. In this review, we summarized the conflicting results and issues about the detection of CMV in glioblastoma or glioma patients. We also provided the clinical data of published and unpublished clinical trials using CMV-specific immunotherapy for glioblastomas.

Effect of Cumulative Dexamethasone Dose during Concomitant Chemoradiation on Lymphopenia in Patients with Newly Diagnosed Glioblastoma

Background@#Lymphopenia frequently occurs after concomitant chemoradiation (CCRT) in patients with glioblastoma (GBM) and is associated with worse overall survival (OS). A few studies have tried to identify risk factors for lymphopenia; however, the results were not clear. We aimed to identify potential risk factors for lymphopenia, focusing on the use of dexamethasone to control cerebral edema in patients with GBM. @*Methods@#The electronic medical records of 186 patients with newly diagnosed GBM treated at our institution between 2009 and 2017 were retrospectively examined. Acute lymphopenia was defined as total lymphocyte count less than 1,000 cells/μL at 4 weeks after completion of CCRT.Multivariate logistic regression analysis was used to identify independent risk factors for lymphopenia, and Cox regression analysis was used to identify independent risk factors for OS. @*Results@#Of the 125 eligible patients, 40 patients (32.0%) developed acute lymphopenia. Female sex and median daily dexamethasone dose ≥2 mg after initiation of CCRT were independent risk factors for acute lymphopenia on multivariate analysis. Acute lymphopenia, extent of surgical resection, and performance status were associated with OS; however, dexamethasone use itself was not an independent risk factor for poor OS. @*Conclusion@#Female sex, median daily dexamethasone dose ≥2 mg after initiation of CCRT until 4 weeks after completion of CCRT may be associated with acute lymphopenia. However, dexamethasone use itself did not affect OS in patients newly diagnosed with GBM. These results should be validated by further prospective studies controlling for other confounding factors.

Complications Following Transradial Cerebral Angiography : An Ultrasound Follow-Up Study

OBJECTIVE: The feasibility and usefulness of transradial catheterization for coronary and neuro-intervention are well known. However, the anatomical change in the catheterized radial artery (RA) is not well understood. Herein, we present the results of ultrasonographic observation of the RA after routine transradial cerebral angiography (TRCA).METHODS: Patients who underwent routine TRCA with pre- and post-procedure Doppler ultrasonography (DUS) of the catheterized RA were enrolled. We then recorded and retrospectively reviewed the diameter and any complicated features of the RA observed on DUS, and the factors associated with the diameter and complications were analyzed.RESULTS: A total of 223 TRCAs across 181 patients were enrolled in the current study. The mean RA diameter was 2.48 mm and was positively correlated with male gender (p < 0.001) and hypertension (p < 0.002). The median change in diameter after TRCA was less than 0.1 mm (range, -1.3 to 1.2 mm) and 90% of changes were between -0.8 and +0.7 mm. Across 228 procedures, there were 12 cases (5.3%) of intimal hyperplasia and 22 cases (9.6%) of asymptomatic local vascular complications found on DUS. Patients with abnormal findings on the first procedure had a smaller pre-procedural RA diameter than that of patients without findings (2.26 vs. 2.53 mm, p=0.0028). There was no significant difference in the incidence of abnormal findings for the first versus subsequent procedures (p=0.68).CONCLUSION: DUS identified the pre- and post-procedural diameter and local complications of RA. Routine TRCA seems to be acceptable with regard to identifying local complications and changes in RA diameter.

Combined Treatment with Methylprednisolone and Human Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Experimental Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although advances have been made in the treatment of MS, such as the use of IFN-β, glucocorticoids and stem cells, the therapeutic effects of these treatments are not sufficient. In the present study, we evaluated whether the combination of methylprednisolone (MP) and human bone marrow-derived mesenchymal stem cells (BM-MSCs) could enhance the therapeutic effectiveness in experimental autoimmune encephalomyelitis (EAE), a model for MS. EAE was induced by immunizing C57BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 (MOG 35-55). The immunized mice received an intraperitoneal injection of MP (20 mg/kg), an intravenous injection of BM-MSCs (1 × 10⁶ cells) or both on day 14 after immunization. Combination treatment significantly ameliorated the clinical symptoms, along with attenuating inflammatory infiltration and demyelination, compared to either treatment alone. Secretion of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17) was significantly reduced, and anti-inflammatory cytokines (IL-4, IL-10) was significantly increased by the combination treatment as compared to either treatment alone. Flow cytometry analysis of MOG-reactivated T cells in spleen showed that combination treatment reduced the number of CD4⁺CD45⁺ and CD8⁺ T cells, and increased the number of CD4⁺CD25⁺Foxp3⁺ regulatory T cells. Furthermore, combination treatment enhanced apoptosis in MOG-reactivated CD4⁺ T cells, a key cellular subset in MS pathogenesis. Combination treatment with MP and BM-MSCs provides a novel treatment protocol for enhancing therapeutic effects in MS.

