Epithelioid glioblastoma (E‐GBM) is a rare aggressive variant of IDH‐wildtype glioblastoma newly recognized in the 2016 World Health Organization classification, composed predominantly of monotonous, ...patternless sheets of round cells with laterally positioned nuclei and plump eosinophilic cytoplasm. Approximately 50% of E‐GBM harbor BRAF V600E, which is much less frequently found in other types of glioblastomas. Most E‐GBM are recognized as primary/de novo lesions; however, several E‐GBM with co‐ or pre‐existing lower‐grade lesions have been reported. To better understand associations between E‐GBM and the lower‐grade lesions, we undertook a histological and molecular analysis of 14 E‐GBM, 10 of which exhibited lower‐grade glioma‐like components (8 E‐GBM with co‐existing diffuse glioma‐like components, 1 E‐GBM with a co‐existing PXA‐like component and 1 E‐GBM with a pre‐existing PXA). Molecular results demonstrated that the prevalence of BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions in E‐GBM were 13/14 (93%), 10/14 (71%) and 11/14 (79%), respectively, and concurrent BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions were observed in 7/14 (50%) of E‐GBM. These alterations were also frequently seen in the lower‐grade lesions irrespective of the histology. Genetic analysis including array comparative genomic hybridization performed for 5 E‐GBM with co‐ and pre‐existing lower‐grade components revealed that all molecular changes found in the lower‐grade components were also observed in the E‐GBM components, and additional changes were detected in the E‐GBM components. In conclusion, E‐GBM frequently exhibit BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions and these alterations tend to coexist in E‐GBM. Taken together with the facts that only one PXA preceded E‐GBM among these lower‐grade lesions, and that co‐occurrence of BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions have been reported to be rare in conventional lower‐grade diffuse gliomas, the diffuse glioma‐like components may be distinct infiltrative components of E‐GBM, reflecting intratumoral heterogeneity.
A 79-year-old woman with a history of resection of the ascending colon cancer presented with conscious disturbance, dysarthria, nausea, and dizziness. Computed tomography (CT) revealed striking ...high-density lesions in the left cerebellum and left frontal lobe with slight perifocal edema. These lesions were suspected the coexistence of spontaneous cerebellar hemorrhage and frontal lobe metastasis, or multiple brain metastases with massive hematoma. Because of the mass effect of the cerebellar lesion and impaired consciousness, she underwent emergency resection of the cerebellar lesion which was found to be composed of grayish abnormal soft solid tissue and did not include an obvious hematoma mass. The pathological findings were consistent with brain metastasis from colon cancer. This is an impressive rare case of intraoperative solid brain metastasis with a clearly homogenous hyper-dense CT appearance mimicking intracerebral hematoma.
This study aimed to assess whether T‐lymphokine‐activated killer cell‐originated protein kinase (TOPK) can be a potent novel biomarker to predict the outcome in patients with primary central nervous ...system lymphoma (PCNSL). This study enrolled 20 patients who were histologically diagnosed as having diffuse large B‐cell type PCNSL between 2005 and 2015. Using surgical specimens, the expression of TOPK and phosphorylated TOPK (p‐TOPK) was analyzed on immunohistochemistry. Clinical features such as age, sex, Karnofsky performance status (KPS), ocular involvement, deep brain structure involvement, the number of lesions, chemotherapy and radiation therapy were also collected. Impacts of TOPK/p‐TOPK expression on their progression‐free survival (PFS) and overall survival (OS) were examined with multivariate analysis. Median PFS/OS were 24.2 and 39.0 months, respectively. On immunostaining, the mean percentage of TOPK‐positive cells was 35.5 ± 20.8%, and the mean number of p‐TOPK‐positive cells was 13.7 ± 15.7 cells/mm2. The higher expression of p‐TOPK was significantly related to multiple lesions (P = 0.003). Multivariate analysis demonstrated that only the higher expression of p‐TOPK was an independent predictor to shorten both PFS (P = 0.029; hazard ratio (HR), 5.5; 95% confidential interval (CI), 1.2–25.3) and OS (P = 0.014; HR, 7.7; 95% CI, 1.5–41.3). These findings strongly suggest that p‐TOPK may be a potent biomarker to determine the outcome of patients with PCNSL and to develop novel drugs to treat PCNSL.
