Volume 1 (6). July 2013.

GLIOMAS.ORG NEWSLETTER
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GLIOMAS.ORG NEWSLETTERS is a short electronic newsletter periodically released by e-mail as a PDF file to subscribers who want to keep updated on the latest advances on glioma research including but not limited to:
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IN THIS ISSUE
IMAGES IN GLIOMAS RESEARCH: The transcription factor FOXP3 Convection enhanced delivery and in vivo imaging of polymeric nanoparticles Glioma Spheroids Obtained Via Ultrasonic Aspiration are Viable and Express Stem Cell Markers Sorafenib plus Daily Low-dose Temozolomide for Relapsed Glioblastoma Prolonged administration of adjuvant temozolomide improves survival Enhanced accumulation of curcumin and temozolomide loaded magnetic nanoparticles in gliomas Detection of EGFRvIII mutant DNA in the peripheral blood of brain tumor patients Salinomycin prevents regrowth and partially depletes surviving glioma cells RETRACTION Glioma grading: sensitivity, specificity, positive and negative predictive values of diffusion and perfusion imaging

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IMAGES IN GLIOMAS RESEARCH

The transcription factor FOXP3 plays an essential role in regulatory T cell development and function. In addition, it has recently been identified as a tumor suppressor in different cancers. Here, we report that FOXP3 is expressed in normal brain but strongly down-regulated in glioblastoma (GB) and in corresponding GB stem-like cells growing in culture as neurospheres (GB-NS), as evaluated by real time-PCR and confirmed by immunohistochemistry on an independent set of GB. FOXP3 expression was higher in low-grade gliomas than in GB. Interestingly, we also found that neurosphere generation, a feature present in 58% of the GB that we examined, correlated with lower expression of FOXP3 and shorter patient survival. FOXP3 silencing in one GB-NS expressing measurable levels of the gene caused a significant increase in proliferation and migration as well as highly aggressive growth in xenografts. Conversely, FOXP3 over-expression impaired GBNS migration and proliferation in vitro. We also demonstrated using ChiP that FOXP3 is a transcriptional regulator of p21 and c-MYC supporting the idea that dysregulated expression of these factors is a major mechanism of tumorigenesis driven by the loss of FOXP3 expression in gliomas. These findings support the assertion that FOXP3 exhibits tumor suppressor activity in glioblastomas.

Two representative GB specimens labelled with anti-human FOXP3 antibody (magnification 20X). The section on the left shows one GB completely negative for FOXP3 reactivity. The section on the right shows one GB with FOXP3+ cells mainly concentrated around blood vessels. B) Left panel. FOXP3 staining is detected in one cell with lymphocyte morphology (small and round nucleus; arrow, brown) and in one cell with the morphologic features of tumor cells (large, irregular nucleus, brown). Central panel: Infiltrating lymphocytes identified using CD3 as the marker are localized near blood vessels (thin arrow, blue). Right panel: one FOXP3+ GFAP+ tumor cell (thick arrow, red) is located around a blood vessel together with a CD3+ lymphocyte (thin arrow) (magnification 40X).

From: Frattini V, Pisati F, Speranza MC, Poliani PL, Frig G, Cantini G, Kapetis D, Cominelli M, Rossi A, Finocchiaro G, Pellegatta S. FOXP3, a novel glioblastoma oncosuppressor, affects proliferation and migration. Oncotarget. 2012 Sep 22;3(10):1146-57. Print 2012 Oct. PMID: 23888189

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NANOMEDICINE Convection enhanced delivery and in vivo imaging of polymeric nanoparticles The authrs of this study describe a polymeric nanoparticle vector that not only delivers viable therapeutic (temozolomide), but can also be tracked in vivo using MRI. The nanoparticles we administered by convection enhanced delivery (CED) that can disperse nanoparticles through the rodent brain and their distribution is accurately visualized by MRI. CED of TMZ bearing nanoparticles prolongs the survival of animals with intracranial xenografts compared to control
Bernal GM, Lariviere MJ, Mansour N, Pytel P, Cahill KE, Voce DJ, Kang S, Spretz R, Welp U, Noriega SE, Nunez L, Larsen GF, Weichselbaum RR, Yamini B. Convection enhanced delivery and in vivo imaging of polymeric nanoparticles for the treatment of malignant glioma.Nanomedicine. 2013 Jul 23. doi:pii: S1549-9634(13)00343-2. 10.1016/j.nano.2013.07.003. [Epub ahead of print] PMID: 23891990

combination was feasible and safe, showing some activity in patients with relapsed GBM.
Zustovich F, Landi L, Lombardi G, Porta C, Galli L, Fontana A, Amoroso D, Galli C, Andreuccetti M, Falcone A, Zagonel V. Sorafenib plus Daily Low-dose Temozolomide for Relapsed Glioblastoma: A Phase II Study. Anticancer Res. 2013 Aug;33(8):3487-94. PMID: 23898124

CHEMOTHERAPY Prolonged administration of adjuvant temozolomide improves survival Radiotherapy with concomitant and adjuvant temozolomide (six cycles) is the standard treatment after surgery in glioblastoma patients. In this study, 38 patients received six cycles, while 20 received nine or more (median=14) cycles. The risk of recurrence was significantly higher in the group receiving six cycles compared to the other group. Prolonged treatment improved progression-free survival (p=0.03) and overall survival (p=0.01) in multivariate analysis without a significant increase in toxicity. Prospective studies in larger populations are needed to better-define the population to whom it can be proposed and its optimal duration
Darlix A, Baumann C, Lorgis V, Ghiringhelli F, Blonski M, Chauffert B, Zouaoui S, Pinelli C, Rech F, Beauchesne P, Taillandier L. Prolonged administration of adjuvant temozolomide improves survival in adult patients with glioblastoma. Anticancer Res. 2013 Aug;33(8):3467-74. PMID: 23898121

