Imaging findings of intraventricular pilocytic astrocytoma.

OBJECTIVE: The aim of this study is to present the clinical and imaging findings of 16 patients with intraventricular pilocytic astrocytomas (PAs). METHODS: 16 patients with histopathological diagnosis of intraventricular PA between February 2016 and January 2022 were evaluated retrospectively. Imaging and clinical findings of the patients, as well as apparent diffusion coefficient (ADC) measurements were analyzed. RESULTS: Of 16 patients, 8 (%50) were male and 8 (%50) were female. The mean age of the patients was 20.8 years (2-44 years range). The most common symptoms in the patients were headache and ataxia. The mean long-axis size of lesions was found to be 48.19 ± 21.59 (range, 15-92 mm). 9 out of 16 lesions (56.2%) were located in the fourth ventricle. The majority of the lesions were iso-hypointense in T1W and hyperintense in T2W images. The mean ADC value of PAs was 1.57 × 10-3 ± 0.2 mm2/s, while the mean thalamic ADC and white matter ADC values were found to be 0.78 × 10-3 ± 0.04 and 0.76 × 10-3 ± 0.06 mm2/s, respectively. There was a statistically significant difference between the ADC values obtained from the solid components of the lesions and the thalami/white matter (p < 0.001). CONCLUSION: PAs often originate from midline structures, however, they can also be located intraventricularly. Although intraventricular PAs are frequently seen in pediatric population, it should be kept in mind that they can also be seen in adults, albeit rarely. ADVANCES IN KNOWLEDGE: PA should be considered in the differential diagnosis of intraventricular neoplasms in case of high ADC values.

Predictors of survival and time to progression following operative management of intramedullary spinal cord astrocytomas.

PURPOSE: Surgical resection is considered standard of care for primary intramedullary astrocytomas, but the infiltrative nature of these lesions often precludes complete resection without causing new post-operative neurologic deficits. Radiotherapy and chemotherapy serve as potential adjuvants, but high-quality data evaluating their efficacy are limited. Here we analyze the experience at a single comprehensive cancer center to identify independent predictors of postoperative overall and progression-free survival. METHODS: Data was collected on patient demographics, tumor characteristics, pre-operative presentation, resection extent, long-term survival, and tumor progression/recurrence. Kaplan-Meier curves modeled overall and progression-free survival. Univariable and multivariable accelerated failure time regressions were used to compute time ratios (TR) to determine predictors of survival. RESULTS: 94 patients were included, of which 58 (62%) were alive at last follow-up. On multivariable analysis, older age (TR = 0.98; p = 0.03), higher tumor grade (TR = 0.12; p < 0.01), preoperative back pain (TR = 0.45; p < 0.01), biopsy [vs GTR] (TR = 0.18; p = 0.02), and chemotherapy (TR = 0.34; p = 0.02) were significantly associated with poorer survival. Higher tumor grade (TR = 0.34; p = 0.02) and preoperative bowel dysfunction (TR = 0.31; p = 0.02) were significant predictors of shorter time to detection of tumor growth. CONCLUSION: Tumor grade and chemotherapy were associated with poorer survival and progression-free survival. Chemotherapy regimens were highly heterogeneous, and randomized trials are needed to determine if any optimal regimens exist. Additionally, GTR was associated with improved survival, and patients should be counseled about the benefits and risks of resection extent.

4-Methoxydalbergione is a potent inhibitor of human astroglioma U87 cells in vitro and in vivo.

