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Author D'Alessandris, Q.G.; Biffoni, M.; Martini, M.; Runci, D.; Buccarelli, M.; Cenci, T.; Signore, M.; Stancato, L.; Olivi, A.; De Maria, R.; Larocca, L.M.; Ricci-Vitiani, L.; Pallini, R. url  doi
openurl 
  Title The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response Type (up) Journal Article
  Year 2017 Publication Neuro-Oncology Abbreviated Journal Neuro Oncol  
  Volume 19 Issue 8 Pages 1097-1108  
  Keywords cancer stem cells; glioblastoma; radiotherapy; temozolomide; treatment outcome  
  Abstract Background: Advances from glioma stemlike cell (GSC) research, though increasing our knowledge of glioblastoma (GBM) biology, do not influence clinical decisions yet. We explored the translational power of GSC-enriched cultures from patient-derived tumorspheres (TS) in predicting treatment response. Methods: The relationship between TS growth and clinical outcome was investigated in 52 GBMs treated with surgical resection followed by radiotherapy and temozolomide (TMZ). The effect on TS of radiation (6 to 60 Gy) and of TMZ (3.9 muM to 1 mM) was related with patients' survival. Results: Generation of TS was an independent factor for poor overall survival (OS) and poor progression-free survival (PFS) (P < .0001 and P = .0010, respectively). Growth rate and clonogenicity of TS predicted poor OS. In general, TS were highly resistant to both radiation and TMZ. Resistance to TMZ was stronger in TS with high clonogenicity and fast growth (P < .02). Shorter PFS was associated with radiation LD50 (lethal dose required to kill 50% of TS cells) >12 Gy of matched TS (P = .0484). A direct relationship was found between sensitivity of TS to TMZ and patients' survival (P = .0167 and P = .0436 for OS and PFS, respectively). Importantly, values for TMZ half-maximal inhibitory concentration <50 muM, which are in the range of plasma levels achieved in vivo, identified cases with longer OS and PFS (P = .0020 and P = .0016, respectively). Conclusions: Analysis of TS holds translational relevance by predicting the response of parent tumors to radiation and, particularly, to TMZ. Dissecting the clonogenic population from proliferating progeny in TS can guide therapeutic strategies to a more effective drug selection and treatment duration.  
  Address Institute of Neurosurgery, Universita Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy; Institute of Pathology, Universita Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1522-8517 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28204560 Approved no  
  Call Number ref @ user @ Serial 96607  
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Author Howard, C.M.; Valluri, J.; Alberico, A.; Julien, T.; Mazagri, R.; Marsh, R.; Alastair, H.; Cortese, A.; Griswold, M.; Wang, W.; Denning, K.; Brown, L.; Claudio, P.P. url  doi
openurl 
  Title Analysis of Chemopredictive Assay for Targeting Cancer Stem Cells in Glioblastoma Patients Type (up) Journal Article
  Year 2017 Publication Translational Oncology Abbreviated Journal Transl Oncol  
  Volume 10 Issue 2 Pages 241-254  
  Keywords  
  Abstract INTRODUCTION: The prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy remains very poor (less than 15 months). GBMs have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. The highly invasive nature of high-grade gliomas and their inherent resistance to therapy lead to very high rates of recurrence. For these reasons, not all patients with similar diagnoses respond to the same chemotherapy, schedule, or dose. Administration of ineffective anticancer therapy is not only costly but more importantly burdens the patient with unnecessary toxicity and selects for the development of resistant cancer cell clones. We have developed a drug response assay (ChemoID) that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. Providing the treating physician with drug response information on a panel of approved drugs will aid in personalized therapy selections of the most effective chemotherapy for individual patients, thereby improving outcomes. A prospective study was conducted evaluating the use of the ChemoID drug response assay in GBM patients treated with standard of care. METHODS: Forty-one GBM patients (mean age 54 years, 59% male), all eligible for a surgical biopsy, were enrolled in an Institutional Review Board-approved protocol, and fresh tissue samples were collected for drug sensitivity testing. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk tumor, and combined assay responses for the standard-of-care TMZ treatment; sensitivities/specificities, areas under the curve (AUCs), and risk reclassification components were examined. RESULTS: Median follow-up was 8 months (range 3-49 months). For every 5% increase in in vitro CSC cell kill by TMZ, 12-month patient response (nonrecurrence of cancer) increased two-fold, OR=2.2 (P=.016). Similar but somewhat less supported associations with the bulk tumor test were seen, OR=2.75 (P=.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 (P=.036), but a much attenuated remaining bulk tumor association, OR=1.46 (P=.472). AUCs and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC=0.989 [sensitivity=100/specificity=97], 0.972 [100/89], and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification nonevent net reclassification improvement [NRI] and overall NRI=0.111, P=.030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months for those with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS outcomes. Panel results across 14 potential other treatments indicated that 34/41 (83%) potentially more optimal alternative therapies may have been chosen using CSC results, whereas 27/41 (66%) alternative therapies may have been chosen using bulk tumor results. CONCLUSIONS: The ChemoID CSC drug response assay has the potential to increase the accuracy of bulk tumor assays to help guide individualized chemotherapy choices. GBM cancer recurrence may occur quickly if the CSC test has a low in vitro cell kill rate even if the bulk tumor test cell kill rate is high.  
