Telomerase reverse transcriptase (TERT) is up-regulated in a variety of human neoplasms. Mutations in the core promoter region of the
TERT
gene, which increases promoter activity, have been reported ...in melanomas and a variety of human neoplasms, including gliomas. In the present study, we screened for
TERT
promoter mutations by direct DNA sequencing in a population-based collection of 358 glioblastomas.
TERT
promoter mutations (C228T, C250T) were detected in 55 % glioblastomas analysed. Of these, 73 % had a C228T mutation, and 27 % had a C250T mutation; only one glioblastoma had both C228T and C250T mutations.
TERT
promoter mutations were significantly more frequent in primary (
IDH1
wild-type) glioblastomas (187/322; 58 %) than in secondary (
IDH1
mutated) glioblastomas (10/36, 28 %;
P
= 0.0056). They showed significant inverse correlations with
IDH1
mutations (
P
= 0.0056) and
TP53
mutations (
P
= 0.043), and a significant positive correlation with
EGFR
amplification (
P
= 0.048). Glioblastoma patients with
TERT
mutations showed a shorter survival than those without
TERT
mutations in univariate analysis (median, 9.3 vs. 10.5 months;
P
= 0.015) and multivariate analysis after adjusting for age and gender (HR 1.38, 95 % CI 1.01–1.88,
P
= 0.041). However,
TERT
mutations had no significant impact on patients’ survival in multivariate analysis after further adjusting for other genetic alterations, or when primary and secondary glioblastomas were separately analysed. These results suggest that the prognostic value of
TERT
mutations for poor survival is largely due to their inverse correlation with
IDH1
mutations, which are a significant prognostic marker of better survival in patients with secondary glioblastomas.
Delayed radiation necrosis is a well-known adverse event following radiotherapy for brain diseases and has been studied since the 1930s. The primary pathogenesis is thought to be the direct damage to ...endothelial and glial cells, particularly oligodendrocytes, which causes vascular hyalinization and demyelination. This primary pathology leads to tissue inflammation and ischemia, inducing various tissue protective responses including angiogenesis. Macrophages and lymphocytes then infiltrate the surrounding areas of necrosis, releasing inflammatory cytokines such as interleukin (IL)-1α, IL-6, and tumor necrosis factor (TNF)-α. Microglia also express these inflammatory cytokines. Reactive astrocytes play an important role in angiogenesis, expressing vascular endothelial growth factor (VEGF). Some chemokine networks, like the CXCL12/CXCR4 axis, are upregulated by tissue inflammation. Hypoxia may mediate the cell–cell interactions among reactive astrocytes, macrophages, and microglial cells around the necrotic core. Recently, bevacizumab, an anti-VEGF antibody, has demonstrated promising results as an alternative treatment for radiation necrosis. The importance of VEGF in the pathophysiology of brain radiation necrosis is being recognized. The discovery of new molecular targets could facilitate novel treatments for radiation necrosis. This literature review will focus on recent work characterizing delayed radiation necrosis in the brain.
Spinal intramedullary tumors such as ependymoma or vascular lesions such as cavernous malformation are often at risk of intramedullary hemorrhage. Surgical procedures involving the high cervical ...spinal cord are often challenging. This technical note included four patients who presented with acute, subacute, or gradual onset of spinal cord dysfunction associated with intramedullary hemorrhage at the C1 or C1/2 level of the high cervical spine. The mean age was 46.3 years (16-74 years). All patients underwent posterior spinal cord myelotomy of the posterior median sulcus or posterolateral sulcus. It was not to exceed the caudal opening of the fourth ventricle (foramen of Magendie) and was assumed to be as high as the caudal medulla oblongata. Total removal of the intramedullary ependymoma or cavernous malformation occurred in three of four cases, and the remaining case had subtotal removal of the ependymoma. None of the patients showed postoperative deterioration of the neurological condition. Pathological examination of all cases revealed intramedullary hemorrhage was associated with ependymoma or cavernous malformation. Posterior spinal myelotomy should be limited to the caudal opening of the fourth ventricle (foramen of Magendie), that is the caudal medulla oblongata, to avoid the significant deterioration after surgery.
Giant cell tumor (GCT) of bone is essentially benign but locally aggressive, and the rate of local recurrence is high when the resection is not enough. En bloc resection is recommended as an ideal ...solution for GCT to decrease the risk of local recurrence, but it remains challenging for cervical GCT. In this technical case report, we present a case of extensively infiltrating GCT of the cervical spine completely encasing the vertebral artery (VA) on one side. The tumor was distributed to layers A-D, sectors 3-8 based on the Weinstein-Boriani-Biagini staging. Combined posterior and anterior surgical approach for the cervical spine was successfully performed and followed by postoperative adjuvant pharmacological therapy. This kind of multimodal management may be one of the solutions for advanced cervical GCT.
Frameless stereotactic brain biopsy (FSB) with navigation system has been widely used. We reported preliminary experience of FSB with intraoperative computed tomography (iCT) and examined the ...usefulness of this novel adjuvant technique and real target registration error (rTRE) of FSB. The FSB with 5-aminolevulinic acid (5-ALA) and iCT was performed on 10 patients. The gadolinium-enhanced lesions on magnetic resonance image were defined as the biopsy target. In the procedure, iCTs were scanned twice, for autoregistration of the navigation system and for confirmation of the position of the actual inserted biopsy needle. The red fluorescence of the samples was observed under excitation with violet-blue light through a low-cut filter of neurosurgical microscope. The distance between the planned target and the tip of the biopsy needle in the image of iCT was calculated in a workstation for the assessment of rTRE. The median volume of the target was 12.13 mL (0.06-39.15 mL). We performed the surgical procedure in a prone position in four patients. None to faint 5-ALA-induced fluorescence was observed in six samples. There existed no sampling errors. The mean target distance between the planned and real targets of the mean rTRE of FSB was 2.7 ± 0.56 mm. The real TRE of FSB was first reported and was larger than the reported rTRE exactly calculated from the fiducial registration error. iCT guarantees accurate tumor sampling with autoregistration regardless of the surgical position and prevents inaccurate biopsy to occur even with ALA fluorescence assistance.