Astroglioma is the most common primary tumor in the central nervous system without effective treatment strategies. Temozolomide (TMZ) is a chemotherapeutic drug to treat astroglioma but exhibits low potency and has side effects. Therefore, there is an urgent need to develop new compounds to treat astroglioma. Dalbergia sissoo Roxb was the source of Dalbergia odorifera in traditional Chinese medicine (TCM) and has been clinically used as an anti-tumor medicine. 4-Methoxydalbergione (4MOD) is purified from Dalbergia sissoo Roxb., and shows an inhibitory effect on osteosarcoma, but its effects on astroglioma have not been reported. Here, we evaluate its anti-astroglioma effects on both in vitro and in vivo models. In cultured astroglioma U87 cells, 4MOD inhibited cell proliferation and induced cell apoptosis in a time- and concentration-dependent manner. Compared with TMZ, 4MOD exhibited a tenfold greater potency of anti-astroglioma effects. 4MOD effectively stalled the cell cycle in G2 phase. Transcriptome sequencing (RNA-seq) showed that 4MOD upregulated 158 genes and downregulated 204 genes that are mainly enriched in cell membrane, cell division, cell cycle, p53, TNF, and MAPK signaling pathways, which may underlie its anti-tumor mechanisms. In a nude mouse xenograft model transplanted with U87 cells, 10 mg/kg 4MOD slowed down tumor growth rate, while at 30 mg/kg dose, it reduced tumor size. Collectively, this study demonstrates that 4MOD is a potent native compound that remarkably inhibits U87 astroglioma growth in both in vitro and in vivo models.

Yokukansan, a Japanese Herbal Medicine, Suppresses Substance PInduced Production of Interleukin-6 and Interleukin-8 by Human U373 MG Glioblastoma Astrocytoma Cells.

BACKGROUND: Yokukansan is a traditional Japanese herbal medicine that has an antiallodynic effect in patients with chronic pain. However, the mechanisms by which yokukansan inhibits neuropathic pain are unclear. OBJECTIVE: This study aimed to investigate the molecular effects of yokukansan on neuroinflammation in U373 MG glioblastoma astrocytoma cells, which express a functional high-affinity neurokinin 1 receptor (substance P receptor), and produce interleukin (IL)-6 and IL-8 in response to stimulation by substance P (SP). METHODS: We assessed the effect of yokukansan on the expression of ERK1/2, P38 MAPK, nuclear factor (NF)-κB, and cyclooxygenase-2 (COX-2) in U373 cells by western blot assay. Levels of IL-6 and IL-8 in conditioned medium obtained after stimulation of cells with SP for 24 h were measured by enzyme-linked immunosorbent assay. All experiments were conducted in triplicate. Results were analyzed by one-way ANOVA, and significance was accepted at p < 0.05. RESULTS: Yokukansan suppressed SP-induced production of IL-6 and IL-8 by U373 MG cells, and downregulated SP-induced COX-2 expression. Yokukansan also inhibited phosphorylation of ERK1/2 and p38 MAPK, as well as nuclear translocation of NF-κB, induced by SP stimulation of U373 MG cells. CONCLUSION: Yokukansan exhibits anti-inflammatory activity by suppressing SP-induced production of IL-6 and IL-8 and downregulating COX-2 expression in U373 MG cells, possibly via inhibition of the activation of signaling molecules, such as ERK1/2, p38 MAPK, and NF-κB.

Eliciting Smiles and Laughter During Intraoperative Electric Stimulation of the Cingulum: Surgical Scenario.

Laughter has a major role in daily social interactions; consequently, its biologic bases have been previously studied. Nevertheless, its cerebral representation remains unclear. The most accepted hypothesis has postulated that laughter has 2 components: mirth, related to the temporal and frontal neocortical areas, and motor aspect, related to the limbic system and brainstem. Furthermore, in prior studies, laughter has been elicited during electric stimulation with depth electrodes in the supplementary motor area and the cingulum. This Video 1 reports resection of a right superior frontal gyrus diffuse astrocytoma (isocitrate dehydrogenase mutant, World Health Organization grade II) with awake intraoperative electric cortical and subcortical stimulation mapping. Diffusion tensor imaging (DTI) tractography, including all the tracts in relation to the tumor, was obtained preoperatively and postoperatively. Stimulation of the cingulum medially and inferiorly to the tumor elicited a patient's smile and laugh without mirth or merriment. Also, this point correlated with the reconstructed cingulum in the intraoperatively navigated DTI tractography. In conclusion, these findings support the anatomic subdivision of the laughter's mechanism and the role of the cingulum in its motor component. Furthermore, smiles and laughter could be useful functional landmarks to identify the cingulum during subcortical mapping. Although it remains unclear whether pursuing resection beyond this point would have caused permanent postoperative deficits, considering laughter's role in social interaction and other emotion-processing functions associated with the cingulum, in the future it could be potentially considered a functional limit of the resection of intrinsic tumors.

