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Sample records for glioblastoma treatment reason

  1. KIF11 inhibition for glioblastoma treatment: reason to hope or a struggle with the brain?

    International Nuclear Information System (INIS)

    Valensin, Silvia; Ghiron, Chiara; Lamanna, Claudia; Kremer, Andreas; Rossi, Marco; Ferruzzi, Pietro; Nievo, Marco; Bakker, Annette

    2009-01-01

    Glioblastomas (GBM) are typically comprised of morphologically diverse cells. Despite current advances in therapy, including surgical resection followed by radiation and chemotherapy, the prognosis for patients with GBM remains poor. Unfortunately, most patients die within 2 years of diagnosis of their disease. Molecular abnormalities vary among individual patients and also within each tumor. Indeed, one of the distinguishing features of GBM is its marked genetic heterogeneity. Due to the brain location of the tumor, the potential target inhibition for anticancer therapy must exhibit a manageable neurotoxicity profile in the concentration range in which the compounds show anti-proliferative activity. Kinesin KIF11 inhibition by small molecules such as Monastrol or Ispinesib is currently under investigation in the field of malignant tumors. In the current study we have assessed the relevance of the anti-mitotic Kinesin-like protein KIF11 in human GBM cell-lines. In this study the target was validated using a set of well characterised and potentially specific small molecule inhibitors of KIF11: an ispinesib analog, Monastrol, a Merck compound and 3 simplified derivatives of the Merck compound. Following an in silico selection, those compounds predicted to bear a favorable BBB permeation profile were assessed for their phenotypic effect on cell lines derived both from primary (U87MG) as well as treated (DBTRG-05-MG) glioblastomas. For some compounds, these data could be compared to their effect on normal human astrocytes, as well as their neurotoxicity on primary rat cortical neurons. The ispinesib analogue 1 showed an anti-proliferative effect on GBM cell lines by blocking them in the G2/M phase in a concentration range which was shown to be harmless to primary rat cortical neurons. Furthermore, ispinesib analog increased caspase 3/7-induced apoptosis in U87MG cells. In the area of cell cycle inhibition, KIF11 is critical for proper spindle assembly and represents an

  2. Immunotherapy for the Treatment of Glioblastoma

    Science.gov (United States)

    Thomas, Alissa A.; Ernstoff, Marc S.; Fadul, Camilo E.

    2012-01-01

    Glioblastoma, the most aggressive primary brain tumor, thrives in a microenvironment of relative immunosuppression within the relatively immune-privileged central nervous system. Despite treatments with surgery, radiation therapy, and chemotherapy, prognosis remains poor. The recent success of immunotherapy in the treatment of other cancers has renewed interest in vaccine therapy for the treatment of gliomas. In this article, we outline various immunotherapeutic strategies, review recent clinical trials data, and discuss the future of vaccine therapy for glioblastoma. PMID:22290259

  3. Treatment of glioblastoma with herbal medicines.

    Science.gov (United States)

    Trogrlić, Ivo; Trogrlić, Dragan; Trogrlić, Darko; Trogrlić, Amina Kadrić

    2018-02-13

    In the latest years, a lot of research studies regarding the usage of active agents from plants in the treatment of tumors have been published, but there is no data about successful usage of herbal remedies in the treatment of glioblastoma in humans. The phytotherapy involved five types of herbal medicine which the subjects took in the form of tea, each type once a day at regular intervals. Three patients took herbal medicine along with standard oncological treatment, while two patients applied for phytotherapy after completing medical treatment. The composition of herbal medicine was modified when necessary, which depended on the results of the control scans using the nuclear magnetic resonance technique and/or computed tomography. Forty-eight months after the introduction of phytotherapy, there were no clinical or radiological signs of the disease, in three patients; in one patient, the tumor was reduced and his condition was stable, and one patient lived for 48 months in spite of a large primary tumor and a massive recurrence, which developed after the treatment had been completed. The results achieved in patients in whom tumor regression occurred exclusively through the use of phytotherapy deserve special attention. In order to treat glioblastoma more effectively, it is necessary to develop innovative therapeutic strategies and medicines that should not be limited only to the field of conventional medicine. The results presented in this research paper are encouraging and serve as a good basis for further research on the possibilities of phytotherapy in the treatment of glioblastoma.

  4. Strategies of temozolomide in future glioblastoma treatment

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    Lee CY

    2017-01-01

    Full Text Available Chooi Yeng Lee School of Pharmacy, Monash University Malaysia, Selangor, Malaysia Abstract: Glioblastoma multiforme (GBM may be one of the most challenging brain tumors to treat, as patients generally do not live more than 2 years. This review aimed to give a timely review of potential future treatments for GBM by looking at the latest strategies, involving mainly the use of temozolomide (TMZ. Although these studies were carried out either in vitro or in rodents, the findings collectively suggested that we are moving toward developing a more efficacious therapy for GBM patients. Nanoparticles preparation was, by far, the most extensively studied strategy for targeted brain delivery. Therefore, the first section of this review presents a treatment strategy using TMZ-loaded nanocarriers, which encompassed nanoparticles, nanoliposomes, and nanosponges. Besides nanocarriers, new complexes that were formed between TMZ and another chemical agent or molecule have shown increased cytotoxicity and antitumor activity. Another approach was by reducing GBM cell resistance to TMZ, and this was achieved either through the suppression of metabolic change occurring in the cells, inhibition of the DNA repair protein, or up-regulation of the protein that mediates autophagy. Finally, the review collates a list of substances that have demonstrated the ability to suppress tumor cell growth. Keywords: cellular resistance, glioblastoma multiforme, nanoparticles, targeted delivery, temozolomide

  5. Therapeutic Advances using Combinational Therapy in the Treatment of Glioblastoma

    DEFF Research Database (Denmark)

    Staberg, Mikkel

    2017-01-01

    Glioblastoma is the most malignant brain tumor in adults. Median survival is only about 15 months despite aggressive treatment, consisting of surgery followed by radio- and chemotherapy, stressing the need for new therapies. Development of glioblastoma is thought to be a result of both genetic...... and epigenetic alterations, ultimately leading to oncogenic transformation of normal glia cells. Several features are suggested to give rise to the poor prognosis of glioblastoma including treatment resistance, a high degree of abnormal blood vessels, and high heterogeneity, both within the single tumor and from...... patient to patient. Thus, investigations are needed to identify the genetic-molecular alterations that glioblastoma tumors depend on in order to overcome treatment and regrow after initial surgery. The findings presented in this thesis illustrate the promising potential of combinational treatments...

  6. Treatment options and outcomes for glioblastoma in the elderly patient

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    Arvold ND

    2014-02-01

    Full Text Available Nils D Arvold,1 David A Reardon2 1Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA; 2Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA Abstract: Age remains the most powerful prognostic factor among glioblastoma (GBM patients. Half of all patients with GBM are aged 65 years or older at the time of diagnosis, and the incidence rate of GBM in patients aged over 65 years is increasing rapidly. Median survival for elderly GBM patients is less than 6 months and reflects less favorable tumor biologic factors, receipt of less aggressive care, and comorbid disease. The standard of care for elderly GBM patients remains controversial. Based on limited data, extensive resection appears to be more beneficial than biopsy. For patients with favorable Karnofsky performance status (KPS, adjuvant radiotherapy (RT has a demonstrated survival benefit with no observed decrement in quality of life. Concurrent and adjuvant temozolomide (TMZ along with RT to 60 Gy have not been prospectively studied among patients aged over 70 years but should be considered for patients aged 65–70 years with excellent KPS. Based on the recent NOA-08 and Nordic randomized trials, testing for O6-methylguanine-DNA-methyltransferase (MGMT promoter methylation should be performed routinely immediately after surgery to aid in adjuvant treatment decisions. Patients aged over 70 years with favorable KPS, or patients aged 60–70 years with borderline KPS, should be considered for monotherapy utilizing standard TMZ dosing for patients with MGMT-methylated tumors, and hypofractionated RT (34 Gy in ten fractions or 40 Gy in 15 fractions for patients with MGMT-unmethylated tumors. The ongoing European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial will help clarify the role for concurrent TMZ with hypofractionated RT. For elderly patients with poor KPS, reasonable

  7. Radiation induced sarcoma after treatment of glioblastoma: case report

    International Nuclear Information System (INIS)

    Rosa, Victor Domingos Lisita; Anjos, Caroline Souza dos; Candido, Priscila Barile Marchi; Dias Junior, Antonio Soares; Santos, Evandro Airton Sordi dos; Godoy, Antonio Carlos Cavalcante; Saggioro, Fabiano P.; Carlotti Junior, Carlos Gilberto; Oliveira, Harley Francisco de; Peria, Fernanda Maris

    2016-01-01

    Introduction: Glioblastoma multiform is the most lethal central nervous system neoplasm, with a median survival of around 13 months and the worst prognosis among all gliomas. The therapeutic approach of glioblastoma consists in neurosurgery with maximum possible resection of tumor volume, followed by radiotherapy and chemotherapy. Radiotherapy reduces the risk of tumor recurrence through direct and indirect damage to tumor deoxyribonucleic acid. The long-term effects of radiation therapy include tissue necrosis, vasculopathy, and radiation-induced neoplasia. The most reported secondary intracranial malignant tumors include meningiomas, gliomas, and sarcomas. The latency period between skull radiotherapy and the appearance of radioinduced lesions varies in the literature from six months to 47 years, with an average of 18.7 years. Case report: The present report describes the appearance of high-grade spindle cell sarcoma after ten months in a patient who received glioblastoma treatment at Hospital das Clínicas of Ribeirão Preto of the University of São Paulo. Conclusion: The rarity of this association is probably due to the poor survival of patients with glioblastoma, thus limiting the time to development of secondary neoplasia

  8. Tonsillary carcinoma after temozolomide treatment for glioblastoma multiforme: treatment-related or dual-pathology?

    Science.gov (United States)

    Binello, E; Germano, I M

    2009-08-01

    Glioblastoma multiforme is a primary malignant brain tumor with a prognosis of typically less than 2 years. Standard treatment paradigms include surgery, radiation therapy and temozolomide. Little data exists for temozolomide recommendations after the first 6 months. We present a case of a patient with glioblastoma multiforme treated with surgery, radiation and chronic temozolomide for 6 years. He continues to survive glioblastoma-recurrence-free, but developed tonsillary carcinoma. This case raises the question of whether this secondary solid-organ malignancy is treatment-related or dual pathology.

  9. A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

    Science.gov (United States)

    Kast, Richard E.; Boockvar, John A.; Brüning, Ansgar; Cappello, Francesco; Chang, Wen-Wei; Cvek, Boris; Dou, Q. Ping; Duenas-Gonzalez, Alfonso; Efferth, Thomas; Focosi, Daniele; Ghaffari, Seyed H.; Karpel-Massler, Georg; Ketola, Kirsi; Khoshnevisan, Alireza; Keizman, Daniel; Magné, Nicolas; Marosi, Christine; McDonald, Kerrie; Muñoz, Miguel; Paranjpe, Ameya; Pourgholami, Mohammad H.; Sardi, Iacopo; Sella, Avishay; Srivenugopal, Kalkunte S.; Tuccori, Marco; Wang, Weiguang; Wirtz, Christian R.; Halatsch, Marc-Eric

    2013-01-01

    To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma's compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed. PMID:23594434

  10. Glioblastoma: background, standard treatment paradigms, and supportive care considerations.

    Science.gov (United States)

    Ellor, Susan V; Pagano-Young, Teri Ann; Avgeropoulos, Nicholas G

    2014-01-01

    Glioblastoma is a brain tumor condition marked by rapid neurological and clinical demise, resulting in disproportionate disability for those affected. Caring for this group of patients is complex, intense, multidisciplinary in nature, and fraught with the need for expensive treatments, surveillance imaging, physician follow-up, and rehabilitative, psychological, and social support interventions. Few of these patients return to the workforce for any meaningful time frame, and because of the enormity of the financial burden that patients, their caregivers, and society face, utilization reviews become the focus of ethical scrutiny. © 2014 American Society of Law, Medicine & Ethics, Inc.

  11. Assessment and treatment relevance in elderly glioblastoma patients.

    Science.gov (United States)

    Bauchet, Luc; Zouaoui, Sonia; Darlix, Amélie; Menjot de Champfleur, Nicolas; Ferreira, Ernestine; Fabbro, Michel; Kerr, Christine; Taillandier, Luc

    2014-11-01

    Glioblastoma (GBM) is the most common malignant primary brain tumor. Its incidence continues to increase in the elderly because the older segment of the population is growing faster than any other age group. Most clinical studies exclude elderly patients, and "standards of care" do not exist for GBM patients aged >70 years. We review epidemiology, tumor biology/molecular factors, prognostic factors (clinical, imaging data, therapeutics), and their assessments as well as classic and specific endpoints plus recent and ongoing clinical trials for elderly GBM patients. This work includes perspectives and personal opinions on this topic. Although there are no standards of care for elderly GBM patients, we can hypothesize that (i) Karnofsky performance status (KPS), probably after steroid treatment, is one of the most important clinical factors for determining our oncological strategy; (ii) resection is superior to biopsy, at least in selected patients (depending on location of the tumor and associated comorbidities); (iii) specific schedules of radiotherapy yield a modest but significant improvement; (iv) temozolomide has an acceptable tolerance, even when KPS life and toxicity measures) will aid clinicians in determining the balance of potential benefits and risks of each oncological strategy. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. Treatment outcome and prognostic factors of adult glioblastoma multiforme.

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    Ahmadloo, Niloofar; Kani, Amir-Abbas; Mohammadianpanah, Mohammad; Nasrolahi, Hamid; Omidvari, Shapour; Mosalaei, Ahmad; Ansari, Mansour

    2013-03-01

    This study aimed to report the characteristics, prognostic factors and treatment outcome of 223 patients with glioblastoma multiforme (GBM). This retrospective study was carried out by reviewing the medical records of 223 adult patients diagnosed at a tertiary academic hospital between 1990 and 2008. Patients' follow up ranged from 1 to 69 months (median 11 months). Surgery was attempted in all patients in whom complete resection in 15 patients (7%), subtotal resection in 77 patients (34%), partial resection in 73 patients (33%) and biopsy alone in 58 patients (26%) were done. In addition, we performed a literature review of PubMed to find out and analyze major related series. In all, we collected and analyzed the data of 33 major series including more than 11,000 patients with GBM. There were 141 men and 82 women. The median progression free- and overall survival were 6 (95% CI=5.711-8.289) and 11 (95% CI=9.304-12.696) months respectively. In univariate analysis for overall survival, age (P=0.003), tumor size (P<0.013), performance status (P<0.001), the extent of surgical resection (P=0.009), dose of radiation (P<0.001), and adjuvant chemotherapy (P<0.001) were prognostic factors. However, in multivariate analysis, only radiation dose, extent of surgical resection, and adjuvant chemotherapy were independent prognostic factors for overall survival. The prognosis of adult patients with GBM remains poor; however, complete surgical resection and adjuvant treatments improve progression-free and overall survival. Copyright © 2012. Production and hosting by Elsevier B.V.

  13. Treatment outcome and prognostic factors of adult glioblastoma multiforme

    International Nuclear Information System (INIS)

    Ahmadloo, N.; Mohammadianpanah, M.; Nasrolahi, H.; Omidvari, Sh.; Ansari, M.; Kani, A.A.; Mosalaei, A.

    2013-01-01

    Introduction: This study aimed to report the characteristics, prognostic factors and treatment outcome of 223 patients with glioblastoma multiforme (GBM). Subjects and method: This retrospective study was carried out by reviewing the medical records of 223 adult patients diagnosed at a tertiary academic hospital between 1990 and 2008. Patients’ follow up ranged from 1 to 69 months (median 11 months). Surgery was attempted in all patients in whom complete resection in 15 patients (7%), subtotal resection in 77 patients (34%), partial resection in 73 patients (33%) and biopsy alone in 58 patients (26%) were done. In addition, we performed a literature review of Pub Med to find out and analyze major related series. In all, we collected and analyzed the data of 33 major series including more than 11,000 patients with GB M. Results: There were 141 men and 82 women. The median progression free- and overall survival were 6 (95% Cl = 5.711-8.289) and 11 (95% Cl = 9.304-12.696) months respectively. In univariate analysis for overall survival, age (P = 0.003), tumor size (P < 0.013), performance status (P < 0.001), the extent of surgical resection (P - 0.009), dose of radiation (P < 0.001), and adjuvant chemotherapy (P < 0.001) were prognostic factors. However, in multivariate analysis, only radiation dose, extent of surgical resection, and adjuvant chemotherapy were independent prognostic factors for overall survival. Conclusion: The prognosis of adult patients with GBM remains poor; however, complete surgical resection and adjuvant treatments improve progression-free and overall survival

  14. CDK4/6 inhibitor PD0332991 in glioblastoma treatment: does it have a future?

    Directory of Open Access Journals (Sweden)

    Lisette eSchroder

    2015-11-01

    Full Text Available Glioblastoma is aggressive, highly infiltrating, and the most frequent malignant form of brain cancer. With a median survival time of only 14.6 months, when treated with the standard of care, it is essential to find new therapeutic options. A specific CDK4/6 inhibitor, PD0332991, obtained accelerated approval from the Food and Drug Administration for the treatment of patients with advanced estrogen receptor-positive and HER2-negative breast cancer. Common alterations in the cyclin D1-Cyclin Dependent Kinase 4/6-Retinoblastoma 1 pathway in glioblastoma make PD0332991 also an interesting drug for the treatment of glioblastoma. Promising results in in vitro studies, where patient derived glioblastoma cell lines showed sensitivity to PD0332991, gave motive to start in vivo studies. Outcomes of these studies have been contrasting in terms of PD0332991 efficacy within the brain: more research is necessary to conclude whether CDK4/6 inhibitor can be beneficial in the treatment of glioblastoma.

  15. Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

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    Parra, N. Andres [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Maudsley, Andrew A. [Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida (United States); Gupta, Rakesh K. [Department of Radiology and Imaging, Fortis Memorial Research Institute, Gurgaon, Haryana (India); Ishkanian, Fazilat; Huang, Kris [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Walker, Gail R. [Biostatistics and Bioinformatics Core Resource, Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (United States); Padgett, Kyle [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida (United States); Roy, Bhaswati [Department of Radiology and Imaging, Fortis Memorial Research Institute, Gurgaon, Haryana (India); Panoff, Joseph; Markoe, Arnold [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Stoyanova, Radka, E-mail: RStoyanova@med.miami.edu [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States)

    2014-10-01

    Purpose: Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Methods and Materials: Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV{sub 46} and CTV{sub 60}, respectively). MTV{sub Cho} and MTV{sub NAA} were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. Results: The MRSI coverage of the brain was between 70% and 76%. The MTV{sub NAA} were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTV{sub Cho} was outside of the edema (median, 33%) and for some patients it was also outside of the CTV{sub 46} and CTV{sub 60}. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTV{sub Cho} for these patients were outside of CTV{sub 60}. Conclusions: This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on

  16. Evaluation of photodynamic treatment efficiency on glioblastoma cells received from malignant lesions: initial studies

    Science.gov (United States)

    Borisova, Ekaterina; Kyurkchiev, Dobroslav; Tumangelova-Yuzeir, Kalina; Angelov, Ivan; Genova-Hristova, Tsanislava; Semyachkina-Glushkovskaya, Oxana; Minkin, Krassimir

    2018-04-01

    Photodynamic therapy is well-established and extensively used method in treatment of different cancer types. This research reveals its potential in the treatment of cultivated human glioblastoma cells with adherent morphology. As the blood-brain barrier (BBB) permeability of the drugs is a significant problem that could not be solved easily for large biomolecules, we search for an appropriate low-molecular weight photosensitizer that could be applied for photodynamic treatment of glioblastoma cells. We used delta-aminolevulinic acid (5-ALA), which could pass BBB and plays the role of precursor of a protoporphyrin IX (PpIX) - photosensitizer, that is accumulated selectively in the tumour cells and could be a proper tool in PDT of glioblastoma. However, differences from patient to patient and between the cell activities could also lead to different effectiveness of the PDT treatment of the tumour areas. Therefore in our study we investigated not only the effect of using different fluence rates and light doses, but aims to establish more efficient values for further clinical applications for each sub-type of the GBM lesions. For the needs of PDT application an illumination device was developed in Laboratory of Biophotonics, BAS based on light-emitting diode (LED) matrix light sources for therapeutic application emitting at 635 nm. The device is optimized for PDT in combination with aminolevulinic acid/protoporphyrin IX applied as a photosensitizer drug. By the means of FACSCalibur flow cytometer (Becton Dickinson, USA) and Cell Quest Software was made evaluation of PDT effect on used human glioblastoma cells. Treatment of glioblastoma tumours continues to be a very serious issue and there is growing need in development of new concepts, methods and cancer-fighting strategies. PDT may contribute in accomplishing better results in cancer treatment and can be applied as well in combination with other techniques.

  17. Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation

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    Garry Ceccon

    2018-04-01

    Full Text Available Novel therapeutic targets in malignant glioma patients are urgently needed. Point mutations of the v-Raf murine sarcoma viral oncogene homolog B (BRAF gene occur predominantly in melanoma patients, but may also occur in gliomas. Thus, this is a target of great interest for this group of patients. In a nine-year-old male patient, an anaplastic astrocytoma in the left temporoparietal region was diagnosed histologically. After first- and second-line treatment, a malignant progression to a secondary glioblastoma was observed ten years after the initial diagnosis. Within the following seven years, all other conventional treatment options were exhausted. At this time point, recurrent tumor histology revealed an epithelioid glioblastoma, without a mutation in the isocitrate dehydrogenase gene (IDH wild-type. In order to identify a potential target for an experimental salvage therapy, mutational tumor analysis showed a BRAF V600E mutation. Consecutively, dabrafenib treatment was initiated. The patient remained clinically stable, and follow-up magnetic resonance images (MRI were consistent with “Stable Disease” according to the Response Assessment in Neuro-Oncology Working Group (RANO criteria for the following ten months until tumor progression was detected. The patient died 16 months after dabrafenib treatment initiation. Particularly in younger glioma patients as well as in patients with an epithelioid glioblastoma, screening for a V600E BRAF mutation is promising since, in these cases, targeted therapy with BRAF inhibitors seems to be a useful salvage treatment option.

  18. Radiation induced sarcoma after treatment of glioblastoma: case report; Sarcoma radioinduzido pós-tratamento de glioblastoma: relato de caso

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    Rosa, Victor Domingos Lisita; Anjos, Caroline Souza dos; Candido, Priscila Barile Marchi; Dias Junior, Antonio Soares; Santos, Evandro Airton Sordi dos; Godoy, Antonio Carlos Cavalcante; Saggioro, Fabiano P.; Carlotti Junior, Carlos Gilberto; Oliveira, Harley Francisco de; Peria, Fernanda Maris, E-mail: fernandaperia@fmrp.usp.br, E-mail: victor_lisita@yahoo.com.br, E-mail: carolinesanjos@gmail.com, E-mail: priscilabarile@yahoo.com.br [Universidade de Sao Paulo (USP), Ribeirão Preto, SP (Brazil). Hospital das Clinicas

    2016-07-01

    Introduction: Glioblastoma multiform is the most lethal central nervous system neoplasm, with a median survival of around 13 months and the worst prognosis among all gliomas. The therapeutic approach of glioblastoma consists in neurosurgery with maximum possible resection of tumor volume, followed by radiotherapy and chemotherapy. Radiotherapy reduces the risk of tumor recurrence through direct and indirect damage to tumor deoxyribonucleic acid. The long-term effects of radiation therapy include tissue necrosis, vasculopathy, and radiation-induced neoplasia. The most reported secondary intracranial malignant tumors include meningiomas, gliomas, and sarcomas. The latency period between skull radiotherapy and the appearance of radioinduced lesions varies in the literature from six months to 47 years, with an average of 18.7 years. Case report: The present report describes the appearance of high-grade spindle cell sarcoma after ten months in a patient who received glioblastoma treatment at Hospital das Clínicas of Ribeirão Preto of the University of São Paulo. Conclusion: The rarity of this association is probably due to the poor survival of patients with glioblastoma, thus limiting the time to development of secondary neoplasia.

  19. Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma

    OpenAIRE

    Jue, Toni Rose; Nozue, Kyoko; Lester, Ashleigh J.; Joshi, Swapna; Schroder, Lisette B. W.; Whittaker, Shane P.; Nixdorf, Sheri; Rapkins, Robert W.; Khasraw, Mustafa; McDonald, Kerrie L.

    2017-01-01

    Background The O 6 -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM. Methods The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination ...

  20. Concurrent bevacizumab and temozolomide alter the patterns of failure in radiation treatment of glioblastoma multiforme

    International Nuclear Information System (INIS)

    Shields, Lisa BE; Kadner, Robert; Vitaz, Todd W; Spalding, Aaron C

    2013-01-01

    We investigated the pattern of failure in glioblastoma multiforma (GBM) patients treated with concurrent radiation, bevacizumab (BEV), and temozolomide (TMZ). Previous studies demonstrated a predominantly in-field pattern of failure for GBM patients not treated with concurrent BEV. We reviewed the treatment of 23 patients with GBM who received 30 fractions of simultaneous integrated boost IMRT. PTV60 received 2 Gy daily to the tumor bed or residual tumor while PTV54 received 1.8 Gy daily to the surrounding edema. Concurrent TMZ (75 mg/m 2 ) daily and BEV (10 mg/kg every 2 weeks) were given during radiation therapy. One month after RT completion, adjuvant TMZ (150 mg/m 2 × 5 days) and BEV were delivered monthly until progression or 12 months total. With a median follow-up of 12 months, the median disease-free and overall survival were not reached. Four patients discontinued therapy due to toxicity for the following reasons: bone marrow suppression (2), craniotomy wound infection (1), and pulmonary embolus (1). Five patients had grade 2 or 3 hypertension managed by oral medications. Of the 12 patients with tumor recurrence, 7 suffered distant failure with either subependymal (5/12; 41%) or deep white matter (2/12; 17%) spread detected on T2 FLAIR sequences. Five of 12 patients (41%) with a recurrence demonstrated evidence of GAD enhancement. The patterns of failure did not correlate with extent of resection or number of adjuvant cycles. Treatment of GBM patients with concurrent radiation, BEV, and TMZ was well tolerated in the current study. The majority of patients experienced an out-of-field pattern of failure with radiation, BEV, and TMZ which has not been previously reported. Further investigation is warranted to determine whether BEV alters the underlying tumor biology to improve survival. These data may indicate that the currently used clinical target volume thought to represent microscopic disease for radiation may not be appropriate in combination with TMZ

  1. Systematic Evaluation of Promising Clinical Trials-Gene Silencing for the Treatment of Glioblastoma.

    Science.gov (United States)

    Karaarslan, Numan; Yilmaz, Ibrahim; Ozbek, Hanefi; Caliskan, Tezcan; Topuk, Savas; Sirin, Duygu Yasar; Ates, Ozkan

    2018-04-06

    The aim of this study was to systematically investigate the role of artificial small interfering RNA (siRNA) molecules in glioblastoma treatment and to give a detailed overview of the literature concerning studies performed in this field worldwide in the last 31 years. Articles about clinical trials conducted between December 1, 1949 and November 8, 2017, were identified from the Cochrane Collaboration, the Cochrane Library, Ovid MEDLINE, ProQuest, the National Library of Medicine, and PubMed electronic databases, using the terms "post transcriptional gene silencing," "small interfering RNA," "siRNA," and "glioblastoma," either individually or combined (\\"OR\\" and \\"AND"), without language and country restrictions. Articles that met the examination criteria were included in the study. After descriptive statistical evaluation, the results were reported in frequency (%). After scanning 2.752 articles, five articles were found that met the research criteria. Examination of full texts of the five identified articles provided no sufficient evidence for research conducted with regard to the use of gene silencing via siRNAs in glioblastoma treatment. To be able to evaluate the clinical use of siRNAs, there is an urgent need for in-vivo studies and for trials with randomized, controlled, and clinical designs that provide long-term functional outcomes.

  2. Tectal glioblastoma Glioblastoma tetal

    Directory of Open Access Journals (Sweden)

    Feres Chaddad Neto

    2007-12-01

    Full Text Available Brain stem gliomas are a heterogeneous group of neoplasms arising mostly in paediatric patients. Tectal plate gliomas represent a particular type of brain stem tumours usually with a benign, indolent clinical course, presenting with signs of raised intracranial hipertension due to supra-tentorialhydrocephalous caused by aqueductal stenosis. Seldom high-grade lesions arise in this location with tremendous therapeutic implications. When a malignant tumour is clinically and radiographically suspected a biopsy should be performed to obtain histhological confirmation. Treatment is then planned in a case-by-case basis. We present the case of a glioblastoma of the tectal plate in a 22 years-old woman operated upon by a supracerebellar-infratentorial approach.Os gliomas do tronco cerebral são um grupo heterogêneo de neoplasias que acometem habitualmente crianças. Os gliomas da placa quadrigeminal representam um tipo particular de tumores do tronco cerebral, habitualmente com um curso benigno e indolente, surgindo com sinais de hipertensão intracraniana devido a hidrocefalia supra-tentorial provocada por compressão do aqueduto cerebral. Raramente surgem lesões de alto grau nesta região, mas as implicações terapêuticas são tremendas. Quando existe suspeita clínica e imagiológica de que se trata de lesão maligna, esta deve ser biopsada para se obter confirmação histológica. O tratamento deve então ser planejado caso a caso. Apresentamos o caso de glioblastoma da placa quadrigeminal em uma paciente de 22 anos intervencionado por via supracerebelar-infratentorial.

  3. Multimodality therapy approaches, local and systemic treatment, compared with chemotherapy alone in recurrent glioblastoma

    International Nuclear Information System (INIS)

    Scorsetti, Marta; Navarria, Pierina; Pessina, Federico; Ascolese, Anna Maria; D’Agostino, Giuseppe; Tomatis, Stefano; De Rose, Fiorenza; Villa, Elisa; Maggi, Giulia; Simonelli, Matteo; Clerici, Elena; Soffietti, Riccardo; Santoro, Armando; Cozzi, Luca; Bello, Lorenzo

    2015-01-01

    Long-term local control in Glioblastoma is rarely achieved and nearly all patients relapse. In this study we evaluated the clinical effect of different treatment approaches in recurrent patients. Forty-three patients, with median age of 51 years were evaluated for salvage treatment: re-resection and/or re-irradiation plus chemotherapy or chemotherapy alone. Response was recorded using the Response Assessment in Neuro-Oncology criteria. Hematologic and non-hematologic toxicities were graded according to Common Terminology Criteria for Adverse Events 4.0. Twenty-one patients underwent chemotherapy combined with local treatment, surgery and/or radiation therapy, and 22 underwent chemotherapy only. The median follow up was 7 months (range 3–28 months). The 1 and 2-years Progression Free Survival was 65 and 10 % for combined treatment and 22 and 0 % for chemotherapy alone (p < 0.01). The 1 and 2-years overall survival was 69 and 29 % for combined and 26 and 0 % for chemotherapy alone (p < 0.01). No toxicity greater than grade 2 was recorded. These data showed that in glioblastoma recurrence the combination of several approaches in a limited group of patients is more effective than a single treatment alone. This stress the importance of multimodality treatment whenever clinically feasible

  4. Mathematical modeling identifies optimum lapatinib dosing schedules for the treatment of glioblastoma patients.

    Directory of Open Access Journals (Sweden)

    Shayna Stein

    2018-01-01

    Full Text Available Human primary glioblastomas (GBM often harbor mutations within the epidermal growth factor receptor (EGFR. Treatment of EGFR-mutant GBM cell lines with the EGFR/HER2 tyrosine kinase inhibitor lapatinib can effectively induce cell death in these models. However, EGFR inhibitors have shown little efficacy in the clinic, partly because of inappropriate dosing. Here, we developed a computational approach to model the in vitro cellular dynamics of the EGFR-mutant cell line SF268 in response to different lapatinib concentrations and dosing schedules. We then used this approach to identify an effective treatment strategy within the clinical toxicity limits of lapatinib, and developed a partial differential equation modeling approach to study the in vivo GBM treatment response by taking into account the heterogeneous and diffusive nature of the disease. Despite the inability of lapatinib to induce tumor regressions with a continuous daily schedule, our modeling approach consistently predicts that continuous dosing remains the best clinically feasible strategy for slowing down tumor growth and lowering overall tumor burden, compared to pulsatile schedules currently known to be tolerated, even when considering drug resistance, reduced lapatinib tumor concentrations due to the blood brain barrier, and the phenotypic switch from proliferative to migratory cell phenotypes that occurs in hypoxic microenvironments. Our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment schedules in search for optimal dosing strategies for glioblastoma and other cancer types.

  5. Modeling the Treatment of Glioblastoma Multiforme and Cancer Stem Cells with Ordinary Differential Equations.

    Science.gov (United States)

    Abernathy, Kristen; Burke, Jeremy

    2016-01-01

    Despite improvements in cancer therapy and treatments, tumor recurrence is a common event in cancer patients. One explanation of recurrence is that cancer therapy focuses on treatment of tumor cells and does not eradicate cancer stem cells (CSCs). CSCs are postulated to behave similar to normal stem cells in that their role is to maintain homeostasis. That is, when the population of tumor cells is reduced or depleted by treatment, CSCs will repopulate the tumor, causing recurrence. In this paper, we study the application of the CSC Hypothesis to the treatment of glioblastoma multiforme by immunotherapy. We extend the work of Kogan et al. (2008) to incorporate the dynamics of CSCs, prove the existence of a recurrence state, and provide an analysis of possible cancerous states and their dependence on treatment levels.

  6. Agomelatine or ramelteon as treatment adjuncts in glioblastoma and other M1- or M2-expressing cancers.

    Science.gov (United States)

    Kast, Richard E

    2015-01-01

    The impressive but sad list of over forty clinical studies using various cytotoxic chemotherapies published in the last few years has failed to increase median survival of glioblastoma beyond two years after diagnosis. In view of this apparent brick wall, adjunctive non-cytotoxic growth factor blocking drugs are being tried, as in the CUSP9* protocol. A related theme is searching for agonists at growth inhibiting receptors. One such dataset is that of melatonin agonism at M1 or M2 receptors found on glioblastoma cells, being a negative regulator of these cells' growth. Melatonin itself is an endogenous hormone, but when used as an exogenously administered drug it has many disadvantages. Agomelatine, marketed as an antidepressant, and ramelteon, marketed as a treatment for insomnia, are currently-available melatonin receptor agonists. These melatonin receptor agonists have significant advantages over the natural ligand: longer half-life, better oral absorption, and higher affinity to melatonin receptors. They have an eminently benign side effect profile. As full agonists they should function to inhibit glioblastoma growth, as demonstrated for melatonin. A potentially helpful ancillary attribute of melatonergic agonists in glioblastoma treatment is an increase in interleukin-2 synthesis, expected, at least partially, to reverse some of the immunosuppression associated with glioblastoma.

  7. Radio-induced glioblastoma and myxoma after treatment of undifferentiated carcinoma of the nasopharynx

    International Nuclear Information System (INIS)

    Daoud, J.; Ben Salah, H.; Kammoun, W.; Ghorbel, A.; Drira, M.M.; Frikha, M.; Jlidi, R.; Besbes, M.; Maalej, M.