This study aimed to evaluate the biological features of T‐lymphokine‐activated killer cell‐originating protein kinase (TOPK) in vitro and to assess clinical impact of TOPK on the outcome in patients ...with malignant glioma. TOPK protein level and TOPK mRNA and protein levels in six glioma cell lines were examined using Western blot and reverse transcription‐polymerase chain reaction (RT‐PCR), respectively. Immunohistochemistry was performed to examine their subcellular localization of TOPK. Using surgical specimens from 57 patients with gliomas, TOPK and Ki‐67 expressions were examined by immunohistochemistry. Their co‐localization was also examined with double immunofluorescence immunohistochemistry. Impacts of TOPK/Ki‐67 expression on the overall survival (OS) and progression‐free survival (PFS) in 32 patients with glioblastoma multiforme (GBM) were examined, using Kaplan–Meier and Cox proportion hazard models. Immunohistochemistry revealed that approximately 20–30% of glioma cells were positive for TOPK in vitro. TOPK mRNA was identified in all glioma cell lines on RT‐PCR. The value of TOPK/GAPDH was 0.27 ± 0.11. TOPK and Ki‐67 expressions were significantly higher in GBM patients than in non‐GBM patients. A majority of TOPK‐positive cells were also positive for Ki‐67 and vice versa. Multivariate analysis revealed that a low TOPK expression (≤ 12.7%) was an independent predictor of longer OS (P = 0.0372), and that gross total removal and a low TOPK expression (≤ 12.7%) were independent predictors of longer PFS (P = 0.0470 and P = 0.0189, respectively). The findings strongly suggest biological and clinical importance of TOPK expression in gliomas, indicating a novel therapeutic potential of TOPK inhibitors to treat malignant gliomas.
The intrinsic radioresistance of certain cancer cells may be closely associated with the constitutive activation of nuclear factor-kappa B (NF-kappaB) activity, which may lead to protection from ...apoptosis. Recently, nonapoptotic cell death, or autophagy, has been revealed as a novel response of cancer cells to ionizing radiation. In the present study, the authors analyzed the effect of pitavastatin as a potential inhibitor of NF-kappaB activation on the radiosensitivity of A172, U87, and U251 human glioma cell lines.
The pharmacological inhibition of NF-kappaB activation was achieved using pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Growth and radiosensitivity assays were performed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Hoechst 33258 staining, supravital acridine orange staining, and electron microscopy were performed utilizing 3 glioma cell lines with or without pitavastatin pretreatment to identify apoptosis or autophagy after irradiation.
The growth of these 3 glioma cell lines was not significantly inhibited by pitavastatin at a concentration of up to 1 microM. Treatment with 0.1 microM of pitavastatin enhanced radiation-induced cell death in all glioma cell lines, with different sensitivity. Apoptosis did not occur in any pretreated or untreated (no pitavastatin) cell line following irradiation. Instead, autophagic cell changes were observed regardless of the radiosensitivity of the cell line. An inhibitor of autophagy, 3-methyladenine suppressed the cytotoxic effect of irradiation with pitavastatin, indicating that autophagy is a result of an antitumor mechanism. Using the most radiosensitive A172 cell line, the intracellular localization of p50, a representative subunit of NF-kappaB, was evaluated through immunoblotting and immunofluorescence studies. The NF-kappaB of A172 cells was immediately activated and translocated from the cytosol to the nucleus in response to irradiation. Pitavastatin inhibited this activation and translocation of NF-kappaB.
Autophagic cell death rather than apoptosis is a possible mechanism of radiation-induced and pitavastatin-enhanced cell damage, and radiosensitization by the pharmacological inhibition of NF-kappaB activation may be a novel therapeutic strategy for malignant gliomas.