Functionalized selenium nanoparticles enhance the anti-EV71 activity of oseltamivir in human astrocytoma cell model.

Enterovirus 71 (EV71) which commonly caused the hand-foot-mouth disease (HFMD) has become one of public health challenges worldwide. However, no effective vaccines or drugs for this disease has been developed. Thus, there is an urgent need to find a new strategy for treating the EV71 infection. Oseltamivir (OT) is an effective antiviral agent, but continuous use of oseltamivir leads to a diminished therapeutic effect in the clinic. In order to improve the antiviral activity of oseltamivir, oseltamivir was loaded onto surfaces of selenium nanoparticles (SeNPs) to fabricate a functionalized antiviral nanoparticles SeNPs@OT. The size of SeNPs@OT was tested by TEM and dynamic light scattering. The chemical structure and elemental composition of SeNPs@OT were analyzed by FT-IR and EDX, respectively. SeNPs@OT exhibited good stability and effective drug release in serum and PBS. SeNPs@OT efficiently entered into human astrocyte U251 cells (host cells) via clathrin-associated endocytosis and inhibited EV71 proliferation, which could protect EV71-infected U251 cells from apoptosis through mitochondrial pathway. Furthermore, SeNPs@OT inhibited EV71 activity probably by reducing the generation of reactive oxygen species in EV71-infected U251 cells. Interestingly, SeNPs obviously enhanced antiviral activity of oseltamivir in the anti-EV71 cell model. Taken together, SeNPs@OT is a promising antiviral drug candidate for EV71 infection.

Effects of photobiomodulation on mitochondria of brain, muscle, and C6 astroglioma cells.

The purpose of this study was to investigate the effect of different doses of photobiomodulation (PBM) on mitochondrial respiratory complexes and oxidative cellular energy metabolic enzymes in the mitochondria of brain, muscle, and C6 glioma cells after different time intervals. C6 cells were irradiated with an AlGaInP laser at 10, 30, and 60 J/cm2 for 20, 60, and 120 s, respectively. After irradiation, the cells were maintained in serum-free Dulbecco's Modified Eagle's medium for 24 h, and biochemical measurements were made subsequently. Mitochondrial suspensions from adult rat skeletal muscles/brains were irradiated with an AlGaInP laser at the abovementioned doses. In one group, the reaction was stopped 5 min after irradiation and in the other 60 min after irradiation. Both the C6 cells that received the doses of 10 and 30 J/cm² showed increased complex I activity; the cells that were irradiated at 30 J/cm2 showed increased hexokinase activity. Five minutes after the introduction of PBM of the muscle mitochondria (at 30 and 60 J/cm2), the activity of complex I increased, while the activity of complex IV increased only at 60 J/cm2. One hour after the laser session, complex II activity increased in the cells treated with 10 and 60 J/cm²; however, complex IV activity showed an increase in all PBM groups. In brain mitochondria, 5 min after irradiation only the activity of complex IV increased in all PBM groups. One hour after the laser session, complex II activity increased at 60 J/cm2, and complex IV activity increased for all PBM groups when compared to controls. PBM could increase the activity of respiratory chain complexes in an apparently dose- and time-dependent manner.

Slowdown intracranial glioma progression by optical hyperthermia therapy: study on a CT-2A mouse astrocytoma model.

Metallic nanorods are promising agents for a wide range of biomedical applications. We report an optical hyperthermia method capable of inducing slowdown tumor progression of an experimental in vivo CT-2A glioblastoma tumor. The tumor model used in this research is based on the transplantation of mouse astrocytoma CT-2A cells in the striatum of mice by intracranial stereotaxic surgery. Two weeks after cell implant, the resulting tumor is treated by irradiating intratumoral injected gold nanorods, biofunctionalized with CD133 antibody (B-GNRs), using a continuous wave laser. Nanoparticles convert the absorbed light into localized heat (reaching up to 44 °C) due to the effect of surface plasmon resonance. A significant slowdown in CT-2A tumor progression is evident, by histology and magnetic resonance imaging, at one (p = 0.03) and two weeks (p = 0.008) after irradiation treatment. A notable deceleration in tumor size (15%-75%) as compared to the control untreated groups, it is observed. Thus, laser irradiation of B-GNRs is found to be effective for the treatment of CT-2A tumor progression. Similarities between the pre-clinical CT-2A tumor model and the human astrocytoma disease, in terms of anatomy, metastatic behavior and histopathology, suggest that hyperthermic treatment by laser irradiation of B-GNRs administered into high-grade human astrocytoma might constitute a promising alternative treatment to limit the progression of this deadly disease.

