Recurrence Of Glioblastoma Multiforme Research Articles

Demethoxycurcumin was superior to temozolomide in the inhibition of the growth of glioblastoma stem cells in vivo.

Temozolomide (TMZ) is widely used in the treatment of glioblastoma multiforme (GBM) as it can effectively inhibit the growth of GBM for some months; however, this cancer type is still incurable. The existence of glioma stem cells (GSCs) is thought to be responsible for the invariable recurrence of GBM after treatment, but GSCs are insensitive to TMZ. Our recent research showed that demethoxycurcumin (DMC), a component of curcumin, was superior to TMZ in its ability to inhibit proliferation and induce apoptosis of GSCs in vitro. In addition, the combined treatment of TMZ + DMC induced more obvious anti-GSC effects. However, in this study, no obvious synergistic anti-GSC effects of TMZ + DMC were found in vivo, while DMC was still superior to TMZ with respect to growth inhibition of GSCs in vivo. Furthermore, immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed that such inhibitory effects were mainly related to the inhibition of cell proliferation rather than to apoptosis. However, a high concentration of DMC (50mg/kg) alone or combined with TMZ could also induce approximately 10% of the cells to undergo apoptosis according to a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Finally, an investigation of the underlying mechanism revealed that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) 3 signaling pathway played an important role in the anti-GSC effects. When the JAK inhibitor AG490 was applied, the anti-GSC effects of DMC were enhanced. Taken together, the present work reveals that DMC is superior to TMZ with respect to its anti-GSC effects in vivo, which are mediated through the inhibition of the activation of the JAK/STAT3 pathway; however, DMC demonstrated no synergistic effects with TMZ.

Predicting Glioblastoma Recurrence by Early Changes in the Apparent Diffusion Coefficient Value and Signal Intensity on FLAIR Images.

Recurrence of glioblastoma multiforme (GBM) arises from areas of microscopic tumor infiltration that have yet to disrupt the blood-brain barrier. We hypothesize that these microscopic foci of invasion cause subtle variations in the apparent diffusion coefficient (ADC) and FLAIR signal detectable with the use of computational big-data modeling. Twenty-six patients with native GBM were studied immediately after undergoing gross total tumor resection. Within the peritumoral region, areas of future GBM recurrence were identified through coregistration of follow-up MRI examinations. The likelihood of tumor recurrence at each individual voxel was assessed as a function of signal intensity on ADC maps and FLAIR images. Both single and combined multivariable logistic regression models were created. A total of 419,473 voxels of data (105,477 voxels of data within tumor recurrence and 313,996 voxels of data on surrounding peritumoral edema) were analyzed. For future areas of recurrence, a 9.5% decrease in the ADC value (p < 0.001) and a 9.2% decrease in signal intensity on FLAIR images (p < 0.001) were shown, compared with findings for the surrounding peritumoral edema. Logistic regression revealed that the amount of signal loss on both ADC maps and FLAIR images correlated with the likelihood of tumor recurrence. A combined multiparametric logistic regression model was more specific in the prediction of tumor recurrence than was either single-variable model alone. Areas of future GBM recurrence exhibit small but highly statistically significant differences in signal intensity on ADC maps and FLAIR images months before the development of abnormal enhancement occurs. A multiparametric logistic model calibrated to these changes can be used to estimate the burden of microscopic nonenhancing tumor and predict the location of recurrent disease. Computational big-data modeling performed at the voxel level is a powerful technique capable of discovering important but subtle patterns in imaging data.

Rapid progression of glioblastoma multiforme: A case report.

Glioblastoma multiforme (GBM) tumors are intracranial lesions with varying shapes that grow rapidly. GBM tumors most commonly present as solitary lesions and multiple lesions are rare. The aim of the present case report was to investigate the imaging features of glioblastoma multiforme (GBM). In this study, the case of a 60-year-old patient who was hospitalized due to seizures is presented. Magnetic resonance imaging (MRI) revealed multiple lesions, heterogeneous in size, with peritumoral edema and ring-shaped enhancement. The lesions grew rapidly within 10 days of hospitalization and were initially misdiagnosed as either infections or intracranial metastatic tumors as a result of imaging examinations. The patient was subsequently administered mannitol, diazepam, Tegretol and ceftriaxone. After treatment, the patient recovered and regained full consciousness. However, MRI examination 23 days after hospitalization revealed that the multiple lesions in the left temporal and left occipital lobes had increased in size. Therefore, resection of the tumor in the left temporal occipital lobe was performed. Histopathological examination identified GBM (grade IV) in the left temporal and parietal lobes. The patient succumbed to the disease 7 months after surgery due to GBM recurrence. The findings of the present case indicate that GBM may progress rapidly with a doubling time of 10 days and multiple cystic alterations. Furthermore, if diagnosis of GBM is unclear, early biopsy is recommended.