Spinal intramedullary metastasis is an extremely rare event that occurs in advanced cancer. The surgical indications for spinal intramedullary metastasis are highly limited because of surgical ...difficulty and poor prognosis. In this technical case report, we present a rare case of spinal intramedullary metastasis from the lung that recurred late after local radiation to the spinal cord. The patient progressively experienced relapsed buttock pain and developed gait and urination disorders late after treatment for lung cancer. Imaging examinations suggested the recurrence of spinal intramedullary metastasis in the conus medullaris. Systemic examinations revealed no apparent recurrence in other organs, including the primary lung lesions. Gross total resection of the tumor within the conus medullaris was safely performed using the unilateral posterolateral (PLS) approach and by addition of the contralateral PLS approach. To the best of our knowledge, this is the first case in which a spinal intramedullary metastatic tumor was successfully removed using a bilateral PLS approach.
Radiation therapy is one of standard treatment for malignant glioma after surgery. The microenvironment after irradiation is considered not to be suitable for the survival of tumor cells (tumor bed ...effect). This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy affect the recurrence and progression of glioma. 65-Gy irradiation had been applied to the right hemisphere of Fisher rats. After 3 months from irradiation, we extracted RNA and protein from the irradiated rat brain. To study effects of proteins extracted from the brains, we performed WST-8 assay and tube formation assay in vitro. Cytokine production were investigated for qPCR. Additionally, we transplanted glioma cell into the irradiated and sham animals and the median survival time of F98 transplanted rats was also examined in vivo. Immunohistochemical analyses and invasiveness of implanted tumor were evaluated. X-ray irradiation promoted the secretion of cytokines such as CXCL12, VEGF-A, TGF-β1 and TNFα from the irradiated brain. Proteins extracted from the irradiated brain promoted the proliferation and angiogenic activity of F98 glioma cells. Glioma cells implanted in the irradiated brains showed significantly high proliferation, angiogenesis and invasive ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group. The current study suggests that the microenvironment around the brain tissue in the chronic phase after exposure to X-ray radiation becomes suitable for glioma cell growth and invasion.
Airway complications that occur after anterior cervical spine surgery pose a life-threatening risk, which encompasses complications including prolonged intubation, unplanned reintubation, and/or ...necessity of tracheostomy. The present study aimed to identify the surgical risks associated with postoperative airway complications in neurosurgical training institutes. A retrospective, multicenter, observational review of data from 365 patients, who underwent anterior cervical spine surgery between 2018 and 2022, at three such institutes was carried out. Postoperative airway complication was defined as either the need for prolonged intubation on the day of surgery or the need for unplanned reintubation. The perioperative medical information was obtained from their medical records. The average age of the cohort was over 60 years, with males comprising approximately 70%. Almost all surgeries predominantly involved anterior cervical discectomy and fusion or anterior cervical corpectomy and fusion, with most surgeries occurring at the level of C5/6. In total, 363 of 365 patients (99.5%) were extubated immediately after surgery, and the remaining two patients were kept under intubation because of the risk of airway complications. Of the 363 patients who underwent extubation immediately after surgery, two (0.55%) required reintubation because of postoperative airway complications. Patients who experienced airway complications were notably older and exhibited a significantly lower body mass index. The results of this study suggested that older and frailer individuals are at an elevated risk for postoperative airway complications, with immediate postoperative extubation generally being safe but requiring careful judgment in specific cases.
The aim of this study was to evaluate the influence of skin distortion due to surgical positioning on the clinical accuracy of the navigation system. The distance errors were measured in four ...fiducial markers (anterior, posterior, right, and left of the head) after the registration of the navigation system. The distance errors were compared between the surface-merge registration (SMR) method using preoperative imaging and the automatic intraoperative registration (AIR) method using intraoperative imaging. The comparison of the distance errors were performed in various surgical positions. The AIR method had the significant accuracy in the lateral markers than the SMR method (lateral position, 3.8 mm vs. 8.95 mm; p < 0.0001; prone position, 4.5 mm vs. 13.9 mm; p = 0.0001; 5.2 mm vs. 11.5 mm; p = 0.0070). The smallest distance errors were obtained close to the surgical field in the AIR method (3.25-3.85 mm) and in the forehead in the SMR method (3.3-8.1 mm). The AIR method was accurate and recommended for all the surgical positions if intraoperative imaging was available. The SMR method was only recommended for the supine position, because skin distortion was frequently observed in the lateral region.
The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild‐type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic ...astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. We determined the genetic patterns of 36 gliosarcomas and 19 giant cell glioblastomas. IDH1 and IDH2 mutations were absent in all 36 gliosarcomas and in 18 of 19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy number profiling using the 450k methylome array in 5 gliosarcomas revealed CDKN2A homozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas. These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastoma occupies a hybrid position between primary and secondary glioblastomas.
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