[Clinicopathological characteristics and prognosis of diffuse midline gliomas with histone H3K27M mutation: an analysis of 30 cases].

Objective: To analyze the clinicopathological characteristics and prognosis of diffuse midline glioma (DMG) with H3K27M mutation. Methods: Thirty cases of DMG were collected in Guangdong Sanjiu Brain Hospital from October 2016 to May 2018. The patients' clinicopathological data including age, tumor site and histological grade, treatment and follow-up data were collected and analyzed. Results: There were 21 males and 9 females, with a mean age of 26 years (range 5-53 years). Fourteen tumors were located in thalamus, 12 in brainstem (one involved both thalamus and brainstem), and one each in hypothalamus, fourth ventricle, and sellar region, respectively. Two cases presented as diffuse intracranial lesions. Three cases (10.0%) were of WHO grade Ⅰ, 10 cases (33.3%) were grade Ⅱ, eight cases (26.7%) were grade Ⅲ, and nine cases (30.0%) were grade Ⅳ.All patients with gradeⅠ tumors were older than 20 years. Histologically, all were pilocytic astrocytoma-like. Immunohistochemical staining demonstrated that all tumors were IDH1 negative. Twenty-eight tumors showed diffuse expression of H3K27M, and two showed focal expression. Twenty-one tumors(100.0%, 21/21) showed absent expression of H3K27me3. Sixteen tumors (57.1%, 16/28) showed strongly positive expression of p53, and ATRX was negative in eight tumors (38.1%, 8/21). The Ki-67 proliferation index ranged from 5% to 40%. Eight cases (including two cases of H3K27M expression of individual cells) showed K27M mutation in H3F3A gene. Intracranial and spinal cord dissemination occurred in six cases (20.0%, 6/30). Median progression-free survival (PFS) was 9.5 months and median overall survival (OS) was 34 months. Mean PFS was 11.2 months and mean OS was 24.3 months. Compared with adults (>20 years old), children/adolescents (no more than 20 years old) had significantly shorter median OS (8 months vs. 34 months, P=0.013). There was no significant difference in PFS and OS between DMGs located in the brain stem/thalamus and other sites within midline (P>0.05). There was no significant difference in PFS and OS between WHO grade ⅠDMGs and WHO grade Ⅱ-Ⅳ DMGs (P>0.05). Conclusions: DMGs occur more commonly in children and adolescents with male predominance. DMGs present with WHO Ⅰ-Ⅳ tumors morphologically, and pilocytic astrocytoma-like lesions with WHO Ⅰ are more common in adults. Expression of H3K27M but not H3K27me3 is helpful for diagnosis of DMG. The prognosis of children/adolescents is significantly worse than that of adults, whereas histological grade and tumor location do not affect prognosis.

Stachydrine suppresses viability & migration of astrocytoma cells via CXCR4/ERK & CXCR4/Akt pathway activity.

AIM: Pilocytic astrocytomas (PAs) are a common adolescent malignancy. We evaluated the effects of the betaine stachydrine on human PA cells as well as its associated molecular mechanism(s). MATERIALS & METHODS: Various experiments assessing stachydrine's effects on the human PA cell line Res186 were performed. RESULTS & CONCLUSION: Stachydrine dose-dependently suppressed proliferation and colony formation in Res186 cells with no such effect on normal astrocytes. Stachydrine downregulated CXCR4 transcription through enhancing IκBα-based NF-κB inhibition. Stachydrine promoted apoptosis and cyclin D1/p27Kip1-associated G0/G1 phase arrest in a CXCR4/ERK- and CXCR4/Akt-dependent manner. Stachydrine suppressed MMP-associated migration and invasiveness via inhibiting CXCR4/Akt/MMP-9/2 and CXCR4/ERK/MMP-9/2 pathway activity. Stachydrine inhibits the viability, migration and invasiveness of human PA cells via inhibiting CXCR4/ERK and CXCR4/Akt signaling.