    2000-01-01

    Radio-induced tumor have been known for a long time to occur after treatment of cancer during childhood. This entity is exceptional following radiotherapy of the cavum. Skull and facial osteosarcoma were described after treatment of UCNT. We report two observations of radio-induced tumors arising respectively three and seven years after treatment of UCNT. The first one is a temporo-parietal glioblastoma and the second is a rhino- and pharyngeal myxoma. The two patients are alive after treatment of the second tumor. The delay of appearance of these tumors, their situation in the field's irradiated and dose received suggests their radioinduced nature. However, the cytogenetic study is necessary to confirm the implication of radiotherapy in the genesis of these cancers. (authors)

  8. Reassessing the Role of Intra-Arterial Drug Delivery for Glioblastoma Multiforme Treatment

    Directory of Open Access Journals (Sweden)

    Jason A. Ellis

    2015-01-01

    Full Text Available Effective treatment for glioblastoma (GBM will likely require targeted delivery of several specific pharmacological agents simultaneously. Intra-arterial (IA delivery is one technique for targeting the tumor site with multiple agents. Although IA chemotherapy for glioblastoma (GBM has been attempted since the 1950s, the predicted benefits remain unproven in clinical practice. This review focuses on innovative approaches to IA drug delivery in treating GBM. Guided by novel in vitro and in vivo optical measurements, newer pharmacokinetic models promise to better define the complex relationship between background cerebral blood flow and drug injection parameters. Advanced optical technologies and tracers, unique nanoparticles designs, new cellular targets, and rational drug formulations are continuously modifying the therapeutic landscape for GBM. Personalized treatment approaches are emerging; however, such tailored approaches will largely depend on effective drug delivery techniques and on the ability to simultaneously deliver multidrug regimens. These new paradigms for tumor-selective drug delivery herald dramatic improvements in the effectiveness of IA chemotherapy for GBM. Therefore, within this context of so-called “precision medicine,” the role of IA delivery for GBM is thoroughly reassessed.

  9. Prospective of curcumin, a pleiotropic signalling molecule from Curcuma longa in the treatment of Glioblastoma.

    Science.gov (United States)

    Luthra, Pratibha Mehta; Lal, Neetika

    2016-02-15

    GBM (Glioblastoma) is the most malignant human brain tumor with median survival of one year. The treatment involves surgery, radiotherapy and adjuvant chemotherapy mostly with the alkylation agents such as temozolomide (TMZ). Dietary polyphenol curcumin, isolated from the rhizome of the Curcuma longa (turmeric), has emerged as remarkable anti-cancer agent in the treatment of various peripheral cancers such as blood, lymphomas, multiple myeloma, melanoma as well as skin, lung, prostate, breast, ovarian, bladder, liver, gastrointestinal tract, pancreatic and colorectal epithelial cancers with a pleiotropic mode of action and also showed promise in alleviation of GBM. In this review, the mechanism of anticancer effect of curcumin in GBM has been discussed extensively. The clinical safety and pharmacokinetics of curcumin has been scrutinized to combat the challenges for the treatment of GBM. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  10. Adenoid glioblastoma

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    Cui-yun SUN

    2018-04-01

    Full Text Available Objective To report the diagnosis and treatment of one case of adenoid glioblastoma and investigate the clinicopathological features, diagnosis and differential diagnosis. Methods and Results A 63-year-old male patient suffered from left-skewed corner of the mouth for more than 10 d. Brain enhanced MRI revealed a cystic mass in left frontotemporal lobe and metastatic tumor was considered. 18F-fluoro-2-deoxy-D-glucose (18F-FDG PET did not detected any sign of malignant neoplasm in the whole body. Under the guide of neuronavigation and ultrasound, the tumor was totally removed under microscope. Histologically, the tumor was located in brain parenchyma and presented a growing pattern of multicentric sheets or nests. Mucus scattered in some regions. Tumor cells were arranged in strip, cribriform, adenoid or papillary patterns. Tumor cells contained few cytoplasm with round or oval uniform hyperchromatic nuclei and occasionally obvious nucleoli. Proliferation of glomeruloid vascular endothelial cells could be seen. Immunohistochemical staining showed the cytoplasm of tumor cells was diffusively positive for glial fibrillary acidic protein (GFAP, vimentin (Vim and phosphatase and tensin homologue (PTEN; nuclei was positive for oligodendrocytes transcription factor-2 (Olig-2 and P53; cytoplasm and nuclei were positive for S-100 protein (S-100; membrane was positive for epidermal growth factor receptor (EGFR. The tumor cells showed a negative reaction for cytokeratin (CK, epithelial membrane antigen (EMA, carcinoembryonic antigen (CEA, thyroid transcription factor-1 (TTF-1, CD31, CD34, CAM5.2 and isocitrate dehydrogenase 1 (IDH1. Ki-67 labeling index was 76.80%. The final pathological diagnosis was adenoid glioblastoma. The patient died of respiratroy failure and circulation function failure 12 d after operation. Conclusions Adenoid glioblastoma was a rare glioblastoma subtype. A clear diagnosis depends on histological findings and immunohistochemical

  11. 3-Bromopyruvate treatment induces alterations of metabolic and stress-related pathways in glioblastoma cells.

    Science.gov (United States)

    Chiasserini, Davide; Davidescu, Magdalena; Orvietani, Pier Luigi; Susta, Federica; Macchioni, Lara; Petricciuolo, Maya; Castigli, Emilia; Roberti, Rita; Binaglia, Luciano; Corazzi, Lanfranco

    2017-01-30

    Glioblastoma (GBM) is the most common and aggressive brain tumour of adults. The metabolic phenotype of GBM cells is highly dependent on glycolysis; therefore, therapeutic strategies aimed at interfering with glycolytic pathways are under consideration. 3-Bromopyruvate (3BP) is a potent antiglycolytic agent, with a variety of targets and possible effects on global cell metabolism. Here we analyzed the changes in protein expression on a GBM cell line (GL15 cells) caused by 3BP treatment using a global proteomic approach. Validation of differential protein expression was performed with immunoblotting and enzyme activity assays in GL15 and U251 cell lines. The results show that treatment of GL15 cells with 3BP leads to extensive changes in the expression of glycolytic enzymes and stress related proteins. Importantly, other metabolisms were also affected, including pentose phosphate pathway, aminoacid synthesis, and glucose derivatives production. 3BP elicited the activation of stress response proteins, as shown by the phosphorylation of HSPB1 at serine 82, caused by the concomitant activation of the p38 pathway. Our results show that inhibition of glycolysis in GL15 cells by 3BP influences different but interconnected pathways. Proteome analysis may help in the molecular characterization of the glioblastoma response induced by pharmacological treatment with antiglycolytic agents. Alteration of the glycolytic pathway characterizes glioblastoma (GBM), one of the most common brain tumours. Metabolic reprogramming with agents able to inhibit carbohydrate metabolism might be a viable strategy to complement the treatment of these tumours. The antiglycolytic agent 3-bromopyruvate (3BP) is able to strongly inhibit glycolysis but it may affect also other cellular pathways and its precise cellular targets are currently unknown. To understand the protein expression changes induced by 3BP, we performed a global proteomic analysis of a GBM cell line (GL15) treated with 3BP. We

  12. Nanotechnology applications for glioblastoma.

    Science.gov (United States)

    Nduom, Edjah K; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G

    2012-07-01

    Glioblastoma remains one of the most difficult cancers to treat and represents the most common primary malignancy of the brain. Although conventional treatments have found modest success in reducing the initial tumor burden, infiltrating cancer cells beyond the main mass are responsible for tumor recurrence and ultimate patient demise. Targeting residual infiltrating cancer cells requires the development of new treatment strategies. The emerging field of cancer nanotechnology holds promise in the use of multifunctional nanoparticles for imaging and targeted therapy of glioblastoma. This article examines the current state of nanotechnology in the treatment of glioblastoma and directions of further study. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Improved survival for elderly married glioblastoma patients. Better treatment delivery, less toxicity, and fewer disease complications

    International Nuclear Information System (INIS)

    Putz, Florian; Goerig, Nicole; Knippen, Stefan; Gryc, Thomas; Semrau, Sabine; Lettmaier, Sebastian; Fietkau, Rainer; Putz, Tobias; Eyuepoglu, Ilker; Roessler, Karl

    2016-01-01

    Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies. A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail. Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m"2 vs. 33.1 mg/m"2; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004). We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies. (orig.) [de

  14. Improved survival for elderly married glioblastoma patients : Better treatment delivery, less toxicity, and fewer disease complications.

    Science.gov (United States)

    Putz, Florian; Putz, Tobias; Goerig, Nicole; Knippen, Stefan; Gryc, Thomas; Eyüpoglu, Ilker; Rössler, Karl; Semrau, Sabine; Lettmaier, Sebastian; Fietkau, Rainer

    2016-11-01

    Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies. A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail. Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m² vs. 33.1 mg/m²; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004). We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies.

  15. Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches

    International Nuclear Information System (INIS)

    Beal, Kathryn; Abrey, Lauren E; Gutin, Philip H

    2011-01-01

    Surgical resection followed by radiotherapy and temozolomide in newly diagnosed glioblastoma can prolong survival, but it is not curative. For patients with disease progression after frontline therapy, there is no standard of care, although further surgery, chemotherapy, and radiotherapy may be used. Antiangiogenic therapies may be appropriate for treating glioblastomas because angiogenesis is critical to tumor growth. In a large, noncomparative phase II trial, bevacizumab was evaluated alone and with irinotecan in patients with recurrent glioblastoma; combination treatment was associated with an estimated 6-month progression-free survival (PFS) rate of 50.3%, a median overall survival of 8.9 months, and a response rate of 37.8%. Single-agent bevacizumab also exceeded the predetermined threshold of activity for salvage chemotherapy (6-month PFS rate, 15%), achieving a 6-month PFS rate of 42.6% (p < 0.0001). On the basis of these results and those from another phase II trial, the US Food and Drug Administration granted accelerated approval of single-agent bevacizumab for the treatment of glioblastoma that has progressed following prior therapy. Potential antiangiogenic agents-such as cilengitide and XL184-also show evidence of single-agent activity in recurrent glioblastoma. Moreover, the use of antiangiogenic agents with radiation at disease progression may improve the therapeutic ratio of single-modality approaches. Overall, these agents appear to be well tolerated, with adverse event profiles similar to those reported in studies of other solid tumors. Further research is needed to determine the role of antiangiogenic therapy in frontline treatment and to identify the optimal schedule and partnering agents for use in combination therapy

  16. Acyclovir inhibition of IDO to decrease Tregs as a glioblastoma treatment adjunct

    Directory of Open Access Journals (Sweden)

    Söderlund Johan

    2010-08-01

    Full Text Available Abstract Regulatory T cells, Tregs, are a subset of lymphocytes that have immunosuppressive attributes. They are elevated in blood of glioblastoma patients and within this tumor's tissue itself. Indoleamine 2,3-dioxygenase, IDO, converts tryptophan to kynurenine. IDO activity enhances Treg formation by pathways that are unknown. Experimentally, inhibition of IDO decreases Treg function and number in rodents. The common anti-viral agent acyclovir inhibits IDO. Acyclovir may thereby decrease Treg function in glioblastoma. If it can be confirmed that Treg counts are elevated in glioblastoma patients' tumor tissue, and if we can document acyclovir's lowering of tissue Treg counts by a small trial of acyclovir in pre-operative glioblastoma patients, a trial of acyclovir effect on survival should be done given the current poor prognosis of glioblastoma and the well-established safety and low side effect burden of acyclovir.

  17. Farnesylthiosalicylic acid-loaded lipid-polyethylene glycol-polymer hybrid nanoparticles for treatment of glioblastoma.

    Science.gov (United States)

    Kaffashi, Abbas; Lüle, Sevda; Bozdağ Pehlivan, Sibel; Sarısözen, Can; Vural, İmran; Koşucu, Hüsnü; Demir, Taner; Buğdaycı, Kadir Emre; Söylemezoğlu, Figen; Karlı Oğuz, Kader; Mut, Melike

    2017-08-01

    We aimed to develop lipid-polyethylene glycol (PEG)-polymer hybrid nanoparticles, which have high affinity to tumour tissue with active ingredient, a new generation antineoplastic drug, farnesylthiosalicylic acid (FTA) for treatment of glioblastoma. Farnesylthiosalicylic acid-loaded poly(lactic-co-glycolic acid)-1,2 distearoyl-glycerol-3-phospho-ethanolamine-N [methoxy (PEG)-2000] ammonium salt (PLGA-DSPE-PEG) with or without 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) hybrid nanoparticles has been prepared and evaluated for in-vitro characterization. Cytotoxicity of FTA-loaded nanoparticles along with its efficacy on rat glioma-2 (RG2) cells was also evaluated both in vitro (in comparison with non-malignant cell line, L929) and in vivo. Scanning electron microscopy studies showed that all formulations prepared had smooth surface and spherical in shape. FTA and FTA-loaded nanoparticles have cytotoxic activity against RG2 glioma cell lines in cell culture studies, which further increases with addition of DOTAP. Magnetic resonance imaging and histopathologic evaluation on RG2 tumour cells in rat glioma model (49 female Wistar rats, 250-300 g) comparing intravenous and intratumoral injections of the drug have been performed and FTA-loaded nanoparticles reduced tumour size significantly in in-vivo studies, with higher efficiency of intratumoral administration than intravenous route. Farnesylthiosalicylic acid-loaded PLGA-DSPE-PEG-DOTAP hybrid nanoparticles are proven to be effective against glioblastoma in both in-vitro and in-vivo experiments. © 2017 Royal Pharmaceutical Society.

  18. Therapeutic Potential of Thymoquinone in Glioblastoma Treatment: Targeting Major Gliomagenesis Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Fabliha Ahmed Chowdhury

    2018-01-01

    Full Text Available Glioblastoma multiforme (GBM is one of the most devastating brain tumors with median survival of one year and presents unique challenges to therapy because of its aggressive behavior. Current treatment strategy involves surgery, radiotherapy, immunotherapy, and adjuvant chemotherapy even though optimal management requires a multidisciplinary approach and knowledge of potential complications from both the disease and its treatment. Thymoquinone (TQ, the main bioactive component of Nigella sativa L., has exhibited anticancer effects in numerous preclinical studies. Due to its multitargeting nature, TQ interferes in a wide range of tumorigenic processes and counteract carcinogenesis, malignant growth, invasion, migration, and angiogenesis. TQ can specifically sensitize tumor cells towards conventional cancer treatments and minimize therapy-associated toxic effects in normal cells. Its potential to enter brain via nasal pathway due to volatile nature of TQ adds another advantage in overcoming blood-brain barrier. In this review, we summarized the potential role of TQ in different signaling pathways in GBM that have undergone treatment with standard therapeutic modalities or with TQ. Altogether, we suggest further comprehensive evaluation of TQ in preclinical and clinical level to delineate its implied utility as novel therapeutics to combat the challenges for the treatment of GBM.

  19. The impact of bevacizumab treatment on survival and quality of life in newly diagnosed glioblastoma patients

    International Nuclear Information System (INIS)

    Poulsen, Hans Skovgaard; Urup, Thomas; Michaelsen, Signe Regner; Staberg, Mikkel; Villingshøj, Mette; Lassen, Ulrik

    2014-01-01

    Glioblastoma multiforme (GBM) remains one of the most devastating tumors, and patients have a median survival of 15 months despite aggressive local and systemic therapy, including maximal surgical resection, radiation therapy, and concomitant and adjuvant temozolomide. The purpose of antineoplastic treatment is therefore to prolong life, with a maintenance or improvement of quality of life. GBM is a highly vascular tumor and overexpresses the vascular endothelial growth factor A, which promotes angiogenesis. Preclinical data have suggested that anti-angiogenic treatment efficiently inhibits tumor growth. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A, and treatment has shown impressive response rates in recurrent GBM. In addition, it has been shown that response is correlated to prolonged survival and improved quality of life. Several investigations in newly diagnosed GBM patients have been performed during recent years to test the hypothesis that newly diagnosed GBM patients should be treated with standard multimodality treatment, in combination with bevacizumab, in order to prolong life and maintain or improve quality of life. The results of these studies along with relevant preclinical data will be described, and pitfalls in clinical and paraclinical endpoints will be discussed

  20. Alcohol and drug abusers' reasons for seeking treatment.

    Science.gov (United States)

    Cunningham, J A; Sobell, L C; Sobell, M B; Gaskin, J

    1994-01-01

    Clients at two different treatment facilities were asked at assessment how influential each of 10 possible reasons were in their decision to change their alcohol or drug use. Clients at both facilities most often endorsed "weighing the pros and cons of drinking or drug use" and a "warning from spouse." Client's reasons for seeking treatment were also examined in relation to treatment compliance. Three reasons--"weighing the pros and cons," "hitting rock bottom," and experiencing a "major lifestyle change"--were predictive of treatment compliance. Clients who rated any of these reasons as influential were more likely to enter and complete treatment. Although more research is needed, knowledge of clients' reasons for seeking treatment might be useful in treatment matching.

  1. Targeted Proteomics to Assess the Response to Anti-Angiogenic Treatment in Human Glioblastoma (GBM).

    Science.gov (United States)

    Demeure, Kevin; Fack, Fred; Duriez, Elodie; Tiemann, Katja; Bernard, Amandine; Golebiewska, Anna; Bougnaud, Sébastien; Bjerkvig, Rolf; Domon, Bruno; Niclou, Simone P

    2016-02-01

    Glioblastoma (GBM) is a highly aggressive primary brain tumor with dismal outcome for affected patients. Because of the significant neo-angiogenesis exhibited by GBMs, anti-angiogenic therapies have been intensively evaluated during the past years. Recent clinical studies were however disappointing, although a subpopulation of patients may benefit from such treatment. We have previously shown that anti-angiogenic targeting in GBM increases hypoxia and leads to a metabolic adaptation toward glycolysis, suggesting that combination treatments also targeting the glycolytic phenotype may be effective in GBM patients. The aim of this study was to identify marker proteins that are altered by treatment and may serve as a short term readout of anti-angiogenic therapy. Ultimately such proteins could be tested as markers of efficacy able to identify patient subpopulations responsive to the treatment. We applied a proteomics approach based on selected reaction monitoring (SRM) to precisely quantify targeted protein candidates, selected from pathways related to metabolism, apoptosis and angiogenesis. The workflow was developed in the context of patient-derived intracranial GBM xenografts developed in rodents and ensured the specific identification of human tumor versus rodent stroma-derived proteins. Quality control experiments were applied to assess sample heterogeneity and reproducibility of SRM assays at different levels. The data demonstrate that tumor specific proteins can be precisely quantified within complex biological samples, reliably identifying small concentration differences induced by the treatment. In line with previous work, we identified decreased levels of TCA cycle enzymes, including isocitrate dehydrogenase, whereas malectin, calnexin, and lactate dehydrogenase A were augmented after treatment. We propose the most responsive proteins of our subset as potential novel biomarkers to assess treatment response after anti-angiogenic therapy that warrant future

  2. Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma

    Science.gov (United States)

    Jiang, Wei; Finniss, Susan; Cazacu, Simona; Xiang, Cunli; Brodie, Ziv; Mikkelsen, Tom; Poisson, Laila; Shackelford, David B.; Brodie, Chaya

    2016-01-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor with poor prognosis. Here, we studied the effects of phenformin, a mitochondrial complex I inhibitor and more potent chemical analog of the diabetes drug metformin on the inhibition of cell growth and induction of apoptosis of glioma stem cells (GSCs) using both in vitro and in vivo models. Phenformin inhibited the self-renewal of GSCs, decreased the expression of stemness and mesenchymal markers and increased the expression of miR-124, 137 and let-7. Silencing of let-7 abrogated phenformin effects on the self-renewal of GSCs via a pathway associated with inhibition of H19 and HMGA2 expression. Moreover, we demonstrate that phenformin inhibited tumor growth and prolonged the overall survival of mice orthotopically transplanted with GSCs. Combined treatments of phenformin and temozolomide exerted an increased antitumor effect on GSCs in vitro and in vivo. In addition, dichloroacetate, an inhibitor of the glycolysis enzyme pyruvate dehydrogenase kinase, that decreases lactic acidosis induced by biguanides, enhanced phenformin effects on the induction of cell death in GSCs and prolonged the survival of xenograft-bearing mice. Our results demonstrate for the first time that phenformin targets GSCs and can be efficiently combined with current therapies for GBM treatment and GSC eradication. PMID:27486821

  3. Hypofractionated High-Dose Irradiation with Positron Emission Tomography Data for the Treatment of Glioblastoma Multiforme

    Directory of Open Access Journals (Sweden)

    Kazuhiro Miwa

    2014-01-01

    Full Text Available This research paper presents clinical outcomes of hypofractionated high-dose irradiation by intensity-modulated radiation therapy (Hypo-IMRT with 11C-methionine positron emission tomography (MET-PET data for the treatment of glioblastoma multiforme (GBM. A total of 45 patients with GBM were treated with Hypo-IMRT after surgery. Gross tumor volume (GTV was defined as the area of enhanced lesion on MRI, including MET-PET avid region; clinical target volume (CTV was the area with 5 mm margin surrounding the GTV; planning target volume (PTV was the area with 15 mm margin surrounding the CTV, including MET-PET moderate region. Hypo-IMRT was performed in 8 fractions; planning the dose for GTV was escalated to 68 Gy and that for CTV was escalated to 56 Gy, while keeping the dose delivered to the PTV at 40 Gy. Concomitant and adjuvant TMZ chemotherapy was administered. At a median follow-up of 18.7 months, median overall survival (OS was 20.0 months, and median progression-free survival was 13.0 months. The 1- and 2-year OS rates were 71.2% and 26.3%, respectively. Adjuvant TMZ chemotherapy was significantly predictive of OS on multivariate analysis. Late toxicity included 7 cases of Grade 3-4 radiation necrosis. Hypo-IMRT with MET-PET data appeared to result in favorable survival outcomes for patients with GBM.

  4. Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin.

    Science.gov (United States)

    Kim, Eui Hyun; Lee, Ji-Hyun; Oh, Yoonjee; Koh, Ilkyoo; Shim, Jin-Kyoung; Park, Junseong; Choi, Junjeong; Yun, Mijin; Jeon, Jeong Yong; Huh, Yong Min; Chang, Jong Hee; Kim, Sun Ho; Kim, Kyung-Sup; Cheong, Jae-Ho; Kim, Pilnam; Kang, Seok-Gu

    2017-02-01

    Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness- and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  5. Marital status, treatment, and survival in patients with glioblastoma multiforme: a population based study.

    Science.gov (United States)

    Chang, Susan M; Barker, Fred G

    2005-11-01

    Social factors influence cancer treatment choices, potentially affecting patient survival. In the current study, the authors studied the interrelations between marital status, treatment received, and survival in patients with glioblastoma multiforme (GM), using population-based data. The data source was the Surveillance, Epidemiology, and End Results (SEER) Public Use Database, 1988-2001, 2004 release, all registries. Multivariate logistic, ordinal, and Cox regression analyses adjusted for demographic and clinical variables were used. Of 10,987 patients with GM, 67% were married, 31% were unmarried, and 2% were of unknown marital status. Tumors were slightly larger at the time of diagnosis in unmarried patients (49% of unmarried patients had tumors larger than 45 mm vs. 45% of married patients; P = 0.004, multivariate analysis). Unmarried patients were less likely to undergo surgical resection (vs. biopsy; 75% of unmarried patients vs. 78% of married patients) and were less likely to receive postoperative radiation therapy (RT) (70% of unmarried patients vs. 79% of married patients). On multivariate analysis, the odds ratio (OR) for resection (vs. biopsy) in unmarried patients was 0.88 (95% confidence interval [95% CI], 0.79-0.98; P = 0.02), and the OR for RT in unmarried patients was 0.69 (95% CI, 0.62-0.77; P Unmarried patients more often refused both surgical resection and RT. Unmarried patients who underwent surgical resection and RT were found to have a shorter survival than similarly treated married patients (hazard ratio for unmarried patients, 1.10; P = 0.003). Unmarried patients with GM presented with larger tumors, were less likely to undergo both surgical resection and postoperative RT, and had a shorter survival after diagnosis when compared with married patients, even after adjustment for treatment and other prognostic factors. (c) 2005 American Cancer Society.

  6. Dormant glioblastoma cells acquire stem cell characteristics and are differentially affected by Temozolomide and AT101 treatment.

    Science.gov (United States)

    Adamski, Vivian; Hempelmann, Annika; Flüh, Charlotte; Lucius, Ralph; Synowitz, Michael; Hattermann, Kirsten; Held-Feindt, Janka

    2017-12-08

    Cellular dormancy is defined as a state in which cells enter quiescence driven by intrinsic or extrinsic factors, and striking parallels exist between the concept of cellular dormancy in malignancies and the cancer stem cell theory. We showed now that the proven dormancy markers insulin-like growth factor-binding protein 5, ephrin receptor A5 and histone cluster 1 H2B family member K were expressed in human glioblastomas in situ , were located in single tumor cells, and could be co-stained with each other and with the stem cell markers krüppel-like factor 4, octamer binding transcription factor 4 and sex determining region Y-box 2. Human non-stem glioblastoma cell lines and primary cultures were characterized by expression of individual, cell-type specific dormancy- and stemness-associated markers, which were (up)regulated and could be co-stained in a cell-type specific manner upon Temozolomide-induced dormancy in vitro . The induction patterns of dormancy- and stemness-associated markers were reflected by cell-type specific responses to Temozolomide-induced and combined Temozolomide/AT101-mediated cytotoxicity in different glioblastoma cell lines and primary cultures in vitro , and accompanied by higher self-renewal capacity and lower TMZ-sensitivity of Temozolomide-pretreated cells. We postulate that a better understanding of the dormant state of tumor cells is essential to further improve efficiency of treatment.

  7. Integration method of 3D MR spectroscopy into treatment planning system for glioblastoma IMRT dose painting with integrated simultaneous boost

    International Nuclear Information System (INIS)

    Ken, Soléakhéna; Cassol, Emmanuelle; Delannes, Martine; Celsis, Pierre; Cohen-Jonathan, Elizabeth Moyal; Laprie, Anne; Vieillevigne, Laure; Franceries, Xavier; Simon, Luc; Supper, Caroline; Lotterie, Jean-Albert; Filleron, Thomas; Lubrano, Vincent; Berry, Isabelle

    2013-01-01

    To integrate 3D MR spectroscopy imaging (MRSI) in the treatment planning system (TPS) for glioblastoma dose painting to guide simultaneous integrated boost (SIB) in intensity-modulated radiation therapy (IMRT). For sixteen glioblastoma patients, we have simulated three types of dosimetry plans, one conventional plan of 60-Gy in 3D conformational radiotherapy (3D-CRT), one 60-Gy plan in IMRT and one 72-Gy plan in SIB-IMRT. All sixteen MRSI metabolic maps were integrated into TPS, using normalization with color-space conversion and threshold-based segmentation. The fusion between the metabolic maps and the planning CT scans were assessed. Dosimetry comparisons were performed between the different plans of 60-Gy 3D-CRT, 60-Gy IMRT and 72-Gy SIB-IMRT, the last plan was targeted on MRSI abnormalities and contrast enhancement (CE). Fusion assessment was performed for 160 transformations. It resulted in maximum differences <1.00 mm for translation parameters and ≤1.15° for rotation. Dosimetry plans of 72-Gy SIB-IMRT and 60-Gy IMRT showed a significantly decreased maximum dose to the brainstem (44.00 and 44.30 vs. 57.01 Gy) and decreased high dose-volumes to normal brain (19 and 20 vs. 23% and 7 and 7 vs. 12%) compared to 60-Gy 3D-CRT (p < 0.05). Delivering standard doses to conventional target and higher doses to new target volumes characterized by MRSI and CE is now possible and does not increase dose to organs at risk. MRSI and CE abnormalities are now integrated for glioblastoma SIB-IMRT, concomitant with temozolomide, in an ongoing multi-institutional phase-III clinical trial. Our method of MR spectroscopy maps integration to TPS is robust and reliable; integration to neuronavigation systems with this method could also improve glioblastoma resection or guide biopsies

  8. Treatment results of glioblastoma during the last 30 years in a single institute

    International Nuclear Information System (INIS)

    Kumabe, Toshihiro; Saito, Ryuta; Kanamori, Masayuki

    2013-01-01

    Treatment results of glioblastoma (GB) during the last 30 years in Tohoku University were analyzed to identify any improvements in patient outcome in all 332 histologically proven cases of newly diagnosed GB treated consecutively in our department between 1982 and 2011. These 30 years was divided into 5 treatment eras, Group 1 (1982-1988, without preoperative evaluation by magnetic resonance [MR] imaging, n=46), Group 2 (1989-1996, with preoperative MR imaging, n=41), Group 3 (1997-1999, additionally underwent intraoperative functional brain mapping and neuronavigation system, n=38), Group 4 (2000-August 2006, underwent 30 Gy of whole brain radiation followed by 30 Gy of extended local accelerated hyperfractionated radiation therapy, n=96), and Group 5 (September 2006-2011, adjuvant usage of temozolomide [TMZ], n=111). Overall survival (OS) was calculated from the date of surgery to the death from any cause. The median survival time/2-year OS/5-year OS of Groups 1 to 5 were 10.7 months/10.9%/0%, 17.3 months/26.2%/6.9%, 15.9 months/23.7%/5.3%, 20.1 months/34.8%/15.5%, and 20.9 months/45.5%/19.7%. The prognosis for patients with GB improved significantly after the introduction of MR imaging. Younger GB, defined as patients aged below 60 years, or total tumor resection with all ages in Group 5 had 5-year OS of 31.0% and 30.1%, respectively. The prognosis of GB was improved significantly after the introduction of TMZ for elderly GB, recursive partitioning analysis class 5, or totally resected GB. Introduction of MR imaging and TMZ, and total resection of the tumor were important in the improvement of outcome for patients with GB. (author)

  9. Improved survival for elderly married glioblastoma patients. Better treatment delivery, less toxicity, and fewer disease complications

    Energy Technology Data Exchange (ETDEWEB)

    Putz, Florian; Goerig, Nicole; Knippen, Stefan; Gryc, Thomas; Semrau, Sabine; Lettmaier, Sebastian; Fietkau, Rainer [Friedrich-Alexander-University Erlangen-Nuremberg, Department of Radiation Oncology, Erlangen (Germany); Putz, Tobias [University of Bamberg, Professorship of Demography, Bamberg (Germany); Eyuepoglu, Ilker; Roessler, Karl [Friedrich-Alexander-University Erlangen-Nuremberg, Department of Neurosurgery, Erlangen (Germany)

    2016-11-15

    Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies. A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail. Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m{sup 2} vs. 33.1 mg/m{sup 2}; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004). We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies. (orig.) [German] Fuer verheiratete Patienten mit malignen Gliomen ist ein verbessertes Gesamtueberleben gut beschrieben. Die zugrunde liegenden Mechanismen konnten bislang jedoch in den verfuegbaren bevoelkerungsbezogenen Arbeiten nicht erklaert werden. Eine Serie von 57 aelteren Patienten mit

  10. Multifuntional Nanotherapeutics for the Combinatorial Drug and Gene Therapy in the Treatment of Glioblastoma Multiforme

    Science.gov (United States)

    Hourigan, Breanne

    Glioblastoma multiforme (GBM), a grade IV glioma, is the most common primary brain tumor, affecting about 3 out of 100,000 persons per year in the United States. GBM accounts for about 80% of primary malignant brain tumors, and is also the most aggressive of malignant brain tumors. With exhaustive treatment, survival only averages between 12 and 15 months, with a 2-year survival rate less than 25%. New therapeutic strategies are necessary to improve the outcomes of this disease. Chemotherapy with temozolomide (TMZ), a DNA alkylating agent, is used as a first-line of treatment for GBM. However, GBM tumors develop resistance to TMZ over time due to increased expression of O6-methylguanine-DNA methyltransferase (MGMT), a gene responsible for DNA repair. We previously developed cationic, amphiphilic copolymer poly(lactide-co-glycolide)-g-polyethylenimine (PgP) and demonstrated its utility for nucleic acid delivery. Here, we examine the ability of PgP polyplexes to overcome TMZ resistance and improve therapeutic efficacy through combination drug and gene therapy for GBM treatment. In this study, we evaluated the ability of PgP to deliver siRNA targeting to MGMT (siMGMT), a gene responsible for drug resistance in GBM. Our results demonstrated that PgP effectively forms stable complex with siRNA and protects siRNAs from heparin competition assay, serum- and ribonuclease-mediated degradation, confirming the potential of the polyplex for in vivo delivery. Results from MTT assays showed that PgP/siRNA polyplexes exhibited minimal cytotoxicity compared to untreated cells when incubated with T98G human GBM cells. We also demonstrated that PgP/siMGMT polyplexes mediate knockdown of MGMT protein as well as a significant ˜56% and ˜68% knockdown of MGMT mRNA in T98G GBM cells compared to cells treated with PgP complexed with non-targeting siRNA (siNT) at a 60:1 and 80:1 nitrogen:phosphate (N:P) ratio, respectively. Further, co-incubation of PgP/siMGMT polyplexes with TMZ

  11. Profound blockage of CXCR4 signaling at multiple points using the synergy between plerixafor, mirtazapine, and clotrimazole as a new glioblastoma treatment adjunct.

    Science.gov (United States)

    Kast, Richard E

    2010-10-01

    CXCL12 signaling at CXCR4 is important in glioblastoma growth promotion as a migration-directing chemokine and as a mitosis-stimulating cytokine system. Recent developments in other areas of medicine may have made it now possible to comprehensively block glioblastoma's use of CXCL12 signaling. CXCL12 signaling at CXCR4 requires an active intermediate conductance Ca2+-activated K+ channel to function. Plerixafor (AMD3100) is a new small molecular weight inhibitor of CXCR4, FDA approved to aid in stem cell mobilization. Inhibition of CXCR4 by plerixafor is expected to inhibit particularly the glioblastoma stem cell population by inhibiting that sub-population's homing to the protective hypoxic niche. Histamine signals through the H1 receptor in glioblastoma cells to activate the intermediate conductance Ca2+-activated K+ channel also, thereby forming a potential bypass for inhibition of CXCR4-initiated signaling. The antidepressant mirtazapine is perhaps the most potent H1 antagonist in common clinical use. By inhibiting H1 stimulation of intermediate conductance Ca2+-activated K+ channels, it could prevent circumvention of CXCR4 inhibition by that path. The anti-fungal clotrimazole directly inhibits the intermediate conductance Ca2+- activated K+ channel at clinically achievable and well-tolerated doses. These three drugs used simultaneously are potential low morbidity paths to deeply inhibit CXCR4/CXCL12 signaling during cytotoxic glioblastoma treatment.