Complications Following Transradial Cerebral Angiography : An Ultrasound Follow-Up Study

OBJECTIVE: The feasibility and usefulness of transradial catheterization for coronary and neuro-intervention are well known. However, the anatomical change in the catheterized radial artery (RA) is not well understood. Herein, we present the results of ultrasonographic observation of the RA after routine transradial cerebral angiography (TRCA). METHODS: Patients who underwent routine TRCA with pre- and post-procedure Doppler ultrasonography (DUS) of the catheterized RA were enrolled. We then recorded and retrospectively reviewed the diameter and any complicated features of the RA observed on DUS, and the factors associated with the diameter and complications were analyzed.

Extra-Axial and Clear Cell Type Ependymoma, Mimicking a Convexity Meningioma

A 33-year-old woman presented with tingling and paresthesia on left extremity for 2 months. Magnetic resonance imaging revealed that the tumor was iso- and hypo-intensity on T1-weighted image, mixed iso- and high-signal intensity on T2-weighted images and heterogeneously enhanced with rim enhancement. Neither arachnoid cleft nor dural tail was certain but mass was located extra-axially so meningioma was suspected. During operation, tumor wasn't attached to dura at all but arachnoid attachment was seen. Pathologically, clear cell type ependymoma was confirmed. Details of diagnosis and treatment of this tumor is described.

Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells

OBJECTIVE: Autophagy is one of the key responses of cells to programmed cell death. Memantine, an approved anti-dementia drug, has an antiproliferative effect on cancer cells but the mechanism is poorly understood. The aim of the present study was to test the possibility of induction of autophagic cell death by memantine in glioma cell lines. METHODS: Glioma cell lines (T-98 G and U-251 MG) were used for this study. RESULTS: The antiproliferative effect of memantine was shown on T-98 G cells, which expressed N-methyl-D-aspartate 1 receptor (NMDAR1). Memantine increased the autophagic-related proteins as the conversion ratio of light chain protein 3-II (LC3-II)-/LC3-I and the expression of beclin-1. Memantine also increased formation of autophagic vacuoles observed under a transmission electron microscope. Transfection of small interfering RNA (siRNA) to knock down NMDAR1 in the glioma cells induced resistance to memantine and decreased the LC3-II/LC3-I ratio in T-98 G cells. CONCLUSION: Our study demonstrates that in glioma cells, memantine inhibits proliferation and induces autophagy mediated by NMDAR1.

Acute Paraplegia as a Result of Hemorrhagic Spinal Ependymoma Masked by Spinal Anesthesia: Case Report and Review of Literature

Ependymomas are the most common intramedullary spinal cord tumors in adults. Although a hemorrhage within spinal ependymoma on imaging studies is not uncommon, it has rarely been reported to bea cause of acute neurological deficit. In the present report, we describe a case of a 24-year-old female patient who developed acute paraplegia as a result of hemorrhagic spinal ependymoma immediately after a cesarean delivery under spinal regional anesthesia. We review the literature of hemorrhagic spinal ependymomas presenting with acute neurological deficit and discuss the most appropriate treatment for a good neurological recovery.

Acute Paraplegia as a Result of Hemorrhagic Spinal Ependymoma Masked by Spinal Anesthesia: Case Report and Review of Literature

Ependymomas are the most common intramedullary spinal cord tumors in adults. Although a hemorrhage within spinal ependymoma on imaging studies is not uncommon, it has rarely been reported to bea cause of acute neurological deficit. In the present report, we describe a case of a 24-year-old female patient who developed acute paraplegia as a result of hemorrhagic spinal ependymoma immediately after a cesarean delivery under spinal regional anesthesia. We review the literature of hemorrhagic spinal ependymomas presenting with acute neurological deficit and discuss the most appropriate treatment for a good neurological recovery.