  Address Department of BioMolecular Sciences, National Center for Natural Products Research, University of Mississippi, University, MS; Department of Radiation Oncology, University of Mississippi Medical Center Cancer Institute, Jackson, MS 39216. Electronic address: pclaudio@olemiss.edu  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1936-5233 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28199863 Approved no  
  Call Number ref @ user @ Serial 96608  
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Author Gersey, Z.C.; Rodriguez, G.A.; Barbarite, E.; Sanchez, A.; Walters, W.M.; Ohaeto, K.C.; Komotar, R.J.; Graham, R.M. url  doi
openurl 
  Title Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species Type (up) Journal Article
  Year 2017 Publication BMC Cancer Abbreviated Journal BMC Cancer  
  Volume 17 Issue 1 Pages 99  
  Keywords Acetylcysteine/pharmacology; Adult; Antineoplastic Agents/*pharmacology; Cell Proliferation/drug effects; Cell Survival/drug effects; Curcumin/*pharmacology; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Free Radical Scavengers; Glioblastoma/drug therapy/pathology; Humans; Inhibitor of Apoptosis Proteins/metabolism; Inhibitory Concentration 50; Mitogen-Activated Protein Kinases/metabolism; Neoplastic Stem Cells/*drug effects; Oxidative Stress; Reactive Oxygen Species/*metabolism; STAT3 Transcription Factor/metabolism; Tumor Cells, Cultured; Brain tumor; Curcumin; Glioblastoma; Natural product; Reactive oxygen species; Stat3; Stem cell  
  Abstract BACKGROUND: Glioblastoma Multiforme (GBM) is the most common and lethal form of primary brain tumor in adults. Following standard treatment of surgery, radiation and chemotherapy, patients are expected to survive 12-14 months. Theorized cause of disease recurrence in these patients is tumor cell repopulation through the proliferation of treatment-resistant cancer stem cells. Current research has revealed curcumin, the principal ingredient in turmeric, can modulate multiple signaling pathways important for cancer stem cell self-renewal and survival. METHODS: Following resection, tumor specimens were dissociated and glioblastoma stem cells (GSCs) were propagated in neurosphere media and characterized via immunocytochemistry. Cell viability was determined with MTS assay. GSC proliferation, sphere forming and colony forming assays were conducted through standard counting methods. Reactive oxygen species (ROS) production was examined using the fluorescent molecular probe CM-H2DCFA. Effects on cell signaling pathways were elucidated by western blot. RESULTS: We evaluate the effects of curcumin on patient-derived GSC lines. We demonstrate a curcumin-induced dose-dependent decrease in GSC viability with an approximate IC50 of 25 muM. Treatment with sub-toxic levels (2.5 muM) of curcumin significantly decreased GSC proliferation, sphere forming ability and colony forming potential. Curcumin induced ROS, promoted MAPK pathway activation, downregulated STAT3 activity and IAP family members. Inhibition of ROS with the antioxidant N-acetylcysteine reversed these effects indicating a ROS dependent mechanism. CONCLUSIONS: Discoveries made in this investigation may lead to a non-toxic intervention designed to prevent recurrence in glioblastoma by targeting glioblastoma stem cells.  