Temozolomide (TMZ) is the standard chemotherapy treatment for glioblastoma. Lymphocytopenia is reported to be the most frequent and severe adverse effect of TMZ and leads to opportunistic infections. ...Few cases of TMZ-induced cytomegalovirus (CMV) reactivation have so far been reported, and there are no guidelines regarding the use of chemotherapy after recovery from CMV reactivation. We herein report the case of a 45-year-old man with glioblastoma who developed CMV hepatitis following surgery and chemoradiotherapy with concomitant TMZ and steroids. After successful treatment of the CMV infection with an antiviral agent and recovery from the lymphocytopenia were achieved, the patient resumed maintenance therapy with TMZ under careful monitoring of his lymphocyte count and CMV pp65 antigenemia level.
Extradural procedures in an anterior transpetrosal approach (ATPA) may interrupt the route of drainage from the superficial middle cerebral veins (SMCVs) and the cavernous sinus (CS) to the pterygoid ...venous plexus at the temporal skull base. Patterns of drainage of the SMCV and the CS and the results of surgery were examined in 12 patients with petroclival lesions treated using the ATPA between 2000 and 2008. The angiographic patterns of drainage of the SMCV were examined in 22 sides of the 12 patients. The SMCV drained into the sphenoparietal sinus in 12 sides, the sphenobasal veins in 4 sides, and the cortical veins in 6 sides. The patterns of drainage of the CS were examined on 12 sides in which the SMCV drained into the sphenoparietal sinus. The CS drained into the inferior petrosal sinus (IPS) in 7 sides and equally into the pterygoid plexus and IPS in 3 sides. The CS drained mainly into the pterygoid plexus in 2 sides of 2 patients, who both suffered temporal lobe swelling postoperatively. The pattern of venous drainage of the CS must be considered in planning surgical approaches to petroclival lesions. In patients with a well-developed pterygoid plexus, surgical interruption of this drainage route may be a cause of injury of the temporal lobe.
A 33‐year‐old woman presented with visual field defects. Magnetic resonance imaging demonstrated a pituitary tumor with suprasellar extension. The tumor was partially removed by trans‐sphenoidal ...surgery. Histologically, the tumor was composed of fascicles of spindle cells which were immunohistochemically positive for S‐100 protein, Galectin‐3, vimentin and EMA. Based on the morphology and immunostaining pattern, diagnosis of folliculostellate cell tumor in the pituitary gland was given.
Clear cell meningioma (CCM) is an uncommon variant of meningioma, corresponding to WHO grade II. We present a case of CCM with histologically aggressive appearance and clinically aggressive behavior. ...The tumor demonstrated rapid regrowth and brain metastasis. The histological progression from the ordinal CCM to the atypical area and higher MIB‐1 index was observed. We assume that the short time of recurrence and metastasis may result from atypical histological features in our case. If the CCM has a histologically aggressive appearance as in our case, we suggest that postoperative adjuvant radiotherapy should be performed despite total resection of the tumor.
Recurrence of clear cell ependymoma is not a rare condition, but malignant transformation of clear cell ependymoma has not yet been well presented. The authors report a 44‐year‐old man who presented ...with progressive right hemiparesis. A brain tumor in the left frontal premotor area was removed and an initial pathological diagnosis of oligodendroglioma was made. The tumor recurred 4 months later, and reoperation of the tumor and adjuvant local radiotherapy were performed. The patient subsequently underwent surgical removal of recurrent tumors on another four occasions (6 times in total) during a period of 11 years and finally died of the original disease. Histopathological studies of all surgical and autopsy specimens were carried out. The first and second surgical specimens did not contain any ependymal rosettes or pseudorosettes, and thus a diagnosis of oligodendroglioma was made. However, the third surgical specimen showed pseudorosettes. At this time, the tumor had an ultrastructural appearance compatible with ependymoma. Thereafter, the recurrent tumors showed anaplastic features such as nuclear pleomorphisms and necrosis with pseudopallisading. The autopsy specimens resembled a feature of glioblastoma but the tumor was sharply demarcated from the surrounding parenchyma.
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