Decompression of the Sciatic Nerve Entrapment Caused by Post-Inflammatory Scarring

A rare case of chronic pain of entrapment neuropathy of the sciatic nerve successfully relieved by surgical decompression is presented. A 71-year-old male suffered a chronic right buttock pain of duration of 7 years which radiating to the right distal leg and foot. His pain developed gradually over one year after underwenting drainage for the gluteal abscess seven years ago. A cramping buttock and intermittently radiating pain to his right foot on sitting, walking, and voiding did not respond to conventional treatment. An MRI suggested a post-inflammatory adhesion encroaching the proximal course of the sciatic nerve beneath the piriformis as it emerges from the sciatic notch. Upon exploration of the sciatic nerve, a fibrotic tendinous scar beneath the piriformis was found and released proximally to the sciatic notch. His chronic intractable pain was completely relieved within days after the decompression. However, thigh weakness and hypesthesia of the foot did not improve. This case suggest a need for of more prompt investigation and decompression of the chronic sciatic entrapment neuropathy which does not improve clinically or electrically over several months.

Thrombosed Large Middle Cerebral Artery Aneurysm Mimicking an Intra-Axial Brain Tumor: Case Report and Review of Literature

This case report presents a fully thrombosed large aneurysm of middle cerebral artery mimicking an intra-axial brain tumor in a 54-year-old male patient. A small mass like lesion was found incidentally in right frontal area. Brain magnetic resonance image showed dark signal intensity on T2-weighted images and peripheral high signal intensity on T1-weighted images with peripheral rim enhancement. We considered intra-axial tumors such as glioma or metastatic tumor as a differential diagnosis. The lesion was approached transcortically, and intraoperatively, the lesion was found to be a large thrombosed aneurysm originating from the lateral lenticulostriate artery of right middle cerebral artery. One vascular clip was applied at the parent artery, and the thrombosed aneurysm was totally removed. There have been many reports of other intracranial lesions wrongly diagnosed as intracranial neoplasms. And thrombosed aneurysms mimicking intracranial neoplasm have been reported in 4 cases previously. According to those case reports, there were no efficient imaging tools to differentiate between these thrombosed aneurysms and intracranial neoplasms. We reviewed those reports and considered about the efficient method to diagnosed accurately before surgery. To sum up, when a patient presents with an intracranial lesion lying on the course of major or distal cerebral arteries, the surgeon should have thrombosed aneurysm in mind as one of the differential diagnosis and be prepared when surgically treating such lesions.

Neuroimaging and Clinicopathologic Findings of Lymphoplasmacyte-rich Meningioma, Mimicking Malignancy: Case Report

Lymphoplasmacyte-rich meningioma is a rare WHO Grade I subtype of meningioma. The lymphoplasmacyte-rich meningioma does not have typical imaging features of a meningioma so it can mimic intracranial inflammatory condition or brain neoplasm. We report the clinicopathologic features of lymphoplasmacyte-rich meningioma in a 35-year-old woman. She suffered from progressive headache, dizziness and tinnitus over two years. The tumor exhibited atypical neuroimaging features, including obvious peritumoral edema and irregular enhancing components. She underwent total resection and histologic examination revealed a meningioma with numerous plasma cells. Her symptoms have since resolved and there has been no evidence of tumor recurrence after one year of follow-up.

Combination Therapy for Gliomas Using Temozolomide and Interferon-Beta Secreting Human Bone Marrow Derived Mesenchymal Stem Cells

OBJECTIVE: Malignant gliomas are the most common primary tumors of the central nervous system and the prognosis of patients with gliomas is poor. The combination of interferon-bata (IFN-beta) and temozolomide (TMZ) has shown significant additive antitumor effects in human glioma xenograft models. Considering that the poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor, the tropism of human bone marrow-derived mesenchymal stem cells (MSC) for malignant gliomas can be exploited to therapeutic advantages. We investigated the combination effects of TMZ and MSCs that secrete IFN-beta on gliomas. METHODS: We engineered human MSCs to secret mouse IFN-beta (MSC-IFN-beta) via adenoviral transduction and confirmed their secretory capacity using enzyme-linked immunosorbent assays. In vitro and in vivo experiments were performed to determine the effects of the combined TMZ and MSC-IFN-beta treatment. RESULTS: In vitro, the combination of MSC-IFN-beta and TMZ showed significantly enhanced antitumor effects in GL26 mouse glioma cells. In vivo, the combined MSC-IFN-beta and TMZ therapy significantly reduced the tumor size and improved the survival rates compared to each treatment alone. CONCLUSION: These results suggest that MSCs can be used as an effective delivery vehicle so that the combination of MSC-IFN-beta and TMZ could be considered as a new option for the treatment of malignant gliomas.

Remote Postoperative Epidural Hematoma after Brain Tumor Surgery

A postoperative epidural hematoma (EDH) is a serious and embarrassing complication, which usually occurs at the site of operation after intracranial surgery. However, remote EDH is relatively rare. We report three cases of remote EDH after brain tumor surgery. All three cases seemed to have different causes of remote postoperative EDH; however, all patients were managed promptly and showed excellent outcomes. Although the exact mechanism of remote postoperative EDH is unknown, surgeons should be cautious of the speed of lowering intracranial pressure and implement basic procedures to prevent this hazardous complication of brain tumor surgery.