The Added Prognostic Value of Metabolic Tumor Size on FDG‐PET at First Suspected Recurrence of Glioblastoma Multiforme

Patients with glioblastoma multiforme (GBM) face a dismal prognosis, with an average survival of 6-7 months after recurrence. There remains no consensus for managing these patients due to the heterogeneity of these tumors. Imaging may affect treatment decisions by helping to stratify patient prognosis. The purpose of this analysis was to evaluate the added utility of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) over magnetic resonance (MR) imaging metrics in predicting survival. Forty-four consecutive patients who underwent FDG-PET for first recurrence of GBM were included in this analysis. Tumor sizes, using cross products, and volumes on FDG-PET and MRI, maximum standardized uptake value (SUV), minimum apparent diffusion coefficient (ADC) value, presence of satellite lesions, presence of multifocal lesions, and presence of bilateral tumor were considered as prognostic variables. Survival was assessed using Cox hazard and logistic regression models based on the time interval between the PET scan and the patient's date of death. Tumor volumes on FDG-PET (P = .046), tumor cross products on FDG-PET (P = .017), and tumor cross products on MRI (P = .031) were significant prognostic variables, adjusting for the extent of the initial resection. Enhancing tumor volume, tumor cross product on a T2-weighted MRI sequence, maximum SUV on FDG-PET, minimum ADC value, presence of satellites, multifocality, and bilaterality were not prognostic (P > .5). Prognostic accuracy of predicting short survival increased from 58% with tumor cross product on MRI alone to 74% after including tumor cross product from PET. Tumor size on FDG-PET adds prognostic information to enhancing tumor size on MRI at first suspected recurrence of GBM.

Cost-effectiveness analysis of the bevacizumab-irinotecan regimen in the treatment of primary glioblastoma multiforme recurrences.

The purpose of the present study was to calculate the cost-effectiveness of the inclusion of the bevacizumab (BVZ) + irinotecan (CPT-11) regimen in the second-line of treatment for primary glioblastoma multiforme. A retrospective cohort study with a control group was performed in which the cost-effectiveness of a course of chemotherapy was calculated based on survival time and the incremental cost between the two lines of treatment. A total of 77 patients were included, 36 of who formed the BVZ/CPT-11 cohort. The median survival time for the non-BVZ control cohort was 13.23 months [95% confidence interval (CI), 11.79-14.68], while for the BVZ/CPT-11 treatment cohort, the median survival time was 17.63 months (95% CI, 15.38-19.89). Overall, each year of life gained for each patient treated with BVZ/CPT-11 would cost €46,401.99. These results demonstrate the effectiveness of the BVZ/CPT-11 combination, but its incremental cost compared with other lines of treatment or the best care available does not appear to be acceptable for public health systems in the current situation of budgetary adjustments.

Pre-irradiation tumour volumes defined by MRI and dual time-point FET-PET for the prediction of glioblastoma multiforme recurrence: A prospective study

Background and purposeThe diagnostic accuracy of magnetic resonance imaging (MRI) for glioblastoma multiforme (GBM) is suboptimal. We analysed pre-treatment MRI- and dual time-point 18F-fluoroethylthyrosine-PET (FET-PET)-based target volumes and GBM recurrence patterns following radiotherapy with temozolomide. Materials and methodsThirty-four patients with primary GBM were treated according to MRI-based treatment volumes (GTVRM). Patients underwent dual time-point FET-PET scans prior to treatment, and biological tumour volumes (GTVPET) were contoured but not used for target definition. Progressions were classified based on location of primary GTVs. Volume and uniformity of MRI- vs. FET-PET/CT-derived GTVs and progression patterns assessed by MRI were analysed. ResultsFET-based GTVs measured 10min after radionuclide injection (a.r.i.; median 37.3cm3) were larger than GTVs measured 60min a.r.i. (median 27.7cm3). GTVPET volumes were significantly larger than corresponding MRI-based GTVs. MRI and PET concordance for the identification of glioblastoma GTVs was poor (mean uniformity index 0.4). 74% of failures were inside primary GTVPET volumes, with no solitary progressions inside the MRI-defined margin +20mm but outside the GTVPET detected. ConclusionsThe size and geometry of GTVs differed in the majority of patients. The GTVPET volume depends on time after radionuclide injection. FET-PET better defined failure site than MRI alone.