  12. Prospective study evaluating the radiosensitizing effect of reduced doses of temozolomide in the treatment of Egyptian patients with glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Gaber M

    2013-10-01

    Full Text Available May Gaber, Hanan Selim, Tamer El-NahasDepartment of Clinical Oncology, Cairo University, Cairo, EgyptPurpose: In view of the documented toxicity of continuous daily radiosensitizer doses of temozolomide concomitant with radiation in the treatment of glioblastoma multiforme, we aimed to compare it with a different schedule of abbreviated radiosensitizer dosing.Patients and methods: This was a randomized prospective study comparing toxicity and survival in 60 Egyptian patients with glioblastoma multiforme. Patients in arm I received temozolomide at a dose of 75 mg/m2 daily with radiotherapy for 42 days, starting 4 weeks after surgery and reaching to a total radiation dose of 60 Gy/30 Fractions/6 weeks, while patients in arm II received temozolomide at a dose of 75 mg/m2 concomitantly with the same radiotherapy schedule daily in the first and last weeks of the same radiotherapy program.Results: Common grade 1–2 adverse events were malaise in 28 patients (46.7%, followed by alopecia (40% and nausea (26.7%. Grade 3–4 convulsion and decreased level of consciousness was seen in only four patients who were all from arm I. The median progression-free survival (PFS for the entire study population was 10.6 months (95% confidence interval [CI] 7.3–14, and PFS at 12 months was 32%. The median PFS in arm I was 8.8 months (95% CI 5.9–11.7 and in arm II 11.5 months (95% CI 8.9–14.2, and PFS at 12 months for both arms was 32% and 30% respectively (P=0.571. The median overall survival (OS of the whole group of patients was 14.2 months (95% CI 13–15.5, and OS was 70% at 12 months and 25% at 18 months. The median OS for patients in arm I was 12.3 months (95% CI 7.7–16.9, whereas in arm II it was 14.3 months (95% CI 14–14.7 (P=0.83.Conclusion: Reduced radiosensitizer dosing of temozolomide concomitant with radiotherapy in glioblastoma multiforme exhibited comparable efficacy with a classic continuous daily schedule, though with better tolerability

  13. Reasons for non-compliance to treatment among patients with ...

    African Journals Online (AJOL)

    Other reasons were respondents' different belief systems, poor insight about their illness, ineffectivity of some medication, dislike for injections, lack of continuity of care and family support, non-involvement of patients in their own management. Social stigma, objection by a particular religious group to treatment and ...

  14. [Glioblastoma in 2017].

    Science.gov (United States)

    Duffau, Hugues

    2017-02-01

    Glioblastomas are serious tumours of the central nervous system. Recurrence is systematic and prognosis poor. Radiotherapy and chemotherapy follow surgery, when surgery is possible, to lengthen survival, while preserving quality of life as much as possible. In this respect, symptomatic treatments and supportive care are necessary. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Nanotechnology Applications for Glioblastoma

    Science.gov (United States)

    Nduom, Edjah; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G.

    2012-01-01

    Synopsis Glioblastoma remains one of the most difficult cancers to treat and represents the most common primary malignancy of the brain. While conventional treatments have found modest success in reducing the initial tumor burden, infiltrating cancer cells beyond the main mass are responsible for tumor recurrence and ultimate patient demise. Targeting the residual infiltrating cancer cells requires the development of new treatment strategies. The emerging field of cancer nanotechnology holds much promise in the use of multifunctional nanoparticles for the imaging and targeted therapy of GBM.. Nanoparticles have emerged as potential “theranostic” agents that can permit the diagnosis and therapeutic treatment of GBM tumors. A recent human clinical trial with magnetic nanoparticles has provided feasibility and efficacy data for potential treatment of GBM patients with thermotherapy. Here we examine the current state of nanotechnology in the treatment of glioblastoma and interesting directions of further study. PMID:22748656

  16. Incorporating Cancer Stem Cells in Radiation Therapy Treatment Response Modeling and the Implication in Glioblastoma Multiforme Treatment Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Victoria Y.; Nguyen, Dan; Pajonk, Frank; Kupelian, Patrick; Kaprealian, Tania; Selch, Michael; Low, Daniel A.; Sheng, Ke, E-mail: ksheng@mednet.ucla.edu

    2015-03-15

    Purpose: To perform a preliminary exploration with a simplistic mathematical cancer stem cell (CSC) interaction model to determine whether the tumor-intrinsic heterogeneity and dynamic equilibrium between CSCs and differentiated cancer cells (DCCs) can better explain radiation therapy treatment response with a dual-compartment linear-quadratic (DLQ) model. Methods and Materials: The radiosensitivity parameters of CSCs and DCCs for cancer cell lines including glioblastoma multiforme (GBM), non–small cell lung cancer, melanoma, osteosarcoma, and prostate, cervical, and breast cancer were determined by performing robust least-square fitting using the DLQ model on published clonogenic survival data. Fitting performance was compared with the single-compartment LQ (SLQ) and universal survival curve models. The fitting results were then used in an ordinary differential equation describing the kinetics of DCCs and CSCs in response to 2- to 14.3-Gy fractionated treatments. The total dose to achieve tumor control and the fraction size that achieved the least normal biological equivalent dose were calculated. Results: Smaller cell survival fitting errors were observed using DLQ, with the exception of melanoma, which had a low α/β = 0.16 in SLQ. Ordinary differential equation simulation indicated lower normal tissue biological equivalent dose to achieve the same tumor control with a hypofractionated approach for 4 cell lines for the DLQ model, in contrast to SLQ, which favored 2 Gy per fraction for all cells except melanoma. The DLQ model indicated greater tumor radioresistance than SLQ, but the radioresistance was overcome by hypofractionation, other than the GBM cells, which responded poorly to all fractionations. Conclusion: The distinct radiosensitivity and dynamics between CSCs and DCCs in radiation therapy response could perhaps be one possible explanation for the heterogeneous intertumor response to hypofractionation and in some cases superior outcome from

  17. Incorporating Cancer Stem Cells in Radiation Therapy Treatment Response Modeling and the Implication in Glioblastoma Multiforme Treatment Resistance

    International Nuclear Information System (INIS)

    Yu, Victoria Y.; Nguyen, Dan; Pajonk, Frank; Kupelian, Patrick; Kaprealian, Tania; Selch, Michael; Low, Daniel A.; Sheng, Ke

    2015-01-01

    Purpose: To perform a preliminary exploration with a simplistic mathematical cancer stem cell (CSC) interaction model to determine whether the tumor-intrinsic heterogeneity and dynamic equilibrium between CSCs and differentiated cancer cells (DCCs) can better explain radiation therapy treatment response with a dual-compartment linear-quadratic (DLQ) model. Methods and Materials: The radiosensitivity parameters of CSCs and DCCs for cancer cell lines including glioblastoma multiforme (GBM), non–small cell lung cancer, melanoma, osteosarcoma, and prostate, cervical, and breast cancer were determined by performing robust least-square fitting using the DLQ model on published clonogenic survival data. Fitting performance was compared with the single-compartment LQ (SLQ) and universal survival curve models. The fitting results were then used in an ordinary differential equation describing the kinetics of DCCs and CSCs in response to 2- to 14.3-Gy fractionated treatments. The total dose to achieve tumor control and the fraction size that achieved the least normal biological equivalent dose were calculated. Results: Smaller cell survival fitting errors were observed using DLQ, with the exception of melanoma, which had a low α/β = 0.16 in SLQ. Ordinary differential equation simulation indicated lower normal tissue biological equivalent dose to achieve the same tumor control with a hypofractionated approach for 4 cell lines for the DLQ model, in contrast to SLQ, which favored 2 Gy per fraction for all cells except melanoma. The DLQ model indicated greater tumor radioresistance than SLQ, but the radioresistance was overcome by hypofractionation, other than the GBM cells, which responded poorly to all fractionations. Conclusion: The distinct radiosensitivity and dynamics between CSCs and DCCs in radiation therapy response could perhaps be one possible explanation for the heterogeneous intertumor response to hypofractionation and in some cases superior outcome from

  18. CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide.

    Science.gov (United States)

    Kast, Richard E; Karpel-Massler, Georg; Halatsch, Marc-Eric

    2014-09-30

    CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs--aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.

  19. EGFR and EGFRvIII Promote Angiogenesis and Cell Invasion in Glioblastoma: Combination Therapies for an Effective Treatment

    Directory of Open Access Journals (Sweden)

    Stefanie Keller

    2017-06-01

    Full Text Available Epidermal growth factor receptor (EGFR and the mutant EGFRvIII are major focal points in current concepts of targeted cancer therapy for glioblastoma multiforme (GBM, the most malignant primary brain tumor. The receptors participate in the key processes of tumor cell invasion and tumor-related angiogenesis and their upregulation correlates with the poor prognosis of glioma patients. Glioma cell invasion and increased angiogenesis share mechanisms of the degradation of the extracellular matrix (ECM through upregulation of ECM-degrading proteases as well as the activation of aberrant signaling pathways. This review describes the role of EGFR and EGFRvIII in those mechanisms which might offer new combined therapeutic approaches targeting EGFR or EGFRvIII together with drug treatments against proteases of the ECM or downstream signaling to increase the inhibitory effects of mono-therapies.

  20. Immunological Evasion in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Roxana Magaña-Maldonado

    2016-01-01

    Full Text Available Glioblastoma is the most aggressive tumor in Central Nervous System in adults. Among its features, modulation of immune system stands out. Although immune system is capable of detecting and eliminating tumor cells mainly by cytotoxic T and NK cells, tumor microenvironment suppresses an effective response through recruitment of modulator cells such as regulatory T cells, monocyte-derived suppressor cells, M2 macrophages, and microglia as well as secretion of immunomodulators including IL-6, IL-10, CSF-1, TGF-β, and CCL2. Other mechanisms that induce immunosuppression include enzymes as indolamine 2,3-dioxygenase. For this reason it is important to develop new therapies that avoid this immune evasion to promote an effective response against glioblastoma.

  1. Genome-wide transcriptional profiling of human glioblastoma cells in response to ITE treatment.

    Science.gov (United States)

    Kang, Bo; Zhou, Yanwen; Zheng, Min; Wang, Ying-Jie

    2015-09-01

    A ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is recently revealed to play a key role in embryogenesis and tumorigenesis (Feng et al. [1], Safe et al. [2]) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) (Song et al. [3]) is an endogenous AhR ligand that possesses anti-tumor activity. In order to gain insights into how ITE acts via the AhR in embryogenesis and tumorigenesis, we analyzed the genome-wide transcriptional profiles of the following three groups of cells: the human glioblastoma U87 parental cells, U87 tumor sphere cells treated with vehicle (DMSO) and U87 tumor sphere cells treated with ITE. Here, we provide the details of the sample gathering strategy and show the quality controls and the analyses associated with our gene array data deposited into the Gene Expression Omnibus (GEO) under the accession code of GSE67986.

  2. Assessment of the proliferation status of glioblastoma cell and tumour tissue after nanoplatinum treatment

    DEFF Research Database (Denmark)

    Kutwin, Marta; Sawosz, Ewa; Jaworski, Slawomir

    2017-01-01

    nanoparticles (NP-Pt). The aim of the study was to evaluate and compare the antiproliferative properties of NP-Pt and cisplatin against U87 and U118 glioma cell lines and U87 tumour tissue. NP-Pt and cisplatin were incubated with U87 and U118 glioma cells or administered directly into glioma tumour tissue. Cell...... and the migration of cancer cells but also downregulated the level of PCNA protein expression in tumour tissue. Furthermore, NP-Pt caused oxidative DNA damage in tumour tissue to a higher degree than cisplatin. Consequently, NP-Pt can be considered as an effective inhibitor of glioblastoma tumour cell proliferation....... However, the mechanism of action and potential side effects need to be elucidated further...

  3. A potential non-invasive glioblastoma treatment: Nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles.

    Science.gov (United States)

    Sekerdag, Emine; Lüle, Sevda; Bozdağ Pehlivan, Sibel; Öztürk, Naile; Kara, Aslı; Kaffashi, Abbas; Vural, Imran; Işıkay, Ilkay; Yavuz, Burҫin; Oguz, Kader Karlı; Söylemezoğlu, Figen; Gürsoy-Özdemir, Yasemin; Mut, Melike

    2017-09-10

    New drug delivery systems are highly needed in research and clinical area to effectively treat gliomas by reaching a high antineoplastic drug concentration at the target site without damaging healthy tissues. Intranasal (IN) administration, an alternative route for non-invasive drug delivery to the brain, bypasses the blood-brain-barrier (BBB) and eliminates systemic side effects. This study evaluated the antitumor efficacy of farnesylthiosalicylic acid (FTA) loaded (lipid-cationic) lipid-PEG-PLGA hybrid nanoparticles (HNPs) after IN application in rats. FTA loaded HNPs were prepared, characterized and evaluated for cytotoxicity. Rat glioma 2 (RG2) cells were implanted unilaterally into the right striatum of female Wistar rats. 10days later, glioma bearing rats received either no treatment, or 5 repeated doses of 500μM freshly prepared FTA loaded HNPs via IN or intravenous (IV) application. Pre-treatment and post-treatment tumor sizes were determined with MRI. After a treatment period of 5days, IN applied FTA loaded HNPs achieved a significant decrease of 55.7% in tumor area, equal to IV applied FTA loaded HNPs. Herewith, we showed the potential utility of IN application of FTA loaded HNPs as a non-invasive approach in glioblastoma treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.

    Directory of Open Access Journals (Sweden)

    Kuo-Chen Wei

    Full Text Available The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI-monitored focused ultrasound (FUS-induced blood-brain barrier (BBB disruption to enhance Temozolomide (TMZ delivery for improving Glioblastoma Multiforme (GBM treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI, animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.

  5. Glioblastoma familiar

    Directory of Open Access Journals (Sweden)

    Walter O. Arruda

    1995-06-01

    Full Text Available The authors describe a family with three members affected by glioblastoma. The proband patient, a 7 year-old girl, developed a rare complication, a pulmonary metastasis. Chromosomal analysis of her peripheral blood lymphocytes showed a normal karyotype (46, XX, without structural abnormalities. Cytogenetic study of the tumor cells disclosed several abnormalities: 46, XX, 7q - / 46, XX, -2, 4p-, 7p-, +15/ 46, XX. Some aspects about genetics of glial neoplasms are discussed.

  6. Glioblastoma: does the pre-treatment geometry matter? A postcontrast T1 MRI-based study

    International Nuclear Information System (INIS)

    Perez-Beteta, Julian; Martinez-Gonzalez, Alicia; Molina, David; Amo-Salas, Mariano; Luque, Belen; Perez-Garcia, Victor M.; Arregui, Elena; Calvo, Manuel; Borras, Jose M.; Lopez, Carlos; Claramonte, Marta; Barcia, Juan A.; Iglesias, Lidia; Avecillas, Josue; Albillo, David; Navarro, Miguel; Villanueva, Jose M.; Paniagua, Juan C.; Perez-Romasanta, Luis; Martino, Juan; Velasquez, Carlos; Asenjo, Beatriz; Benavides, Manuel; Herruzo, Ismael; Delgado, Maria del Carmen; Valle, Ana del; Falkov, Anthony; Schucht, Philippe; Arana, Estanislao

    2017-01-01

    The potential of a tumour's volumetric measures obtained from pretreatment MRI sequences of glioblastoma (GBM) patients as predictors of clinical outcome has been controversial. Mathematical models of GBM growth have suggested a relation between a tumour's geometry and its aggressiveness. A multicenter retrospective clinical study was designed to study volumetric and geometrical measures on pretreatment postcontrast T1 MRIs of 117 GBM patients. Clinical variables were collected, tumours segmented, and measures computed including: contrast enhancing (CE), necrotic, and total volumes; maximal tumour diameter; equivalent spherical CE width and several geometric measures of the CE ''rim''. The significance of the measures was studied using proportional hazards analysis and Kaplan-Meier curves. Kaplan-Meier and univariate Cox survival analysis showed that total volume [p = 0.034, Hazard ratio (HR) = 1.574], CE volume (p = 0.017, HR = 1.659), spherical rim width (p = 0.007, HR = 1.749), and geometric heterogeneity (p = 0.015, HR = 1.646) were significant parameters in terms of overall survival (OS). Multivariable Cox analysis for OS provided the later two parameters as age-adjusted predictors of OS (p = 0.043, HR = 1.536 and p = 0.032, HR = 1.570, respectively). Patients with tumours having small geometric heterogeneity and/or spherical rim widths had significantly better prognosis. These novel imaging biomarkers have a strong individual and combined prognostic value for GBM patients. (orig.)

  7. Glioblastoma: does the pre-treatment geometry matter? A postcontrast T1 MRI-based study

    Energy Technology Data Exchange (ETDEWEB)

    Perez-Beteta, Julian; Martinez-Gonzalez, Alicia; Molina, David; Amo-Salas, Mariano; Luque, Belen; Perez-Garcia, Victor M. [Universidad de Castilla-La Mancha, Laboratory of Mathematical Oncology, Edificio Politecnico, Instituto de Matematica Aplicada a la Ciencia y la Ingenieria, Ciudad Real (Spain); Arregui, Elena; Calvo, Manuel; Borras, Jose M.; Lopez, Carlos; Claramonte, Marta [Hospital General de Ciudad Real, Ciudad Real (Spain); Barcia, Juan A.; Iglesias, Lidia; Avecillas, Josue [Hospital Clinico San Carlos, Madrid (Spain); Albillo, David; Navarro, Miguel; Villanueva, Jose M.; Paniagua, Juan C.; Perez-Romasanta, Luis [Hospital Universitario de Salamanca, Salamanca (Spain); Martino, Juan; Velasquez, Carlos [Hospital Marques de Valdecilla, Santander (Spain); Asenjo, Beatriz; Benavides, Manuel; Herruzo, Ismael [Hospital Carlos Haya, Malaga (Spain); Delgado, Maria del Carmen; Valle, Ana del [Universidad de Sevilla, Facultad de Matematicas, Sevilla (Spain); Falkov, Anthony [Auckland Radiation Oncology, Auckland (New Zealand); Schucht, Philippe [Bern Inselspital, Neurosurgery Department, Bern (Switzerland); Arana, Estanislao [Instituto Valenciano de Oncologia, Valencia (Spain)

    2017-03-15

    The potential of a tumour's volumetric measures obtained from pretreatment MRI sequences of glioblastoma (GBM) patients as predictors of clinical outcome has been controversial. Mathematical models of GBM growth have suggested a relation between a tumour's geometry and its aggressiveness. A multicenter retrospective clinical study was designed to study volumetric and geometrical measures on pretreatment postcontrast T1 MRIs of 117 GBM patients. Clinical variables were collected, tumours segmented, and measures computed including: contrast enhancing (CE), necrotic, and total volumes; maximal tumour diameter; equivalent spherical CE width and several geometric measures of the CE ''rim''. The significance of the measures was studied using proportional hazards analysis and Kaplan-Meier curves. Kaplan-Meier and univariate Cox survival analysis showed that total volume [p = 0.034, Hazard ratio (HR) = 1.574], CE volume (p = 0.017, HR = 1.659), spherical rim width (p = 0.007, HR = 1.749), and geometric heterogeneity (p = 0.015, HR = 1.646) were significant parameters in terms of overall survival (OS). Multivariable Cox analysis for OS provided the later two parameters as age-adjusted predictors of OS (p = 0.043, HR = 1.536 and p = 0.032, HR = 1.570, respectively). Patients with tumours having small geometric heterogeneity and/or spherical rim widths had significantly better prognosis. These novel imaging biomarkers have a strong individual and combined prognostic value for GBM patients. (orig.)

  8. Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma.

    Science.gov (United States)

    Hicks, Martin J; Funato, Kosuke; Wang, Lan; Aronowitz, Eric; Dyke, Jonathan P; Ballon, Douglas J; Havlicek, David F; Frenk, Esther Z; De, Bishnu P; Chiuchiolo, Maria J; Sondhi, Dolan; Hackett, Neil R; Kaminsky, Stephen M; Tabar, Viviane; Crystal, Ronald G

    2015-01-01

    The median survival of glioblastoma multiforme (GBM) is approximately 1 year. Following surgical removal, systemic therapies are limited by the blood-brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu. The human U87MG GBM cell line or patient-derived early passage GBM cells were administered to the striatum of NOD/SCID immunodeficient mice. AAVrh.10BevMab, an AAVrh.10-based vector coding for bevacizumab (Avastin), an anti-human vascular endothelial growth factor (VEGF) monoclonal antibody, was delivered to the area of the GBM xenograft. Localized expression of bevacizumab was demonstrated by quantitative PCR, ELISA and western blotting. Immunohistochemistry showed that bevacizumab was expressed in neurons. Concurrent administration of AAVrh.10BevMab with the U87MG tumor reduced tumor blood vessel density and tumor volume, and increased survival. Administration of AAVrh.10BevMab 1 week after U87MG xenograft reduced growth and increased survival. Studies with patient-derived early passage GBM primary cells showed a reduction in primary tumor burden with an increased survival. These data support the strategy of AAV-mediated central nervous system gene therapy to treat GBM, overcoming the blood-brain barrier through local, persistent delivery of an anti-angiogenesis monoclonal antibody.

  9. A comprehensive profile of recurrent glioblastoma

    DEFF Research Database (Denmark)

    Campos, B.; Olsen, Lars Rønn; Urup, T.

    2016-01-01

    In spite of relentless efforts to devise new treatment strategies, primary glioblastomas invariably recur as aggressive, therapy-resistant relapses and patients rapidly succumb to these tumors. Many therapeutic agents are first tested in clinical trials involving recurrent glioblastomas. Remarkab...... 2016; doi:10.1038/onc.2016.85....

  10. Chimeric Mouse model to track the migration of bone marrow derived cells in glioblastoma following anti-angiogenic treatments.

    Science.gov (United States)

    Achyut, B R; Shankar, Adarsh; Iskander, A S M; Ara, Roxan; Knight, Robert A; Scicli, Alfonso G; Arbab, Ali S

    2016-01-01

    Bone marrow derived cells (BMDCs) have been shown to contribute in the tumor development. In vivo animal models to investigate the role of BMDCs in tumor development are poorly explored. We established a novel chimeric mouse model using as low as 5 × 10(6) GFP+ BM cells in athymic nude mice, which resulted in >70% engraftment within 14 d. In addition, chimera was established in NOD-SCID mice, which displayed >70% with in 28 d. Since anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels in glioblastoma (GBM), which resulted into marked hypoxia and recruited BMDCs to the tumor microenvironment (TME). We exploited chimeric mice in athymic nude background to develop orthotopic U251 tumor and tested receptor tyrosine kinase inhibitors and CXCR4 antagonist against GBM. We were able to track GFP+ BMDCs in the tumor brain using highly sensitive multispectral optical imaging instrument. Increased tumor growth associated with the infiltration of GFP+ BMDCs acquiring suppressive myeloid and endothelial phenotypes was seen in TME following treatments. Immunofluorescence study showed GFP+ cells accumulated at the site of VEGF, SDF1 and PDGF expression, and at the periphery of the tumors following treatments. In conclusion, we developed a preclinical chimeric model of GBM and phenotypes of tumor infiltrated BMDCs were investigated in context of AATs. Chimeric mouse model could be used to study detailed cellular and molecular mechanisms of interaction of BMDCs and TME in cancer.

  11. Glioblastoma update: molecular biology, diagnosis, treatment, response assessment, and translational clinical trials [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Frank Lieberman

    2017-10-01

    Full Text Available This is an exciting time in neuro-oncology. Discoveries elucidating the molecular mechanisms of oncogenesis and the molecular subtypes of glioblastoma multiforme (GBM have led to new diagnostic and classification schemes with more prognostic power than histology alone. Molecular profiling has become part of the standard neuropathological evaluation of GBM. Chemoradiation followed by adjuvant temozolomide remains the standard therapy for newly diagnosed GBM, but survival remains unsatisfactory. Patients with recurrent GBM continue to have a dismal prognosis, but neuro-oncology centers with active clinical trial programs are seeing a small but increasing cadre of patients with longer survival. Molecularly targeted therapeutics, personalized therapy based on molecular profiling of individual tumors, and immunotherapeutic strategies are all being evaluated and refined in clinical trials. Understanding of the molecular mechanisms of tumor-mediated immunosuppression, and specifically interactions between tumor cells and immune effector cells in the tumor microenvironment, has led to a new generation of immunotherapies, including vaccine and immunomodulatory strategies as well as T-cell-based treatments. Molecularly targeted therapies, chemoradiation, immunotherapies, and anti-angiogenic therapies have created the need to develop more reliable neuroimaging criteria for differentiating the effects of therapy from tumor progression and changes in blood–brain barrier physiology from treatment response. Translational clinical trials for patients with GBM now incorporate quantitative imaging using both magnetic resonance imaging and positron emission tomography techniques. This update presents a summary of the current standards for therapy for newly diagnosed and recurrent GBM and highlights promising translational research.

  12. Autonomy and reason: treatment choice in breast cancer.

    Science.gov (United States)

    Twomey, Mary

    2012-10-01

    The practice of offering choice to those women with breast cancer for whom either breast conserving surgery or mastectomy would be equally beneficial has come to be seen as an important aspect of medical care. As well as improving satisfaction with treatment, this is seen as satisfying the ethical principle of respect for autonomy. A number of studies, however, show that women are not always comfortable with such choice, preferring to leave treatment decisions to their surgeons. A question then arises as to the extent that these women can be seen as autonomous or as exercising autonomy. This paper argues, however, that the understanding of autonomy which is applied in current approaches to breast cancer care does not adequately support the exercise of autonomy, and that the clinical context of care means that women are not able to engage in the kind of reasoning that might promote the exercise of autonomy. Where respect for autonomy is limited to informed consent and choice, there is a danger that women's interests are overlooked in those aspects of their care where choice is not appropriate, with very real, long-term consequences for some women. Promoting the exercise of autonomy, it is argued, needs to go beyond the conception of autonomy as rational individuals making their own decisions, and clinicians need to work with an understanding of autonomy as relational in order to better involve women in their care. © 2012 Blackwell Publishing Ltd.

  13. FUNCTIONAL SUBCLONE PROFILING FOR PREDICTION OF TREATMENT-INDUCED INTRA-TUMOR POPULATION SHIFTS AND DISCOVERY OF RATIONAL DRUG COMBINATIONS IN HUMAN GLIOBLASTOMA

    Science.gov (United States)

    Reinartz, Roman; Wang, Shanshan; Kebir, Sied; Silver, Daniel J.; Wieland, Anja; Zheng, Tong; Küpper, Marius; Rauschenbach, Laurèl; Fimmers, Rolf; Shepherd, Timothy M.; Trageser, Daniel; Till, Andreas; Schäfer, Niklas; Glas, Martin; Hillmer, Axel M.; Cichon, Sven; Smith, Amy A.; Pietsch, Torsten; Liu, Ying; Reynolds, Brent A.; Yachnis, Anthony; Pincus, David W.; Simon, Matthias; Brüstle, Oliver; Steindler, Dennis A.; Scheffler, Björn

    2016-01-01

    Purpose Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and inter-individual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacological sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential anti-glioblastoma compounds. A more comprehensive intra-tumoral analysis revealed that stable genetic and phenotypic characteristics of co-existing subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacological profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions Our data provide a previously unrecognized strategy for revealing functional consequences of intra-tumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. PMID:27521447

  14. Perfusion of surgical cavity wall enhancement in early post-treatment MR imaging may stratify the time-to-progression in glioblastoma.

    Directory of Open Access Journals (Sweden)

    Ji Eun Park

    Full Text Available To determine if perfusion in surgical cavity wall enhancement (SCWE obtained in early post-treatment MR imaging can stratify time-to-progression (TTP in glioblastoma.This study enrolled 60 glioblastoma patients with more than 5-mm-thick SCWEs as detected on contrast-enhanced MR imaging after concurrent chemoradiation therapy. Two independent readers categorized the shape and perfusion state of SCWEs as nodular or non-nodular and as having positive or negative perfusion compared with the contralateral grey matter on arterial spin labeling (ASL. The perfusion fraction on ASL within the contrast-enhancing lesion was calculated. The independent predictability of TTP was analyzed using the Kaplan-Meier method and Cox proportional hazards modelling.The perfusion fraction was higher in the non-progression group, significantly for reader 2 (P = 0.03 and borderline significantly for reader 1 (P = 0.08. A positive perfusion state and (P = 0.02 a higher perfusion fraction of the SCWE were found to become an independent predictor of longer TTP (P = 0.001 for reader 1 and P < 0.001 for reader 2. The contrast enhancement pattern did not become a TTP predictor.Assessment of perfusion in early post-treatment MR imaging can stratify TTP in patients with glioblastoma for adjuvant temozolomide therapy. Positive perfusion in SCWEs can become a predictor of a longer TTP.

  15. An Optimized Method for Manufacturing a Clinical Scale Dendritic Cell-Based Vaccine for the Treatment of Glioblastoma

    Science.gov (United States)

    Pogliani, Simona; Pellegatta, Serena; Antozzi, Carlo; Baggi, Fulvio; Gellera, Cinzia; Pollo, Bianca; Parati, Eugenio A.; Finocchiaro, Gaetano; Frigerio, Simona

    2012-01-01

    Immune-based treatments represent a promising new class of therapy designed to boost the immune system to specifically eradicate malignant cells. Immunotherapy may generate specific anti-tumor immune responses, and dendritic cells (DC), professional antigen-presenting cells, are widely used in experimental cancer immunotherapy. Several reports describe methods for the generation of mature, antigen-pulsed DC for clinical use. Improved quality and standardization are desirable to obtain GMP-compliant protocols. In this study we describe the generation of DC from 31 Glioblastoma (GB) patients starting from their monocytes isolated by immunomagnetic CD14 selection using the CliniMACS® device. Upon differentiation of CD14+ with IL-4 and GM-CSF, DC were induced to maturation with TNF-α, PGE2, IL-1β, and IL-6. Whole tumor lysate was obtained, for the first time, in a closed system using the semi-automated dissociator GentleMACS®. The yield of proteins improved by 130% compared to the manual dissociation method. Interestingly the Mean Fluorescence Intensity for CD83 increased significantly in DC pulsed with “new method” lysate compared to DC pulsed with “classical method” lysate. Our results indicate that immunomagnetic isolation of CD14+ monocytes using the CliniMACS® device and their pulsing with whole tumor lysate proteins is a suitable method for clinical-scale generation of high quality, functional DC under GMP-grade conditions. PMID:23284979

  16. The future role of personalized medicine in the treatment of glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Jing Li

    2010-08-01

    Full Text Available Jing Li1,2, Chunhui Di1,2, Austin K Mattox1,2, Linda Wu1,2, D Cory Adamson1,2,3,41Preston Robert Tisch Brain Tumor Center, Duke Medical Center, Durham, North Carolina, USA; 2Department of Surgery (Neurosurgery, Duke Medical Center, Durham, North Carolina, USA; 3Department of Neurobiology, Duke Medical Center, Durham, North Carolina, USA; 4Neurosurgery Section, Durham VA Medical Center, Durham, North Carolina, USAAbstract: Glioblastoma multiforme (GBM remains one of the most malignant primary central nervous system tumors. Personalized therapeutic approaches have not become standard of care for GBM, but science is fast approaching this goal. GBM’s heterogeneous genomic landscape and resistance to radiotherapy and chemotherapy make this tumor one of the most challenging to treat. Recent advances in genome-wide studies and genetic profiling show that there is unlikely to be a single genetic or cellular event that can be effectively targeted in all patients. Instead, future therapies will likely require personalization for each patient’s tumor genotype or proteomic profile. Over the past year, many investigations specifically focused simultaneously on strategies to target oncogenic pathways, angiogenesis, tumor immunology, epigenomic events, glioma stem cells (GSCs, and the highly migratory glioma cell population. Combination therapy targeting multiple pathways is becoming a fast growing area of research, and many studies put special attention on small molecule inhibitors. Because GBM is a highly vascular tumor, therapy that directs monoclonal antibodies or small molecule tyrosine kinase inhibitors toward angiogenic factors is also an area of focus for the development of new therapies. Passive, active, and adoptive immunotherapies have been explored by many studies recently, and epigenetic regulation of gene expression with microRNAs is also becoming an important area of study. GSCs can be useful targets to stop tumor recurrence and

  17. The use of hypofractionated intensity-modulated irradiation in the treatment of glioblastoma multiforme: preliminary results of a prospective trial.

    Science.gov (United States)

    Sultanem, Khalil; Patrocinio, Horacio; Lambert, Christine; Corns, Robert; Leblanc, Richard; Parker, William; Shenouda, George; Souhami, Luis

    2004-01-01

    Despite major advances in treatment modalities, the prognosis of patients with glioblastoma multiforme (GBM) remains poor. Exploring hypofractionated regimens to replace the standard 6-week radiotherapy schedule is an attractive strategy as an attempt to prevent accelerated tumor cell repopulation. There is equally interest in dose escalation to the gross tumor volume where the majority of failures occur. We report our preliminary results using hypofractionated intensity-modulated accelerated radiotherapy regimen in the treatment of patients with GBM. Between July 1998 and December 2001, 25 patients with histologically proven diagnosis of GBM, Karnofsky performance status > or =60, and a postoperative tumor volume step-and-shoot technique), 60 Gy in 20 daily fractions of 3 Gy each were given to the GTV, whereas the planning target volume received a minimum of 40 Gy in 20 fractions of 2 Gy each at its periphery. Treatments were delivered over a 4-week period using 5 daily fractions per week. Dose was prescribed at the isocenter (ICRU point). Three beam angles were used in all of the cases. Treatments were well tolerated. Acute toxicity was limited to increased brain edema during radiotherapy in 2 patients who were on tapering doses of corticosteroids. This was corrected by increasing the steroid dose. At a median follow-up of 8.8 months, no late toxicity was observed. One patient experienced visual loss at 9 months after completion of treatment. MRI suggested nonspecific changes to the optic chiasm. On review of the treatment plan, the total dose to the optic chiasm was confirmed to be equal to or less than 40 Gy in 20 fractions. When Radiation Therapy Oncology Group recursive partitioning analysis was used, 10 patients were class III-IV, and 15 patients were class V-VI. To date, 21 patients have had clinical and/or radiologic evidence of disease progression, and 16 patients have died. The median survival was 9.5 months (range: 2.8-22.9 months), the 1-year survival

  18. Combining Immunotherapy with Standard Glioblastoma Therapy

    Science.gov (United States)

    This clinical trial is testing standard therapy (surgery, radiation and temozolomide) plus immunotherapy with pembrolizumab with or without a cancer treatment vaccine for patients with newly diagnosed glioblastoma, a common and deadly type of brain tumor.

  19. CCR 20th Anniversary Commentary: Bevacizumab in the Treatment of Glioblastoma--The Progress and the Limitations.

    Science.gov (United States)

    Mar, Nataliya; Desjardins, Annick; Vredenburgh, James J

    2015-10-01

    Vredenburgh and colleagues conducted the first phase II study of bevacizumab plus irinotecan in recurrent malignant glioma, confirming the safety and efficacy of bevacizumab. This study, which was published in the February 15, 2007, issue of Clinical Cancer Research, was a stepping stone for subsequent research, leading to regulatory approval of bevacizumab for recurrent glioblastoma. ©2015 American Association for Cancer Research.

  20. The impact of bevacizumab treatment on survival and quality of life in newly diagnosed glioblastoma patients

    DEFF Research Database (Denmark)

    Poulsen, Hans Skovgaard; Urup, Thomas; Michaelsen, Signe Regner

    2014-01-01

    in newly diagnosed GBM patients have been performed during recent years to test the hypothesis that newly diagnosed GBM patients should be treated with standard multimodality treatment, in combination with bevacizumab, in order to prolong life and maintain or improve quality of life. The results...... treatment is therefore to prolong life, with a maintenance or improvement of quality of life. GBM is a highly vascular tumor and overexpresses the vascular endothelial growth factor A, which promotes angiogenesis. Preclinical data have suggested that anti-angiogenic treatment efficiently inhibits tumor...... growth. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A, and treatment has shown impressive response rates in recurrent GBM. In addition, it has been shown that response is correlated to prolonged survival and improved quality of life. Several investigations...

