Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review.

Meningiomas are extra-axial neoplasms that originate from the arachnoid cap cells located on the inner surface of the meninges. Approximately 36% of central nervous system tumors are meningiomas. Based on earlier findings to be benign in most cases, they are categorized as slow-growing tumors that form gradually over time. Meningiomas are usually asymptomatic and discovered inadvertently. They rarely present with immediate clinical symptoms or abrupt hemorrhagic strokes. However, tumor hemorrhage can be fatal in high-grade meningiomas, particularly those with vascularization. We describe a 58-year-old man who was hospitalized after experiencing an unexpectedly acute headache. The right cerebellar hemisphere and vermis cerebellar hemorrhage were detected on computed tomography (CT), and the cerebellar hemorrhage was explained by a diagnosis of hypertension. When additional analysis of the patient's chest CT indicated lung mass lesions, we assumed that the lung cancer had spread to the brain. However, the pathological outcomes of a guided definite pulmonary aspiration biopsy, in conjunction with resection of the cerebellar tumor, suggested a subtentorial meningioma with ruptured hemorrhage and pulmonary meningioma metastasis. The patient was transferred to a hospital closer to home for ongoing follow-up and, after 2 months, he had recovered well.

Clinicopathologic features and prognosis of epithelioid glioblastoma.

OBJECTIVE: To improve the understanding of epithelioid glioblastoma (E-GBM) and provide accurate basis for clinical diagnosis, treatment, and prognosis through the analysis of clinicopathologic characteristics, immunohistochemical expression, molecular characteristics, and prognosis of E-GBM. METHODS: The clinicopathologic characteristics of 33 cases of E-GBM in our hospital from January 2015 to September 2019 were analyzed retrospectively. Kaplan Meier method was used for survival analysis. Multivariate Cox regression analysis was used to screen the independent risk factors affecting the survival time of patients. RESULTS: Among 33 patients with E-GBM, 16 were male and 17 were female. The age ranged from 9 to 67 years old, with the median age of 36 years old and the average age of 38 years old. The tumor size (calculated by the largest diameter): 1-6 cm, average size: 3.5 cm. The ratio of smoking and non-smoking is 17:16. All the tumors were located in the cerebral hemisphere, and 26 cases (78.79%) of brain MR showed that the tumors invaded the cortex (white matter). CLINICAL SYMPTOMS: asymptomatic physical examination was found in 6 cases (18.18%), 5 cases (15.15%) had epilepsy history, 2 cases (6.06%) had malignant vomiting, 3 cases (9.09%) had hypertension history, and 17 cases (51.52%) had headache and dizziness. All patients received surgery (total or partial resection). Postoperative radiotherapy was given in 7 cases (21.00%), chemotherapy (TMZ temozolomide) in 3 cases (1.00%), and combined chemoradiotherapy in 16 cases (48.40%). Immunohistochemical staining: the positive rates of CK, GFAP, IDH-1, IDH-2, HMB45, Desmin, BRAF, P53, ATRX, INI-1, S-100, Ki-67 were 20/33, 30/33, 1/33, 1/33, 0/33, 0/33, 33/33, 5/33, 30/33, 33/33, 6/33, Ki-67 of all cases were higher than 40%, among which 11 cases were higher than 60%. The detection of related genes showed that 33 cases (100%) had BRAF V600E mutation. TERT mutation was found in 18 cases (54.5%); IDH1 mutation was found in 1 case (3%); MGMT promoter methylation was found in 15 cases (45.4%); EGFR amplification and 1p/19q co-deletion were not found in any cases. CONCLUSION: E-GBM is a highly invasive and rare malignant nervous system tumor, with poor prognosis and lack of clinical specificity. Immunohistochemically, the higher expression of CK, GFAP and Ki67 proliferation index is more conducive to the diagnosis and differential diagnosis of E-GBM. Smoking, brain MR showing tumor invasion of cortex, TERT mutation, radiotherapy, and chemotherapy are independent risk factors affecting the prognosis (survival time) of patients.

Diagnosis of intracranial embryonal carcinoma by cerebrospinal fluid cytology: a case report.

BACKGROUND: The incidence of primary intracranial germ cell tumors (GCTs) is relatively low comparing to other ones. Embryonal carcinoma (EC) is an especially rare subtype and the diagnosis presents to be a challenge. Few cases have been reported. CASE PRESENTATION: We report a case of intracranial EC located in the temporal lobe with malignant tumor cells occasionally detected by the cytology of cerebrospinal fluid (CSF). The pathology confirmed the diagnosis after the patient underwent tumor resection. CONCLUSION: This is the first report about one case of intracranial primary EC located in the temporal lobe. It is also the first report of tumor cells of EC detected in the CSF.