STEM CELL BIOLOGY Glioma Spheroids Obtained Via Ultrasonic Aspiration are Viable and Express Stem Cell Markers Tissue fragments removed by ultrasonic aspirators were able to produce cell lines that were both capable of spheroid formation at clonal density and tumor formation in vivo. The cells expressed the stem cell markers CD133, Bmi-1, nestin and Sox2. Thus, ultrasonic spheroids are a new tissue resource for glioma research.
Jensen SS, Aaberg-Jessen C, Andersen C, Schrder HD, Kristensen BW. Glioma Spheroids Obtained Via Ultrasonic Aspiration are Viable and Express Stem Cell Markers: A New Tissue Resource for Glioma Research. Neurosurgery. 2013 Jul 24. [Epub ahead of print] PMID:23887192

Enhanced accumulation of curcumin and temozolomide loaded magnetic nanoparticles in gliomas

PHASE II CLINICAL TRIAL Sorafenib plus Daily Low-dose Temozolomide for Relapsed Glioblastoma

In the present study, magnetic nanoparticles (MNPs) based drug delivery approach for co- delivering of potent chemotherapeutic drugs such as Curcumin (herbal drug) and Temozolomide (DNA methylating agent) has been implemented. The dual drug loaded MNPs formulations demonstrated higher cytotoxic effect than single drug loaded MNPs formulations as compared to their corresponding native drugs in 2-D and 3-D culture. The combination index (CI) analysis revealed synergistic mode of action of dual drug loaded MNPs formulations, which was further confirmed by cell death induction assay mediated by acridine orange (AO) / propidium iodide (PI) staining, illustrating higher efficacy of the formulation towards GBM therapy gliomas.
Dilnawaz F, Sahoo SK. Enhanced accumulation of curcumin and temozolomide loaded magnetic nanoparticles executes profound cytotoxic effect in glioblastoma spheroid model. Eur J Pharm Biopharm. 2013 Jul 24. doi:pii: S0939-6411(13)00258-0. 10.1016/j.ejpb.2013.07.013. [Epub ahead of print] PMID:23891772

Sorafenib Structure

In a phase II trial Forty-three patients (median age=60.0 years) naive for antiangiogenic agents received 400 mg sorafenib twice daily plus TMZ 40 mg/m(2)/day until disease progression. Five patients (12%) achieved partial response, 18 (43%) stable disease, 20 (48%) showed progression. The median time-toprogression was 3.2 months, 6-month progression-free survival was 26%, and median overall survival was 7.4 months. This

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BIOMARKERS
Detection of EGFRvIII mutant DNA in the peripheral blood of brain tumor patients

II Anticancer Drugs Meeting 22-23 August, 2013 Stockholm, Sweden

The EGFRvIII, a truncated extracellular mutant of the EGF receptor (EGFR) found in about a third of GBMs is associated with chemo- and radio-resistance. In this study, the authors developed a strategy to detect EGFRvIII deletion in the circulating tumor DNA. In three patients carrying the EGFRvIII deletion the circulating DNA status for EGFRvIII correlated with the analysis performed on the respective tumor samples, and its level seems to correlate with the extent of the tumor resection. Thus, EGFRvIII used as a semi-quantitative blood biomarker may represent a strategy to (1) screen patients for an antiEGFRvIII therapy and (2) monitor the patients' response to treatment
Salkeni MA, Zarzour A, Ansay TY, McPherson CM, Warnick RE, Rixe O, Bahassi EM. Detection of EGFRvIII mutant DNA in the peripheral blood of brain tumor patients. J Neurooncol. 2013 Jul 23. [Epub ahead of print] PMID: 23877363

Confirmed Speakers from US Germany France UK Sweden Egypt Australia Israel Japan Saudi Arabia Mexico Russia and other countries will present their work

UPCOMING ARTICLES Salinomycin prevents regrowth and partially depletes surviving glioma cells www.anticancerdrugs.org/2013

Low concentration of salinomycin prevents regrowth and partially depletes human glioma cells surviving high concentrations of alkylating agents. (In Press) Delwar Zahid M, Avramidis Dimitrios, Siden ke, Cruz Mabel, Paulsson Kajsa and Yakisich J. Sebastian
Source: http://benthamscience.com/UpcomingArticles.php?JCode=CCAND

RETRACTION Glioma grading: sensitivity, specificity, positive and negative predictive values of diffusion and perfusion imaging

An article published in 2009 in the Journal of Neurooncologyhas been retracted citing as it contains portions of other authors writings on the same topic in other publications , withut sufficient attribution to these earlier works were given.
Arvinda HR, Kesavadas C, Sarma PS, Thomas B, Radhakrishnan VV, Gupta AK, Kapilamoorthy TR, Nair S. Retraction Note to: Glioma rading: sensitivity, specificity, positive and negative predictive values of diffusion and perfusion imaging. J Neurooncol. 2013 Jul 24. [Epub ahead of print] No abstract available. PMID: 23881261 ARTICLE RETRACTED: Arvinda HR, Kesavadas C, Sarma PS, Thomas B, Radhakrishnan VV, Gupta AK, Kapilamoorthy TR, Nair S. Glioma grading: sensitivity, specificity, positive and negative predictive values of diffusion and perfusion imaging. J Neurooncol. 2009 Aug;94(1):87-96. doi: 10.1007/s11060-009-9807-6. Epub 2009 Feb 20. PMID: 19229590

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