  1. Immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances antitumor activity in glioblastoma treatment.

    Science.gov (United States)

    Hardcastle, Jayson; Mills, Lisa; Malo, Courtney S; Jin, Fang; Kurokawa, Cheyne; Geekiyanage, Hirosha; Schroeder, Mark; Sarkaria, Jann; Johnson, Aaron J; Galanis, Evanthia

    2017-04-01

    Glioblastoma (GBM) is the most common primary malignant brain tumor and has a dismal prognosis. Measles virus (MV) therapy of GBM is a promising strategy due to preclinical efficacy, excellent clinical safety, and its ability to evoke antitumor pro-inflammatory responses. We hypothesized that combining anti- programmed cell death protein 1 (anti-PD-1) blockade and MV therapy can overcome immunosuppression and enhance immune effector cell responses against GBM, thus improving therapeutic outcome. In vitro assays of MV infection of glioma cells and infected glioma cells with mouse microglia ± aPD-1 blockade were established to assess damage associated molecular pattern (DAMP) molecule production, migration, and pro-inflammatory effects. C57BL/6 or athymic mice bearing syngeneic orthotopic GL261 gliomas were treated with MV, aPD-1, and combination treatment. T2* weighted immune cell-specific MRI and fluorescence activated cell sorting (FACS) analysis of treated mouse brains was used to examine adaptive immune responses following therapy. In vitro, MV infection induced human GBM cell secretion of DAMP (high-mobility group protein 1, heat shock protein 90) and upregulated programmed cell death ligand 1 (PD-L1). MV infection of GL261 murine glioma cells resulted in a pro-inflammatory response and increased migration of BV2 microglia. In vivo, MV+aPD-1 therapy synergistically enhanced survival of C57BL/6 mice bearing syngeneic orthotopic GL261 gliomas. MRI showed increased inflammatory cell influx into the brains of mice treated with MV+aPD-1; FACS analysis confirmed increased T-cell influx predominantly consisting of activated CD8+ T cells. This report demonstrates that oncolytic measles virotherapy in combination with aPD-1 blockade significantly improves survival outcome in a syngeneic GBM model and supports the potential of clinical/translational strategies combining MV with αPD-1 therapy in GBM treatment. © The Author(s) 2016. Published by Oxford University Press

  2. Glioblastoma multiforme (GBM) in the elderly: initial treatment strategy and overall survival.

    Science.gov (United States)

    Glaser, Scott M; Dohopolski, Michael J; Balasubramani, Goundappa K; Flickinger, John C; Beriwal, Sushil

    2017-08-01

    The EORTC trial which solidified the role of external beam radiotherapy (EBRT) plus temozolomide (TMZ) in the management of GBM excluded patients over age 70. Randomized studies of elderly patients showed that hypofractionated EBRT (HFRT) alone or TMZ alone was at least equivalent to conventionally fractionated EBRT (CFRT) alone. We sought to investigate the practice patterns and survival in elderly patients with GBM. We identified patients age 65-90 in the National Cancer Data Base (NCDB) with histologically confirmed GBM from 1998 to 2012 and known chemotherapy and radiotherapy status. We analyzed factors predicting treatment with EBRT alone vs. EBRT plus concurrent single-agent chemotherapy (CRT) using multivariable logistic regression. Similarly, within the EBRT alone cohort we compared CFRT (54-65 Gy at 1.7-2.1 Gy/fraction) to HFRT (34-60 Gy at 2.5-5 Gy/fraction). Multivariable Cox proportional hazards model (MVA) with propensity score adjustment was used to compare survival. A total of 38,862 patients were included. Initial treatments for 1998 versus 2012 were: EBRT alone = 50 versus 10%; CRT = 6 versus 50%; chemo alone = 1.6% (70% single-agent) versus 3.2% (94% single-agent). Among EBRT alone patients, use of HFRT (compared to CFRT) increased from 13 to 41%. Numerous factors predictive for utilization of CRT over EBRT alone and for HFRT over CFRT were identified. Median survival and 1-year overall survival were higher in the CRT versus EBRT alone group at 8.6 months vs. 5.1 months and 36.0 versus 15.7% (p GBM patients in the United States, CRT is the most common initial treatment and appears to offer a survival advantage over EBRT alone. Adoption of hypofractionation has increased over time but continues to be low.

  3. Reasons for Treatment Changes in Patients With Moderate to Severe Psoriasis.

    Science.gov (United States)

    Anderson, Kathryn L; Feldman, Steven R

    2015-01-01

    Psoriasis treatment involves multiple treatment arms. Treatment choice depends on many factors and may change, due to the chronicity of psoriasis. The purpose of our study is to explore reasons for treatment changes in patients with moderate to severe psoriasis. Ten charts of patients with moderate to severe psoriasis were reviewed. The medication changes and reasons for change were extracted. A "treatment change" was defined as switching between medication classes, adding or removing a medication class, or switching medications within the oral or biologic medication class. Seventy-seven treatment changes were identified. On average, 1 treatment change occurred per year of follow-up. The most common reason for treatment change was inadequate disease control. Inadequate disease control with current therapy is the most common reason a physician changes treatment for moderate to severe psoriasis. More efficacious treatments or ways to improve efficacy may help improve the long-term outcomes of psoriasis. © The Author(s) 2015.

  4. TH-A-BRF-09: Integration of High-Resolution MRSI Into Glioblastoma Treatment Planning

    Energy Technology Data Exchange (ETDEWEB)

    Schreibmann, E; Cordova, J; Shu, H; Crocker, I; Curran, W; Holder, C; Shim, H [Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA (United States)

    2014-06-15

    Purpose: Identification of a metabolite signature that shows significant tumor cell infiltration into normal brain in regions that do not appear abnormal on standard MRI scans would be extremely useful for radiation oncologists to choose optimal regions of brain to treat, and to quantify response beyond the MacDonald criteria. We report on integration of high-resolution magnetic resonance spectroscopic imaging (HR-MRSI) with radiation dose escalation treatment planning to define and target regions at high risk for recurrence. Methods: We propose to supplement standard MRI with a special technique performed on an MRI scanner to measure the metabolite levels within defined volumes. Metabolite imaging was acquired using an advanced MRSI technique combining 3D echo-planar spectroscopic imaging (EPSI) with parallel acquisition (GRAPPA) using a multichannel head coil that allows acquisition of whole brain metabolite maps with 108 μl resolution in 12 minutes implemented on a 3T MR scanner. Elevation in the ratio of two metabolites, choline (Cho, elevated in proliferating high-grade gliomas) and N-acetyl aspartate (NAA, a normal neuronal metabolite), was used to image infiltrating high-grade glioma cells in vivo. Results: The metabolite images were co-registered with standard contrast-enhanced T1-weighted MR images using in-house registration software and imported into the treatment-planning system. Regions with tumor infiltration are identified on the metabolic images and used to create adaptive IMRT plans that deliver a standard dose of 60 Gy to the standard target volume and an escalated dose of 75 Gy (or higher) to the most suspicious regions, identified as areas with elevated Cho/NAA ratio. Conclusion: We have implemented a state-of-the-art HR-MRSI technology that can generate metabolite maps of the entire brain in a clinically acceptable scan time, coupled with introduction of an imaging co-registration/ analysis program that combines MRSI data with standard imaging

  5. TH-A-BRF-09: Integration of High-Resolution MRSI Into Glioblastoma Treatment Planning

    International Nuclear Information System (INIS)

    Schreibmann, E; Cordova, J; Shu, H; Crocker, I; Curran, W; Holder, C; Shim, H

    2014-01-01

    Purpose: Identification of a metabolite signature that shows significant tumor cell infiltration into normal brain in regions that do not appear abnormal on standard MRI scans would be extremely useful for radiation oncologists to choose optimal regions of brain to treat, and to quantify response beyond the MacDonald criteria. We report on integration of high-resolution magnetic resonance spectroscopic imaging (HR-MRSI) with radiation dose escalation treatment planning to define and target regions at high risk for recurrence. Methods: We propose to supplement standard MRI with a special technique performed on an MRI scanner to measure the metabolite levels within defined volumes. Metabolite imaging was acquired using an advanced MRSI technique combining 3D echo-planar spectroscopic imaging (EPSI) with parallel acquisition (GRAPPA) using a multichannel head coil that allows acquisition of whole brain metabolite maps with 108 μl resolution in 12 minutes implemented on a 3T MR scanner. Elevation in the ratio of two metabolites, choline (Cho, elevated in proliferating high-grade gliomas) and N-acetyl aspartate (NAA, a normal neuronal metabolite), was used to image infiltrating high-grade glioma cells in vivo. Results: The metabolite images were co-registered with standard contrast-enhanced T1-weighted MR images using in-house registration software and imported into the treatment-planning system. Regions with tumor infiltration are identified on the metabolic images and used to create adaptive IMRT plans that deliver a standard dose of 60 Gy to the standard target volume and an escalated dose of 75 Gy (or higher) to the most suspicious regions, identified as areas with elevated Cho/NAA ratio. Conclusion: We have implemented a state-of-the-art HR-MRSI technology that can generate metabolite maps of the entire brain in a clinically acceptable scan time, coupled with introduction of an imaging co-registration/ analysis program that combines MRSI data with standard imaging

  6. Appearance vs. health reasons for seeking treatment among obese patients with binge eating disorder.

    Science.gov (United States)

    Reas, Deborah L; Masheb, Robin M; Grilo, Carlos M

    2004-05-01

    This study examined reasons for seeking treatment reported by obese patients diagnosed with binge eating disorder (BED). Participants were 248 adults (58 men and 190 women) who met DSM criteria for BED. Participants were recruited through advertisements for treatment studies looking for persons who wanted to "stop binge eating and lose weight." Patients' reasons for seeking treatment were examined with respect to demography (gender and age), obesity (BMI and age of onset), features of eating disorders, and associated psychological functioning (depression and self-esteem). Of the 248 participants, 64% reported health concerns and 36% reported appearance concerns as their primary reason for seeking treatment. Reasons for seeking treatment did not differ significantly by gender. Patients seeking treatment because of appearance-related reasons had lower BMIs than those reporting health-related reasons (34.8 vs. 38.5, respectively), but they reported greater body dissatisfaction, more features of eating disorders, and lower self-esteem. Reasons that prompt treatment seeking among obese individuals with BED reflect meaningful patient characteristics and, therefore, warrant assessment and consideration during treatment planning. Further research is needed to determine whether reasons for treatment seeking among different obese patient groups affect treatment outcomes. Copyright 2004 NAASO

  7. Improving Tumor Treating Fields Treatment Efficacy in Patients With Glioblastoma Using Personalized Array Layouts

    Energy Technology Data Exchange (ETDEWEB)

    Wenger, Cornelia, E-mail: cwenger@fc.ul.pt [Institute of Biophysics and Biomedical Engineering, Faculdade de Ciências, Universidade de Lisboa, Lisbon (Portugal); Salvador, Ricardo [Institute of Biophysics and Biomedical Engineering, Faculdade de Ciências, Universidade de Lisboa, Lisbon (Portugal); Basser, Peter J. [Section on Tissue Biophysics and Biomimetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (United States); Miranda, Pedro C. [Institute of Biophysics and Biomedical Engineering, Faculdade de Ciências, Universidade de Lisboa, Lisbon (Portugal)

    2016-04-01

    Purpose: To investigate tumors of different size, shape, and location and the effect of varying transducer layouts on Tumor Treating Fields (TTFields) distribution in an anisotropic model. Methods and Materials: A realistic human head model was generated from MR images of 1 healthy subject. Four different virtual tumors were placed at separate locations. The transducer arrays were modeled to mimic the TTFields-delivering commercial device. For each tumor location, varying array layouts were tested. The finite element method was used to calculate the electric field distribution, taking into account tissue heterogeneity and anisotropy. Results: In all tumors, the average electric field induced by either of the 2 perpendicular array layouts exceeded the 1-V/cm therapeutic threshold value for TTFields effectiveness. Field strength within a tumor did not correlate with its size and shape but was higher in more superficial tumors. Additionally, it always increased when the array was adapted to the tumor's location. Compared with a default layout, the largest increase in field strength was 184%, and the highest average field strength induced in a tumor was 2.21 V/cm. Conclusions: These results suggest that adapting array layouts to specific tumor locations can significantly increase field strength within the tumor. Our findings support the idea of personalized treatment planning to increase TTFields efficacy for patients with GBM.

  8. Improving Tumor Treating Fields Treatment Efficacy in Patients With Glioblastoma Using Personalized Array Layouts

    International Nuclear Information System (INIS)

    Wenger, Cornelia; Salvador, Ricardo; Basser, Peter J.; Miranda, Pedro C.

    2016-01-01

    Purpose: To investigate tumors of different size, shape, and location and the effect of varying transducer layouts on Tumor Treating Fields (TTFields) distribution in an anisotropic model. Methods and Materials: A realistic human head model was generated from MR images of 1 healthy subject. Four different virtual tumors were placed at separate locations. The transducer arrays were modeled to mimic the TTFields-delivering commercial device. For each tumor location, varying array layouts were tested. The finite element method was used to calculate the electric field distribution, taking into account tissue heterogeneity and anisotropy. Results: In all tumors, the average electric field induced by either of the 2 perpendicular array layouts exceeded the 1-V/cm therapeutic threshold value for TTFields effectiveness. Field strength within a tumor did not correlate with its size and shape but was higher in more superficial tumors. Additionally, it always increased when the array was adapted to the tumor's location. Compared with a default layout, the largest increase in field strength was 184%, and the highest average field strength induced in a tumor was 2.21 V/cm. Conclusions: These results suggest that adapting array layouts to specific tumor locations can significantly increase field strength within the tumor. Our findings support the idea of personalized treatment planning to increase TTFields efficacy for patients with GBM.

  9. The Survey of Treatment Entry Pressures (STEP): identifying client's reasons for entering substance abuse treatment.

    Science.gov (United States)

    Dugosh, Karen Leggett; Festinger, David S; Lynch, Kevin G; Marlowe, Douglas B

    2014-10-01

    Systematically identifying reasons that clients enter substance abuse treatment may allow clinicians to immediately focus on issues of greatest relevance to the individual and enhance treatment engagement. We developed the Survey of Treatment Entry Pressures (STEP) to identify the specific factors that precipitated an individual's treatment entry. The instrument contains 121 items from 6 psychosocial domains (i.e., family, financial, social, medical, psychiatric, legal). The current study examined the STEP's psychometric properties. A total of 761 participants from various treatment settings and modalities completed the STEP prior to treatment admission and 4-7 days later. Analyses were performed to examine the instrument's psychometric properties including item response rates, test-retest reliability, internal consistency, and factor structure. The items displayed adequate test-retest reliability and internal consistency within each psychosocial domain. Generally, results from exploratory and confirmatory factor analyses support a 2-factor structure reflecting type of reinforcement schedule. The study provides preliminary support for the psychometric properties of the STEP. The STEP may provide a reliable way for clinicians to characterize and capitalize on a client's treatment motivation early on which may serve to improve treatment retention and therapeutic outcomes. © 2014 Wiley Periodicals, Inc.

  10. An anatomic transcriptional atlas of human glioblastoma.

    Science.gov (United States)

    Puchalski, Ralph B; Shah, Nameeta; Miller, Jeremy; Dalley, Rachel; Nomura, Steve R; Yoon, Jae-Guen; Smith, Kimberly A; Lankerovich, Michael; Bertagnolli, Darren; Bickley, Kris; Boe, Andrew F; Brouner, Krissy; Butler, Stephanie; Caldejon, Shiella; Chapin, Mike; Datta, Suvro; Dee, Nick; Desta, Tsega; Dolbeare, Tim; Dotson, Nadezhda; Ebbert, Amanda; Feng, David; Feng, Xu; Fisher, Michael; Gee, Garrett; Goldy, Jeff; Gourley, Lindsey; Gregor, Benjamin W; Gu, Guangyu; Hejazinia, Nika; Hohmann, John; Hothi, Parvinder; Howard, Robert; Joines, Kevin; Kriedberg, Ali; Kuan, Leonard; Lau, Chris; Lee, Felix; Lee, Hwahyung; Lemon, Tracy; Long, Fuhui; Mastan, Naveed; Mott, Erika; Murthy, Chantal; Ngo, Kiet; Olson, Eric; Reding, Melissa; Riley, Zack; Rosen, David; Sandman, David; Shapovalova, Nadiya; Slaughterbeck, Clifford R; Sodt, Andrew; Stockdale, Graham; Szafer, Aaron; Wakeman, Wayne; Wohnoutka, Paul E; White, Steven J; Marsh, Don; Rostomily, Robert C; Ng, Lydia; Dang, Chinh; Jones, Allan; Keogh, Bart; Gittleman, Haley R; Barnholtz-Sloan, Jill S; Cimino, Patrick J; Uppin, Megha S; Keene, C Dirk; Farrokhi, Farrokh R; Lathia, Justin D; Berens, Michael E; Iavarone, Antonio; Bernard, Amy; Lein, Ed; Phillips, John W; Rostad, Steven W; Cobbs, Charles; Hawrylycz, Michael J; Foltz, Greg D

    2018-05-11

    Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor's molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  11. Combination Treatment with PPARγ Ligand and Its Specific Inhibitor GW9662 Downregulates BIS and 14-3-3 Gamma, Inhibiting Stem-Like Properties in Glioblastoma Cells.

    Science.gov (United States)

    Im, Chang-Nim

    2017-01-01

    PPAR γ is a nuclear receptor that regulates differentiation and proliferation and is highly expressed in many cancer cells. Its synthetic ligands, such as rosiglitazone and ciglitazone, and its inhibitor GW9662, were shown to induce cellular differentiation, inhibit proliferation, and lead to apoptosis. Glioblastoma is a common brain tumor with poor survival prospects. Recently, glioblastoma stem cells (GSCs) have been examined as a potential target for anticancer therapy; however, little is known about the combined effect of various agents on GSCs. In this study, we found that cotreatment with PPAR γ ligands and GW9662 inhibited stem-like properties in GSC-like spheres, which significantly express SOX2. In addition, this treatment decreased the activation of STAT3 and AKT and decreased the amounts of 14-3-3 gamma and BIS proteins. Moreover, combined administration of small-interfering RNA (siRNA) transfection with PPAR γ ligands induced downregulation of SOX2 and MMP2 activity together with inhibition of sphere-forming activity regardless of poly(ADP-ribose) polymerase (PARP) cleavage. Taken together, our findings suggest that a combination therapy using PPAR γ ligands and its inhibitor could be a potential therapeutic strategy targeting GSCs.

  12. Combination Treatment with PPARγ Ligand and Its Specific Inhibitor GW9662 Downregulates BIS and 14-3-3 Gamma, Inhibiting Stem-Like Properties in Glioblastoma Cells

    Directory of Open Access Journals (Sweden)

    Chang-Nim Im

    2017-01-01

    Full Text Available PPARγ is a nuclear receptor that regulates differentiation and proliferation and is highly expressed in many cancer cells. Its synthetic ligands, such as rosiglitazone and ciglitazone, and its inhibitor GW9662, were shown to induce cellular differentiation, inhibit proliferation, and lead to apoptosis. Glioblastoma is a common brain tumor with poor survival prospects. Recently, glioblastoma stem cells (GSCs have been examined as a potential target for anticancer therapy; however, little is known about the combined effect of various agents on GSCs. In this study, we found that cotreatment with PPARγ ligands and GW9662 inhibited stem-like properties in GSC-like spheres, which significantly express SOX2. In addition, this treatment decreased the activation of STAT3 and AKT and decreased the amounts of 14-3-3 gamma and BIS proteins. Moreover, combined administration of small-interfering RNA (siRNA transfection with PPARγ ligands induced downregulation of SOX2 and MMP2 activity together with inhibition of sphere-forming activity regardless of poly(ADP-ribose polymerase (PARP cleavage. Taken together, our findings suggest that a combination therapy using PPARγ ligands and its inhibitor could be a potential therapeutic strategy targeting GSCs.

  13. Reasons for dropout from drug abuse treatment: symptoms, personality, and motivation.

    Science.gov (United States)

    Ball, Samuel A; Carroll, Kathleen M; Canning-Ball, Monica; Rounsaville, Bruce J

    2006-02-01

    Previous research has identified risk factors for early attrition from substance abuse treatment, but has not assessed reasons for dropout from the client's perspective. Interview and self-report assessment data were collected from 24 clients who prematurely terminated outpatient treatment to evaluate their subjective reasons for dropping out and the association of these reasons with demographic and clinical variables. Items from scales indicating problems with client motivation or conflicts with program staff were the most commonly endorsed. The severity of participant's symptoms and logistical problems interfering with appointments were less commonly reported as reasons for dropping out. Demographic, substance abuse, and motivational stage indicators were infrequently associated with subjective reasons for dropout. In contrast, indicators of maladaptive personality functioning were strongly associated with many reasons for dropping out, especially concerns about privacy and boundary issues within the program. Results from this preliminary evaluation will guide the development of an instrument and intervention focused on dropout risk factors and treatment reengagement.

  14. Treatment of newly diagnosed glioblastoma multiforme with carmustine, cisplatin and etoposide followed by radiotherapy. A phase II study

    DEFF Research Database (Denmark)

    Lassen, U; Kristjansen, P E; Wagner, A

    1999-01-01

    fractions. Twenty-nine patients with newly diagnosed glioblastoma multiforme (GBM), mean age 50 (27-66) and performance status (PS) 0-2 were included. Using the Macdonald criteria 33% had partial remission (PR), 41% stable disease (SD) and 26% progressive disease (PD) after chemotherapy. After additional...... (6.0-9.1) and median survival was 11.4 months (10.1-12.7). We conclude that this regimen is effective and feasible in patients with GBM. The short course pre-irradiatory chemotherapy may be less cumbersome than adjuvant chemotherapy and the regimen may be even more active in grade III gliomas....

  15. Advance Care Planning in Glioblastoma Patients

    Directory of Open Access Journals (Sweden)

    Lara Fritz

    2016-11-01

    Full Text Available Despite multimodal treatment with surgery, radiotherapy and chemotherapy, glioblastoma is an incurable disease with a poor prognosis. During the disease course, glioblastoma patients may experience progressive neurological deficits, symptoms of increased intracranial pressure such as drowsiness and headache, incontinence, seizures and progressive cognitive dysfunction. These patients not only have cancer, but also a progressive brain disease. This may seriously interfere with their ability to make their own decisions regarding treatment. It is therefore warranted to involve glioblastoma patients early in the disease trajectory in treatment decision-making on their future care, including the end of life (EOL care, which can be achieved with Advance Care Planning (ACP. Although ACP, by definition, aims at timely involvement of patients and proxies in decision-making on future care, the optimal moment to initiate ACP discussions in the disease trajectory of glioblastoma patients remains controversial. Moreover, the disease-specific content of these ACP discussions needs to be established. In this article, we will first describe the history of patient participation in treatment decision-making, including the shift towards ACP. Secondly, we will describe the possible role of ACP for glioblastoma patients, with the specific aim of treatment of disease-specific symptoms such as somnolence and dysphagia, epileptic seizures, headache, and personality changes, agitation and delirium in the EOL phase, and the importance of timing of ACP discussions in this patient population.

  16. An individual patient data meta-analysis on characteristics, treatments and outcomes of the glioblastoma/gliosarcoma patients with central nervous system metastases reported in literature until 2013

    DEFF Research Database (Denmark)

    Pietschmann, Sophie; von Bueren, André O; Henke, Guido

    2014-01-01

    Dissemination of high-grade gliomas (WHO IV) has been investigated poorly so far. We conducted an extensive analysis of the characteristics, treatments and outcomes of the glioblastoma multiforme (GBM)/gliosarcoma (GS) patients with central nervous system (CNS) metastases reported in literature...... until April 2013. PubMed and Web of Science searches for peer-reviewed articles pertaining to GBM/GS patients with metastatic disease were conducted using predefined keywords. Additionally, we performed hand search following the references from the selected papers. Cases in which the metastases...... exclusively occurred outside the CNS were excluded. 110 publications reporting on 189 patients were eligible. There was a significant increase in the number of reported cases over the last decades. We calculated a median overall survival from diagnosis of metastasis (from initial diagnosis of GBM/GS) of 3...

  17. The use of positron emission tomography in BNCT treatment planning for metastatic malignant melanoma and glioblastoma multiforme

    International Nuclear Information System (INIS)

    Kabalka, G.; Nichols, T.; Smith, G.; Miller, L.; Kahn, M.

    2000-01-01

    Positron emission tomography (PET) evaluations of six glioblastoma multiforme (GBM) and one metastatic melanoma (MM) patient have been carried out utilizing fluorine-18 labeled p-boronophenylalanine. Four of the GBM patients were imaged both prior to and post BNCT. In one GBM patient, biopsy derived boron distribution data compared favorably to the PET derived data. The PET data have been used as input to dosimetry calculations and the results vary from those obtained using current protocols. In addition, PET images of the thorax would indicate that the utility of PET for staging tumors for BNCT may extend beyond the brain. However, higher than anticipated levels of activity in the lungs (as also seen in salivary glands) indicate the more effective BNCT agents will be required. (author)

  18. Bacterial Carriers for Glioblastoma Therapy

    Directory of Open Access Journals (Sweden)

    Nalini Mehta

    2017-03-01

    Full Text Available Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barriers preventing efficient drug dosing to tumors. To overcome these barriers, bacterial carriers that are actively motile and programmed to migrate and localize to tumor zones were designed. These carriers can induce apoptosis via hypoxia-controlled expression of a tumor suppressor protein p53 and a pro-apoptotic drug, Azurin. In a xenograft model of human glioblastoma in rats, bacterial carrier therapy conferred a significant survival benefit with 19% overall long-term survival of >100 days in treated animals relative to a median survival of 26 days in control untreated animals. Histological and proteomic analyses were performed to elucidate the safety and efficacy of these carriers, showing an absence of systemic toxicity and a restored neural environment in treated responders. In the treated non-responders, proteomic analysis revealed competing mechanisms of pro-apoptotic and drug-resistant activity. This bacterial carrier opens a versatile avenue to overcome diffusion barriers in glioblastoma by virtue of its active motility in extracellular space and can lead to tailored therapies via tumor-specific expression of tumoricidal proteins.

  19. Ion channels in glioblastoma.

    Science.gov (United States)

    Molenaar, Remco J

    2011-01-01

    Glioblastoma is the most common primary brain tumor with the most dismal prognosis. It is characterized by extensive invasion, migration, and angiogenesis. Median survival is only 15 months due to this behavior, rendering focal surgical resection ineffective and adequate radiotherapy impossible. At this moment, several ion channels have been implicated in glioblastoma proliferation, migration, and invasion. This paper summarizes studies on potassium, sodium, chloride, and calcium channels of glioblastoma. It provides an up-to-date overview of the literature that could ultimately lead to new therapeutic targets.

  20. Radiological protection considerations during the treatment of glioblastoma patients by boron neutron capture therapy at the high flux reactor in Petten, The Netherlands

    International Nuclear Information System (INIS)

    Moss, R.L.; Rassow, J.; Finke, E.; Sauerwein, W.; Stecher-Rasmussen, F.

    2001-01-01

    A clinical trial of Boron Neutron Capture Therapy (BNCT) for glioblastoma patients has been in progress at the High Flux Reactor (HFR) at Petten since October 1997. The JRC (as licence holder of the HFR) must ensure that radiological protection measures are provided. The BNCT trial is a truly European trial, whereby the treatment takes place at a facility in the Netherlands under the responsibility of clinicians from Germany and patients are treated from several European countries. Consequently, radiological protection measures satisfy both German and Dutch laws. To respect both laws, a BNCT radioprotection committee was formed under the chairmanship of an independent radioprotection expert, with members representing all disciplines in the trial. A special nuance of BNCT is that the radiation is provided by a mixed neutron/gamma beam. The radiation dose to the patient is thus a complex mix due to neutrons, gammas and neutron capture in boron, nitrogen and hydrogen, which, amongst others, need to be correctly calculated in non-commercial and validated treatment planning codes. Furthermore, due to neutron activation, measurements on the patient are taken regularly after treatment. Further investigations along these lines include dose determination using TLDs and boron distribution measurements using on-line gamma ray spectroscopy. (author)

  1. Dynamic contrast-enhanced MR imaging in predicting progression of enhancing lesions persisting after standard treatment in glioblastoma patients: a prospective study

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, Roh-Eul; Choi, Hye Jeong; You, Sung-Hye; Kang, Koung Mi; Yun, Tae Jin; Kim, Ji-Hoon; Sohn, Chul-Ho [Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Choi, Seung Hong [Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Seoul National University, Center for Nanoparticle Research, Institute for Basic Science, and School of Chemical and Biological Engineering, Seoul (Korea, Republic of); Seoul National University, School of Chemical and Biological Engineering, Seoul (Korea, Republic of); Kim, Tae Min [Seoul National University College of Medicine, Department of Internal Medicine, Cancer Research Institute, Seoul (Korea, Republic of); Park, Chul-Kee [Seoul National University College of Medicine, Department of Neurosurgery, Biomedical Research Institute, Seoul (Korea, Republic of); Park, Sung-Hye; Won, Jae-Kyung [Seoul National University College of Medicine, Department of Pathology, Seoul (Korea, Republic of); Kim, Il Han [Seoul National University College of Medicine, Department of Radiation Oncology, Cancer Research Institute, Seoul (Korea, Republic of); Lee, Soon Tae [Seoul National University College of Medicine, Department of Neurology, Seoul (Korea, Republic of)

    2017-08-15

    To prospectively explore the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting the progression of enhancing lesions persisting after standard treatment in patients with surgically resected glioblastoma (GBM). Forty-seven GBM patients, who underwent near-total tumorectomy followed by concurrent chemoradiation therapy (CCRT) with temozolomide (TMZ) between May 2014 and February 2016, were enrolled. Twenty-four patients were finally analyzed for measurable enhancing lesions persisting after standard treatment. DCE-MRI parameters were calculated at enhancing lesions. Mann-Whitney U tests and multivariable stepwise logistic regression were used to compare parameters between progression (n = 16) and non-progression (n = 8) groups. Mean K{sup trans} and v{sub e} were significantly lower in progression than in non-progression (P = 0.037 and P = 0.037, respectively). The 5th percentile of the cumulative K{sup trans} histogram was also significantly lower in the progression than in non-progression group (P = 0.017). Mean v{sub e} was the only independent predictor of progression (P = 0.007), with a sensitivity of 100%, specificity of 63%, and an overall accuracy of 88% at a cut-off value of 0.873. DCE-MRI may help predict the progression of enhancing lesions persisting after the completion of standard treatment in patients with surgically resected GBM, with mean v{sub e} serving as an independent predictor of progression. (orig.)

  2. Dynamic contrast-enhanced MR imaging in predicting progression of enhancing lesions persisting after standard treatment in glioblastoma patients: a prospective study

    International Nuclear Information System (INIS)

    Yoo, Roh-Eul; Choi, Hye Jeong; You, Sung-Hye; Kang, Koung Mi; Yun, Tae Jin; Kim, Ji-Hoon; Sohn, Chul-Ho; Choi, Seung Hong; Kim, Tae Min; Park, Chul-Kee; Park, Sung-Hye; Won, Jae-Kyung; Kim, Il Han; Lee, Soon Tae

    2017-01-01

    To prospectively explore the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting the progression of enhancing lesions persisting after standard treatment in patients with surgically resected glioblastoma (GBM). Forty-seven GBM patients, who underwent near-total tumorectomy followed by concurrent chemoradiation therapy (CCRT) with temozolomide (TMZ) between May 2014 and February 2016, were enrolled. Twenty-four patients were finally analyzed for measurable enhancing lesions persisting after standard treatment. DCE-MRI parameters were calculated at enhancing lesions. Mann-Whitney U tests and multivariable stepwise logistic regression were used to compare parameters between progression (n = 16) and non-progression (n = 8) groups. Mean K trans and v e were significantly lower in progression than in non-progression (P = 0.037 and P = 0.037, respectively). The 5th percentile of the cumulative K trans histogram was also significantly lower in the progression than in non-progression group (P = 0.017). Mean v e was the only independent predictor of progression (P = 0.007), with a sensitivity of 100%, specificity of 63%, and an overall accuracy of 88% at a cut-off value of 0.873. DCE-MRI may help predict the progression of enhancing lesions persisting after the completion of standard treatment in patients with surgically resected GBM, with mean v e serving as an independent predictor of progression. (orig.)

  3. Evaluation of Concurrent Radiation, Temozolomide and ABT-888 Treatment Followed by Maintenance Therapy with Temozolomide and ABT-888 in a Genetically Engineered Glioblastoma Mouse Model.

    Science.gov (United States)

    Lemasson, Benjamin; Wang, Hanxiao; Galbán, Stefanie; Li, Yinghua; Zhu, Yuan; Heist, Kevin A; Tsein, Christina; Chenevert, Thomas L; Rehemtulla, Alnawaz; Galbán, Craig J; Holland, Eric C; Ross, Brian D

    2016-02-01

    Despite the use of ionizing radiation (IR) and temozolomide (TMZ), outcome for glioblastoma (GBM) patients remains dismal. Poly (ADP-ribose) polymerase (PARP) is important in repair pathways for IR-induced DNA damage and TMZ-induced alkylation at N7-methylguanine and N3-methyldenine. However, optimized protocols for administration of PARP inhibitors have not been delineated. In this study, the PARP inhibitor ABT-888 was evaluated in combination with and compared to current standard-of-care in a genetically engineered mouse GBM model. Results demonstrated that concomitant TMZ/IR/ABT-888 with adjuvant TMZ/ABT-888 was more effective in inducing apoptosis and reducing proliferation with significant tumor growth delay and improved overall survival over concomitant TMZ/IR with adjuvant TMZ. Diffusion-weighted MRI, an early translatable response biomarker detected changes in tumors reflecting response at 1 day post TMZ/IR/ABT-888 treatment. This study provides strong scientific rationale for the development of an optimized dosing regimen for a PARP inhibitor with TMZ/IR for upfront treatment of GBM. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Evaluation of Concurrent Radiation, Temozolomide and ABT-888 Treatment Followed by Maintenance Therapy with Temozolomide and ABT-888 in a Genetically Engineered Glioblastoma Mouse Model

    Directory of Open Access Journals (Sweden)

    Benjamin Lemasson

    2016-02-01

    Full Text Available Despite the use of ionizing radiation (IR and temozolomide (TMZ, outcome for glioblastoma (GBM patients remains dismal. Poly (ADP-ribose polymerase (PARP is important in repair pathways for IR-induced DNA damage and TMZ-induced alkylation at N7-methylguanine and N3-methyldenine. However, optimized protocols for administration of PARP inhibitors have not been delineated. In this study, the PARP inhibitor ABT-888 was evaluated in combination with and compared to current standard-of-care in a genetically engineered mouse GBM model. Results demonstrated that concomitant TMZ/IR/ABT-888 with adjuvant TMZ/ABT-888 was more effective in inducing apoptosis and reducing proliferation with significant tumor growth delay and improved overall survival over concomitant TMZ/IR with adjuvant TMZ. Diffusion-weighted MRI, an early translatable response biomarker detected changes in tumors reflecting response at 1 day post TMZ/IR/ABT-888 treatment. This study provides strong scientific rationale for the development of an optimized dosing regimen for a PARP inhibitor with TMZ/IR for upfront treatment of GBM.

  5. Glioblastoma with spinal seeding

    International Nuclear Information System (INIS)

    Fakhrai, N.; Fazeny-Doerner, B.; Marosi, C.; Czech, T.; Diekmann, K.; Birner, P.; Hainfellner, J.A.; Prayer, D.