Treatment Strategy of Intracranial Hemangiopericytoma

BACKGROUND: Recent studies suggest aggressive management combining a grossly total resection (GTR) with adjuvant radiotherapy (RT) as a treatment of choice for intracranial hemangiopericytoma (HPC). However, in these papers, the definitions of complete or GTR are equivocal. In the present study, we reviewed the relevant cases from our experience focused on the clinical efficacy of surgical grading of resection, and analyzed the optimal treatment strategies as well. METHODS: From January 1995 through December 2014, 17 patients treated for intracranial HPC were included in this study. We analyzed clinical presentation, radiologic appearance, pathologic diagnosis, extent of resection, and follow-up outcomes. RESULTS: A total of 26 operations were performed including 9 recurrent intracranial HPCs. Every tumor was single and had no evidence of metastasis. Most common area of tumor was parasagittal (8 patients, 47.1%), which is adjoined to superior sagittal sinus. For the initial operation, GTR was performed in 16 cases (61.5%), partial resection (PR) in 8 cases (30.8%), and an endoscopic biopsy in 2 patients (7.7%). In Simpson grading system, grade 1 was done in 2 patients (7.7%), grade 2 in 11 patients (42.3%) and grade 3 in 3 patients (11.5%). Postoperative RT was delivered in 16 patients (94.1%) regardless of the extent of resection. The median 57.57 Gy (range, 50-60 Gy) was delivered in median 33 fractions (range, 30-40). The extent of resection (conventional classification and Simpson grading system) and adjuvant RT were significantly associated with recurrence-free survival. CONCLUSION: Surgical resection of intracranial HPC, in an attempt to reach Simpson grade 1 removal, is necessary for better outcome. Adjuvant RT should be done as recommended before, to prevent recurrence, regardless of surgical resection and pathological diagnosis.

Extra-Axial Medulloblastoma in the Cerebellar Hemisphere

Extra-axial medulloblastoma is a rare phenomenon. We report a case in a 5-year-old boy who presented with nausea, vomiting, and gait disturbance. He was treated with total removal of the tumor. This is the first case of an extra-axially located medulloblastoma occurring in the cerebellar hemisphere posteriolateral to the cerebellopontine angle in Korea. Although the extra-axial occurrence of medulloblastoma is rare, it should be considered in the differential diagnosis of extra-axial lesions of the posterior fossa in children.

Disseminated Hemangioblastoma of the Central Nervous System without Von Hippel-Lindau Disease

Hemangioblastoma (HB) of the central nervous system may occur sporadically or in association with von Hippel-Lindau (VHL) disease. Disseminated HB means malignant spread of the original primary HB without local recurrence at surgically resected site. It has been rarely reported previously, and rarer especially without VHL gene mutation. We report a case of disseminated HB without VHL disease. A 59-year-old man underwent a surgery for total removal of a cerebellar HB. From five years after the surgery, multiple dissemination of HB was identified intracranially and he subsequently underwent cyberknife radiosurgery. The lesions got smaller temporarily, but they soon grew larger. Nine years after the initial surgery for cerebellar HB, he showed severe back pain. His magnetic resonance image of spine revealed intradural extramedullary mass at T6-7 level. Complete surgical removal of the mass was performed and the pathological diagnosis was identical to the previous one. He had no evidence of VHL disease. And there was no recurrence of the tumor at the site of the original operation. The exact mechanism of dissemination is unknown, but the surgeon should be cautious of tumor cell spillage during surgery and prudently consider the decision to perform ventriculo-peritoneal shunt. In addition, continuous follow-up for recurrence or dissemination is necessary for patients even who underwent complete removal of cerebellar HB.

An Intracranial Chondroma with Intratumoral Hemorrhage: A Case Report and Review of the Literature

A 55-year-old female presented to the emergency room with a complaint of aphasia. Her initial brain computed tomography scan showed an intracranial hemorrhage in the left frontal area. After surgery, histopathological examination confirmed the diagnosis of a chondroma. Intradural chondroma is a rare, slow growing, benign intracranial neoplasm, but is even rarer in combination with an intratumoral hemorrhage. Chondromas are generally avascular cartilaginous lesions. Our case was thought to be caused by the rupture of abnormally weak vessels derived from the friable tumor. Intradural chondromas may be included in the differential diagnosis of intracranial tumors with acute hemorrhages.