Apatinib (YN968D1) and Temozolomide in Recurrent Invasive Pituitary Adenoma: Case Report and Literature Review.

BACKGROUND: Invasive pituitary adenomas often recurred after postoperative radiotherapy and are difficult to treat. Temozolomide is an alkylating cytostaticum and has been reported to reduce pituitary tumor size and hormone hypersecretion. However, this is far from enough. Pituitary adenomas have relatively high expression of vascular endothelial growth factor. Therefore an antiangiogenic agent has been used in a small number of aggressive or malignant pituitary tumors after recurrence. Apatinib (YN968D1) is a small-molecule antiangiogenic agent that selectively inhibits VEGFR-2 and also mildly inhibits c-Kit and c-Src tyrosine kinases, abundant in invasive pituitary adenomas. CASE DESCRIPTION: We present a 41-year-old female with a growth hormone (GH)-secreting invasive pituitary adenoma causing menstrual disorder and headache symptoms. Over 3 years, she underwent 4 surgeries and a stereotactic radiosurgery, but the results were poor. Two months after the fourth operation, she started treatment with temozolomide (200 mg/m2, days 1-5, 28 days, orally) and apatinib (0.425 g, daily, orally). Her GH level dropped to normal with a >90% decrease in tumor size, after 1-year treatment. There was no evidence of recurrence by imaging or by serum GH levels over 31.5 months of follow-up. CONCLUSIONS: We successfully treated this patient with recurrent invasive pituitary adenoma with temozolomide and apatinib for 31.5 months without recurrence. Angiogenesis is an active process in the cases of invasive pituitary adenomas that cannot be controlled by conventional therapy.

Phase II Study of the Efficacy and Safety of High-dose Pemetrexed in Combination with Cisplatin Versus Temozolomide for the Treatment of Non-small Cell Lung Cancer with Brain Metastases.

The aim of this study was to explore the efficacy and safety of high-dose pemetrexed with cisplatin versus combination with temozolomide in patients with brain metastases (BM) of lung adenocarcinoma. After standard whole-brain radiotherapy (WBRT, 30 Gy/10 fractions), patients with BM of non-small cell lung cancer (NSCLC) were given high-dose pemetrexed (900 mg/m2) on day 1 of each cycle (3 weeks), and cisplatin was administered on days 1-3 in the cisplatin-treated group. The temozolomide-treated group was treated as follows: 75 mg/m2 temozolomide orally with concurrent WBRT followed by 150 mg/m2 temozolomide on days 1-5 with high-dose pemetrexed (900 mg/m2) on day 1 of each cycle (3 weeks). Six cycles later, high-dose pemetrexed (900 mg/m2) monotherapy or the best available supportive therapy was administered to both groups. An evaluation was carried out every 2-3 cycles. The primary end-points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Secondary end-points included safety and tolerability. Thirty-two patients in the pemetrexed plus cisplatin (PC) group and 28 patients in the pemetrexed plus temozolomide (PT) group were enrolled from November 2013 to October 2015. The ORR was 68.8% and 75%, in the PC and PT groups, respectively, and there was no statistically significant difference between the two groups (p=0.711). The median PFS rates of the PC and PT groups were 13.6 months and 16.9 months, respectively, and the median OS rates of the PC and PT groups were 18.9 months and 19.3 months, respectively. There were no differences in PFS and OS between the two groups. There were no grade 4 or higher side-effects in either group, but grade 3 side-effects such as leucopenia (2/32, 6.3%), nausea/vomiting (2/32, 6.3%), alopecia (1/32, 3.1%), rash (3/32, 9.4%) and renal insufficiency (1/32, 3.1%) were observed in the PC group, whereas the PT-group-only showed the following grade 3 side-effects: leucopenia (1/28, 3.6%) and nausea/vomiting (2/28, 7.1%). The data showed that the PT group achieved the same efficacy in PFS and OS as the PC group but with fewer toxicities. Therefore, high-dose pemetrexed plus temozolomide may be a better regimen for treating NSCLC with BM due to its better safety.

Effect of Aster tataricus on production of inflammatory mediators in LPS stimulated rat astrocytoma cell line (C6) and THP-1 cells.