    2004-01-01

    Background: extracranial seeding of glioblastoma multiforme (GBM) is very rare and its development depends on several factors. This case report describes two patients suffering from GBM with spinal seeding. In both cases, the anatomic localization of the primary tumor close to the cerebrospinal fluid (CSF) was the main factor for spinal seeding. Case reports: two patients with GBM and spinal seeding are presented. After diagnosis of spinal seeding, both patients were highly symptomatic from their spinal lesions. Case 1 experienced severe pain requiring opiates, and case 2 had paresis of lower limbs as well as urinary retention/incontinence. Both patients were treated with spinal radiation therapy. Nevertheless, they died 3 months after diagnosis of spinal seeding. Results: in both patients the diagnosis of spinal seeding was made at the time of cranial recurrence. Both tumors showed close contact to the CSF initially. Even though the patients underwent intensive treatment, it was not possible to keep them in a symptom-free state. Conclusion: because of short survival periods, patients deserve optimal pain management and dedicated palliative care. (orig.)

  6. Glioblastoma with spinal seeding

    Energy Technology Data Exchange (ETDEWEB)

    Fakhrai, N.; Fazeny-Doerner, B.; Marosi, C. [Clinical Div. of Oncology, Dept. of Medicine I, Univ. of Vienna (Austria); Czech, T. [Dept. of Neurosurgery, Univ. of Vienna (Austria); Diekmann, K. [Dept. of Radiooncology, Univ. of Vienna (Austria); Birner, P.; Hainfellner, J.A. [Clinical Inst. for Neurology, Univ. of Vienna (Austria); Prayer, D. [Dept. of Neuroradiology, Univ. of Vienna (Austria)

    2004-07-01

    Background: extracranial seeding of glioblastoma multiforme (GBM) is very rare and its development depends on several factors. This case report describes two patients suffering from GBM with spinal seeding. In both cases, the anatomic localization of the primary tumor close to the cerebrospinal fluid (CSF) was the main factor for spinal seeding. Case reports: two patients with GBM and spinal seeding are presented. After diagnosis of spinal seeding, both patients were highly symptomatic from their spinal lesions. Case 1 experienced severe pain requiring opiates, and case 2 had paresis of lower limbs as well as urinary retention/incontinence. Both patients were treated with spinal radiation therapy. Nevertheless, they died 3 months after diagnosis of spinal seeding. Results: in both patients the diagnosis of spinal seeding was made at the time of cranial recurrence. Both tumors showed close contact to the CSF initially. Even though the patients underwent intensive treatment, it was not possible to keep them in a symptom-free state. Conclusion: because of short survival periods, patients deserve optimal pain management and dedicated palliative care. (orig.)

  7. Young adults' reasons for dropout from residential substance use disorder treatment.

    Science.gov (United States)

    Nordheim, Kristoffer; Walderhaug, Espen; Alstadius, Ståle; Kern-Godal, Ann; Arnevik, Espen; Duckert, Fanny

    2018-01-01

    Dropout from substance use disorder treatment is usually investigated and understood from a perspective of quantitative patient-related factors. Patients' own perspectives (user perspective) are rarely reported. This study, therefore, aimed to explore patients' own understanding of their dropout from residential substance use disorder treatment. The participants were 15 males and females, aged 19-29 years, who had dropped out of residential substance use disorder treatment at the Department of Addiction Treatment, Oslo University Hospital, Norway. Qualitative methodology with semistructured interviews was used to explore how the participants described their dropout and their reasons for doing so. Thematic analysis was used as the framework for analyzing the data derived from the interviews. Dropout had different meanings for different participants. It was understood as a break from treatment, as an end to treatment, or as a means of reduced treatment intensity . Against that background, four main themes for dropout were found: drug craving , negative emotions , personal contact, and activity . Patient and treatment factors seem to interact when participants explore reasons for their dropout. A complex pattern of variables is involved. As remedies, participants suggested that substance use disorder treatment should provide more focus on drug craving and training to understand and tolerate emotional discomfort. They also wanted closer contact with the staff during treatment, more activities, and rigorous posttreatment follow-up. These findings from the user perspective have important implications for substance use disorder treatment, clinical and social work practice, management, and research.

  8. Early post-treatment pseudo-progression amongst glioblastoma multiforme patients treated with radiotherapy and temozolomide: a retrospective analysis

    International Nuclear Information System (INIS)

    Gunjur, Ashray; Lau, Eddie; Taouk, Yamna; Ryan, Gail

    2011-01-01

    To evaluate the incidence and impact of early post-chemoradiation (cRT) 'pseudoprogression' (PsPD) amongst glioblastoma multiforme (GBM) patients treated with the current standard of care – 60 Gy conformal radiotherapy with concurrent low-dose temozolomide, followed by six cycles of high-dose temozolomide (the 'Stupp protocol'). Clinical notes and radiology reports for GBM patients treated as per the Stupp protocol were reviewed. PsPD was defined as apparent radiological progression on the first post-cRT scan, with further imaging within 3 months being stable or improving, while true early progression (ePD) was confirmed by continued progression in the subsequent 3 months following the first post-cRT scan. Of the 68 patients evaluated, 14 (21%) and 27 (40%) experienced PsPD and ePD, respectively; 3/14 (21%) patients experiencing PsPD and 14/27(52%), ePD were symptomatic for progression on first post-cRT follow-up (P = 0.096 for difference). Median survival for patients with ePD, PsPD and neither were 10.4, 27.4 and 13.0 months, respectively (P = 0.003 for ePD vs. PsPD, P = 0.19 for neither vs. PsPD groups). These data confirm a significant incidence of PsPD in post-cRT GBM patients, associated with improved median survival compared with those with neither ePD nor PsPD (not statistically significant). It appears likely that PsPD actually represents tumour response, conflicting with the traditional notion that increase in lesion size on contrast-enhanced imaging represents disease progression. Early post-cRT imaging should thus be interpreted with caution. Accompanying clinical symptoms are more commonly associated with ePD, but do not reliably distinguish PsPD from ePD.

  9. MicroRNA biomarkers in glioblastoma

    DEFF Research Database (Denmark)

    Hermansen, Simon Kjær; Kristensen, Bjarne Winther

    2013-01-01

    tissues. Understanding these alterations is key to developing new biomarkers and intelligent treatment strategies. This review presents an overview of current knowledge about miRNA alterations in glioblastoma while focusing on the clinical future of miRNAs as biomarkers and discussing the strengths...

  10. Nanoparticles for hyperthermic therapy: synthesis strategies and applications in glioblastoma

    NARCIS (Netherlands)

    Verma, Jyoti; Lal, Sumit; van Noorden, Cornelis J. F.

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. Current GBM treatment includes surgery, radiation therapy, and chemotherapy, sometimes supplemented with novel therapies. Despite recent advances, survival of GBM patients remains poor.

  11. Refusal of medical treatment in the pediatric emergency service: analysis of reasons and aspects.

    Science.gov (United States)

    Gündüz, Ramiz Coşkun; Halil, Halit; Gürsoy, Cüneyt; Çifci, Atilla; Özgün, Seher; Kodaman, Tuğba; Sönmez, Mehtap

    2014-01-01

    Refusal of treatment for acutely ill children is still an important problem in the emergency service. When families refuse medical treatment for their acutely ill children, healthcare professionals may attempt to provide information and negotiate with the family concerning treatment refusal and its possible adverse outcomes, and request consent for refusal of medical treatment. There is insufficient data about refusal of treatment in our country. The purpose of this study was to analyze the causes of treatment refusal in the pediatric emergency service. We collected data recorded on informed consent forms. During a 2-year-study period, 215 patients refused treatment recommended by acute health care professionals. The majorty of patients were in the 0-2 year age group. Hospitalization was the type of treatment most commonly refused; restrictions regarding family members staying with their children during hospitalization and admission to another hospital were the major reasons for refusal of treatment. Clarifying the reasons for treatment refusal may help us to overcome deficiencies, improve conditions, resolve problems and build confidence between healthcare providers and service users, increasing users' satisfaction in the future.

  12. Drop-out from a drug treatment clinic and associated reasons.

    Science.gov (United States)

    Hoseinie, Leila; Gholami, Zhaleh; Shadloo, Behrang; Mokri, Azarakhsh; Amin-Esmaeili, Masoumeh; Rahimi-Movaghar, Afarin

    2017-05-01

    The aim of this study was to assess drop-out rates and associated reasons among patients at the Iranian National Center for Addiction Studies (INCAS) clinic. In a one-year period (April 2014 to March 2015), all patients with drug dependence who had been referred for treatment and attended for a first assessment were included in this study (N=242). Those who received treatment were followed until March 2016. Survival analysis showed that 70.2% had dropped out from treatment. Log rank test showed that treatment drop-out rates differed between the different approaches used (P < 0.001), with the lowest slope inbuprenorphine maintenance treatment and the highest in the detoxification programme. Drop-out rates within the first three months was 62% (SE= 0.05) and 82.4% (SE=0.03) for opioids and stimulants dependence, respectively. Analyses were performed using SPSS (Version 21.0) and STATA software, (version 13.0). From the patients' perspective, motivational inconsistencies were considered as the main reason for not starting or leaving treatment. The findings of this study could give service providers a better grasp of drop-out rates and the associated reasons.

  13. Reason analysis and preventive treatment countermeasure of impaired vision after LASIK

    Directory of Open Access Journals (Sweden)

    Zhang-Bing Mu

    2015-02-01

    Full Text Available AIM: To analyze the reasons of impaired vision after LASIK and explore its preventive treatment measures preliminarily. METHODS: In this retrospective study, 175 eyes of 134 patients whose vision was decreased after LASIK were included. The constituent ratio of every reason was counted and uncorrected visual acuity(UCVAbetween pre-treatment and post-treatment were compared by paired t-test respectively. RESULTS: The overall incidence of impaired vision after LASIK was 1.86%. The constituent ratio of regression was 51.43% and UCVA increased from 0.61±0.22 to 0.90±0.38(t=8.00, Pt=20.00, Pt=8.14, Pt=6.33, Pt=2.53, P0.05after treatment. The constituent ratio of fundus lesions and diffuse lamellar keratitis(DLKwas 2.86% and UCVA all increased by different degrees after treatment. CONCLUSION: The reasons of impaired vision after LASIK are many and varied. These cases could recover their vision by discovery and treatment in time, and the appropriate preventive measures were essential.

  14. Prognosis prediction of non-enhancing T2 high signal intensity lesions in glioblastoma patients after standard treatment: application of dynamic contrast-enhanced MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Rihyeon; Yun, Tae Jin; Kim, Ji-Hoon; Sohn, Chul-Ho [Seoul National University Hospital, Department of Radiology, 101 Daehak-ro, Jongno-gu, Seoul (Korea, Republic of); Choi, Seung Hong [Seoul National University Hospital, Department of Radiology, 101 Daehak-ro, Jongno-gu, Seoul (Korea, Republic of); Seoul National University Medical Research Center, Department of Radiology, Seoul National University College of Medicine, and Institute of Radiation Medicine, 103 Daehak-ro, Jongno-gu, Seoul (Korea, Republic of); Seoul National University, Center for Nanoparticle Research, Institute for Basic Science (IBS), Daehak-dong, Gwanak-gu, Seoul (Korea, Republic of); Seoul National University, School of Chemical and Biological Engineering, Daehak-dong, Gwanak-gu, Seoul (Korea, Republic of); Lee, Soon-Tae [Seoul National University Hospital, Department of Neurology, Seoul (Korea, Republic of); Park, Chul-Kee [Seoul National University Hospital, Department of Neurosurgery, Seoul (Korea, Republic of); Kim, Tae Min [Seoul National University Hospital, Department of Internal Medicine, Seoul (Korea, Republic of); Park, Sun-Won [Seoul National University College of Medicine, Department of Radiology, SMG-SNU Boramae Medical Center, Seoul (Korea, Republic of); Park, Sung-Hye [Seoul National University Hospital, Department of Pathology, Seoul (Korea, Republic of); Kim, Il Han [Seoul National University Hospital, Department of Radiation Oncology, Seoul (Korea, Republic of)

    2017-03-15

    To identify candidate imaging biomarkers for early disease progression in glioblastoma multiforme (GBM) patients by analysis of dynamic contrast-enhanced (DCE) MR parameters of non-enhancing T2 high signal intensity (SI) lesions. Forty-nine GBM patients who had undergone preoperative DCE MR imaging and received standard treatment were retrospectively included. According to the Response Assessment in Neuro-Oncology criteria, patients were classified into progression (n = 21) or non-progression (n = 28) groups. We analysed the pharmacokinetic parameters of Ktrans, Ve and Vp within non-enhancing T2 high SI lesions of each tumour. The best percentiles of each parameter from cumulative histograms were identified by the area under the receiver operating characteristic curve (AUC) and were compared using multivariate stepwise logistic regression. For the differentiation of early disease progression, the highest AUC values were found in the 99th percentile of Ktrans (AUC 0.954), the 97th percentile of Ve (AUC 0.815) and the 94th percentile of Vp (AUC 0.786) (all p < 0.05). The 99th percentile of Ktrans was the only significant independent variable from the multivariate stepwise logistic regression (p = 0.002). We found that the Ktrans of non-enhancing T2 high SI lesions in GBM patients holds potential as a candidate prognostic marker in future prospective studies. (orig.)

  15. Metabolomics of Therapy Response in Preclinical Glioblastoma: A Multi-Slice MRSI-Based Volumetric Analysis for Noninvasive Assessment of Temozolomide Treatment

    Science.gov (United States)

    Arias-Ramos, Nuria; Ferrer-Font, Laura; Lope-Piedrafita, Silvia; Mocioiu, Victor; Julià-Sapé, Margarida; Pumarola, Martí; Arús, Carles; Candiota, Ana Paula

    2017-01-01

    Glioblastoma (GBM) is the most common aggressive primary brain tumor in adults, with a short survival time even after aggressive therapy. Non-invasive surrogate biomarkers of therapy response may be relevant for improving patient survival. Previous work produced such biomarkers in preclinical GBM using semi-supervised source extraction and single-slice Magnetic Resonance Spectroscopic Imaging (MRSI). Nevertheless, GBMs are heterogeneous and single-slice studies could prevent obtaining relevant information. The purpose of this work was to evaluate whether a multi-slice MRSI approach, acquiring consecutive grids across the tumor, is feasible for preclinical models and may produce additional insight into therapy response. Nosological images were analyzed pixel-by-pixel and a relative responding volume, the Tumor Responding Index (TRI), was defined to quantify response. Heterogeneous response levels were observed and treated animals were ascribed to three arbitrary predefined groups: high response (HR, n = 2), TRI = 68.2 ± 2.8%, intermediate response (IR, n = 6), TRI = 41.1 ± 4.2% and low response (LR, n = 2), TRI = 13.4 ± 14.3%, producing therapy response categorization which had not been fully registered in single-slice studies. Results agreed with the multi-slice approach being feasible and producing an inverse correlation between TRI and Ki67 immunostaining. Additionally, ca. 7-day oscillations of TRI were observed, suggesting that host immune system activation in response to treatment could contribute to the responding patterns detected. PMID:28524099

  16. Metabolomics of Therapy Response in Preclinical Glioblastoma: A Multi-Slice MRSI-Based Volumetric Analysis for Noninvasive Assessment of Temozolomide Treatment

    Directory of Open Access Journals (Sweden)

    Nuria Arias-Ramos

    2017-05-01

    Full Text Available Glioblastoma (GBM is the most common aggressive primary brain tumor in adults, with a short survival time even after aggressive therapy. Non-invasive surrogate biomarkers of therapy response may be relevant for improving patient survival. Previous work produced such biomarkers in preclinical GBM using semi-supervised source extraction and single-slice Magnetic Resonance Spectroscopic Imaging (MRSI. Nevertheless, GBMs are heterogeneous and single-slice studies could prevent obtaining relevant information. The purpose of this work was to evaluate whether a multi-slice MRSI approach, acquiring consecutive grids across the tumor, is feasible for preclinical models and may produce additional insight into therapy response. Nosological images were analyzed pixel-by-pixel and a relative responding volume, the Tumor Responding Index (TRI, was defined to quantify response. Heterogeneous response levels were observed and treated animals were ascribed to three arbitrary predefined groups: high response (HR, n = 2, TRI = 68.2 ± 2.8%, intermediate response (IR, n = 6, TRI = 41.1 ± 4.2% and low response (LR, n = 2, TRI = 13.4 ± 14.3%, producing therapy response categorization which had not been fully registered in single-slice studies. Results agreed with the multi-slice approach being feasible and producing an inverse correlation between TRI and Ki67 immunostaining. Additionally, ca. 7-day oscillations of TRI were observed, suggesting that host immune system activation in response to treatment could contribute to the responding patterns detected.

  17. SU-F-R-42: Association of Radiomic and Metabolic Tumor Volumes in Radiation Treatment of Glioblastoma Multiforme

    International Nuclear Information System (INIS)

    Lopez, C; Nagornaya, N; Parra, N; Kwon, D; Ishkanian, F; Markoe, A; Maudsley, A; Stoyanova, R

    2016-01-01

    Purpose: High-throughput extraction of imaging and metabolomic quantitative features from MRI and MR Spectroscopy Imaging (MRSI) of Glioblastoma Multiforme (GBM) results in tens of variables per patient. In radiotherapy (RT) of GBM, the relevant metabolic tumor volumes (MTVs) are related to aberrant levels of N-acetyl Aspartate (NAA) and Choline (Cho). Corresponding Clinical Target Volumes (CTVs) for RT planning are based on Contrast Enhancing T1-weighted MRI (CE-T1w) and T2-weighted/Fluid Attenuated Inversion Recovery (FLAIR) MRI. The objective is to build a framework for investigation of associations between imaging, CTV, and MTV features better understanding of the underlying information in the CTVs and dependencies between these volumes. Methods: Necrotic portions, enhancing lesion and edema were manually contoured on T1w/T2w images for 17 GBM patients. CTVs and MTVs for NAA (MTV NAA ) and Cho (MTV Cho ) were constructed. Tumors were scored categorically for ten semantic imaging traits by neuroradiologist. All features were investigated for redundancy. Two-way correlations between imaging and RT/MTV features were visualized as heat maps. Associations between MTV NAA , MTV Cho and imaging features were studied using Spearman correlation. Results: 39 imaging features were computed per patient. Half of the imaging traits were replaced with automatically extracted continuous variables. 21 features were extracted from MTVs/CTVs. There were a high number (43) of significant correlations of imaging with CTVs/MTV NAA while very few (10) significant correlations were with CTVs/MTV Cho . MTV NAA was found to be closely associated with MRI volumes, MTV Cho remains elusive for characterization with imaging. Conclusion: A framework for investigation of co-dependency between MRI and RT/metabolic features is established. A series of semantic imaging traits were replaced with automatically extracted continuous variables. The approach will allow for exploration of relationships

  18. SU-F-R-42: Association of Radiomic and Metabolic Tumor Volumes in Radiation Treatment of Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Lopez, C; Nagornaya, N; Parra, N; Kwon, D; Ishkanian, F; Markoe, A; Maudsley, A; Stoyanova, R [University of Miami, Miami, Florida (United States)

    2016-06-15

    Purpose: High-throughput extraction of imaging and metabolomic quantitative features from MRI and MR Spectroscopy Imaging (MRSI) of Glioblastoma Multiforme (GBM) results in tens of variables per patient. In radiotherapy (RT) of GBM, the relevant metabolic tumor volumes (MTVs) are related to aberrant levels of N-acetyl Aspartate (NAA) and Choline (Cho). Corresponding Clinical Target Volumes (CTVs) for RT planning are based on Contrast Enhancing T1-weighted MRI (CE-T1w) and T2-weighted/Fluid Attenuated Inversion Recovery (FLAIR) MRI. The objective is to build a framework for investigation of associations between imaging, CTV, and MTV features better understanding of the underlying information in the CTVs and dependencies between these volumes. Methods: Necrotic portions, enhancing lesion and edema were manually contoured on T1w/T2w images for 17 GBM patients. CTVs and MTVs for NAA (MTV{sub NAA}) and Cho (MTV{sub Cho}) were constructed. Tumors were scored categorically for ten semantic imaging traits by neuroradiologist. All features were investigated for redundancy. Two-way correlations between imaging and RT/MTV features were visualized as heat maps. Associations between MTV{sub NAA}, MTV{sub Cho} and imaging features were studied using Spearman correlation. Results: 39 imaging features were computed per patient. Half of the imaging traits were replaced with automatically extracted continuous variables. 21 features were extracted from MTVs/CTVs. There were a high number (43) of significant correlations of imaging with CTVs/MTV{sub NAA} while very few (10) significant correlations were with CTVs/MTV{sub Cho}. MTV{sub NAA} was found to be closely associated with MRI volumes, MTV{sub Cho} remains elusive for characterization with imaging. Conclusion: A framework for investigation of co-dependency between MRI and RT/metabolic features is established. A series of semantic imaging traits were replaced with automatically extracted continuous variables. The approach will

  19. Survey of reasons for discontinuation from in vitro fertilization treatment among couples attending infertility clinic

    Directory of Open Access Journals (Sweden)

    Grishma Kulkarni

    2014-01-01

    Full Text Available Background: With the increase in infertility burden, more and more couples are opting for in vitro fertilization (IVF. Despite the availability of various treatment options, the major concern that needs to be addressed is the reasons why such couples, initially motivated so strongly, drop out in fairly high numbers from IVF cycles. With this point of view the study was designed. AIM: The objective of this study was to explore the reasons why couples discontinue fertility treatment. Settings and Design: This retrospective study was carried out among couples in the age group of 20-40 years who opted for IVF at Tertiary care hospital and a private infertility center. Materials and Methods: Medical records for 3 years (2009-2012 were taken out and included in the study for analysis. Socio-demographic details along with indication for IVF and reasons for drop-separate IVF therapy were recorded on case record form and were analyzed. Results: Twenty-one percent of the patients had tubal pathology, thus making it the commonest female related factor for indication of IVF. Oligoasthenospermia (13% was the commonest cause of male related infertility factor. Financial burden was the primary cause for terminating treatment in majority of the IVF cases. Conclusions: Financial burden (62.5% was the commonest reason for drop out among couples from IVF cycle.

  20. Primary care: constipation and encopresis treatment strategies and reasons to refer.

    Science.gov (United States)

    Philichi, Lisa; Yuwono, Melawati

    2010-01-01

    The purpose of the study was to assess constipation and encopresis treatment strategies of primary care providers and determine reasons to refer to a pediatric gastroenterology specialist. A closed-ended questionnaire was mailed to a convenience sampling of 237 pediatric primary care providers. Ninety-one questionnaires were returned with a 38% response rate: 74 (81%) pediatricians and 17 (19%) nurse practitioners. The majority of responders recommended pharmacologic treatment and diet changes. Many providers (73%) estimated a 75%-100% success rate when managing constipation, whereas 19% providers estimated a greater than 80% success rate with encopresis patients. The number one reason to refer was unresponsiveness to treatment (71%), followed by parents want a second opinion (15%), rule out organic cause (9%), and management is too time-consuming (5%). Both primary care providers and pediatric gastroenterologists use medication strategies, but diet recommendations are not the same. Unresponsiveness to treatment is the main reason for referral. If better management can occur in the primary care setting, costly specialty services may be avoided and possibly reduce healthcare costs.

  1. Added value of amide proton transfer imaging to conventional and perfusion MR imaging for evaluating the treatment response of newly diagnosed glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Park, Kye Jin; Kim, Ho Sung; Park, Ji Eun; Shim, Woo Hyun; Kim, Sang Joon [University of Ulsan College of Medicine, Asan Medical Center, Department of Radiology and Research Institute of Radiology, Seoul (Korea, Republic of); Smith, Seth A. [Vanderbilt University Institute of Imaging Science, Vanderbilt University, Department of Radiology and Radiological Sciences, Nashville, TN (United States)

    2016-12-15

    To determine the added value of amide proton transfer (APT) imaging to conventional and perfusion MRI for differentiating tumour progression (TP) from the treatment-related effect (TE) in patients with post-treatment glioblastomas. Sixty-five consecutive patients with enlarging contrast-enhancing lesions following concurrent chemoradiotherapy were assessed using contrast-enhanced T1-weighted MRI (CE-T1WI), 90th percentile histogram parameters of normalized cerebral blood volume (nCBV90) and APT asymmetry value (APT90). Diagnostic performance was determined using the area under the receiver operating characteristic curve (AUC) and cross validations. There were statistically significant differences in the mean APT90 between the TP and the TE groups (3.87-4.01 % vs. 1.38-1.41 %; P <.001). Compared with CE-T1WI alone, the addition of APT90 to CE-T1WI significantly improved cross-validated AUC from 0.58-0.74 to 0.89-0.91 for differentiating TP from TE. The combination of CE-T1WI, nCBV90 and APT90 resulted in greater diagnostic accuracy for differentiating TP from TE than the combination of CE-T1WI and nCBV90 (cross-validated AUC, 0.95-0.97 vs. 0.84-0.91). The inter-reader agreement between the expert and trainee was excellent for the measurements of APT90 (intraclass correlation coefficient, 0.94). Adding APT imaging to conventional and perfusion MRI improves the diagnostic performance for differentiating TP from TE. (orig.)

  2. Reasons for entering treatment reported by initially treatment-resistant patients with substance use disorders

    NARCIS (Netherlands)

    Meyers, Robert J.; Roozen, Hendrik G.; Smith, Jane Ellen; Evans, Brittany E.

    2014-01-01

    Many individuals with substance use disorders are resistant to entering formal treatment, despite the negative consequences that plague their own lives and the lives of concerned significant others (CSOs). Community Reinforcement and Family Training (CRAFT) has been developed as an effective

  3. Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: a phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

    Science.gov (United States)

    Brandes, Alba A; Tosoni, A; Franceschi, E; Blatt, V; Santoro, A; Faedi, M; Amistà, P; Gardiman, M; Labianca, R; Bianchini, C; Ermani, M; Reni, M

    2009-09-01

    Standardized salvage treatment has not yet proved effective in glioblastoma multiforme (GBM) patients who receive prior standard radiotherapy plus concomitant and adjuvant temozolomide. Patients with progressive GBM after radiotherapy plus concomitant and/or adjuvant temozolomide received three-weekly doses (100-75 mg m(2)) of fotemustine followed, after a 5-week rest, by fotemustine (100 mg m(2)) every 3 weeks for nitrosourea activity. Moreover, this is the first study to evaluate correlation between MGMT promoter status and outcome of fotemustine for relapsing GBM previously treated with radiotherapy and temozolomide.

  4. Electronic cigarettes in adults in outpatient substance use treatment: Awareness, perceptions, use, and reasons for use.

    Science.gov (United States)

    Peters, Erica N; Harrell, Paul T; Hendricks, Peter S; O'Grady, Kevin E; Pickworth, Wallace B; Vocci, Frank J

    2015-04-01

    Most studies on e-cigarettes have come from population-based surveys. The current research aimed to provide initial data on e-cigarette awareness, perceptions, use, and reasons for use among adults seeking substance use treatment. A survey was conducted among 198 participants ≥18 years old in a community-based outpatient substance use treatment program. Of the 198 participants, 69% currently smoked cigarettes, 92% were aware of e-cigarettes, and 58% had ever used e-cigarettes. The proportion of the number of participants who had ever used e-cigarettes to the number who currently smoked (89.7%) appeared higher than the corresponding proportion in the 2012-13 National Adult Tobacco Survey (78.3%). Almost half of the sample who reported ever using e-cigarettes endorsed quitting or reducing smoking as a reason for use, and 32% endorsed reasons for use relating to curiosity/experimentation. A greater likelihood of e-cigarette ever-use was significantly associated with younger age (adjusted odds ratio [AOR] = 0.94, 95%confidence interval [CI] = 0.90, 0.98) and perceptions related to using e-cigarettes in public places where smoking cigarettes is not allowed (AOR = 2.96, 95%CI = 1.18, 7.42) but was not associated with primary drug of choice. E-cigarette use in adults seeking substance use treatment appears higher than it is in the US general population of smokers. The high frequency of use may be due to curiosity/experimentation or attempts to quit or reduce smoking. Future research may consider how e-cigarettes interact with other substance use and affect high rates of nicotine and tobacco use in this population. © American Academy of Addiction Psychiatry.

  5. Reasons for non-adherence to obesity treatment in children and adolescents

    Directory of Open Access Journals (Sweden)

    Thaïs Florence D. Nogueira

    2013-09-01

    Full Text Available OBJECTIVE To analyze the reasons for non-adherence to follow-up at a specialized outpatient clinic for obese children and adolescents. METHODS Descriptive study of 41 patients, including information from medical records and phone recorded questionnaires which included two open questions and eight closed ones: reason for abandonment, financial and structural difficulties (distance and transport costs, relationship with professionals, obesity evolution, treatment continuity, knowledge of difficulties and obesity complications. RESULTS Among the interviewees, 29.3% reported that adherence to the program spent too much time and it was difficult to adjust consultations to patientsâ€(tm and parentsâ€(tm schedules. Other reasons were: childrenâ€(tms refusal to follow treatment (29.3%, dissatisfaction with the result (17.0%, treatment in another health service (12.2%, difficulty in schedule return (7.3% and delay in attendance (4.9%. All denied any relationship problems with professionals. Among the respondents, 85.4% said they are still overweight. They reported hurdles to appropriate nutrition and physical activity (financial difficulty, lack of parentsâ€(tm time, physical limitation and insecure neighborhood. Among the 33 respondents that reported difficulties with obesity, 78.8% had emotional disorders such as bullying, anxiety and irritability; 24.2% presented fatigue, 15.1% had difficulty in dressing up and 15.1% referred pain. The knowledge of the following complications prevailed: cardicac (97.6%, aesthetic (90.2%, psychological (90.2%, presence of obesity in adulthood (90.2%, diabetes (85.4% and cancer (31.4%. CONCLUSIONS According to the results, it is possible to create weight control public programs that are easier to access, encouraging appropriate nutrition and physical activities in order to achieve obesity prevention.

  6. Stereotactic Radiosurgery and Hypofractionated Radiotherapy for Glioblastoma.

    Science.gov (United States)

    Shah, Jennifer L; Li, Gordon; Shaffer, Jenny L; Azoulay, Melissa I; Gibbs, Iris C; Nagpal, Seema; Soltys, Scott G

    2018-01-01

    Glioblastoma is the most common primary brain tumor in adults. Standard therapy depends on patient age and performance status but principally involves surgical resection followed by a 6-wk course of radiation therapy given concurrently with temozolomide chemotherapy. Despite such treatment, prognosis remains poor, with a median survival of 16 mo. Challenges in achieving local control, maintaining quality of life, and limiting toxicity plague treatment strategies for this disease. Radiotherapy dose intensification through hypofractionation and stereotactic radiosurgery is a promising strategy that has been explored to meet these challenges. We review the use of hypofractionated radiotherapy and stereotactic radiosurgery for patients with newly diagnosed and recurrent glioblastoma. Copyright © 2017 by the Congress of Neurological Surgeons.

  7. Survival effect of first- and second-line treatments for patients with primary glioblastoma: a cohort study from a prospective registry, 1997–2010

    Science.gov (United States)

    Nava, Francesca; Tramacere, Irene; Fittipaldo, Andrea; Bruzzone, Maria Grazia; DiMeco, Francesco; Fariselli, Laura; Finocchiaro, Gaetano; Pollo, Bianca; Salmaggi, Andrea; Silvani, Antonio; Farinotti, Mariangela; Filippini, Graziella

    2014-01-01

    Background Prospective follow-up studies of large cohorts of patients with glioblastoma (GBM) are needed to assess the effectiveness of conventional treatments in clinical practice. We report GBM survival data from the Brain Cancer Register of the Fondazione Istituto Neurologico Carlo Besta (INCB) in Milan, Italy, which collected longitudinal data for all consecutive patients with GBM from 1997 to 2010. Methods Survival data were obtained from 764 patients (aged>16 years) with histologically confirmed primary GBM who were diagnosed and treated over a 7-year period (2004–2010) with follow-up to April 2012 (cohort II). Equivalent data from 490 GBM patients diagnosed and treated over the preceding 7 years (1997–2003) with follow-up to April 2005 (cohort I) were available for comparison. Progression-free survival (PFS) was available from 361 and 219 patients actively followed up at INCB in cohorts II and I, respectively. Results Survival probabilities were 54% at 1 year, 21% at 2 years, and 11% at 3 years, respectively, in cohort II compared with 47%, 11%, and 5%, respectively, in cohort I. PFS was 22% and 12% at 1 year in cohorts II and I. Better survival and PFS in cohort II was significantly associated with introduction of the Stupp protocol into clinical practice, with adjusted hazard ratios (HRs) of 0.78 for survival and 0.73 for PFS, or a 22% relative decrease in the risk of death and a 27% relative decrease in the risk of recurrence. After recurrence, reoperation was performed in one-fifth of cohort I and in one-third of cohort II but was not effective (HR, 1.05 in cohort I and 1.02 in cohort II). Second-line chemotherapy, mainly consisting of nitrosourea-based chemotherapy, temozolomide, mitoxantrone, fotemustine, and bevacizumab, improved survival in both cohorts (HR, 0.57 in cohort I and 0.74 in cohort II). Radiosurgery was also effective (HR, 0.52 in cohort II). Conclusions We found a significant increase in overall survival, PFS, and survival after

  8. Survival effect of first- and second-line treatments for patients with primary glioblastoma: a cohort study from a prospective registry, 1997-2010.

    Science.gov (United States)

    Nava, Francesca; Tramacere, Irene; Fittipaldo, Andrea; Bruzzone, Maria Grazia; Dimeco, Francesco; Fariselli, Laura; Finocchiaro, Gaetano; Pollo, Bianca; Salmaggi, Andrea; Silvani, Antonio; Farinotti, Mariangela; Filippini, Graziella

    2014-05-01

    Prospective follow-up studies of large cohorts of patients with glioblastoma (GBM) are needed to assess the effectiveness of conventional treatments in clinical practice. We report GBM survival data from the Brain Cancer Register of the Fondazione Istituto Neurologico Carlo Besta (INCB) in Milan, Italy, which collected longitudinal data for all consecutive patients with GBM from 1997 to 2010. Survival data were obtained from 764 patients (aged>16 years) with histologically confirmed primary GBM who were diagnosed and treated over a 7-year period (2004-2010) with follow-up to April 2012 (cohort II). Equivalent data from 490 GBM patients diagnosed and treated over the preceding 7 years (1997-2003) with follow-up to April 2005 (cohort I) were available for comparison. Progression-free survival (PFS) was available from 361 and 219 patients actively followed up at INCB in cohorts II and I, respectively. Survival probabilities were 54% at 1 year, 21% at 2 years, and 11% at 3 years, respectively, in cohort II compared with 47%, 11%, and 5%, respectively, in cohort I. PFS was 22% and 12% at 1 year in cohorts II and I. Better survival and PFS in cohort II was significantly associated with introduction of the Stupp protocol into clinical practice, with adjusted hazard ratios (HRs) of 0.78 for survival and 0.73 for PFS, or a 22% relative decrease in the risk of death and a 27% relative decrease in the risk of recurrence. After recurrence, reoperation was performed in one-fifth of cohort I and in one-third of cohort II but was not effective (HR, 1.05 in cohort I and 1.02 in cohort II). Second-line chemotherapy, mainly consisting of nitrosourea-based chemotherapy, temozolomide, mitoxantrone, fotemustine, and bevacizumab, improved survival in both cohorts (HR, 0.57 in cohort I and 0.74 in cohort II). Radiosurgery was also effective (HR, 0.52 in cohort II). We found a significant increase in overall survival, PFS, and survival after recurrence after 2004, likely due to

  9. MRI assessment of relapsed glioblastoma during treatment with bevacizumab: Volumetric measurement of enhanced and FLAIR lesions for evaluation of response and progression—A pilot study

    International Nuclear Information System (INIS)

    Pichler, Josef; Pachinger, Corinna; Pelz, Manuela; Kleiser, Raimund

    2013-01-01

    Purpose: To develop a magnetic resonance imaging (MRI) metric that is useful for therapy monitoring in patients with relapsed glioblastoma (GBM) during treatment with the antiangiogenic monoclonal antibody bevacizumab (Bev). We evaluated the feasibility of tumour volume measurement with our software tool in clinical routine and tried to establish reproducible and quantitative parameters for surveillance of patients on treatment with antiangiogenic drugs. Materials and methods: In this retrospective institutional pilot study, 18 patients (11 men, 7 women; mean age 53.5) with recurrent GBM received bevacizumab and irinotecan every two weeks as second line therapy. Follow up scans were assessed every two to four months. Data were collected on a 1.5 T MR System (Siemens, Symphony) with the standard head coil using our standardized tumour protocol. Volumetric measurement was performed with a commercial available software stroketool in FLAIR and T1-c imaging with following procedure: Pre-processing involved cutting noise and electing a Gaussian of 3 × 3 to smooth images, selecting a ROI (region of interest) in healthy brain area of the contra lateral side with quantifying the intensity value, adding 20% to this value to define the threshold level. Only values above this threshold are left corresponding to the tumour lesion. For the volumetric measurement the detected tumour area was circuited in all slices and finally summing up all values and multiplied by slice thickness to get the whole volume. Results: With McDonalds criteria progression was indicated in 14 out of 18 patients. In contrast, volumetric measurement showed an increase of contrast enhancement of >25%, defined as threshold for progression, in 11 patients (78%) and in 12 patients (85%) in FLAIR volume, respectively. 6 patients revealed that volumes in MRI increased earlier than the last scan, which was primarily defined as the date of progression with McDonald criteria, changing PFS after re-evaluation of

  10. MRI assessment of relapsed glioblastoma during treatment with bevacizumab: volumetric measurement of enhanced and FLAIR lesions for evaluation of response and progression--a pilot study.