Lead Optimization of 2-Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas.

In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through a structure-activity relationship study, we developed derivatives 4-10 with improved potencies toward both TSPO and MDM2. As a result, compound 9: (i) reactivated the p53 functionality; (ii) inhibited the viability of two human GBM cells; (iii) impaired the proliferation of glioma cancer stem cells (CSCs), more resistant to chemotherapeutics and responsible of GBM recurrence; (iv) sensitized GBM cells and CSCs to the activity of temozolomide; (v) directed its effects preferentially toward tumor cells with respect to healthy ones. Thus, 9 may represent a promising cytotoxic agent, which is worthy of being further developed for a therapeutic approach against GBM, where the downstream p53 signaling is intact and TSPO is overexpressed.

SPOCK1 is upregulated in recurrent glioblastoma and contributes to metastasis and Temozolomide resistance.

Glioblastoma multiforme (GBM) is the most aggressive brain tumour type in humans. Its poor prognosis is largely attributed to its invasiveness and high rate of recurrence. Recurring GBM is commonly resistant to chemotherapeutic drugs, making it specially difficult to treat. Recent studies have revealed that matricellular glycoprotein SPOCK1 to be upregulated in several cancer types and to be specifically expressed in invasive GBM, but not in other types of non-invasive brain tumour, which prompted us to study the mechanism of action of SPOCK1 in invasion, recurrence and drug resistance of GBM cells. SPOCK1 expression in GBM tissues was evaluated using qPCR, Western blotting and immunohistochemical staining. Cell migration was tested by the wound healing method and cell invasion was assessed using transwell plates with Matrigel coating. Western blotting was performed for E-cadherin, vimentin, N-cadherin, p-Akt and Akt. Cell viability was examined using the MTT assay. We found that the expression of SPOCK1 was significantly upregulated in recurrent GBM. We also demonstrated that SPOCK1 positively regulated migration, invasion and EMT process of GBM cells. Furthermore, SPOCK1 mediated TMZ resistance in GBM, as knockdown of SPOCK1 expression in TMZ-resistant GBM cells substantially sensitized these cells to TMZ. SPOCK1 results were positive and it mediated TMZ resistance in GBM. In addition, SPOCK1 regulated invasion and TMZ resistance in GBM cells via the Akt signalling pathway.

Irradiation induces glioblastoma cell senescence and senescence-associated secretory phenotype.

Glioblastoma multiforme (GBM) is one of the most aggressive and fatal primary brain tumors in humans. The standard therapy for the treatment of GBM is surgical resection, followed by radiotherapy and/or chemotherapy. However, the frequency of tumor recurrence in GBM patients is very high, and the survival rate remains poor. Delineating the mechanisms of GBM recurrence is essential for therapeutic advances. Here, we demonstrate that irradiation rendered 17-20% of GBM cells dead, but resulted in 60-80% of GBM cells growth-arrested with increases in senescence markers, such as senescence-associated beta-galactosidase-positive cells, H3K9me3-positive cells, and p53-p21(CIP1)-positive cells. Moreover, irradiation induced expression of senescence-associated secretory phenotype (SASP) mRNAs and NFκB transcriptional activity in GBM cells. Strikingly, compared to injection of non-irradiated GBM cells into immune-deficient mice, the co-injection of irradiated and non-irradiated GBM cells resulted in faster growth of tumors with the histological features of human GBM. Taken together, our findings suggest that the increases in senescent cells and SASP in GBM cells after irradiation is likely one of main reasons for tumor recurrence in post-radiotherapy GBM patients.