Neuroinflammation is the commonest cause of neurodegenerative diseases such as Alzheimer's disease. Present investigation evaluates the inhibitory effect of ethanolic root extract of Aster tataricus (AS) on inflammatory mediators production in lipopolysaccharide (LPS) stimulated C6 cells. C6 cells were treated with AS (20 and 40 mg/kg) and nimesulide (NSL, 1.5 µg/ml) for 1 day. Thereafter various parameters such as production of ROS, release of nitrite, MDA, glutathione level and NF-κB translocation were estimated in C6 cell lines. Effect of AS was estimated on the expressions of tumor necrosis factor α (TNF-α) of human monocytic leukemia cell line (THP-1). It was observed that AS (20 and 40 mg/ml) treated group shows significant (p < 0.01) decrease in production of ROS, Nitrite release and MDA level in LPS activated C6 cell lines compared to negative control group. Moreover, treatment with it decreases glutathione level and inhibits the translocation of NF-κB in LPS activated C6 cell lines compared to negative control group. There were significant (p < 0.01) decreases in expression of TNF-α in AS treated group compared to negative control group in THP-1 cell lines. Present investigation concludes the anti neuroinflammatory effect of ethanolic extract of AS root by decreasing oxidative stress and attenuates the cytokine.

Phase II Study of High-Dose Pemetrexed Plus Cisplatin as First-Line Chemotherapy In the Treatment of Patients with Brain Metastases from Lung Adenocarcinoma.

BACKGROUND: Brain metastases (BMs) occur in up to 40% of patients with nonsmall-cell lung cancer (NSCLC). When surgery or radiosurgery is not possible, whole-brain radiotherapy (WBRT) is the standard treatment, with a cerebral response rate of approximately 30%. Pemetrexed-based chemotherapy presents an approximately 40% response rate on brain lesions of NSCLC with brain metastases. METHODS: This trial assessed the efficacy and safety of high-dose pemetrexed plus cisplatin in NSCLC with BMs after WBRT. Thirty-two patients with Karnofsky Performance Status ≥70 were enrolled. Patients of NSCLC with brain metastases were eligible for WBRT, which was administered at 30 Gy/10f. Thereafter, high-dose pemetrexed plus cisplatin was given up to 6 cycles. Primary end point was objective response rate (RR) and progression-free survival on BM. Secondary end points included extracerebral and overall RR, safety profile, and survival. RESULTS: The objective cerebral RR (complete and partial response) was 68.8 % (22 of 32 patients). Extracerebral and globe RR was 37.5% and 31.3%, respectively. The median progression-free survival of BM was 13.6 months, and median overall survival was 19.1 months. CONCLUSIONS: This modality of treatment appears to a better efficacy and a good safety of BM, as well as extracerebral. Further clinical studies are warranted.

MiR-200a impairs glioma cell growth, migration, and invasion by targeting SIM2-s.

Recently, single-minded homolog 2-short form (SIM2-s) was reported to be related to tumor development and progression and to be elevated in many human cancer cells. In this study, we investigated the factors that contribute to the regulation of SIM2-s expression in gliomas. The results showed that SIM2-s was elevated in gliomas. In addition, inhibition of SIM2-s reduced glioma cell growth, migration, and invasion. Next, we demonstrated that SIM2-s is a functional target of miR-200a. Further, miR-200a is downregulated in human glioma and inhibition of miR-200a caused upregulation of SIM2-s in T98G cells and promoted their motility. Finally, blockage of miR-200a expression in a mouse model of human glioma resulted in significant promotion of tumor growth. These findings suggest that miR-200a could serve as a therapeutic tool for glioma.

Single minded 2-s (SIM2-s) gene is expressed in human GBM cells and involved in GBM invasion.

The human single-minded 2 (SIM2) gene is mapped within the Down syndrome critical region (DSCR) of chromosome 21 and its short splice variant SIM2-s is suggested to be a molecular target for cancer therapy. It has been shown that SIM2-s is expressed in colon, pancreatic and prostate tumors but not in their corresponding normal tissues. In present study, we found that SIM2-s was expressed in glioma tissues as well as in glioblastoma (GBM) cell lines but not in other brain tumors or normal cortex. The invasive potential of GBM cells was significantly decreased by RNA interference targeting SIM2-s, while the proliferation was not affected. Further investigation showed that the mRNA and protein levels of matrix metalloproteinase 2 (MMP-2) were downregulated in cells treated with SIM2-s siRNA, concomitance with the upregulation of tissue inhibitor of matrix metalloproteinase 2 (TIMP-2). Moreover, the enzymatic activity of MMP-2 was clearly decreased. Our results collectively suggested that SIM2-s expressed in gliomas selectively and played a role in GBM cells invasion, which may be partly associated with the expression of MMP-2 and TIMP-2.

Rho-kinase inhibitor, fasudil, suppresses glioblastoma cell line progression in vitro and in vivo.