    Science.gov (United States)

    Pichler, Josef; Pachinger, Corinna; Pelz, Manuela; Kleiser, Raimund

    2013-05-01

    To develop a magnetic resonance imaging (MRI) metric that is useful for therapy monitoring in patients with relapsed glioblastoma (GBM) during treatment with the antiangiogenic monoclonal antibody bevacizumab (Bev). We evaluated the feasibility of tumour volume measurement with our software tool in clinical routine and tried to establish reproducible and quantitative parameters for surveillance of patients on treatment with antiangiogenic drugs. In this retrospective institutional pilot study, 18 patients (11 men, 7 women; mean age 53.5) with recurrent GBM received bevacizumab and irinotecan every two weeks as second line therapy. Follow up scans were assessed every two to four months. Data were collected on a 1.5 T MR System (Siemens, Symphony) with the standard head coil using our standardized tumour protocol. Volumetric measurement was performed with a commercial available software stroketool in FLAIR and T1-c imaging with following procedure: Pre-processing involved cutting noise and electing a Gaussian of 3 × 3 to smooth images, selecting a ROI (region of interest) in healthy brain area of the contra lateral side with quantifying the intensity value, adding 20% to this value to define the threshold level. Only values above this threshold are left corresponding to the tumour lesion. For the volumetric measurement the detected tumour area was circuited in all slices and finally summing up all values and multiplied by slice thickness to get the whole volume. With McDonalds criteria progression was indicated in 14 out of 18 patients. In contrast, volumetric measurement showed an increase of contrast enhancement of >25%, defined as threshold for progression, in 11 patients (78%) and in 12 patients (85%) in FLAIR volume, respectively. 6 patients revealed that volumes in MRI increased earlier than the last scan, which was primarily defined as the date of progression with McDonald criteria, changing PFS after re-evaluation of the tumour volumes from 6.8 to 5.6 months

  11. MRI assessment of relapsed glioblastoma during treatment with bevacizumab: Volumetric measurement of enhanced and FLAIR lesions for evaluation of response and progression—A pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Pichler, Josef, E-mail: josef.pichler@gespag.at [Wagner Jauregg Weg 15, 4020 Linz, Landesnervenklinik Linz (Austria); Pachinger, Corinna, E-mail: pachingercorinna@gmx.at [Wagner Jauregg Weg 15, 4020 Linz, Landesnervenklinik Linz (Austria); Pelz, Manuela, E-mail: mauela.pelz@gespag.at [Wagner Jauregg Weg 15, 4020 Linz, Landesnervenklinik Linz (Austria); Kleiser, Raimund, E-mail: raimund.kleiser@gespag.at [Wagner Jauregg Weg 15, 4020 Linz, Landesnervenklinik Linz (Austria)

    2013-05-15

    Purpose: To develop a magnetic resonance imaging (MRI) metric that is useful for therapy monitoring in patients with relapsed glioblastoma (GBM) during treatment with the antiangiogenic monoclonal antibody bevacizumab (Bev). We evaluated the feasibility of tumour volume measurement with our software tool in clinical routine and tried to establish reproducible and quantitative parameters for surveillance of patients on treatment with antiangiogenic drugs. Materials and methods: In this retrospective institutional pilot study, 18 patients (11 men, 7 women; mean age 53.5) with recurrent GBM received bevacizumab and irinotecan every two weeks as second line therapy. Follow up scans were assessed every two to four months. Data were collected on a 1.5 T MR System (Siemens, Symphony) with the standard head coil using our standardized tumour protocol. Volumetric measurement was performed with a commercial available software stroketool in FLAIR and T1-c imaging with following procedure: Pre-processing involved cutting noise and electing a Gaussian of 3 × 3 to smooth images, selecting a ROI (region of interest) in healthy brain area of the contra lateral side with quantifying the intensity value, adding 20% to this value to define the threshold level. Only values above this threshold are left corresponding to the tumour lesion. For the volumetric measurement the detected tumour area was circuited in all slices and finally summing up all values and multiplied by slice thickness to get the whole volume. Results: With McDonalds criteria progression was indicated in 14 out of 18 patients. In contrast, volumetric measurement showed an increase of contrast enhancement of >25%, defined as threshold for progression, in 11 patients (78%) and in 12 patients (85%) in FLAIR volume, respectively. 6 patients revealed that volumes in MRI increased earlier than the last scan, which was primarily defined as the date of progression with McDonald criteria, changing PFS after re-evaluation of

  12. Perceptions of Harm and Reasons for Misuse of Prescription Opioid Drugs and Reasons for Not Seeking Treatment for Physical or Emotional Pain Among a Sample of College Students.

    Science.gov (United States)

    Kenne, Deric R; Hamilton, Kelsey; Birmingham, Lauren; Oglesby, Willie H; Fischbein, Rebecca L; Delahanty, Douglas L

    2017-01-02

    Since the early 1990s, the United States has seen a significant increase in the prevalence of prescription opioid misuse. Despite benefits prescription opioids provide, misuse can be fatal. The current study was designed to investigate the prevalence of prescription opioid misuse, perceived harm of misuse, and reasons for misuse for physical or emotional pain instead of seeking professional medical or mental health treatment. Survey data were collected in the fall of 2013 via an online survey to a random sample of 668 students from a public Midwestern university. Lifetime prevalence of prescription opioid misuse was 9.5%. Misusers of prescription opioid drugs generally reported lower ratings of perceived harm as compared to individuals not reporting misuse of prescription opioid drugs. Primary reasons for misuse of prescription opioid drugs was to relieve pain (33.9%), "to feel good/get high" (23.2%) and experimentation (21.4%). Lifetime misuse of a prescription opioid drug for physical or emotional pain was reported by 8.1% and 2.2% of respondents, respectively. Primary reasons for misuse for physical pain included because pain was temporary, immediate relief was needed, and no health insurance/financial resources. Primary reasons for misuse for emotional pain included not wanting others to find out, embarrassment and fear. Conclusions/Importance: Reasons for misuse of prescription opioid drugs vary by type of prescription opioid drug. Reasons for not seeking treatment that ultimately lead to misuse, vary by type of pain being treated and may be important considerations in the effort to stem the misuse of prescription opioid drugs among college students.

  13. Development of an exercise intervention as part of rehabilitation in a glioblastoma multiforme survivor during irradiation treatment

    DEFF Research Database (Denmark)

    Hansen, Anders; Søgaard, Karen; Minet, Lisbeth Rosenbek

    2018-01-01

    completed a supervised six-week exercise intervention during irradiation treatment beginning 42 d after resection. Exercise modalities of cardiorespiratory, resistance, and balance training were designed on generic recommendations of various cancer populations and literature review. RESULTS: Our case...... attended all possible sessions without experiencing adverse effects, and improved in aerobe power (24%), muscle strength (0-38%), standing balance (71%), walking ability (9%), and QOL domains of "Global Health Status/QoL" and "Physical functioning." CONCLUSIONS: Based on this single case, exercise...

  14. First clinical results from the EORTC phase I Trial ''postoperative treatment of glioblastoma with BNCT at the Petten irradiation facility''

    International Nuclear Information System (INIS)

    Sauerwein, W.; Hideghety, K.; Rassow, J.; Devries, M.J.; Goetz, C.; Paquis, P.; Grochulla, F.; Wolbers, J.G.; Haselsberger, K.; Turowski, B.; Moss, R.L.; Stecher-Rasmussen, F.; Touw, D.; Wiestler, O.D.; Frankhauser, H.; Gabel, D.

    2001-01-01

    Based on the pre-clinical work of the European Collaboration on Boron Neutron Capture Therapy a study protocol was prepared in 1995 to initiate Boron Neutron Capture Therapy (BNCT) in patients at the High Flux Reactor (HFR) in Petten. Bio-distribution and pharmacokinetics data of the boron drug Na 2 B 12 H 11 SH (BSH) as well as the radiobiological effects of BNCT with BSH in healthy brain tissue of dogs were considered in designing the strategy for this clinical Phase I trial. The primary goal of the radiation dose escalation study is the investigation of possible adverse events due to BNCT; i.e. to establish the dose limiting toxicity and the maximal tolerated dose. The treatment is delivered in 4 fractions at a defined average boron concentration in blood. Cohorts of 10 patients are treated per dose group. The starting dose was set at 80% of the dose at which neurological symptoms occurred in preclinical dog experiments following a single fraction. After an observation period of at least 6 months, the dose is increased by 10% for the next cohort if less then three severe side effects related to the treatment occurred. The results of the first cohort are presented here. The evaluated dose level can be considered safe. (author)

  15. First clinical results from the EORTC phase I Trial ''postoperative treatment of glioblastoma with BNCT at the Petten irradiation facility''

    Energy Technology Data Exchange (ETDEWEB)

    Sauerwein, W; Hideghety, K; Rassow, J [Department of Radiotherapy, University of Essen (Germany); Devries, M J [NDDO Oncology, Amsterdam (Netherlands); Goetz, C [Neurochirurgische Klinik, Klinikum Grosshadern Muenchen, Munich (Germany); Paquis, P [Dept. de Neurochirurgie, Hopital Pasteur, Nice (France); Grochulla, F [Klinik fuer Neurochirurgie, Zentralkrankenhaus Bremen (Germany); Wolbers, J G [Department of Neurosurgery, University Hospital ' ' Vrije Universiteit' ' , Amsterdam (Netherlands); Haselsberger, K [Klinik fuer Neurochirurgie, Karl-Franzens-Universitaet, Graz (Austria); Turowski, B [Institut fuer Neuroradiologie, Johann-Wolfgang-von-Goethe-Universitaet, Frankfurt (Germany); Moss, R L [HFR Unit, Joint Research Centre, European Commission, Petten (Netherlands); Stecher-Rasmussen, F [Nuclear Research and Consultancy Group NRG, Petten (Netherlands); Touw, D [Pharmacy, University/Academic Hospital ' ' Vrije Universiteit' ' , Amsterdam (Netherlands); Wiestler, O D [Department of Neuropathology, German Brain Tumour Reference Centre, Universitaetsklinikum Bonn (Germany); Frankhauser, H [Service de Neurochirurgie CHUV, Lausanne (Switzerland); Gabel, D [Chemistry Department, University of Bremen (Germany)

    2001-05-01

    Based on the pre-clinical work of the European Collaboration on Boron Neutron Capture Therapy a study protocol was prepared in 1995 to initiate Boron Neutron Capture Therapy (BNCT) in patients at the High Flux Reactor (HFR) in Petten. Bio-distribution and pharmacokinetics data of the boron drug Na{sub 2}B{sub 12}H{sub 11}SH (BSH) as well as the radiobiological effects of BNCT with BSH in healthy brain tissue of dogs were considered in designing the strategy for this clinical Phase I trial. The primary goal of the radiation dose escalation study is the investigation of possible adverse events due to BNCT; i.e. to establish the dose limiting toxicity and the maximal tolerated dose. The treatment is delivered in 4 fractions at a defined average boron concentration in blood. Cohorts of 10 patients are treated per dose group. The starting dose was set at 80% of the dose at which neurological symptoms occurred in preclinical dog experiments following a single fraction. After an observation period of at least 6 months, the dose is increased by 10% for the next cohort if less then three severe side effects related to the treatment occurred. The results of the first cohort are presented here. The evaluated dose level can be considered safe. (author)

  16. Deregulation of a STAT3-IL8 Signaling Pathway Promotes Human Glioblastoma Cell Proliferation and Invasiveness

    Science.gov (United States)

    de la Iglesia, Núria; Konopka, Genevieve; Lim, Kah Leong; Nutt, Catherine L.; Bromberg, Jacqueline F.; Frank, David A.; Mischel, Paul S.; Louis, David N.; Bonni, Azad

    2009-01-01

    Inactivation of the tumor suppressor PTEN is recognized as a major event in the pathogenesis of the brain tumor glioblastoma. However, the mechanisms by which PTEN loss specifically impacts the malignant behavior of glioblastoma cells including their proliferation and propensity for invasiveness remain poorly understood. Genetic studies suggest that the transcription factor STAT3 harbors a PTEN-regulated tumor suppressive function in mouse astrocytes. Here, we report that STAT3 plays a critical tumor suppressive role in PTEN-deficient human glioblastoma cells. Endogenous STAT3 signaling is specifically inhibited in PTEN-deficient glioblastoma cells. Strikingly, reactivation of STAT3 in PTEN-deficient glioblastoma cells inhibits their proliferation, invasiveness, and ability to spread on myelin. We also identify the chemokine IL8 as a novel target gene of STAT3 in human glioblastoma cells. Activated STAT3 occupies the endogenous IL8 promoter and directly represses IL8 transcription. Consistent with these results, IL8 is upregulated in PTEN-deficient human glioblastoma tumors. Importantly, IL8 repression mediates STAT3-inhibition of glioblastoma cell proliferation, invasiveness, and spreading on myelin. Collectively, our findings uncover a novel link between STAT3 and IL8 whose deregulation plays a key role in the malignant behavior of PTEN-deficient glioblastoma cells. These studies suggest that STAT3 activation or IL8 inhibition may have potential in patient-tailored treatment of PTEN-deficient brain tumors. PMID:18524891

  17. Reasons for discontinuation of subcutaneous biologic therapy in the treatment of rheumatoid arthritis: a patient perspective

    Directory of Open Access Journals (Sweden)

    Bolge SC

    2015-01-01

    Full Text Available Susan C Bolge,1 Amir Goren,2 Neeta Tandon1 1Health Economics and Outcomes Research, Janssen Scientific Affairs, LLC, Horsham, PA, USA; 2Health Outcomes Practice, Kantar Health, New York, NY, USA Objective: To examine reasons why rheumatoid arthritis patients discontinued subcutaneous (SQ anti-tumor necrosis factor (anti-TNF treatment in the past 12 months, so as to help inform successful, uninterrupted therapy.Methods: Data were collected in March and April 2011 using self-reported, internet-based questionnaires. Study inclusion criteria comprised: rheumatoid arthritis diagnosis; discontinuation of SQ anti-TNF medication (adalimumab, certolizumab, etanercept, or golimumab within the past 12 months; aged ≥18 years; United States residency; and consent to participate. Patients reported primary and other reasons for discontinuation of their most recently discontinued anti-TNF.Results: Questionnaires from 250 patients were analyzed; 72.8% were female, 80.8% were white, and median age was 51 years. Patients had discontinued etanercept (n=109, adalimumab (n=98, certolizumab (n=24, or golimumab (n=19 within the past 12 months. When prompted about their primary reason for discontinuation, lack of effectiveness (40.8% was cited most often, followed by injection experience (18.4%. Combining prompted primary and other reasons for discontinuation, 60.8% of patients reported lack of effectiveness, while 40.8% reported injection experience, which included: pain/burning/discomfort after injection (14.4%; pain/burning/discomfort during injection (13.2%; injection reactions such as redness/swelling after injection (12.4%; dislike of self-injection (11.6%; dislike of frequency of injection (10.4%; and fear of injection/needles (6.8%. Conclusion: From the patient perspective, there are unmet needs with regard to the effectiveness and injection experience associated with SQ anti-TNF medications, which may lead to discontinuation. Treatment options with a

  18. Retrieval with Clustering in a Case-Based Reasoning System for Radiotherapy Treatment Planning

    Science.gov (United States)

    Khussainova, Gulmira; Petrovic, Sanja; Jagannathan, Rupa

    2015-05-01

    Radiotherapy treatment planning aims to deliver a sufficient radiation dose to cancerous tumour cells while sparing healthy organs in the tumour surrounding area. This is a trial and error process highly dependent on the medical staff's experience and knowledge. Case-Based Reasoning (CBR) is an artificial intelligence tool that uses past experiences to solve new problems. A CBR system has been developed to facilitate radiotherapy treatment planning for brain cancer. Given a new patient case the existing CBR system retrieves a similar case from an archive of successfully treated patient cases with the suggested treatment plan. The next step requires adaptation of the retrieved treatment plan to meet the specific demands of the new case. The CBR system was tested by medical physicists for the new patient cases. It was discovered that some of the retrieved cases were not suitable and could not be adapted for the new cases. This motivated us to revise the retrieval mechanism of the existing CBR system by adding a clustering stage that clusters cases based on their tumour positions. A number of well-known clustering methods were investigated and employed in the retrieval mechanism. Results using real world brain cancer patient cases have shown that the success rate of the new CBR retrieval is higher than that of the original system.

  19. Retrieval with Clustering in a Case-Based Reasoning System for Radiotherapy Treatment Planning

    International Nuclear Information System (INIS)

    Khussainova, Gulmira; Petrovic, Sanja; Jagannathan, Rupa

    2015-01-01

    Radiotherapy treatment planning aims to deliver a sufficient radiation dose to cancerous tumour cells while sparing healthy organs in the tumour surrounding area. This is a trial and error process highly dependent on the medical staff's experience and knowledge. Case-Based Reasoning (CBR) is an artificial intelligence tool that uses past experiences to solve new problems. A CBR system has been developed to facilitate radiotherapy treatment planning for brain cancer. Given a new patient case the existing CBR system retrieves a similar case from an archive of successfully treated patient cases with the suggested treatment plan. The next step requires adaptation of the retrieved treatment plan to meet the specific demands of the new case. The CBR system was tested by medical physicists for the new patient cases. It was discovered that some of the retrieved cases were not suitable and could not be adapted for the new cases. This motivated us to revise the retrieval mechanism of the existing CBR system by adding a clustering stage that clusters cases based on their tumour positions. A number of well-known clustering methods were investigated and employed in the retrieval mechanism. Results using real world brain cancer patient cases have shown that the success rate of the new CBR retrieval is higher than that of the original system. (paper)

  20. The Reasons for Discontinuation of Infliximab Treatment in Patients with Crohn's Disease: A Review of Practice at NHS Teaching Hospital

    OpenAIRE

    Krupa, Lukasz Z.; Kennedy, Hugh J.; Jamieson, Crawford P.; Fisher, Nicola; Hart, Andrew R.

    2011-01-01

    Introduction. There is little information on the reasons for discontinuing infliximab treatment in patients with Crohn's disease. The aim of this study was to document these reasons to determine if any were preventable which would allow patients to continue the therapy. Aims & Methods. A review of the medical notes was conducted at the Norfolk and Norwich University Hospital on patients with Crohn's disease treated with infliximab between 2002–2008 to determine the reasons for stopping it. Re...

  1. Racial/ethnic differences in perceived reasons for mental health treatment in US adolescents with major depression.

    Science.gov (United States)

    Cummings, Janet R; Case, Brady G; Ji, Xu; Chae, David H; Druss, Benjamin G

    2014-09-01

    Racial/ethnic differences in the course of treatment for a major depressive episode (MDE) among adolescents may arise, in part, from variation in the perceived rationale for treatment. We examined racial/ethnic differences in the perceived reasons for receiving mental health (MH) treatment among adolescents with an MDE. A total of 2,789 adolescent participants who experienced an MDE and received MH treatment in the past year were drawn from the 2005 to 2008 National Survey on Drug Use and Health. Adolescents reported the settings in which they received care and reasons for their most recent visit to each setting. Distributions of specific depressive symptoms were compared across racial/ethnic groups. Racial/ethnic differences in endorsing each of 11 possible reasons for receiving treatment were examined using weighted probit regressions adjusted for sociodemographic characteristics, health and mental health status, treatment setting, and survey year. Despite similar depressive symptom profiles, Hispanic adolescents were more likely than whites to endorse "breaking rules" or getting into physical fights as reasons for MH treatment. Black adolescents were more likely than white adolescents to endorse "problems at school" but less likely to endorse "felt very afraid or tense" or "eating problems" as reasons for treatment. Asian adolescents were more likely to endorse "problems with people other than friends or family" but less likely than whites to endorse "suicidal thoughts/attempt" and "felt depressed" as reasons for treatment. Racial/ethnic minority participants were more likely than white participants to endorse externalizing or interpersonal problems and less likely to endorse internalizing problems as reasons for MH treatment. Understanding racial/ethnic differences in the patient's perceived treatment rationale can offer opportunities to enhance outcomes for depression among diverse populations. Copyright © 2014 American Academy of Child and Adolescent

  2. The theory of reasoned action and patient compliance during orthodontic treatment.

    Science.gov (United States)

    Bos, Annemieke; Hoogstraten, Johan; Prahl-Andersen, Birte

    2005-12-01

    The aim of the present study was to investigate the potential of the theory of reasoned action (TRA) for the prediction and understanding of patients' intention to comply during orthodontic treatment and to analyze the effect of two additional variables in the model, namely perceived behavioral control and anticipated regret. Moreover, (the determinants of) intentions of orthodontic patients to comply during treatment were compared with (the determinants of) intentions of parents to stimulate this cooperation. A questionnaire was handed out to patients and parents visiting the Department of Orthodontics of the Academic Centre of Dentistry in Amsterdam. In both the patient and parent sample, independent-sample t-tests, correlation analyses and stepwise regression analyses were conducted. Variables in both samples were compared and tested. The extended version of the TRA explained 20% of the variance in the patients' intention to comply. The patients' anticipated regret, attitude and motivation to comply were significant determinants of the patients' intention to comply. In addition, the parents' attitude toward compliance was a significant predictor. The role of parents in enhancing patients' intentions to comply cannot be neglected. Our findings suggest that patients' intentions to comply during orthodontic treatment are influenced by factors outside of the TRA. Therefore, it is recommended to develop a new model, in which factors of the TRA are included, which can be used specifically for the study of compliance in orthodontics.

  3. Gender differences in reasons patients delay in seeking treatment for acute myocardial infarction symptoms.

    Science.gov (United States)

    Moser, Debra K; McKinley, Sharon; Dracup, Kathleen; Chung, Misook L

    2005-01-01

    Patients (n = 194) with confirmed acute myocardial infarction (AMI) were interviewed to determine sociodemographic, clinical, social, behavioral, cognitive and emotional factors that contribute to delay in seeking treatment for their symptoms. Initial symptom experience was similar for men and women: both were most commonly at home when symptoms began; both were most commonly in the presence of their spouse or other family member; few patients (trouble others, and prior knowledge of thrombolytics. There was no difference in delay between men and women (median 3.08 versus 3.10 h), but there are important gender differences in the reasons patients delay and in their patterns of decision-making that may assist clinicians trying to tailor interventions.

  4. Experimental heat treatment of silcrete implies analogical reasoning in the Middle Stone Age.

    Science.gov (United States)

    Wadley, Lyn; Prinsloo, Linda C

    2014-05-01

    Siliceous rocks that were not heated to high temperatures during their geological formation display improved knapping qualities when they are subjected to controlled heating. Experimental heat treatment of South African silcrete, using open fires of the kind used during the Middle Stone Age, shows that the process needed careful management, notwithstanding recent arguments to the contrary. Silcrete blocks fractured when heated on the surface of open fires or on coal beds, but were heated without mishap when buried in sand below a fire. Three silcrete samples, a control, a block heated underground with maximum temperature between 400 and 500 °C and a block heated in an open fire with maximum temperature between 700 and 800 °C, were analysed with X-ray powder diffraction (XRD), X-ray fluorescence (XRF), optical microscopy, and both Fourier transform infrared (FTIR) and Raman spectroscopy. The results show that the volume expansion during the thermally induced α- to β-quartz phase transformation and the volume contraction during cooling play a major role in the heat treatment of silcrete. Rapid heating or cooling through the phase transformation at 573 °C will cause fracture of the silcrete. Successful heat treatment requires controlling surface fire temperatures in order to obtain the appropriate underground temperatures to stay below the quartz inversion temperature. Heat treatment of rocks is a transformative technology that requires skilled use of fire. This process involves analogical reasoning, which is an attribute of complex cognition. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Comparison of 18F-FET and 18F-FLT small animal PET for the assessment of anti-VEGF treatment response in an orthotopic model of glioblastoma

    International Nuclear Information System (INIS)

    Nedergaard, Mette Kjoelhede; Michaelsen, Signe Regner; Perryman, Lara; Erler, Janine; Poulsen, Hans Skovgaard; Stockhausen, Marie-Thérése; Lassen, Ulrik; Kjaer, Andreas

    2016-01-01

    Background: The radiolabeled amino acid O-(2- 18 F-fluoroethyl)-L-tyrosine (FET) and thymidine analogue 3′-deoxy-3′- 18 F-fluorothymidine (FLT) are widely used for positron emission tomography (PET) brain tumor imaging; however, comparative studies are scarce. The aim of this study therefore was to compare FLT and FET PET for the assessment of anti-VEGF response in glioblastoma xenografts. Methods: Xenografts with confirmed intracranial glioblastoma were treated with anti-VEGF therapy (B20-4.1) or saline as control. Weekly bioluminescence imaging (BLI), FLT and FET PET/CT were used to follow treatment response. Tracer uptake of FLT and FET was quantified using maximum standardized uptake (SUV max ) values and tumor-to-background ratios (TBRs). Survival, the Ki67 proliferation index and micro-vessel density (MVD) were evaluated. Results: In contrast to FLT TBRs, FET TBRs were significantly lower as early as one week after treatment initiation in the anti-VEGF group as compared to the control group. Following two weeks of treatment, both FLT and FET TBRs were significantly lower in the anti-VEGF group. In contrast, no significant difference between the treatment groups was detected using BLI. Furthermore, we found a significantly lower MVD in the anti-VEGF group as compared to the control group. However, we found no difference in the Ki67 proliferation index or mean survival time. Conclusion: FET appears to be a more sensitive tracer than FLT to measure early response to anti-VEGF therapy with PET. Advances in knowledge and implications for patient care FET PET appears to be an early predictor of anti-VEGF efficacy. Confirmation of these results in clinical studies is needed.

  6. Reasons for Schizophrenia Patients Remaining out of Treatment: Results from a Prospective Study in a Rural South Indian Community.

    Science.gov (United States)

    Kumar, Channaveerachari Naveen; Thirthalli, Jagadisha; Suresha, Kudumallige Krishnappa; Venkatesh, Basappa K; Kishorekumar, Kengeri V; Arunachala, Udupi; Gangadhar, Bangalore N

    2016-01-01

    A few studies have examined the factors associated with schizophrenia patients remaining untreated in India. We identified 184 schizophrenia patients in a rural community, offered the treatment with antipsychotics and followed them up in their Primary Health Centers for 1-year. Twenty-nine (15.8%) patients remained untreated at both the baseline and 1-year follow-up despite our best attempts to keep them under the treatment umbrella. They were interviewed in detail regarding the reasons for remaining untreated. This group was compared with another group of patients (n = 69) who had stopped the treatment at baseline but were successfully brought under the treatment umbrella throughout the 1-year follow-up period. The reasons for remaining untreated were (n; %): (a) Unsatisfactory improvement with previous treatment attempts (19; 65.5%), (b) poor bond between the patients and the families (6; 20.7%), (c) active symptoms not allowing any treatment efforts from the family members (6; 20.7%), (d) magico-religious beliefs about the illness and its treatment (4; 13.8%), (e) poor social support (3; 10.3%), (f) adverse effects of the medications (2; 6.9%), and (g) perception of recovery and cure (1; 3.4%). For many patients, a constellation of these reasons was responsible for them remaining untreated. In contrast, the common reasons for those who restarted medications to have stopped the treatment at some time were the lack of awareness, the need to continue medications (47; 68.1%), and the financial constraints (28; 40.6%). The predominant reason for schizophrenia patients not remaining on the treatment in this rural community was the families' lack of faith in antipsychotic treatment. Provision of comprehensive treatment package including medical, psychosocial and rehabilitative services, and sensitizing the community about benefits of the treatment may help in ensuring that all patients with psychosis receive the best care.

  7. Phase II Pilot Study of Bevacizumab in Combination with Temozolomide and Regional Radiation Therapy for Up-Front Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Interim Analysis of Safety and Tolerability

    International Nuclear Information System (INIS)

    Lai, Albert; Filka, Emese; McGibbon, Bruce; Nghiemphu, Phioanh Leia; Graham, Carrie; Yong, William H.; Mischel, Paul; Liau, Linda M.; Bergsneider, Marvin; Pope, Whitney; Selch, Michael; Cloughesy, Tim

    2008-01-01

    Purpose: To assess interim safety and tolerability of a 10-patient, Phase II pilot study using bevacizumab (BV) in combination with temozolomide (TMZ) and regional radiation therapy (RT) in the up-front treatment of patients with newly diagnosed glioblastoma. Methods and Materials: All patients received standard external beam regional RT of 60.0 Gy in 30 fractions started within 3 to 5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m 2 for 42 days during RT, and BV was given every 2 weeks at 10 mg/kg starting with the first day of RT/TMZ. After a 2-week interval upon completion of RT, the post-RT phase commenced with resumption of TMZ at 150 to 200 mg/m 2 for 5 days every 4 weeks and continuation of BV every 2 weeks. Results: For these 10 patients, toxicities were compiled until study discontinuation or up to ∼40 weeks from initial study treatment for those remaining on-study. In terms of serious immediate or delayed neurotoxicity, 1 patient developed presumed radiation-induced optic neuropathy. Among the toxicities that could be potentially treatment related, relatively high incidences of fatigue, myelotoxicity, wound breakdown, and deep venous thrombosis/pulmonary embolism were observed. Conclusion: The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment

  8. Can Immunotherapy Succeed in Glioblastoma?

    Science.gov (United States)

    Researchers are hopeful that, for the deadly brain cancer glioblastoma, immunotherapy might succeed where other therapies have not. As this Cancer Currents post reports, different immunotherapy approaches are being tested in clinical trials.

  9. Key concepts in glioblastoma therapy

    DEFF Research Database (Denmark)

    Bartek, Jiri; Ng, Kimberly; Bartek, Jiri

    2012-01-01

    principles that drive the formulation of therapeutic strategies in glioblastoma. Specifically, the concepts of tumour heterogeneity, oncogene addiction, non-oncogene addiction, tumour initiating cells, tumour microenvironment, non-coding sequences and DNA damage response will be reviewed....

  10. Dopamine signaling: target in glioblastoma

    Czech Academy of Sciences Publication Activity Database

    Bartek, Jiří; Hodný, Zdeněk

    2014-01-01

    Roč. 5, č. 5 (2014), 1116-1117 ISSN 1949-2553 Institutional support: RVO:68378050 Keywords : Dopamine signaling * glioblastoma * MAPK Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.359, year: 2014

  11. Diamond, graphite, and graphene oxide nanoparticles decrease migration and invasiveness in glioblastoma cell lines by impairing extracellular adhesion

    DEFF Research Database (Denmark)

    Wierzbicki, Mateusz; Jaworski, Slawomir; Kutwin, Marta

    2017-01-01

    The highly invasive nature of glioblastoma is one of the most significant problems regarding the treatment of this tumor. Diamond nanoparticles (ND), graphite nanoparticles (NG), and graphene oxide nanoplatelets (nGO) have been explored for their biomedical applications, especially for drug...... that nanoparticles could be used in biomedical applications as a low toxicity active compound for glioblastoma treatment....

  12. Human Leukocyte Antigen-G Is Frequently Expressed in a Multicentric Study on Glioblastoma and May Be Induced in Vitro by Combined 5-aza-2'-deoxycytidine and Interferon-γ Treatments

    DEFF Research Database (Denmark)

    Wastowski, Isabela J; Simões, Renata T; Yaghi, Layale

    2012-01-01

    -G protein expression was associated with a better long-term survival rate. The mechanisms underlying HLA-G gene expression were investigated in glioma cell lines U251MG, D247MG, and U138MG. Induction of HLA-G transcriptional activity was dependent of 5-aza-2'-deoxycytidine treatment and enhanced......Human leukocyte antigen-G (HLA-G) is a nonclassical major histocompatibility complex (MHC) class I molecule involved in immune tolerance processes, playing an important role in the maintenance of the semi-allogeneic fetus. Although HLA-G expression is restricted in normal tissues, it is broadly...... expressed in malignant tumors and may favor tumor immune escape. We analyzed HLA-G protein and mRNA expression in tumor samples from patients with glioblastoma collected in France, Denmark, and Brazil. We found HLA-G protein expression in 65 of 108 samples and mRNA in 20 of 21 samples. The absence of HLA...

  13. Treatment effect, postoperative complications, and their reasons in juvenile thoracic and lumbar spinal tuberculosis surgery.

    Science.gov (United States)

    He, Qing-Yi; Xu, Jian-Zhong; Zhou, Qiang; Luo, Fei; Hou, Tianyong; Zhang, Zehua

    2015-10-01

    Fifty-four juvenile cases under 18 years of age with thoracic and lumbar spinal tuberculosis underwent focus debridement, deformity correction, bone graft fusion, and internal fixation. The treatment effects, complications, and reasons were analyzed retrospectively. There were 54 juvenile cases under 18 years of age with thoracolumbar spinal tuberculosis. The average age was 9.2 years old, and the sample comprised 38 males and 16 females. The disease types included 28 thoracic cases, 17 thoracolumbar cases, and 9 lumbar cases. Nerve function was evaluated with the Frankel classification. Thirty-six cases were performed with focus debridement and deformity correction and were supported with allograft or autograft in mesh and fixed with pedicle screws from a posterior approach. Eight cases underwent a combined anterior and posterior surgical approach. Nine cases underwent osteotomy and deformity correction, and one case received focus debridement. The treatment effects, complications, and bone fusions were tracked for an average of 52 months. According to the Frankel classification, paralysis was improved from 3 cases of B, 8 cases of C, 18 cases of D, and 25 cases of E preoperatively. This improvement was found in 3 cases of C, 6 cases of D, and 45 cases of E at a final follow-up postoperatively. No nerve dysfunction was aggravated. VAS was improved from 7.8 ± 1.7 preoperatively to 3.2 ± 2.1 at final follow-up postoperatively. ODI was improved from 77.5 ± 17.3 preoperatively to 28.4 ± 15.9 at final follow-up postoperatively. Kyphosis Cobb angle improved from 62.2° ± 3.7° preoperatively to 37° ± 2.4° at final follow-up postoperatively. Both of these are significant improvements, and all bone grafts were fused. Complications related to the operation occurred in 31.5% (17/54) of cases. Six cases suffered postoperative aggravated kyphosis deformity, eight cases suffered proximal kyphosis deformity, one case suffered pedicle penetration

  14. A Phase 1 trial of intravenous boronophenylalanine-fructose complex in patients with glioblastoma multiforme

    International Nuclear Information System (INIS)

    Bergland, R.; Elowitz, E.; Chadha, M.; Coderre, J.A.; Joel, D.