STEM-15LONG NONCODING RNA REGULATION OF THE CANCER STEM CELL PHENOTYPE IN GLIOBLASTOMA MULTIFORME

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a two-year survival rate of less than 25%. The recurrence of GBM has been attributed to the presence of glioma stem cells (GSC), which are thought to play a central role in tumor development and progression. Long noncoding RNAs (lncRNAs) have been suggested to play a role in maintaining pluripotency, self-renewal, and differentiation in embryonic stem cells (ESCs). We hypothesized that lncRNAs functionally contribute to GBM development and tumor propagation by maintaining the cancer stem cell phenotype in glioblastoma. Initially, an in silico “nearest-neighbor” approach was employed to identify 112 lncRNA candidates that were close to the transcription factors that have been implicated in regulating self-renewal and pluripotency of ESCs or iPSCs, as well as factors that have been used to reprogram GSCs. Based on further in silico analyses and in vitro studies, we have identified three novel long noncoding RNAs, lincSox2, lincPOU5F1, and lincCTNNB1 that show differential expression in stem vs. differentiated normal human fetal neural stem cells (NSCs) and GSCs. The expression of lincSox2 and lincPOU5F1 significantly decreased in differentiated human NSCs compared to controls, and were significantly increased in differentiated GSCs compared to control GSCs. In comparison, the expression of lincCTNNB1 was increased in all differentiated cells, compared to their corresponding stem cell controls. Further knockdown experiments followed by in vivo studies will provide insight into functional relevance of these candidates in maintaining “stemness” in GSCs. Based on in silico and in vitro studies, we have identified two novel long noncoding RNAs that show differential expression in stem vs. differentiated NSCs and GSCs, and may functionally contribute to glioma biology by regulating the cancer stem cell phenotype. However, further characterization is needed to fully understand the role of lncRNAs in glioblastoma multiforme.

CBIO-46SPINDLE CELLS IN EARLY C6-GBM GROWTH ARE STEM CELLS - FUNCTIONAL STUDY WITH MITOCHONDRIAL VOLUME FOR THERAPEUTIC PURPOSE

OBJECTIVE: Recurrence of glioblastoma multiforme (GBM) after total resection is postulated to originate from precursor cells existing in surrounding brain tissue. The authors have found spindle cells in the early stage of rat C6 GBM growth, resembling spongioblasts, the origin of GBM (Bailey and Cushing, 1926). They are stem-like cells with positive CD15 staining, and should be the primary target for treatment in experimental animals (Poster at SPNO meeting in May). Currently, spindle cells are functionally evaluated by mitochondrial volume studies for future development of therapeutic tactics. METHODS: 1. C6 cells were cultured in MEM solution, and morphological cell changes were studied with and without temozolomide (TMZ) treatment. 2. Mitochondrial volume of C6 cell in these conditions was measured by mitochondrial mass specific fluorescence probe. 3. C6 cells were implanted into rat's brain and observed the growth in the normal brain tissue. RESULTS: 1. Spindle cells grew in early period, and formed syncytiums. As syncytiums multiplied, mitotic cells began to appear, and typical GBM features developed. During TMZ treatment, multiform cells were mostly destroyed, while spindle cells survived. 2. By TMZ treatment, the number of survived C6 cells decreased, but the volume of mitochondria per unit of C6 cells increased, as the concentration of TMZ increased. 3. The same cell growth pattern was identified in implanted tumor, as seen in cultured cells growth. DISCUSSION AND CONCLUSION: 1. Histologically CD15-positive spindle cells have much higher resistance for survival against TMZ than fully developed multiform cells. 2. Increased mitochondrial volume in survived C6 cells is likely related to metabolic activation of spindle cells under TMZ treatment. 3. The control of mitochondrial hyperactivity of C6 cells should be one of the important means for GBM treatment in experimental GBM, and probably in humans.

PO58RE-DO SURGERY IN PATIENTS WITH GLIOBLASTOMA MULTIFORME - 8 YEARS OF EXPERIENCE FROM A SINGLE CENTRE

INTRODUCTION: There remains debate on whether patients with recurrence of glioblastoma multiforme (GBM) should undergo further debulking surgery. Here we present the outcomes for all patients that underwent re-do surgery in a single centre as part of preparations for a randomised trial to investigate the benefits of re-do surgery for GBM. METHOD: Case notes for all patients with a diagnosis of GBM that had more than one debulking operation were reviewed from the last 8 years. RESULTS: 29 patients had a total of 2 debulking procedures and 2 patients had 3 debulking procedures. Excluding 3 patients still alive at the time of this review, median duration of survival from diagnosis was 530 days, and median duration of survival after re-do surgery was 193 days. The median interval between first and second procedures was 345 days. The median age at diagnosis was 52, and the average Karnofsky Performance Status at time of first surgery was 94%, which dropped to 80% prior to re-do surgery. 3 patients (9.6%) developed wound infections after re-do surgery, and 4 patients (12.9%) developed new neurological deficits.Duration of survival after re-do surgery was increased in patients that had Gliadel® wafers placed at the time of re-do surgery from a median of 218 days compared to 165 days in patients where Gliadel® was not used. MGMT methylation status was available for 10 patients who had been operated on since 2012. Patients who were methylated had a median survival of 274 days after re-do surgery (excluding one person who was still alive), compared with 167 days for those who were un-methylated. CONCLUSION: Our single centre experience supports existing data on outcomes following re-do surgery for GBM.

Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients.

BackgroundDexamethasone (DXM) is commonly used in the management of cerebral edema in patients diagnosed with glioblastoma multiforme (GBM). Bevacizumab (BEV) is FDA-approved for the progression or recurrence of GBM but has not been shown to improve survival when given for newly diagnosed patients concurrently with radiation (RT) and temozolomide (TMZ). Both DXM and BEV reduce cerebral edema, however, DXM has been shown to induce cytokine cascades which could interfere with cytotoxic therapy. We investigated whether DXM would reduce survival of GBM patients in the setting of concurrent TMZ and BEV administration.MethodsWe reviewed the treatment of all 73 patients with GBM who received definitive therapy at our institution from 2005 to 2013 with RT (60 Gy) delivered with concurrent daily TMZ (75 mg/m2). Of these, 34 patients also were treated with concurrent BEV (10 mg/kg every two weeks). Patients received adjuvant therapy (TMZ or TMZ/Bev) until either progression, discontinuation due to toxicity, or 12 months after radiation completion. All patients who had GBM progression with TMZ were offered BEV for salvage therapy, with 19 (56 %) receiving BEV.ResultsWith a median follow-up of 15.6 months, 67 (91.8 %) patients were deceased. The OS for the entire cohort was 15.9 months, while the PFS was 7.7 months. The extent of resection was a prognostic indicator for OS (p = .0044). The median survival following gross tumor resection (GTR) was 22.5 months, subtotal resection (STR) was 14.9 months, and biopsy was 12.1 months. The addition of BEV to TMZ with RT was borderline significantly associated with increased PFS (9.4 vs. 5.1 months, p = 0.0574) although was not significantly associated with OS (18.1 vs. 15.3 months respectively, p = 0.3064). In patients receiving TMZ, DXM use concurrent with RT was a poor prognostic indicator of both OS (12.7 vs. 22.6 months, p = 0.003) and PFS (3.6 vs. 8.4 months, p <0.0001). DXM did not reduce OS in patients who received TMZ and BEV concurrently with RT (22.9 vs 22.8 months, p = 0.4818). On multivariable analysis, DXM use predicted an unfavorable OS hazard ratio (HR) = 1.72, p = 0.045).ConclusionsOur results with TMZ, BEV, and RT are similar to previous studies in terms of PFS and OS. DXM use during RT with concurrent TMZ correlated with reduced OS and PFS unless BEV was administered.

Resveratrol sensitizes glioblastoma-initiating cells to temozolomide by inducing cell apoptosis and promoting differentiation.

Glioblastoma-initiating cells play crucial roles in the origin, growth, and recurrence of glioblastoma multiforme. The elimination of glioblastoma-initiating cells is believed to be a key strategy for achieving long-term survival of glioblastoma patients due to the highly resistant property of glioblastoma-initiating cells to temozolomide. Resveratrol, a naturally occurring polyphenol, has been widely studied as a promising candidate for cancer prevention and treatment. Whether resveratrol could enhance the sensitivity of glioblastoma-initiating cells to temozolomide therapy has not yet been reported. Here, using patient-derived glioblastoma-initiating cell lines, we found that resveratrol sensitized glioblastoma-initiating cells to temozolomide both in vitro and in vivo. Furthermore, we showed that resveratrol enhanced glioblastoma-initiating cells to temozolomide-induced apoptosis through DNA double-stranded breaks/pATM/pATR/p53 pathway activation, and promoted glioblastoma-initiating cell differentiation involving p-STAT3 inactivation. Our results propose that temozolomide and resveratrol combination strategy may be effective in the management of glioblastoma patients, particularly for those patients who have been present with a high abundance of glioblastoma-initiating cells in their tumors and show slight responsiveness to temozolomide.