  Address Department of Neurological Surgery, University of Miami Brain Tumor Initiative (UMBTI) Research Laboratory, Lois Pope LIFE Center, 2nd Floor, 1095 NW 14th Terrace, Miami, Florida, 33136, USA. rgraham@med.miami.edu  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1471-2407 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28160777 Approved no  
  Call Number ref @ user @ Serial 96610  
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Author Munthe, S.; Halle, B.; Boldt, H.B.; Christiansen, H.; Schmidt, S.; Kaimal, V.; Xu, J.; Zabludoff, S.; Mollenhauer, J.; Poulsen, F.R.; Kristensen, B.W. url  doi
openurl 
  Title Shift of microRNA profile upon glioma cell migration using patient-derived spheroids and serum-free conditions Type (up) Journal Article
  Year 2017 Publication Journal of Neuro-Oncology Abbreviated Journal J Neurooncol  
  Volume 132 Issue 1 Pages 45-54  
  Keywords Glioblastoma; MicroRNA; Migration; Serum-free; Target  
  Abstract Glioblastoma multiforme (GBM) is the most frequent malignant primary brain tumor. A major reason for the overall median survival being only 14.6 months is migrating tumor cells left behind after surgery. Another major reason is tumor cells having a so-called cancer stem cell phenotype being therefore resistant towards traditional chemo- and radiotherapy. A group of novel molecular targets are microRNAs (miRNAs). MiRNAs are small non-coding RNAs exerting post-transcriptional regulation of gene expression. The aim of this study was to identify differentially expressed miRNAs in migrating GBM cells using serum-free stem cell conditions. We used patient-derived GBM spheroid cultures for a novel serum-free migration assay. MiRNA expression of migrating tumor cells isolated at maximum migration speed was compared with corresponding spheroids using an OpenArray Real-Time PCR System. The miRNA profiling revealed 30 miRNAs to be differentially expressed. In total 13 miRNAs were upregulated and 17 downregulated in migrating cells compared to corresponding spheroids. The three most deregulated miRNAs, miR-1227 (up-regulated), miR-32 (down-regulated) and miR-222 (down-regulated), were experimentally overexpressed. A non-significantly increased migration rate was observed after miR-1227 overexpression. A significantly reduced migration rate was observed after miR-32 and miR-222 overexpression. In conclusion a shift in microRNA profile upon glioma cell migration was identified using an assay avoiding serum-induced migration. Both the miRNA profiling and the functional validation suggested that miR-1227 may be associated with increased migration and miR-32 and miR-222 with decreased migration. These miRNAs may represent potential novel targets in migrating glioma cells.  
  Address Institute of Clinical Research, University of Southern Denmark, Winslowparken 19, 5000, Odense C, Denmark. bjarne.winther.kristensen@rsyd.dk  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0167-594X ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28091986 Approved no  
  Call Number ref @ user @ Serial 96611  
Permanent link to this record
 

 
Author Mistry, A.M.; Dewan, M.C.; White-Dzuro, G.A.; Brinson, P.R.; Weaver, K.D.; Thompson, R.C.; Ihrie, R.A.; Chambless, L.B. url  doi
openurl 
  Title Decreased survival in glioblastomas is specific to contact with the ventricular-subventricular zone, not subgranular zone or corpus callosum Type (up) Journal Article
  Year 2017 Publication Journal of Neuro-Oncology Abbreviated Journal J Neurooncol  
  Volume 132 Issue 2 Pages 341-349  
  Keywords Glioblastoma; Stem cells; Subgranular zone; Subventricular zone; Survival; Ventricular-subventricular zone  
  Abstract The clinical effect of radiographic contact of glioblastoma (GBM) with neurogenic zones (NZ)-the ventricular-subventricular (VSVZ) and subgranular (SGZ) zones-and the corpus callosum (CC) remains unclear and, in the case of the SGZ, unexplored. We investigated (1) if GBM contact with a NZ correlates with decreased survival; (2) if so, whether this effect is associated with a specific NZ; and (3) if radiographic contact with or invasion of the CC by GBM is associated with decreased survival. We retrospectively identified 207 adult patients who underwent cytoreductive surgery for GBM followed by chemotherapy and/or radiation. Age, preoperative Karnofsky performance status score (KPS), and extent of resection were recorded. Preoperative MRIs were blindly analyzed to calculate tumor volume and assess its contact with VSVZ, SGZ, CC, and cortex. Overall (OS) and progression free (PFS) survivals were calculated and analyzed with multivariate Cox analyses. Among the 207 patients, 111 had GBM contacting VSVZ (VSVZ+GBMs), 23 had SGZ+GBMs, 52 had CC+GBMs, and 164 had cortex+GBMs. VSVZ+, SGZ+, and CC+ GBMs were significantly larger in size relative to their respective non-contacting controls. Multivariate Cox survival analyses revealed GBM contact with the VSVZ, but not SGZ, CC, or cortex, as an independent predictor of lower OS, PFS, and early recurrence. We hypothesize that the VSVZ niche has unique properties that contribute to GBM pathobiology in adults.  
  Address Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232-2380, USA  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0167-594X ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28074322 Approved no  
  Call Number ref @ user @ Serial 96612  
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