    1996-01-01

    Boron neutron capture therapy (BNCT) of glioblastoma multiforme was initially performed at the Brookhaven National Laboratory in the early 1950's While this treatment for malignant brain tumors has continued in Japan, new worldwide interest has been stimulated by the development of new and more selective boron compounds. Boronophenylalanine (BPA) is a blood-brain barrier penetrating compound that has been used in BNCT of malignant melanomas. SPA has been employed experimentally in BNCT of rat gliosarcoma and has potential use in the treatment of human glioblastoma. As a preface to clinical BNCT trials, we studied the biodistribution of SPA in patients with glioblastoma

  15. MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance

    Science.gov (United States)

    Yip, Stephen; Miao, Jiangyong; Cahill, Daniel P.; Iafrate, A. John; Aldape, Ken; Nutt, Catherine L.; Louis, David N.

    2009-01-01

    Purpose Over the past few years, the alkylating agent temozolomide (TMZ) has become the standard-of-care therapy for patients with glioblastoma, the most common brain tumor. Recently, large-scale cancer genome sequencing efforts have identified a hypermutation phenotype and inactivating MSH6 mismatch repair gene mutations in recurrent, post-TMZ glioblastomas, particularly those growing more rapidly during TMZ treatment. This study aimed to clarify the timing and role of MSH6 mutations in mediating glioblastoma TMZ resistance. Experimental Design MSH6 sequence and microsatellite instability (MSI) status were determined in matched pre- and post-chemotherapy glioblastomas identified by The Cancer Genome Atlas (TCGA) as having post-treatment MSH6 mutations. TMZ-resistant lines were derived in vitro via selective growth under TMZ and the MSH6 gene was sequenced in resistant clones. The role of MSH6 inactivation in mediating resistance was explored using lentiviral shRNA knockdown and MSH6 reconstitution. Results MSH6 mutations were confirmed in post-treatment TCGA glioblastomas but absent in matched pre-treatment tumors. The post-treatment hypermutation phenotype displayed a signature bias toward CpC transitions and was not associated with MSI. In vitro modeling via exposure of an MSH6-wildtype glioblastoma line to TMZ resulted in resistant clones; one clone showed an MSH6 mutation, Thr1219Ile, that had been independently noted in two treated TCGA glioblastomas. Knockdown of MSH6 in the glioblastoma line U251 increased resistance to TMZ cytotoxicity and reconstitution restored cytotoxicity in MSH6-null glioma cells. Conclusions MSH6 mutations are selected for in glioblastomas during TMZ therapy both in vitro and in vivo, and are causally associated with TMZ resistance. PMID:19584161

  16. True progression versus pseudoprogression in the treatment of glioblastomas: a comparison study of normalized cerebral blood volume and apparent diffusion coefficient by histogram analysis.

    Science.gov (United States)

    Song, Yong Sub; Choi, Seung Hong; Park, Chul-Kee; Yi, Kyung Sik; Lee, Woong Jae; Yun, Tae Jin; Kim, Tae Min; Lee, Se-Hoon; Kim, Ji-Hoon; Sohn, Chul-Ho; Park, Sung-Hye; Kim, Il Han; Jahng, Geon-Ho; Chang, Kee-Hyun

    2013-01-01

    The purpose of this study was to differentiate true progression from pseudoprogression of glioblastomas treated with concurrent chemoradiotherapy (CCRT) with temozolomide (TMZ) by using histogram analysis of apparent diffusion coefficient (ADC) and normalized cerebral blood volume (nCBV) maps. Twenty patients with histopathologically proven glioblastoma who had received CCRT with TMZ underwent perfusion-weighted imaging and diffusion-weighted imaging (b = 0, 1000 sec/mm(2)). The corresponding nCBV and ADC maps for the newly visible, entirely enhancing lesions were calculated after the completion of CCRT with TMZ. Two observers independently measured the histogram parameters of the nCBV and ADC maps. The histogram parameters between the true progression group (n = 10) and the pseudoprogression group (n = 10) were compared by use of an unpaired Student's t test and subsequent multivariable stepwise logistic regression analysis to determine the best predictors for the differential diagnosis between the two groups. Receiver operating characteristic analysis was employed to determine the best cutoff values for the histogram parameters that proved to be significant predictors for differentiating true progression from pseudoprogression. Intraclass correlation coefficient was used to determine the level of inter-observer reliability for the histogram parameters. The 5th percentile value (C5) of the cumulative ADC histograms was a significant predictor for the differential diagnosis between true progression and pseudoprogression (p = 0.044 for observer 1; p = 0.011 for observer 2). Optimal cutoff values of 892 × 10(-6) mm(2)/sec for observer 1 and 907 × 10(-6) mm(2)/sec for observer 2 could help differentiate between the two groups with a sensitivity of 90% and 80%, respectively, a specificity of 90% and 80%, respectively, and an area under the curve of 0.880 and 0.840, respectively. There was no other significant differentiating parameter on the nCBV histograms. Inter

  17. The Role of Protein Kinase CK2 in Glioblastoma Development

    OpenAIRE

    Ji, Haitao; Lu, Zhimin

    2013-01-01

    Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor in adults, and its response to current therapies is limited. Protein kinase CK2 is overexpressed in GBM and regulates GBM cell survival, proliferation, and migration and brain tumorigenesis. Targeting CK2 for GBM treatment may benefit GBM patients.

  18. Knowledge-light adaptation approaches in case-based reasoning for radiotherapy treatment planning.

    Science.gov (United States)

    Petrovic, Sanja; Khussainova, Gulmira; Jagannathan, Rupa

    2016-03-01

    Radiotherapy treatment planning aims at delivering a sufficient radiation dose to cancerous tumour cells while sparing healthy organs in the tumour-surrounding area. It is a time-consuming trial-and-error process that requires the expertise of a group of medical experts including oncologists and medical physicists and can take from 2 to 3h to a few days. Our objective is to improve the performance of our previously built case-based reasoning (CBR) system for brain tumour radiotherapy treatment planning. In this system, a treatment plan for a new patient is retrieved from a case base containing patient cases treated in the past and their treatment plans. However, this system does not perform any adaptation, which is needed to account for any difference between the new and retrieved cases. Generally, the adaptation phase is considered to be intrinsically knowledge-intensive and domain-dependent. Therefore, an adaptation often requires a large amount of domain-specific knowledge, which can be difficult to acquire and often is not readily available. In this study, we investigate approaches to adaptation that do not require much domain knowledge, referred to as knowledge-light adaptation. We developed two adaptation approaches: adaptation based on machine-learning tools and adaptation-guided retrieval. They were used to adapt the beam number and beam angles suggested in the retrieved case. Two machine-learning tools, neural networks and naive Bayes classifier, were used in the adaptation to learn how the difference in attribute values between the retrieved and new cases affects the output of these two cases. The adaptation-guided retrieval takes into consideration not only the similarity between the new and retrieved cases, but also how to adapt the retrieved case. The research was carried out in collaboration with medical physicists at the Nottingham University Hospitals NHS Trust, City Hospital Campus, UK. All experiments were performed using real-world brain cancer

  19. Utility of Glioblastoma Patient-Derived Orthotopic Xenografts in Drug Discovery and Personalized Therapy

    Directory of Open Access Journals (Sweden)

    Michele Patrizii

    2018-02-01

    Full Text Available Despite substantial effort and resources dedicated to drug discovery and development, new anticancer agents often fail in clinical trials. Among many reasons, the lack of reliable predictive preclinical cancer models is a fundamental one. For decades, immortalized cancer cell cultures have been used to lay the groundwork for cancer biology and the quest for therapeutic responses. However, cell lines do not usually recapitulate cancer heterogeneity or reveal therapeutic resistance cues. With the rapidly evolving exploration of cancer “omics,” the scientific community is increasingly investigating whether the employment of short-term patient-derived tumor cell cultures (two- and three-dimensional and/or patient-derived xenograft models might provide a more representative delineation of the cancer core and its therapeutic response. Patient-derived cancer models allow the integration of genomic with drug sensitivity data on a personalized basis and currently represent the ultimate approach for preclinical drug development and biomarker discovery. The proper use of these patient-derived cancer models might soon influence clinical outcomes and allow the implementation of tailored personalized therapy. When assessing drug efficacy for the treatment of glioblastoma multiforme (GBM, currently, the most reliable models are generated through direct injection of patient-derived cells or more frequently the isolation of glioblastoma cells endowed with stem-like features and orthotopically injecting these cells into the cerebrum of immunodeficient mice. Herein, we present the key strengths, weaknesses, and potential applications of cell- and animal-based models of GBM, highlighting our experience with the glioblastoma stem-like patient cell-derived xenograft model and its utility in drug discovery.

  20. A study of reasons of non-compliance of psychiatric treatment and patients' attitudes towards illness and treatment in Qatar.

    Science.gov (United States)

    Bener, Abdulbari; Dafeeah, Elnour E; Salem, Mohamad O

    2013-04-01

    The aim of this study was to examine the extent of psychiatric patients' compliance and non-compliance with treatment and examine the factors that affect compliance. Patients were recruited who were between 16 and 60 years of age and who were hospitalized with a psychiatric disorder and treated in the outpatient clinics of the psychiatry department. A total of 689 patients were approached and 564 patients agreed to participate in the study, a response rate of 81.8%. Participants were asked to complete a questionnaire that asked about socio-demographic characteristics (e.g., age, gender, nationality, level of education, occupation, marital status, and life style habits); medication(s) prescribed and the participant's response; the degree of social supervision (rated subjectively by the patient as "poor," "good," or "very good"); data also were obtained from clinical records. Data analyses explored significant associations between compliance and non-compliance and a group of relevant variables. Of the 564 patients studied, 328 (58.2%) were compliant with treatment and 236 (41.8%) were non-compliant. There was no significant difference between compliance and non-compliance in terms of gender (p = 0.471). Patients between 21-30 years of age were significantly more compliant with drug treatment than not. Non-compliance was more common among patients diagnosed with schizophrenia (28.4%), followed by depression (14.4%), and bipolar affective disorder (12.7%) (p = 0.001). Only 25% of compliant patients and 26.3% of non-compliant patients used non-psychotropic medication. Social supervision (40%) was very poor in non-compliant patients whereas 49.4% of compliant patients had very good family support. Notable reasons for non-compliance were irregular attendance to clinic (55.5%), ignorance about side effects of medication (61%), free medicine (45.8%), and a lack of education about medication (58.1%). This study revealed that non-compliance rates among psychiatry patients

  1. Cyclophilin B supports Myc and mutant p53-dependent survival of glioblastoma multiforme cells.

    Science.gov (United States)

    Choi, Jae Won; Schroeder, Mark A; Sarkaria, Jann N; Bram, Richard J

    2014-01-15

    Glioblastoma multiforme is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here, we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in glioblastoma multiforme cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human glioblastoma multiforme cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of glioblastoma multiforme cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-mitogen-activated protein kinase pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1, and Janus-activated kinase/STAT3 signaling. Elevated reactive oxygen species, ER expansion, and abnormal unfolded protein responses in CypB-depleted glioblastoma multiforme cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of glioblastoma multiforme tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for glioblastoma multiforme therapy.

  2. Individualized targeted therapy for glioblastoma: fact or fiction?

    Science.gov (United States)

    Weller, Michael; Stupp, Roger; Hegi, Monika; Wick, Wolfgang

    2012-01-01

    This review will address the current state of individualized cancer therapy for glioblastoma. Glioblastomas are highly malignant primary brain tumors presumably originating from neuroglial progenitor cells. Median survival is less than 1 year. Recent developments in the morphologic, clinical, and molecular classification of glioblastoma were reviewed, and their impact on clinical decision making was analyzed. Glioblastomas can be classified by morphology, clinical characteristics, complex molecular signatures, single biomarkers, or imaging parameters. Some of these characteristics, including age and Karnofsky Performance Scale score, provide important prognostic information. In contrast, few markers help to choose between various treatment options. Promoter methylation of the O-methylguanine methyltransferase gene seems to predict benefit from alkylating agent chemotherapy. Hence, it is used as an entry criterion for alkylator-free experimental combination therapy with radiotherapy. Screening for a specific type of epidermal growth factor receptor mutation is currently being explored as a biomarker for selecting patients for vaccination. Positron emission tomography for the detection of ανβ3/5 integrins could be used to select patients for treatment with anti-integrin antiangiogenic approaches. Despite extensive efforts at defining biological markers as a basis for selecting therapies, most treatment decisions for glioblastoma patients are still based on age and performance status. However, several ongoing clinical trials may enrich the repertoire of criteria for clinical decision making in the very near future. The concept of individualized or personalized targeted cancer therapy has gained significant attention throughout oncology. Yet, data in support of such an approach to glioblastoma, the most malignant subtype of glioma, are limited, and personalized medicine plays a minor role in current clinical neuro-oncology practice. In essence, this concept proposes

  3. Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles.

    Science.gov (United States)

    Behling, Katja; Maguire, William F; Di Gialleonardo, Valentina; Heeb, Lukas E M; Hassan, Iman F; Veach, Darren R; Keshari, Kayvan R; Gutin, Philip H; Scheinberg, David A; McDevitt, Michael R

    2016-11-01

    Tumors escape antiangiogenic therapy by activation of proangiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We previously investigated targeted α-particle therapy with 225 Ac-E4G10 as an antivascular approach and showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here, we investigated changes in tumor vascular morphology and functionality caused by 225 Ac-E4G10. We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of 225 Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphologic changes in the tumor blood-brain barrier microenvironment. Multicolor flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted MR imaged functional changes in the tumor vascular network. The mechanism of drug action is a combination of remodeling of the glioblastoma vascular microenvironment, relief of edema, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis were lessened, resulting in increased perfusion and reduced diffusion. Pharmacologic uptake of dasatinib into tumor was enhanced after α-particle therapy. Targeted antivascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of platelet-derived growth factor-driven glioblastoma. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  4. ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy

    NARCIS (Netherlands)

    Lin, Fan; de Gooijer, Mark C; Roig, Eloy Moreno; Buil, Levi C M; Christner, Susan M; Beumer, Jan H; Würdinger, Thomas; Beijnen, Jos H|info:eu-repo/dai/nl/071919570; van Tellingen, Olaf

    2014-01-01

    PURPOSE: Little is known about the optimal clinical use of ABT-888 (veliparib) for treatment of glioblastoma. ABT-888 is a PARP inhibitor undergoing extensive clinical evaluation in glioblastoma, because it may synergize with the standard-of-care temozolomide (TMZ). We have elucidated important

  5. Glioblastoma chemotherapy adjunct via potent serotonin receptor-7 inhibition using currently marketed high-affinity antipsychotic medicines

    Science.gov (United States)

    Kast, RE

    2010-01-01

    Glioblastoma treatment as now constituted offers increased survival measured in months over untreated patients. Because glioblastomas are active in synthesizing a bewildering variety of growth factors, a systematic approach to inhibiting these is being undertaken as treatment adjunct. The serotonin 7 receptor is commonly overexpressed in glioblastoma. Research documentation showing agonists at serotonin receptor 7 cause increased extracellular regulated kinase 1/2 activation, increased interleukin-6 synthesis, increased signal transducer and activator of transcription-3 activation, increased resistance to apoptosis and other growth enhancing changes in glioblastoma is reviewed in this paper. Because three drugs in wide use to treat thought disorders – paliperidone, pimozide and risperidone – are also potent and well-tolerated inhibitors at serotonin receptor 7, these drugs should be studied for growth factor deprivation in an adjunctive role in glioblastoma treatment. PMID:20880389

  6. Psychotropic Medication Refusal: Reasons and Patients′ Perception at a Secure Forensic Psychiatric Treatment Centre

    Directory of Open Access Journals (Sweden)

    Olajide O Adelugba

    2016-01-01

    Full Text Available Poor adherence to prescribed medication regimens can undermine the effectiveness of medications. This study was conducted to determine the demographic profile of forensic psychiatric inpatients refusing medications and to identify the reasons for refusal. Data were collected through interviews using a questionnaire including Drug Attitude Inventory-10. Medication refusal was more common among Aboriginals (68%, n = 34 than Caucasians (32%, n = 16 and was highest among the patients 21-30 years of age (44%, n = 22. Antisocial personality disorder and substance use disorder featured prominently among patients refusing medications. The main reasons for medication refusal were inconvenience (34%, n = 17 followed by side effects (22%, n = 11, ineffective medication (20%, n = 10, illness-related (16%, n = 8, and no reasons (8%, n = 6. Antipsychotic medications topped the list of the major classes of medications refused followed by Antidepressants and Mood Stabilizers.

  7. Determination of Reasons of Obstruction in the Condensate Stabilizer System of Namconson Gas Treatment Terminal by Radioisotope Techniques

    International Nuclear Information System (INIS)

    Bui Quang Tri; Nguyen Huu Quang; Dang Nguyen The Duy; Tran Tri Hai; Tran Thanh Minh

    2008-01-01

    The Condensate Stabilizer System of Namconson Gas Treatment Terminal was designed with operational flow rate of 60 m 3 /h but for unknown reason it ran efficiently below 20 m 3 /h. The Radiotracer in combination with Gamma Scan was used to investigate in understanding the reasons. The results showed the build up at the bottom of Trap out Tray which caused obstruction of condensate flow in the outlet of Trap out Tray. As a results the feed flow rate to Reboiler from Trap out Tray lowered into 1/3 and the remaining 2/3 by passing the Reboiler by overflow to the Sump. (author)

  8. First clinical results of a personalized immunotherapeutic vaccine against recurrent, incompletely resected, treatment-resistant glioblastoma multiforme (GBM) tumors, based on combined allo- and auto-immune tumor reactivity.

    Science.gov (United States)

    Schijns, Virgil E J C; Pretto, Chrystel; Devillers, Laurent; Pierre, Denis; Hofman, Florence M; Chen, Thomas C; Mespouille, Pascal; Hantos, Peter; Glorieux, Philippe; Bota, Daniela A; Stathopoulos, Apostolos

    2015-05-28

    Glioblastoma multiforme (GBM) patients have a poor prognosis. After tumor recurrence statistics suggest an imminent death within 1-4.5 months. Supportive preclinical data, from a rat model, provided the rational for a prototype clinical vaccine preparation, named Gliovac (or ERC 1671) composed of autologous antigens, derived from the patient's surgically removed tumor tissue, which is administered together with allogeneic antigens from glioma tissue resected from other GBM patients. We now report the first results of the Gliovac treatment for treatment-resistant GBM patients. Nine (9) recurrent GBM patients, after standard of care treatment, including surgery radio- and chemotherapy temozolomide, and for US patients, also bevacizumab (Avastin™), were treated under a compassionate use/hospital exemption protocol. Gliovac was given intradermally, together with human GM-CSF (Leukine(®)), and preceded by a regimen of regulatory T cell-depleting, low-dose cyclophosphamide. Gliovac administration in patients that have failed standard of care therapies showed minimal toxicity and enhanced overall survival (OS). Six-month (26 weeks) survival for the nine Gliovac patients was 100% versus 33% in control group. At week 40, the published overall survival was 10% if recurrent, reoperated patients were not treated. In the Gliovac treated group, the survival at 40 weeks was 77%. Our data suggest that Gliovac has low toxicity and a promising efficacy. A phase II trial has recently been initiated in recurrent, bevacizumab naïve GBM patients (NCT01903330). Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Radiomic features from the peritumoral brain parenchyma on treatment-naive multi-parametric MR imaging predict long versus short-term survival in glioblastoma multiforme: Preliminary findings

    Energy Technology Data Exchange (ETDEWEB)

    Prasanna, Prateek; Patel, Jay; Madabhushi, Anant; Tiwari, Pallavi [Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH (United States); Partovi, Sasan [University Hospitals Case Medical Center, Case Western Reserve School of Medicine, Cleveland, OH (United States)

    2017-10-15

    Despite 90 % of glioblastoma (GBM) recurrences occurring in the peritumoral brain zone (PBZ), its contribution in patient survival is poorly understood. The current study leverages computerized texture (i.e. radiomic) analysis to evaluate the efficacy of PBZ features from pre-operative MRI in predicting long- (>18 months) versus short-term (<7 months) survival in GBM. Sixty-five patient examinations (29 short-term, 36 long-term) with gadolinium-contrast T{sub 1w}, FLAIR and T{sub 2w} sequences from the Cancer Imaging Archive were employed. An expert manually segmented each study as: enhancing lesion, PBZ and tumour necrosis. 402 radiomic features (capturing co-occurrence, grey-level dependence and directional gradients) were obtained for each region. Evaluation was performed using threefold cross-validation, such that a subset of studies was used to select the most predictive features, and the remaining subset was used to evaluate their efficacy in predicting survival. A subset of ten radiomic 'peritumoral' MRI features, suggestive of intensity heterogeneity and textural patterns, was found to be predictive of survival (p = 1.47 x 10{sup -5}) as compared to features from enhancing tumour, necrotic regions and known clinical factors. Our preliminary analysis suggests that radiomic features from the PBZ on routine pre-operative MRI may be predictive of long- versus short-term survival in GBM. (orig.)

  10. Angiotensinogen and HLA class II predict bevacizumab response in recurrent glioblastoma patients

    DEFF Research Database (Denmark)

    Urup, Thomas; Michaelsen, Signe Regner; Olsen, Lars Rønn

    2016-01-01

    Background: Bevacizumab combination therapy is among the most frequently used treatments in recurrent glioblastoma and patients who achieve response to bevacizumab have improved survival as well as quality of life. Accordingly, the aim of this study was to identify predictive biomarkers for bevac......Background: Bevacizumab combination therapy is among the most frequently used treatments in recurrent glioblastoma and patients who achieve response to bevacizumab have improved survival as well as quality of life. Accordingly, the aim of this study was to identify predictive biomarkers...... for bevacizumab response in recurrent glioblastoma patients. Methods: The study included a total of 82 recurrent glioblastoma patients treated with bevacizumab combination therapy whom were both response and biomarker evaluable. Gene expression of tumor tissue was analyzed by using a customized Nano...

  11. The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence

    Science.gov (United States)

    Auffinger, Brenda; Spencer, Drew; Pytel, Peter; Ahmed, Atique U.; Lesniak, Maciej S.

    2016-01-01

    Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and differentiate into other specific GBM subpopulations. Therefore, they have been held responsible for malignant relapse after primary standard therapy and the poor prognosis of recurrent GBM. The failure of current therapies to eliminate specific GSC subpopulations has been considered a major factor contributing to the inevitable recurrence in GBM patients following treatment. Here, we discuss the molecular mechanisms of chemoresistance of GSCs and the reasons why complete eradication of GSCs is so difficult to achieve. We will also describe the targeted therapies currently available towards GSCs and possible mechanisms to overcome such chemoresistance and avoid therapeutic relapse. PMID:26027432

  12. Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

    Science.gov (United States)

    Chen, Qicheng; Ye, Li; Fan, Jiajun; Zhang, Xuyao; Wang, Huan; Liao, Siyang; Song, Ping; Wang, Ziyu; Wang, Shaofei; Li, Yubin; Luan, Jingyun; Wang, Yichen; Chen, Wei; Zai, Wenjing; Yang, Ping; Cao, Zhonglian; Ju, Dianwen

    2017-01-01

    Asparaginase has been reported to be effective in the treatment of various leukemia and several malignant solid cancers. However, the anti-tumor effect of asparaginase is always restricted due to complicated mechanisms. Herein, we investigated the mechanisms of how glioblastoma resisted asparaginase treatment and reported a novel approach to enhance the anti-glioblastoma effect of asparaginase. We found that asparaginase could induce growth inhibition and caspase-dependent apoptosis in U87MG/U251MG glioblastoma cells. Meanwhile, autophagy was activated as indicated by autophagosomes formation and upregulated expression of LC3-II. Importantly, abolishing autophagy using chloroquine (CQ) and LY294002 enhanced the cytotoxicity and apoptosis induced by asparaginase in U87MG/U251MG cells. Further study proved that Akt/mTOR and Erk signaling pathways participated in autophagy induction, while reactive oxygen species (ROS) served as an intracellular regulator for both cytotoxicity and autophagy in asparaginase-treated U87MG/U251MG cells. Moreover, combination treatment with autophagy inhibitor CQ significantly enhanced anti-glioblastoma efficacy of asparaginase in U87MG cell xenograft model. Taken together, our results demonstrated that inhibition of autophagy potentiated the anti-tumor effect of asparagine depletion on glioblastoma, indicating that targeting autophagy and asparagine could be a potential approach for glioblastoma treatment. PMID:29207624

  13. Management of glioblastoma after recurrence: A changing paradigm

    International Nuclear Information System (INIS)

    Mallick, S.; Benson, R.; Hakim, A.; Rath, G.K.

    2016-01-01

    Glioblastoma remains the most common primary brain tumor after the age of 40 years. Maximal safe surgery followed by adjuvant chemoradiotherapy has remained the standard treatment for glioblastoma (GBM). But recurrence is an inevitable event in the natural history of GBM with most patients experiencing it after 6–9 months of primary treatment. Recurrent GBM poses great challenge to manage with no well-defined management protocols. The challenge starts from differentiating radiation necrosis from true local progression. A fine balance needs to be maintained on improving survival and assuring a better quality of life. Treatment options are limited and ranges from re-excision, re-irradiation, systemic chemotherapy or a combination of these. Re-excision and re-irradiation must be attempted in selected patients and has been shown to improve survival outcomes. To facilitate the management of GBM recurrences, a treatment algorithm is proposed

  14. Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas

    International Nuclear Information System (INIS)

    Kaaijk, P.; Academic Medical Center, Amsterdam; Troost, D.; Leenstra, S.; Bosch, D.A.; Sminia, P.; Hulshof, M.C.C.M..; Kracht, A.H.W. van der

    1997-01-01

    The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the radiation effect of glioblastomas. The advantage of OMS is maintenance of the characteristics of the original tumour, which is lost in conventional cell cultures. OMS prepared from four glioblastomas were treated with hypofractionated radiation with a radiobiologically equivalent dose to standard radiation treatment for glioblastomas patients. After treatment, the histology as well as the cell proliferation of the OMS was examined. After radiation, a significant decrease in cell proliferation was found, although no histological damage to the OMS was observed. The modest effects of radiation on the OMS are in agreement with the limited therapeutic value of radiotherapy for glioblastoma patients. Therefore, OMS seems to be a good alternative for cell lines to study the radiobiological effect on glioblastomas. (author)

  15. Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas

    Energy Technology Data Exchange (ETDEWEB)

    Kaaijk, P [Academic Medical Center, Amsterdam (Netherlands). Dept. of (Neuro) Pathology; [Academic Medical Center, Amsterdam (Netherlands). Dept. of Neurosurgery; Troost, D [Academic Medical Center, Amsterdam (Netherlands). Dept. of (Neuro) Pathology; Leenstra, S; Bosch, D A [Academic Medical Center, Amsterdam (Netherlands). Dept. of Neurosurgery; Sminia, P; Hulshof, M C.C.M.; Kracht, A.H.W. van der [Academic Medical Center, Amsterdam (Netherlands). Dept. of (Experimental) Radiotherapy

    1997-04-01

    The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the radiation effect of glioblastomas. The advantage of OMS is maintenance of the characteristics of the original tumour, which is lost in conventional cell cultures. OMS prepared from four glioblastomas were treated with hypofractionated radiation with a radiobiologically equivalent dose to standard radiation treatment for glioblastomas patients. After treatment, the histology as well as the cell proliferation of the OMS was examined. After radiation, a significant decrease in cell proliferation was found, although no histological damage to the OMS was observed. The modest effects of radiation on the OMS are in agreement with the limited therapeutic value of radiotherapy for glioblastoma patients. Therefore, OMS seems to be a good alternative for cell lines to study the radiobiological effect on glioblastomas. (author).

  16. Advanced case of glioblastoma multiforme and pregnancy. An ethical dilemma.

    Science.gov (United States)

    Al-Rasheedy, Intisar M; Al-Hameed, Fahad M

    2015-10-01

    Glioblastoma multiforme (GBM) is the most common and malignant form of the glial tumors. Advanced and treated GBM is rarely associated with pregnancy for many reasons. Glioblastoma multiforme presenting during pregnancy carries unique challenges to the patient, baby, family, and health care providers. We describe an unusual case of advanced GBM that was treated with maximum doses of chemotherapy and radiations, and she became pregnant and presented at eighteenth weeks of gestation. Her medical management was associated with a significant ethical dilemma. We managed to deliver the baby safely through cesarean section at week 28 despite the critical condition of the mother. Unfortunately, the mother died 2 weeks post delivery. We concluded that although recurrent and treated GBM is rarely associated with pregnancy and carries dismal prognosis, but if it occurs, it can still be carried, and a multidisciplinary team work is the key for successful outcome.

  17. Ebselen abrogates TNFα induced pro‐inflammatory response in glioblastoma

    OpenAIRE

    Tewari, Richa; Sharma, Vivek; Koul, Nitin; Ghosh, Abhishek; Joseph, Christy; Hossain Sk, Ugir; Sen, Ellora

    2008-01-01

    We investigated the pro‐inflammatory response mediated by TNFα in glioblastoma and whether treatment with organoselenium Ebselen (2‐phenyl‐1,2‐benzisoselenazol‐3[2H]one) can affect TNFα induced inflammatory response. Exposure to TNFα increased the expression of pro‐inflammatory mediator interleukin IL‐6, IL‐8, monocyte chemoattractant protein‐1 (MCP‐1) and cyclooxygenase (COX‐2). Treatment with Ebselen abrogated TNFα induced increase in pro‐inflammatory mediators. Ebselen not only abrogated T...

  18. Reasons for Choice of Antibiotic for the Empirical Treatment of CAP by Canadian Infectious Disease Physicians

    Directory of Open Access Journals (Sweden)

    Jacob Pendergrast

    1999-01-01

    Full Text Available BACKGROUND: Previous studies have documented substantial variation in physician prescribing practices for the treatment of community-acquired pneumonia. Much of this variation is the result of empirical treatment, in which physicians must choose antibiotics in the a8bsence of culture and sensitivity data.

  19. Reasons for the treatment of users of crack in a therapeutic community

    Directory of Open Access Journals (Sweden)

    Maycon Rogério Seleghim

    2015-07-01

    Full Text Available Objective: Knowing the motivation of crack users for treatment in hospital environments. Method: Descriptive and qualitative search, using the design of some cases. Twenty male crack users, aged over 18 years old, hospitalized in a Therapeutic Community in Southern Brazil, were interviewed. A semi-structured interview was used and the data were analyzed by their thematic content. Results: Were found three categories that reflect the treatment motivations: perception of the crack harmful consequences; the compulsive use of drugs as the treatment initiation; and, the family participation looking for a treatment. Conclusion: Significant events (turning points favored the interruption of the crack use and the family assumed a very important place to the users behavior in relation to the use of the drug, exclusively. Descriptors: Street drugs, Crack Cocaine, Substance Abuse Treatment Centers, Family.

  20. Postoperative treatment of glioblastoma multiforme with radiation therapy plus concomitant and adjuvant temozolomide : A mono-institutional experience of 215 patients

    Directory of Open Access Journals (Sweden)

    Pramod Kumar Julka

    2013-01-01

    Full Text Available Objective: To study the clinical results and prognostic factors of patients with glioblastoma multiforme (GBM treated by postoperative radiation therapy (PORT and concomitant temozolomide followed by adjuvant temozolomide. Methods: From 2005 to 2008, 215 patients (median age 48 years with GBM were treated with PORT plus temozolomide chemotherapy. Radiation therapy (RT was employed with a dose of 60 Gy in 30 fractions over 6 weeks by conventional fractionation with concomitant temozolomide (75 mg/m 2 /day. Adjuvant therapy consisted of 6 cycles of temozolomide (150 mg/m 2 for 5 days, 28 days cycle. The primary end point of the study was overall survival (OS, and the secondary end points were progression free survival (PFS and toxicity. OS was determined with respect to different variables to study the prognostic significance. Results: Median follow up was 11 months (range 2-50 months. Median OS and PFS were 13 months and 11 months respectively. The 1-year and 2-year OS was 44% and 18% respectively. There was no statistical significant impact of age, sex, KP score, anatomical location and extent of surgery. Presentation without seizures (on univariate analysis and 6 cycles of adjuvant temozolomide therapy (on univariate as well as multivariate analysis were found significant prognostic factors. Sixteen patients developed grade III-IV neutropenia/thrombocytopenia during the course of RT. Conclusion: Our results authenticate the role of concomitant and adjuvant temozolomide chemotherapy in combination with PORT for the management of GBM patients. We strongly recommend complete 6 cycle of adjuvant temozolomide since it significantly improved the survival in our study.

  1. Phase I trial of erlotinib with radiation therapy in patients with glioblastoma multiforme: Results of North Central Cancer Treatment Group protocol N0177

    International Nuclear Information System (INIS)

    Krishnan, Sunil; Brown, Paul D.; Ballman, Karla V.; Fiveash, John B.; Uhm, Joon H.; Giannini, Caterina; Jaeckle, Kurt A.; Geoffroy, Francois J.; Nabors, L. Burt; Buckner, Jan C.

    2006-01-01

    Purpose: To evaluate the toxicity and maximum tolerated dose (MTD) of erlotinib plus radiation therapy (RT) in patients with glioblastoma multiforme (GBM) in a multicenter phase I trial. Methods and Materials: Patients were stratified on the basis of the use of enzyme-inducing anticonvulsants (EIACs). After resection or biopsy, patients were treated with erlotinib for 1 week before concurrent erlotinib and 6 weeks (60 Gy) of RT and maintained on erlotinib until progression. The erlotinib dose was escalated in cohorts of 3 starting at 100 mg/day. Results: Twenty patients were enrolled and 19 were evaluable for the MTD and efficacy endpoints. Of these patients, 14 were males and 5 were females, with a median age of 54 years. Seven had undergone biopsy only, 5 had subtotal resections, and 7 had gross total resections. The highest dose level was 150 mg/day erlotinib for patients not on EIACs (Group 1) and 200 mg/day for patients on EIACs (Group 2). MTD was not reached in either group. In Group 1 at 100 mg (n = 6) and at 150 mg (n = 4), only 1 dose-limiting toxicity (DLT) occurred (stomatitis at 100 mg). No DLTs have occurred in Group 2 at 100 mg (n = 3), 150 mg (n = 3), and 200 mg (n = 3). With a median follow-up of 52 weeks, progression was documented in 16 patients and 13 deaths occurred. Median time to progression was 26 weeks, and median survival was 55 weeks. Conclusion: Toxicity is acceptable at the current doses of erlotinib plus RT. The study was modified to include concurrent and adjuvant temozolomide, and accrual is in progress

  2. Reasons of repeat dental treatment under general anaesthesia: A retrospective study.

    Science.gov (United States)

    Guidry, J; Bagher, S; Felemban, O; Rich, A; Loo, C

    2017-12-01

    The purpose of this chart review study was to investigate the common factors that exist in paediatric patients requiring a repeat dental treatment under general anaesthesia (GA2) within four years after the initial dental treatment under general anaesthesia (GA1). The Electronic Health Records of one to 12 year-old children who received dental treatment under general anaesthesia (GA) between April 2004 and October 2009 were identified and analysed by a single examiner. Children who had GA2, within a four year period following GA1 were categorised as cases. Children who had only one dental treatment under GA were considered the control pool. Each case was matched to three controls based on sex and age range at GA1 of ± 6 months. Other recorded variables included: date of birth, date of GAs (GA1 and GA2 for cases; GA1 for controls), type of payment, dmfs before GA1, dental treatments provided under GA, return of 1-week post-GA1 follow-up, frequency of recare/recall visits following one-year post-GA1 visit and the type and frequency of post GA1 emergency visits. Out of 581 subjects, 29 (4.99%) cases were matched to 87 controls. Medically compromised patients had four times the risk of GA2. At GA1, cases received statistically significant less sealants (p=0.026), less extractions (pdental treatment under general anaesthesia were more likely to have a repeat dental treatment under general anaesthesia within 4 years.