Targeting Glioblastoma with the Use of Phytocompounds and Nanoparticles.

Glioblastoma multiforme (GBM) are extremely lethal and still poorly treated primary brain tumors, characterized by the presence of highly tumorigenic cancer stem cell (CSC) subpopulations, considered responsible for tumor relapse. In order to successfully eradicate GBM growth and recurrence, new anti-cancer strategies selectively targeting CSCs should be designed. CSCs might be eradicated by targeting some of their cell surface markers and transporters, inducing their differentiation, impacting their hyper-glycolytic metabolism, inhibiting CSC-related signaling pathways and/or by targeting their microenvironmental niche. In this regard, phytocompounds such as curcumin, isothiocyanates, resveratrol and epigallocatechin-3-gallate have been shown to prevent or reverse cancer-related epigenetic dysfunctions, reducing tumorigenesis, preventing metastasis and/or increasing chemotherapy and radiotherapy efficacy. However, the actual bioavailability and metabolic processing of phytocompounds is generally unknown, and the presence of the blood brain barrier often represents a limitation to glioma treatments. Nowadays, nanoparticles (NPs) can be loaded with therapeutic compounds such as phytochemicals, improving their bioavailability and their targeted delivery within the GBM tumor bulk. Moreover, NPs can be designed to increase their tropism and specificity toward CSCs by conjugating their surface with antibodies specific for CSC antigens, with ligands or with glucose analogues. Here we discuss the use of phytochemicals as anti-glioma agents and the applicability of phytochemical-loaded NPs as drug delivery systems to target GBM. Additionally, we provide some examples on how NPs can be specifically formulated to improve CSC targeting.

Resveratrol Inhibits the Invasion of Glioblastoma-Initiating Cells via Down-Regulation of the PI3K/Akt/NF-κB Signaling Pathway.

Invasion and metastasis of glioblastoma-initiating cells (GICs) are thought to be responsible for the progression and recurrence of glioblastoma multiforme (GBM). A safe drug that can be applied during the rest period of temozolomide (TMZ) maintenance cycles would greatly improve the prognosis of GBM patients by inhibiting GIC invasion. Resveratrol (RES) is a natural compound that exhibits anti-invasion properties in multiple tumor cell lines. The current study aimed to evaluate whether RES can inhibit GIC invasion in vitro and in vivo. GICs were identified using CD133 and Nestin immunofluorescence staining and tumorigenesis in non-obese diabetic severe combined immunodeficient (NOD/SCID) mice. Invasive behaviors, including the adhesion, invasion and migration of GICs, were determined by tumor invasive assays in vitro and in vivo. The activity of matrix metalloproteinases (MMPs) was measured by the gelatin zymography assay. Western blotting analysis and immunofluorescence staining were used to determine the expression of signaling effectors in GICs. We demonstrated that RES suppressed the adhesion, invasion and migration of GICs in vitro and in vivo. Moreover, we proved that RES inhibited the invasion of GICs via the inhibition of PI3K/Akt/NF-κB signal transduction and the subsequent suppression of MMP-2 expression.

Morusin inhibits glioblastoma stem cell growth in vitro and in vivo through stemness attenuation, adipocyte transdifferentiation, and apoptosis induction

Glioblastoma multiforme (GBM) cancer stem cells (GSCs) are responsible for the progression and recurrence of GBM after conventional therapy. Morusin possesses anti-cancer activity in vitro. The purpose of this study is to confirm the growth inhibition effect of morusin on human GSCs growth in vitro and in vivo and to explore the possible mechanism of its activity. Human GSCs were enriched under nonadhesive culture system, and characterized through neurosphere formation, toluidine blue staining, immunofluorescence staining, Western blotting analysis of stemness markers of CD133, nestin, Sox2 and Oct4, and tumorigenecity in vivo; the growth inhibition effect of morusin on human GSCs in vitro and in vivo were tested by cell cytotoxicity, neurosphere formation inhibition, adipogenic differentiation, apoptosis induction, and tumor growth inhibition in vivo assays. The potential molecular mechanisms underlying the growth inhibition effect of morusin on GSCs in vitro and in vivo were investigated with Western blotting evaluation of stemness, adipogenic, and apoptotic proteins in morusin treated GSCs and tumor tissues. GSCs enriched under nonadhesive culture system possess stemness characterstics; Morusin inhibited GSCs growth in vitro and in vivo, it reduced stemness of GSCs, induced them adipocyte-like transdifferention and apoptosis. Morusin has the potential to inhibit human GSCs growth in vitro and in vivo through stemness attenuation, adipocyte transdifferentiation, and apoptosis induction.