Pediatric thalamic glioma with H3F3A K27M mutation, which was detected before and after malignant transformation: a case report.

PURPOSE: Histone H3.3 (H3F3A) mutation in the codon for lysine 27 (K27M) has been found as driver mutations in pediatric glioblastoma and has been suggested to play critical roles in the pathogenesis of thalamic gliomas and diffuse intrinsic pontine gliomas. We report a case of thalamic glioma with H3F3A K27M mutation, which was detected in both the primary tumor diagnosed as diffuse astrocytoma obtained during the first surgery and also in the tumor diagnosed as anaplastic astrocytoma obtained at the second surgery. CASE PRESENTATION: A 14-year-old girl presented with mild headache. Magnetic resonance imaging (MRI) showed a small intraaxial lesion in the left thalamus, which increased in size. Stereotactic tumor biopsy was performed 2 years after the initial diagnosis, and a pathological diagnosis of diffuse astrocytoma (WHO grade 2) was made. The tumor grew further and showed contrast enhancement on MRI despite 16 months of chemotherapy. Surgical removal via the transcallosal approach was then performed, and postoperative pathological diagnosis was anaplastic astrocytoma (WHO grade 3), indicating malignant transformation of the tumor. Molecular diagnosis of tumor tissue obtained at first and second surgeries revealed H3F3A K27M mutation in both primary and secondary specimens. CONCLUSION: This report demonstrates minute neuroradiological and pathological features of malignant transformation from thalamic low grade glioma with H3F3A K27M mutation. It is noteworthy that this mutation was found in this case when the tumor was still a low-grade glioma. Tissue sampling for genetic analysis is useful in patients with thalamic gliomas to predict the clinical course and efficacy of treatments.

Role of Intraoperative Neurophysiologic Monitoring in the Resection of Thalamic Astrocytomas.

BACKGROUND: The thalamus is a deep-seated and crucial structure for the sensorimotor system. It has been long considered a surgically inaccessible area because of the morbidity associated with surgical resections. Astrocytomas of the thalamus are usually treated with bioptic procedures followed by adjuvant treatments. Intraoperative neurophysiologic monitoring (IONM) allows safe and satisfactory resections of lobar gliomas, but few data are available for thalamic lesions. The aim of this study was to review the outcome of a small series of patients with thalamic astrocytomas that were treated with surgical resection with the aid of IONM. METHODS: Surgical resection with IONM was performed in 5 patients with thalamic astrocytomas (1 grade I, 1 grade II, 2 grade III, 1 grade IV). Two astrocytomas were in the dominant hemisphere. Preoperative and postoperative neuropsychological assessments were performed in 3 patients. IONM was tailored to the individual patient and consisted of transcranial motor evoked potential monitoring, cortical motor evoked potential monitoring, somatosensory evoked potential monitoring, direct electrical stimulation, electroencephalography, and electrocorticography. RESULTS: None of the patients experienced permanent motor deficits; 2 patients had a transient hemiparesis requiring rehabilitation; 1 patient had a transient aphasia, and 1 patient had permanent aphasia. None of the patients had intraoperative seizures, but 1 patient experienced postoperative transient status epilepticus. The extent of resection on postoperative volumetric magnetic resonance imaging was >70% in all cases. CONCLUSIONS: Surgical resection of thalamic astrocytomas appeared to be effective and relatively safe when guided by IONM. Larger series of patients are required to confirm these preliminary data.

Anticancer activity of glucomoringin isothiocyanate in human malignant astrocytoma cells.