There is growing evidence that the Rho/Rho-kinase (ROCK) signaling pathway is upregulated in tumors and plays a key role in cancer invasion and proliferation. The aim of this study was to explore the anti-tumor effects of Rho/ROCK inhibitor, fasudil, including the possible mechanisms involved in the suppression of the glioblastoma (GBM) cell line progression in vitro and in vivo. After T98G and U251 cells were treated with various concentrations of fasudil, Y27632, and ROCK siRNA, the effects of ROCK inhibitors on migration, invasion, invasion-related gene expressions, proliferation and apoptosis of cultured tumor cells were examined. The results indicated that fasudil significantly inhibited not only proliferation, migration and invasiveness (p < 0.05) but also the mRNA and protein expressions of matrix metalloproteinase-2 (MMP-2) in a dose-dependent manner. Moreover, fasudil treatment resulted in a dose-dependent increase of apoptosis in T98G and U251. The intracranial xenograft models were established. The cryosection of the tumor and the survival time of mice in each group indicated that fasudil could inhibit glioma invasion and growth in vivo. Based on the results, fasudil suppresses the progression of GBM in vitro and in vivo by inhibiting ROCK. This could be linked to the decreased MMP-2 expression and the induction of apoptosis in tumor cells. The Rho/ROCK signaling pathway may prove to be a promising target in anti-tumor therapy. Fasudil may be an attractive anti-tumor drug candidate for the treatment of GBM.

IL-6 promotion of glioblastoma cell invasion and angiogenesis in U251 and T98G cell lines.

Interleukin-6 (IL-6) is a growth and survival factor in human glioblastoma cells and plays an important role in malignant progression. However, its role in glioblastoma invasion is still unknown. This study shows how IL-6 promotes cell invasion and migration in U251 and T98G glioblastoma cell lines. The underlying mechanism includes both protease-dependent and -independent manners. Stimulation with IL-6 increased MMP9 expression in the two cell lines but had no influence on MMP2 expression. Fascin-1 is a cell skeleton binding protein and plays a key role in cell migration and invasion. Its binding style directly influences cell morphology and tendency to become deformed. After IL-6 exposure, fascin-1 expression increased in an IL-6 dose-dependent manner. Immunofluorescence also revealed that the binding style of fascin-1 had changed after IL-6 exposure, resulting in a more invasive phenotype of the cells. Three most commonly emphasized invasion-associated signaling pathways, including JAK-STAT3, p42/44 MAPK, and PI3K/AKT, were verified to further illustrate its underlying mechanism. Only phosphorylation of STAT3 at ser 727 site paralleled the IL-6 stimulation, and JSI-124, a specific JAK-STAT3 pathway blocker, deterred the invasion and migration promotive effect of IL-6, indicating that the JAK/STAT3 pathway mediates signal transduction. Furthermore, IL-6 also acts in a paracrine fashion to promote vascular endothelial cell migration, thus facilitating tumor angiogenesis and invasion. These results suggest that IL-6 promotes glioblastoma cell invasion and angiogenesis and may be a potential anti-invasion target.

The soluble major histocompatibility complex class I-related chain A protein reduced NKG2D expression on natural killer and T cells from patients with prolactinoma and non-secreting pituitary adenoma.

This study analyses aspects of the immune system in prolactinoma and non-secreting pituitary adenoma. Serum soluble major histocompatibility complex class I-related chain A protein (sMICA) concentrations were measured by enzyme-linked immunosorbent assay. NKG2D-expressing natural killer and T cells were analyzed by flow cytometry. A correlation analysis was also performed to associate sMICA levels with NKG2D expression. The expression of MICA was examined in specific tissues by use of the reverse transcription-polymerase chain reaction. A significant amount of sMICA was detected in the serum of nearly all patients. We found decreased percentage and mean fluorescence intensity of NKG2D-expressing natural killer and T cells from patients with prolactinoma and non-secreting pituitary adenoma compared to those from healthy donors. Pearson analysis showed a negative correlation between sMICA and NKG2D-expressing cells. The immune-escape of pituitary adenoma is related to the down-regulation of NKG2D and the up-regulation of its ligand MICA.

Marchantin C: a potential anti-invasion agent in glioma cells.

Cancer cell migration is a leading cause of tumor recurrence and treatment failure. Previously, we reported that marchantin C exhibited promising antitumor activity by inducing microtubule depolymerization and apoptosis. In the present study, we investigated the effect of marchantin C on inhibition of migration in T98G and U87 cells. The scratch-induced migration, Boyden chamber and cell invasion assays were applied to determine that the migrating capacity and invasiveness of these glioma cell lines were inhibited when exposed to marchantin C at a low concentration. There are no obvious signs of apoptosis with this dose. Western blot analyses confirmed that MMP-2, a key role in cancer cell migration, was reduced after incubation with marchantin C in both glioma cell lines. In addition, signaling pathway investigations demonstrated that ERK/MAPK might be involved in MMP-2 downregulation, rather than the AKT/PI3K or JAK/STAT3 pathways. Moreover, marchantin C potently suppressed angiogenesis activity in vivo by CAM assay. This is the first study to demonstrate that marchantin C can inhibit glioma cell migration and invasiveness.