Modulation of A1 and A2B adenosine receptor activity: a new strategy to sensitise glioblastoma stem cells to chemotherapy.

Therapies that target the signal transduction and biological characteristics of cancer stem cells (CSCs) are innovative strategies that are used in combination with conventional chemotherapy and radiotherapy to effectively reduce the recurrence and significantly improve the treatment of glioblastoma multiforme (GBM). The two main strategies that are currently being exploited to eradicate CSCs are (a) chemotherapeutic regimens that specifically drive CSCs toward cell death and (b) those that promote the differentiation of CSCs, thereby depleting the tumour reservoir. Extracellular purines, particularly adenosine triphosphate, have been implicated in the regulation of CSC formation, but currently, no data on the role of adenosine and its receptors in the biological processes of CSCs are available. In this study, we investigated the role of adenosine receptor (AR) subtypes in the survival and differentiation of CSCs isolated from human GBM cells. Stimulation of A1AR and A2BAR had a prominent anti-proliferative/pro-apoptotic effect on the CSCs. Notably, an A1AR agonist also promoted the differentiation of CSCs toward a glial phenotype. The differential effects of the two AR agonists on the survival and/or differentiation of CSCs may be ascribed to their distinct regulation of the kinetics of ERK/AKT phosphorylation and the expression of hypoxia-inducible factors. Most importantly, the AR agonists sensitised CSCs to the genotoxic activity of temozolomide (TMZ) and prolonged its effects, most likely through different mechanisms, are as follows: (i) by A2BAR potentiating the pro-apoptotic effects of TMZ and (ii) by A1AR driving cells toward a differentiated phenotype that is more sensitive to TMZ. Taken together, the results of this study suggested that the purinergic system is a novel target for a stem cell-oriented therapy that could reduce the recurrence of GBM and improve the survival rate of GBM patients.

AT-05 * PHASE II STUDY OF IFOSFAMIDE, CARBOPLATIN, AND ETOPOSIDE INPATIENTS WITH A FIRST RECURRENCE OF GLIOBLASTOMA MULTIFORME

Object The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a Phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good-quality life. Methods This trial was an open-label, single-center Phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1000 mg/m2 on Days 1, 2, and 3), carboplatin (110 mg/m2 on Day 1), etoposide (100 mg/m2 on Days 1, 2, and 3), every 6 weeks. Results Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22–50%). The median duration of PFS was 17 weeks (95% CI 10–24 weeks). T...

P05 * VARIABILITY IN FOLLOW UP IMAGING GUIDELINES AFTER THE COMPLETION OF PRIMARY THERAPY IN GLIOBLASTOMA MULTIFORME

INTRODUCTION: There is no clear definitive follow up surveillance imaging guideline after the completion of primary therapy in glioblastoma multiforme (GBM). Here we provide the first report analysing international, national and local guidelines in GBM imaging surveillance. METHOD: We performed a systematic review of GBM management guidelines indexed in PUBMED and EMBASE databases up until October 2013. We also searched for GBM guidelines on websites of relevant international and national societies. To clarify local recommendations within the UK, we reviewed all guideline documents produced by local neuro-oncology multidisciplinary teams (MDTs; n = 28) in the UK accessed via the Care Quality Improvement Network (CQuIN) database. For all the relevant guidelines identified, we extracted imaging recommendations for the period following completion of primary therapy. RESULTS: Out of the identified guidelines produced by international and national societies, only 6 had follow up imaging guidelines with variability in imaging frequency ranging from 1-2 monthly (1 guideline), 2-4 monthly (1), 2-3 monthly (2), to 3-4 monthly (2). Twenty out of the 28 neuro-oncology MDTs had imaging guidelines. Of these, 18 had guidelines on imaging after completion of primary therapy, with also a wide variability in imaging frequency from 2 monthly (2 guidelines), 2-4 monthly (1), 3 monthly (6), 3-4 monthly (1), 3-6 monthly (2), 6 monthly (4), and yearly (2). CONCLUSION: The guidelines for follow up imaging surveillance after the completion of primary therapy in GBM are variable. Future studies should assess effectiveness of these guidelines in detecting assymptomatic GBM recurrence.