Isothiocyanates (ITCs) released from their glucosinolate precursors have been shown to inhibit tumorigenesis and they have received significant attention as potential chemotherapeutic agents against cancer. Astrocytoma grade IV is the most frequent and most malignant primary brain tumor in adults without any curative treatment. New therapeutic drugs are therefore urgently required. In the present study, we investigated the in vitro antitumor activity of the glycosylated isothiocyanate moringin [4-(α-l-rhamnopyranosyloxy)benzyl isothiocyanate] produced from quantitative myrosinase-induced hydrolysis of glucomoringin (GMG) under neutral pH value. We have evaluated the potency of moringin on apoptosis induction and cell death in human astrocytoma grade IV CCF-STTG1 cells. Moringin showed to be effective in inducing apoptosis through p53 and Bax activation and Bcl-2 inhibition. In addition, oxidative stress related Nrf2 transcription factor and its upstream regulator CK2 alpha expressions were modulated at higher doses, which indicated the involvement of oxidative stress-mediated apoptosis induced by moringin. Moreover, significant reduction in 5S rRNA was noticed with moringin treatment. Our in vitro results demonstrated the antitumor efficacy of moringin derived from myrosinase-hydrolysis of GMG in human malignant astrocytoma cells.

Effect of cognitive rehabilitation in a case of thalamic astrocytoma.

We describe the effectiveness of rehabilitative training for a neuropsychological deficit following the removal and treatment of a fibrillary astrocytoma (Grade II) in a young man. The rehabilitative training was based on cognitive and motivational techniques and has been carried out for a period of 3 months (2 times per week). The results, even if limited to a single case, seem to support the idea that cognitive rehabilitation should facilitate the brain's reorganization of basic cognitive functions in the neuro-oncologic field.

A case of osteoclast-like giant cell-rich epithelioid glioblastoma with BRAF V600E mutation.

Epithelioid glioblastomas (E-GBMs) are rare, highly aggressive tumors consisting of closely packed tumor cells with smooth, round cell borders and abundant eosinophilic cytoplasm. They tend to affect younger patients compared with conventional GBM. BRAF V600E mutation is characteristically found in approximately 50% of all E-GBMs, compared with a low frequency of this mutation in conventional GBM. Here, we report an unusual case of glioma involving the right frontal lobe, basal ganglia and thalamus in an HIV-positive 30-year-old man on antiretroviral therapy. The lesion was composed of abundant discohesive, monotonous epithelioid cells with extensive necrosis, spindle and polyhedral cells, low-grade oligoastrocytoma-like areas, sarcomatous components, and numerous osteoclast-like giant cells (OLGCs) intermingled with epithelioid tumor cells. As the epithelioid cells accounted for more than one-third of the tumor, a pathological diagnosis of E-GBM was made. BRAF V600E mutation was detected in both oligoastrocytoma-like and epithelioid cell components. Similar to previously reported findings on E-GBM associated with low-grade glioma, this case suggested that low-grade astrocytic glioma with BRAF V600E mutation progressed to E-GBM. OLGCs are rarely observed in gliomas, and this is the first case report of E-GBM associated with abundant OLGC infiltration.

A case report on 1-year follow-up of bilateral thalamic glioma.

Bilateral thalamic glioma is one of the rarest tumor occurrences, representing a small fraction of thalamic gliomas, which only accounts for 1-1.5% of all brain tumors. It is usually a diffuse, low-grade astrocytoma (WHO grade II), seen mainly in adults, with approximately 25% of them involving children under the age of 15. Radiotherapy is the main mode of treatment since surgical intervention is limited to a role of biopsy and management of secondary effects, due to the deep brain location of the lesion and the complexity of the involved structures. We report a 1-year follow-up of a 55-year-old female patient with bilateral WHO grade II thalamic astrocytoma. Following histological and neuroradiological consensus regarding the diagnosis, the patient was referred for radiotherapy. The effectiveness of available therapy and long-term neuroradiological follow-up is not reliably established due to rapid fatal evolution following diagnosis. Contrary to the norm, our patient showed stable disease with radiotherapy for a 1-year period.

Maintenance of Stemlike Glioma Cells and Microglia in an Organotypic Glioma Slice Model.

BACKGROUND: The therapeutic resistance of gliomas is, at least in part, due to stemlike glioma cells (SLGCs), which self-renew, generate the bulk of tumor cells, and sustain tumor growth. SLGCs from glioblastomas (GB) have been studied in cell cultures or mouse models, whereas little is known about SLGCs from lower grade gliomas. OBJECTIVE: To compare cell and organotypic slice cultures from GBs and lower grade gliomas and study the maintenance of SLGCs. METHODS: Cells and tissue slices from astrocytomas, oligodendrogliomas, oligoastrocytomas, and GBs were cultivated in (1) serum-free medium supplemented with the growth factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), (2) medium containing 10% serum plus EGF and bFGF (F+GF medium), or (3) medium containing 10% fetal calf serum (F medium). Maintenance of cells and cytoarchitecture was addressed, using several candidate SLGC markers (Nestin, Sox2, CD133, CD44, CD49f/integrin α6, and Notch) as well as CD31 (endothelial cells), ionized calcium-binding adapter molecule 1 (microglia), and vimentin. Cell vitality was determined. RESULTS: SLGCs were present in tissue slices from lower and higher grade gliomas. Preservation of the cytoarchitecture in slices was possible for >3 weeks. Maintenance of SLGCs required the presence of EGF/bFGF in cell and slice cultures, in which F+GF appeared superior to N medium. Constraints were observed regarding the preservation of the microglia but not of the endothelial cells. Maintenance of the microglia was improved by addition of the cytokine macrophage colony-stimulating factor. CONCLUSION: Medium supplemented with serum and growth factors EGF, bFGF, and macrophage colony-stimulating factor permits the preservation of SLGCs and non-SLGCs in the original glioma microenvironment.

Radiotherapy and temozolomide for anaplastic astrocytic gliomas.

We previously reported results of a phase II non-comparative trial that randomized patients with glioblastoma following radiotherapy to one of two different temozolomide schedules, followed by 13-cis-retinoic acid (RA) maintenance. Here we report the results of an exploratory cohort of patients accrued with anaplastic astrocytic tumors. Patients with newly diagnosed anaplastic astrocytoma (AA) or anaplastic oligo-astrocytoma (AOA) were treated with concurrent radiotherapy (60 Gy over 6 weeks) and temozolomide (75 mg/m(2)), and six adjuvant 28-day cycles of either dose-dense (150 mg/m(2), days 1-7, 15-21) or metronomic (50 mg/m(2), days 1-28) temozolomide. Subsequently, maintenance RA (100 mg/m(2), days 1-21/28) was administered until disease progression. All outcome measures were descriptive without intention to compare between treatment arms. Survival was measured by the Kaplan-Meier method. There were 31 patients (21 men, 10 women) with median age 48 years (range 28-74), median KPS 90 (range 60-100). Extent of resection was gross-total in 35%, subtotal 23%, and biopsy 42%. Histology was AA in 90%, and AOA in 10%. MGMT promoter methylation was methylated in 20%, unmethylated in 50%, and uninformative in 30% of 30 tested. Median progression-free survival was 2.1 years (95% CI 0.95-Not Reached), and overall survival 2.9 years (95 % CI 2.0-Not Reached). We report outcomes among a homogeneously treated population with anaplastic astrocytic tumors. Survival was unexpectedly short compared to other reports. These data may be useful as a contemporary historic control for other ongoing or future randomized trials.

Oligomer procyanidins (F2) isolated from grape seeds inhibits tumor angiogenesis and cell invasion by targeting HIF-1α in vitro.

Overexpression of hypoxia-inducible factor-1 (HIF-1) α, a transcription factor which immortalizes tumors by inducing expression of the genes involved in cell survival, migration and angiogenesis, is closely associated with poor prognosis, increased risk of metastasis and increased mortality. Oligomer procyanidins (F2), a natural fraction from grape seeds, has been demonstrated to have antioxidant and antitumor activities, however the antitumor effect of F2 targeting HIF-1α remains unknown. The present study showed that F2 markedly decreased HIF-1α and the expression of its target genes in cancer cells through inactivating the EGFR-PI3K-AKT-mTOR and MAPK-ERK1/2 pathways. Moreover, F2 suppressed vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)-2 expressions, followed by the inhibition of tumor angiogenesis and cell invasion in a HIF-1α-dependent manner. Collectively, these findings indicate that the antitumor effect of F2 is, at least in part, mediated by suppressing HIF-1α-dependent pathway, and suggest that F2 may be a potentially useful agent for treatment of human cancer.