  3. A clinical review of treatment outcomes in glioblastoma multiforme - the validation in a non-trial population of the results of a randomised Phase III clinical trial: has a more radical approach improved survival?

    LENUS (Irish Health Repository)

    Rock, K

    2012-01-03

    Objective: Glioblastoma multiforme (GBM) accounts for up to 60% of all malignant primary brain tumours in adults, occurring in 2-3 cases per 100 000 in Europe and North America. In 2005, a Phase III clinical trial demonstrated a significant improvement in survival over 2, and subsequently, 5 years with the addition of concurrent and adjuvant temozolomide (TMZ) to radical radiotherapy (RT) (Stupp R, Hegi M, van den Bent M, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009:10:459-66). The aim of this study was to investigate if the demonstrated improved survival in the literature translated to clinical practice.Methods: This was a retrospective study including all patients with histologically proven GBM diagnosed from 1999 to 2008 and treated with adjuvant RT at our institution. A total of 273 patients were identified. Statistical analysis was carried out using SPSS v18.Results: The median survival for the whole group (n = 273) over the 10-year period was 7.6 months (95% confidence interval 6.7-8.4 months). Overall, the cumulative probability of survival at 1 and 2 years was 31.5 and 9.4%, respectively. In total, 146 patients received radical RT. 103 patients were treated with radical RT and TMZ and 43 patients received radical RT alone. The median survival for patients receiving radical RT with TMZ was 13.4 months (95% CI 10.9-15.8 months) vs 8.8 months for radical RT alone (95% CI 6.9 - 10.7 months, p = 0.006). 2-year survival figures were 21.2 vs 4.7%, respectively. On multivariate analysis, independent predictors of survival included KPS, RT dose, TMZ and extent of surgery. The strongest predictors of poorer outcome based on the hazard ratio were palliative RT, followed by not receiving TMZ chemotherapy, then KPS <90 and a biopsy only surgical approach.Conclusion: This paper demonstrates

  4. A clinical review of treatment outcomes in glioblastoma multiforme - the validation in a non-trial population of the results of a randomised Phase III clinical trial: has a more radical approach improved survival?

    LENUS (Irish Health Repository)

    2012-02-01

    Objective: Glioblastoma multiforme (GBM) accounts for up to 60% of all malignant primary brain tumours in adults, occurring in 2-3 cases per 100 000 in Europe and North America. In 2005, a Phase III clinical trial demonstrated a significant improvement in survival over 2, and subsequently, 5 years with the addition of concurrent and adjuvant temozolomide (TMZ) to radical radiotherapy (RT) (Stupp R, Hegi M, van den Bent M, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009:10:459-66). The aim of this study was to investigate if the demonstrated improved survival in the literature translated to clinical practice.Methods: This was a retrospective study including all patients with histologically proven GBM diagnosed from 1999 to 2008 and treated with adjuvant RT at our institution. A total of 273 patients were identified. Statistical analysis was carried out using SPSS v18.Results: The median survival for the whole group (n = 273) over the 10-year period was 7.6 months (95% confidence interval 6.7-8.4 months). Overall, the cumulative probability of survival at 1 and 2 years was 31.5 and 9.4%, respectively. In total, 146 patients received radical RT. 103 patients were treated with radical RT and TMZ and 43 patients received radical RT alone. The median survival for patients receiving radical RT with TMZ was 13.4 months (95% CI 10.9-15.8 months) vs 8.8 months for radical RT alone (95% CI 6.9 - 10.7 months, p = 0.006). 2-year survival figures were 21.2 vs 4.7%, respectively. On multivariate analysis, independent predictors of survival included KPS, RT dose, TMZ and extent of surgery. The strongest predictors of poorer outcome based on the hazard ratio were palliative RT, followed by not receiving TMZ chemotherapy, then KPS <90 and a biopsy only surgical approach.Conclusion: This paper demonstrates improved

  5. Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity.

    Science.gov (United States)

    Angelova, Assia L; Barf, Milena; Geletneky, Karsten; Unterberg, Andreas; Rommelaere, Jean

    2017-12-15

    Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV), show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01), H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood-brain (tumor) barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO) synthase (iNOS) expression in tumor-associated microglia/macrophages (TAM), and accumulation of activated TAM in cluster of differentiation (CD) 40 ligand (CD40L)-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (pre)clinical testing.

  6. Incidence, risk factors and treatment of diarrhoea among Dutch travellers: reasons not to routinely prescribe antibiotics

    NARCIS (Netherlands)

    Belderok, S.M.; van den Hoek, A.; Kint, J.A.; van der Loeff, M.F.S.; Sonder, G.J.B.

    2011-01-01

    Background: Travellers' diarrhoea (TD) is the most common infectious disease among travellers. In the Netherlands, stand-by or prophylactic antibiotics are not routinely prescribed to travellers. This study prospectively assessed the incidence rate, risk factors, and treatment of TD among

  7. Single-Case Analysis to Determine Reasons for Failure of Behavioral Treatment via Telehealth

    Science.gov (United States)

    Schieltz, Kelly M.; Romani, Patrick W.; Wacker, David P.; Suess, Alyssa N.; Huang, Pei; Berg, Wendy K.; Lindgren, Scott D.; Kopelman, Todd G.

    2018-01-01

    Functional communication training (FCT) is a widely used and effective function-based treatment for problem behavior. The purpose of this article is to present two cases in which FCT was unsuccessful in reducing the occurrence of problem behavior displayed by two young children with an autism spectrum disorder. Both children received the same…

  8. When Problem Gambling Is the Primary Reason for Seeking Addiction Treatment

    Science.gov (United States)

    Jamieson, John; Mazmanian, Dwight; Penney, Alexander; Black, Nancy; Nguyen, An

    2011-01-01

    An existing database was used to compare problem gamblers (N = 138) who presented for treatment of their gambling problem to two other groups: alcohol and/or drug addiction clients who also had a gambling problem (N = 280) or who did not have a gambling problem (N = 2178). Clients with gambling as their primary problem were more likely to be…

  9. Quality of life in uncomplicated symptomatic diverticular disease: is it another good reason for treatment?

    Science.gov (United States)

    Comparato, Giuseppe; Fanigliulo, Libera; Aragona, Giovanni; Cavestro, Giulia M; Cavallaro, Lucas G; Leandro, Gioacchino; Pilotto, Alberto; Nervi, Giorgio; Soliani, Paolo; Sianesi, Mario; Franzé, Angelo; Di Mario, Francesco

    2007-01-01

    Quality of life (QoL) is becoming a major issue in the evaluation of any therapeutic intervention. To assess the QoL in patients with uncomplicated symptomatic diverticular disease (DD) and to elucidate the influence of two different treatments either on symptoms or QoL. 58 outpatients affected by uncomplicated symptomatic DD, admitted in our Gastroenterological Unit from October 2003 to March 2004, were enrolled. Patients were randomly assigned to two different treatments consisting of rifaximin or mesalazine for 10 days every month for a period of 6 months. QoL was evaluated by means of an SF-36 questionnaire and clinical evaluation was registered by means of a global symptomatic score (GSS) at baseline and after 6 months. At baseline, lower values in all SF-36 domains were confirmed in patients with DD. Both rifaximin and mesalazine groups showed a significant reduction of their mean GSS (p < 0.01 and p < 0.001, respectively) and improvement of SF-36 mean scores after therapy, even though treatment with mesalazine showed better results. DD has a negative impact on QoL. Cyclic treatment with poorly absorbable antibiotics or anti-inflammatory drugs relieves symptoms and improves QoL. 2007 S. Karger AG, Basel

  10. Incidence, risk factors and treatment of diarrhoea among Dutch travellers: reasons not to routinely prescribe antibiotics

    NARCIS (Netherlands)

    Belderok, Sanne-Meike; van den Hoek, Anneke; Kint, Joan A.; Schim van der Loeff, Maarten F.; Sonder, Gerard Jb

    2011-01-01

    Travellers' diarrhoea (TD) is the most common infectious disease among travellers. In the Netherlands, stand-by or prophylactic antibiotics are not routinely prescribed to travellers. This study prospectively assessed the incidence rate, risk factors, and treatment of TD among immunocompetent

  11. Understanding reasons for treatment interruption amongst patients on antiretroviral therapy – A qualitative study at the Lighthouse Clinic, Lilongwe, Malawi

    Directory of Open Access Journals (Sweden)

    Julia Tabatabai

    2014-09-01

    Full Text Available Background: In recent years, scaling up of antiretroviral therapy (ART in resource-limited settings moved impressively towards universal access. Along with these achievements, public health HIV programs are facing a number of challenges including the support of patients on lifelong therapy and the prevention of temporary/permanent loss of patients in care. Understanding reasons for treatment interruption (TI can inform strategies for improving drug adherence and retention in care. Objective: To evaluate key characteristics of patients resuming ART after TI at the Lighthouse Clinic in Lilongwe, Malawi, and to identify their reasons for interrupting ART. Design: This study uses a mixed methods design to evaluate patients resuming ART after TI. We analysed an assessment form for patients with TI using pre-defined categories and a comments field to identify frequently stated reasons for TI. Additionally, we conducted 26 in-depth interviews to deepen our understanding of common reasons for TI. In-depth interviews also included the patients’ knowledge about ART and presence of social support systems. Qualitative data analysis was based on a thematic framework approach. Results: A total of 347 patients (58.2% female, average age 35.1±11.3 years with TI were identified. Despite the presence of social support and sufficient knowledge of possible consequences of TI, all patients experienced situations that resulted in TI. Analysis of in-depth interviews led to new and distinct categories for TI. The most common reason for TI was travel (54.5%, n=80/147, which further differentiated into work- or family-related travel. Patients also stated transport costs and health-care-provider-related reasons, which included perceived/enacted discrimination by health care workers. Other drivers of TI were treatment fatigue/forgetfulness, the patients’ health status, adverse drug effects, pregnancy/delivery, religious belief or perceived/enacted stigma. Conclusions

  12. Long-term In Vitro Treatment of Human Glioblastoma Cells with Temozolomide Increases Resistance In Vivo through Up-regulation of GLUT Transporter and Aldo-Keto Reductase Enzyme AKR1C Expression

    Directory of Open Access Journals (Sweden)

    Benjamin Le Calvé

    2010-09-01

    Full Text Available Glioblastoma (GBM is the most frequent malignant glioma. Treatment of GBM patients is multimodal with maximum surgical resection, followed by concurrent radiation and chemotherapy with the alkylating drug temozolomide (TMZ. The present study aims to identify genes implicated in the acquired resistance of two human GBM cells of astrocytic origin, T98G and U373, to TMZ. Resistance to TMZ was induced by culturing these cells in vitro for months with incremental TMZ concentrations up to 1 mM. Only partial resistance to TMZ has been achieved and was demonstrated in vivo in immunocompromised mice bearing orthotopic U373 and T98G xenografts. Our data show that long-term treatment of human astroglioma cells with TMZ induces increased expression of facilitative glucose transporter/solute carrier GLUT/SLC2A family members, mainly GLUT-3, and of the AKR1C family of proteins. The latter proteins are phase 1 drug-metabolizing enzymes involved in the maintenance of steroid homeostasis, prostaglandin metabolism, and metabolic activation of polycyclic aromatic hydrocarbons. GLUT-3 has been previously suggested to exert roles in GBM neovascularization processes, and TMZ was found to exert antiangiogenic effects in experimental gliomas. AKR1C1 was previously shown to be associated with oncogenic potential, with proproliferative effects similar to AKR1C3 in the latter case. Both AKR1C1 and AKR1C2 proteins are involved in cancer pro-proliferative cell chemoresistance. Selective targeting of GLUT-3 in GBM and/or AKR1C proteins (by means of jasmonates, for example could thus delay the acquisition of resistance to TMZ of astroglioma cells in the context of prolonged treatment with this drug.

  13. Use of traditional medicine for the treatment of diabetes in Eastern Uganda: a qualitative exploration of reasons for choice

    Directory of Open Access Journals (Sweden)

    Rutebemberwa Elizeus

    2013-01-01

    Full Text Available Abstract Background While there are biomedical drugs for managing diabetes mellitus, some patients with diabetes use traditional medicine. The aim of the study was to explore why patients with diabetes use traditional medicine for the treatment of diabetes. Methods The study was conducted in Iganga and Bugiri districts in Eastern Uganda using four focus group discussions (FGDs with patients with diabetes; two with female patients and two with male patients, thirteen key informant interviews (KIIs; nine with health workers working with patients with diabetes and four with herbalists. FGDs and KIIs focused on what respondents perceived as reasons for patients with diabetes taking traditional medicine. Analysis was done using content analysis. Results Reasons for taking traditional medicine included finding difficulties accessing hospitals, diabetic drugs being out of stock, traditional medicine being acceptable and available within community, as well as being supplied in big quantities. Others were traditional medicine being cheaper than biomedical treatment and payment for it being done in installments. Traditional medicine was also more convenient to take and was marketed aggressively by the herbalists. Influence of family and friends as well as traditional healers contributed to use of traditional medicine. Conclusions Possibilities of putting diabetic drugs at facilities closer to patients need to be considered and health facilities should have a constant supply of diabetic drugs. Community members need to be sensitized on the proper treatment for diabetes mellitus and on the dangers of taking traditional medicine.

  14. The Somatic Genomic Landscape of Glioblastoma

    Science.gov (United States)

    Brennan, Cameron W.; Verhaak, Roel G.W.; McKenna, Aaron; Campos, Benito; Noushmehr, Houtan; Salama, Sofie R.; Zheng, Siyuan; Chakravarty, Debyani; Sanborn, J. Zachary; Berman, Samuel H.; Beroukhim, Rameen; Bernard, Brady; Wu, Chang-Jiun; Genovese, Giannicola; Shmulevich, Ilya; Barnholtz-Sloan, Jill; Zou, Lihua; Vegesna, Rahulsimham; Shukla, Sachet A.; Ciriello, Giovanni; Yung, WK; Zhang, Wei; Sougnez, Carrie; Mikkelsen, Tom; Aldape, Kenneth; Bigner, Darell D.; Van Meir, Erwin G.; Prados, Michael; Sloan, Andrew; Black, Keith L.; Eschbacher, Jennifer; Finocchiaro, Gaetano; Friedman, William; Andrews, David W.; Guha, Abhijit; Iacocca, Mary; O’Neill, Brian P.; Foltz, Greg; Myers, Jerome; Weisenberger, Daniel J.; Penny, Robert; Kucherlapati, Raju; Perou, Charles M.; Hayes, D. Neil; Gibbs, Richard; Marra, Marco; Mills, Gordon B.; Lander, Eric; Spellman, Paul; Wilson, Richard; Sander, Chris; Weinstein, John; Meyerson, Matthew; Gabriel, Stacey; Laird, Peter W.; Haussler, David; Getz, Gad; Chin, Lynda

    2013-01-01

    We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer. PMID:24120142

  15. The non-condition logistic regression analysis of the reason of hypothyroidism after hyperthyroidism with 131I treatment

    International Nuclear Information System (INIS)

    Dang Yaping; Hu Guoying; Meng Xianwen

    1994-01-01

    There are many opinions on the reason of hypothyroidism after hyperthyroidism with 131 I treatment. In this respect, there are a few scientific analyses and reports. The non-condition logistic regression solved this problem successfully. It has a higher scientific value and confidence in the risk factor analysis. 748 follow-up patients' data were analysed by the non-condition logistic regression. The results shown that the half-life and 131 I dose were the main causes of the incidence of hypothyroidism. The degree of confidence is 92.4%

  16. Incidence, risk factors and treatment of diarrhoea among Dutch travellers: reasons not to routinely prescribe antibiotics.

    Science.gov (United States)

    Belderok, Sanne-Meike; van den Hoek, Anneke; Kint, Joan A; Schim van der Loeff, Maarten F; Sonder, Gerard Jb

    2011-10-29

    Travellers' diarrhoea (TD) is the most common infectious disease among travellers. In the Netherlands, stand-by or prophylactic antibiotics are not routinely prescribed to travellers. This study prospectively assessed the incidence rate, risk factors, and treatment of TD among immunocompetent travellers. Persons who attended the travel clinic of the Public Health Service Amsterdam in 2006-2007 before short-term travel to tropical and subtropical countries were invited to answer a questionnaire regarding sociodemographics and travel purpose; they were also asked to keep a daily structured travel diary, recording their itinerary, symptoms, and self-medication or consultation with a doctor. Diarrhoea episodes containing blood or mucous were considered severe. Of 1202 travellers, the median age was 38 years, and the median travel duration 3 weeks. Of all episodes, 96% were mild. The median duration of TD was 2 days and significantly shorter in subsequent episodes compared to first episodes (p sex, a Western country of birth, and tourism as the purpose of travel. The lowest risk was in travellers to South America. An independent risk factor for subsequent episodes was female sex. In total, 5% of travellers used antibiotics; of those, 92% had mild diarrhoea, and 53% received antibiotics over the counter. TD is common among travellers, but the overall course is mild, not requiring treatment. The incidence rates for first and second episodes are comparable. Female sex is a risk factor for the first episode, as well as subsequent ones. Prescription antibiotics are not needed in short-term healthy travellers.

  17. Incidence, risk factors and treatment of diarrhoea among Dutch travellers: reasons not to routinely prescribe antibiotics

    Directory of Open Access Journals (Sweden)

    Belderok Sanne-Meike

    2011-10-01

    Full Text Available Abstract Background Travellers' diarrhoea (TD is the most common infectious disease among travellers. In the Netherlands, stand-by or prophylactic antibiotics are not routinely prescribed to travellers. This study prospectively assessed the incidence rate, risk factors, and treatment of TD among immunocompetent travellers. Methods Persons who attended the travel clinic of the Public Health Service Amsterdam in 2006-2007 before short-term travel to tropical and subtropical countries were invited to answer a questionnaire regarding sociodemographics and travel purpose; they were also asked to keep a daily structured travel diary, recording their itinerary, symptoms, and self-medication or consultation with a doctor. Diarrhoea episodes containing blood or mucous were considered severe. Results Of 1202 travellers, the median age was 38 years, and the median travel duration 3 weeks. Of all episodes, 96% were mild. The median duration of TD was 2 days and significantly shorter in subsequent episodes compared to first episodes (p Conclusions TD is common among travellers, but the overall course is mild, not requiring treatment. The incidence rates for first and second episodes are comparable. Female sex is a risk factor for the first episode, as well as subsequent ones. Prescription antibiotics are not needed in short-term healthy travellers.

  18. A prospective PET study of patients with glioblastoma multiforme

    DEFF Research Database (Denmark)

    Andersen, Preben B.; Blinkenberg, M; Lassen, U

    2006-01-01

    OBJECTIVE: To study the post-surgical metabolic and structural cerebral changes in patients with glioblastoma multiforme (GBM). MATERIALS AND METHODS: We examined ten patients prospectively with newly diagnosed GBM. All patients were primarily treated with surgery, followed by chemotherapy...... compared with structural imaging in the prospective evaluation of GBM. We found a difference in metabolic increase and tumor growth between the two treatment regimens, although this finding has limited relevance due to the design of the study....

  19. Survival benefit of surgery in recurrent glioblastoma multiforme.

    Science.gov (United States)

    Choudry, Usama Khalid; Khan, Saad Akhtar; Shamim, Muhammad Shahzad

    2017-12-01

    There is an ongoing debate regarding role of surgery for recurrent glioblastoma multiforme (GBM). Older literature hinted at only modest survival benefits with surgery and a high rate of morbidity. However, more recent literature suggests better survival that may be attributed to better surgical techniques and better options in adjuvant treatment. Herein the authors review recent literature with regards to the possible role of surgery in recurrent GBM and also look into the key factors impacting second surgery. .

  20. A novel prognostic six-CpG signature in glioblastomas

    OpenAIRE

    Yin , An-An; Lu , Nan; Etcheverry , Amandine; Aubry , Marc; Barnholtz-Sloan , Jill; Zhang , Lu-Hua; Mosser , Jean; Zhang , Wei; Zhang , Xiang; Liu , Yu-He; He , Ya-Long

    2018-01-01

    International audience; Aims: We aimed to identify a clinically useful biomarker using DNA methylation-based information to optimize individual treatment of patients with glioblastoma (GBM). Methods: A six-CpG panel was identified by incorporating genome-wide DNA methylation data and clinical information of three distinct discovery sets and was combined using a risk-score model. Different validation sets of GBMs and lower-grade gliomas and different statistical methods were implemented for pr...

  1. The role of interleukin-18 in glioblastoma pathology implies therapeutic potential of two old drugs-disulfiram and ritonavir.

    Science.gov (United States)

    Kast, Richard E

    2015-04-09

    Based on reporting in the last several years, an impressive but dismal list of cytotoxic chemotherapies that fail to prolong the median overall survival of patients with glioblastoma has prompted the development of treatment protocols designed to interfere with growth-facilitating signaling systems by using non-cytotoxic, non-oncology drugs. Recent recognition of the pro-mobility stimulus, interleukin-18, as a driver of centrifugal glioblastoma cell migration allows potential treatment adjuncts with disulfiram and ritonavir. Disulfiram and ritonavir are well-tolerated, non-cytotoxic, non-oncology chemotherapeutic drugs that are marketed for the treatment of alcoholism and human immunodeficiency virus (HIV) infection, respectively. Both drugs exhibit an interleukin-18-inhibiting function. Given the favorable tolerability profile of disulfiram and ritonavir, the unlikely drug-drug interaction with temozolomide, and the poor prognosis of glioblastoma, trials of addition of disulfiram and ritonavir to current standard initial treatment of glioblastoma would be warranted.

  2. Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress

    International Nuclear Information System (INIS)

    Liu, Yingying; Fang, Shanshan; Sun, Qiushi; Liu, Bo

    2016-01-01

    Glioblastoma is one of the most vascular brain tumour and highly resistant to current therapy. Targeting both glioblastoma cells and angiogenesis may present an effective therapeutic strategy for glioblastoma. In our work, we show that an anthelmintic drug, ivermectin, is active against glioblastoma cells in vitro and in vivo, and also targets angiogenesis. Ivermectin significantly inhibits growth and anchorage-independent colony formation in U87 and T98G glioblastoma cells. It induces apoptosis in these cells through a caspase-dependent manner. Ivermectin significantly suppresses the growth of two independent glioblastoma xenograft mouse models. In addition, ivermectin effectively targets angiogenesis through inhibiting capillary network formation, proliferation and survival in human brain microvascular endothelial cell (HBMEC). Mechanistically, ivermectin decreases mitochondrial respiration, membrane potential, ATP levels and increases mitochondrial superoxide in U87, T98G and HBMEC cells exposed to ivermectin. The inhibitory effects of ivermectin are significantly reversed in mitochondria-deficient cells or cells treated with antioxidants, further confirming that ivermectin acts through mitochondrial respiration inhibition and induction of oxidative stress. Importantly, we show that ivermectin suppresses phosphorylation of Akt, mTOR and ribosomal S6 in glioblastoma and HBMEC cells, suggesting its inhibitory role in deactivating Akt/mTOR pathway. Altogether, our work demonstrates that ivermectin is a useful addition to the treatment armamentarium for glioblastoma. Our work also highlights the therapeutic value of targeting mitochondrial metabolism in glioblastoma. - Highlights: • Ivermectin is effective in glioblastoma cells in vitro and in vivo. • Ivermectin inhibits angiogenesis. • Ivermectin induces mitochondrial dysfunction and oxidative stress. • Ivermectin deactivates Akt/mTOR signaling pathway.

  3. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dae-Hee, E-mail: leedneo@gmail.com [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Kim, Dong-Wook [Department of Microbiology, Immunology, and Cancer Biology, University of VA (United States); Jung, Chang-Hwa [Division of Metabolism and Functionality Research, Korea Food Research Institute (Korea, Republic of); Lee, Yong J. [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Park, Daeho, E-mail: daehopark@gist.ac.kr [School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712 (Korea, Republic of)

    2014-09-15

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway.

  4. Overexpression of endothelin B receptor in glioblastoma: a prognostic marker and therapeutic target?

    KAUST Repository

    Vasaikar, Suhas

    2018-02-06

    BackgroundGlioblastoma (GBM) is the most common malignant brain tumor with median survival of 12-15 months. Owing to uncertainty in clinical outcome, additional prognostic marker(s) apart from existing markers are needed. Since overexpression of endothelin B receptor (ETBR) has been demonstrated in gliomas, we aimed to test whether ETBR is a useful prognostic marker in GBM and examine if the clinically available endothelin receptor antagonists (ERA) could be useful in the disease treatment.MethodsData from The Cancer Genome Atlas and the Gene Expression Omnibus database were analyzed to assess ETBR expression. For survival analysis, glioblastoma samples from 25 Swedish patients were immunostained for ETBR, and the findings were correlated with clinical history. The druggability of ETBR was assessed by protein-protein interaction network analysis. ERAs were analyzed for toxicity in in vitro assays with GBM and breast cancer cells.ResultsBy bioinformatics analysis, ETBR was found to be upregulated in glioblastoma patients, and its expression levels were correlated with reduced survival. ETBR interacts with key proteins involved in cancer pathogenesis, suggesting it as a druggable target. In vitro viability assays showed that ERAs may hold promise to treat glioblastoma and breast cancer.ConclusionsETBR is overexpressed in glioblastoma and other cancers and may be a prognostic marker in glioblastoma. ERAs may be useful for treating cancer patients.

  5. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    International Nuclear Information System (INIS)

    Lee, Dae-Hee; Kim, Dong-Wook; Jung, Chang-Hwa; Lee, Yong J.; Park, Daeho

    2014-01-01

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway

  6. Quantitative radiomic profiling of glioblastoma represents transcriptomic expression.

    Science.gov (United States)

    Kong, Doo-Sik; Kim, Junhyung; Ryu, Gyuha; You, Hye-Jin; Sung, Joon Kyung; Han, Yong Hee; Shin, Hye-Mi; Lee, In-Hee; Kim, Sung-Tae; Park, Chul-Kee; Choi, Seung Hong; Choi, Jeong Won; Seol, Ho Jun; Lee, Jung-Il; Nam, Do-Hyun

    2018-01-19

    Quantitative imaging biomarkers have increasingly emerged in the field of research utilizing available imaging modalities. We aimed to identify good surrogate radiomic features that can represent genetic changes of tumors, thereby establishing noninvasive means for predicting treatment outcome. From May 2012 to June 2014, we retrospectively identified 65 patients with treatment-naïve glioblastoma with available clinical information from the Samsung Medical Center data registry. Preoperative MR imaging data were obtained for all 65 patients with primary glioblastoma. A total of 82 imaging features including first-order statistics, volume, and size features, were semi-automatically extracted from structural and physiologic images such as apparent diffusion coefficient and perfusion images. Using commercially available software, NordicICE, we performed quantitative imaging analysis and collected the dataset composed of radiophenotypic parameters. Unsupervised clustering methods revealed that the radiophenotypic dataset was composed of three clusters. Each cluster represented a distinct molecular classification of glioblastoma; classical type, proneural and neural types, and mesenchymal type. These clusters also reflected differential clinical outcomes. We found that extracted imaging signatures does not represent copy number variation and somatic mutation. Quantitative radiomic features provide a potential evidence to predict molecular phenotype and treatment outcome. Radiomic profiles represents transcriptomic phenotypes more well.

  7. Anaplastology in times of facial transplantation: Still a reasonable treatment option?

    Science.gov (United States)

    Toso, Sabine Maria; Menzel, Kerstin; Motzkus, Yvonne; Klein, Martin; Menneking, Horst; Raguse, Jan-Dirk; Nahles, Susanne; Hoffmeister, Bodo; Adolphs, Nicolai

    2015-09-01

    Optimum functional and aesthetic facial reconstruction is still a challenge in patients who suffer from inborn or acquired facial deformity. It is known that functional and aesthetic impairment can result in significant psychosocial strain, leading to the social isolation of patients who are affected by major facial deformities. Microvascular techniques and increasing experience in facial transplantation certainly contribute to better restorative outcomes. However, these technologies also have some drawbacks, limitations and unsolved problems. Extensive facial defects which include several aesthetic units and dentition can be restored by combining dental prostheses and anaplastology, thus providing an adequate functional and aesthetic outcome in selected patients without the drawbacks of major surgical procedures. Referring to some representative patient cases, it is shown how extreme facial disfigurement after oncological surgery can be palliated by combining intraoral dentures with extraoral facial prostheses using individualized treatment and without the need for major reconstructive surgery. Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  8. Amnesia due to bilateral hippocampal glioblastoma

    International Nuclear Information System (INIS)

    Shimauchi, M.; Wakisaka, S.; Kinoshita, K.

    1989-01-01

    The authors report a unique case of glioblastoma which caused permanent amnesia. Magnetic resonance imaging showed the lesion to be limited to the hippocampal formation bilaterally. Although glioblastoma extends frequently into fiber pathways and expands into the opposite cerebral hemisphere, making a 'butterfly' lesion, it is unusual for it to invade the limbic system selectively to this extent. (orig.)

  9. Comparison of (18)F-FET and (18)F-FLT small animal PET for the assessment of anti-VEGF treatment response in an orthotopic model of glioblastoma

    DEFF Research Database (Denmark)

    Nedergaard, Mette Kjoelhede; Michaelsen, Signe Regner; Perryman, Lara

    2016-01-01

    was to compare FLT and FET PET for the assessment of anti-VEGF response in glioblastoma xenografts. METHODS: Xenografts with confirmed intracranial glioblastoma were treated with anti-VEGF therapy (B20-4.1) or saline as control. Weekly bioluminescence imaging (BLI), FLT and FET PET/CT were used to follow....... Furthermore, we found a significantly lower MVD in the anti-VEGF group as compared to the control group. However, we found no difference in the Ki67 proliferation index or mean survival time. CONCLUSION: FET appears to be a more sensitive tracer than FLT to measure early response to anti-VEGF therapy with PET...

  10. Prediction of clinical course of glioblastomas by MRI during radiotherapy

    International Nuclear Information System (INIS)

    Leitzen, Christina; Schild, Hans H.; Bungart, Birgitta; Luetter, Christiana; Muedder, Thomas; Wilhelm-Buchstab, Timo; Schueller, Heinrich; Herrlinger, Ulrich

    2010-01-01

    Purpose: Determine the value of MR studies in patients undergoing radiotherapy for glioblastomas pre and during radiotherapy to predict the clinical course. Patients and Methods: MR follow-up studies were performed in 33 patients with glioblastomas before radiotherapy, after 30 Gy, after 60 Gy, and in the treatment follow-up. Findings on MR were categorized into: definite progress, questionable progress, status idem. Patients were followed clinically (median for 11 months). Results: After 30 Gy 23/33 (70%) of the MR examination showed status idem. 10/33 (30%) demonstrated definite (n = 6) or questionable (n = 4) progress. Further tumor progress was faster in these patients and patients succumb to their disease earlier (9 vs. 22 months). The 60 Gy study showed definite (n = 8) and questionable (n = 6) progress in 14/33 (42%) cases. All these tumors were progressing faster and were associated with a comparatively reduced life expectancy. Conclusion: MR follow-up studies after 30 Gy in patients undergoing radiotherapy for glioblastomas allow for prognostic appraisal, and potentially early modification of treatment. (orig.)

  11. Predicting substance-abuse treatment providers' communication with clients about medication assisted treatment: a test of the theories of reasoned action and planned behavior.

    Science.gov (United States)

    Roberto, Anthony J; Shafer, Michael S; Marmo, Jennifer

    2014-01-01

    The purpose of this investigation is to determine if the theory of reasoned action (TRA) and theory of planned behavior (TPB) can retrospectively predict whether substance-abuse treatment providers encourage their clients to use medicated-assisted treatment (MAT) as part of their treatment plan. Two-hundred and ten substance-abuse treatment providers completed a survey measuring attitudes, subjective norms, perceived behavioral control, intentions, and behavior. Results indicate that substance-abuse treatment providers have very positive attitudes, neutral subjective norms, somewhat positive perceived behavioral control, somewhat positive intentions toward recommending MAT as part of their clients' treatment plan, and were somewhat likely to engage in the actual behavior. Further, the data fit both the TRA and TPB, but with the TPB model having better fit and predictive power for this target audience and behavior. The theoretical and practical implications for the developing messages for substance-abuse treatment providers and other health-care professionals who provide treatment to patients with substance use disorders are discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Low dopamine transporter occupancy by methylphenidate as a possible reason for reduced treatment effectiveness in ADHD patients with cocaine dependence.

    Science.gov (United States)

    Crunelle, Cleo L; van den Brink, Wim; Veltman, Dick J; van Emmerik-van Oortmerssen, Katelijne; Dom, Geert; Schoevers, Robert A; Booij, Jan

    2013-12-01

    Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the neurobiology of this phenomenon, we examined DAT availability and the effects of MPH treatment on DAT occupancy in ADHD patients with and without cocaine dependence. ADHD patients without a comorbid substance use disorder (N=16) and ADHD patients with comorbid cocaine dependence (N=8) were imaged at baseline and after two weeks MPH treatment using single photon emission computed tomography (SPECT) with the DAT tracer [(123)I]FP-CIT. Changes in ADHD symptoms were measured with the ADHD symptom rating scale (ASRS). At baseline, we observed lower striatal DAT availability in ADHD patients with cocaine dependence. Following fixed MPH treatment, MPH occupied significantly less striatal DATs in cocaine-dependent than in non-cocaine dependent ADHD patients. There were no significant correlations between baseline DAT availability or DAT occupancy by MPH and ADHD symptom improvement. However, we did find significant correlations between DAT occupancy by MPH and decreases in impulsivity scores and years of cocaine use. These preliminary findings suggest that low DAT occupancy is not the reason why ADHD patients with cocaine dependence do not benefit from MPH treatment. It also suggests that higher dosages of MPH in these patients are probably not the solution and that medications directed at other pharmacological targets should be considered in these comorbid ADHD patients. This trial is registered at the Dutch Trial Register, www.trialregister.nl, under Trial ID number NTR3127. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

  13. CONFLICTING REASONS

    OpenAIRE

    Parfit, Derek

    2016-01-01

    Sidgwick believed that, when impartial reasons conflict with self-interested reasons, there are no truths about their relative strength. There are such truths, I claim, but these truths are imprecise. Many self-interested reasons are decisively outweighed by conflicting impar-tial moral reasons. But we often have sufficient self-interested reasons to do what would make things go worse, and we sometimes have sufficient self-interested reasons to act wrongly. If we reject Act Consequentialism, ...

  14. Treatment of male urethral strictures - possible reasons for the use of repeated dilatation or internal urethrotomy rather than urethroplasty.

    Science.gov (United States)

    Heyns, C F; van der Merwe, J; Basson, J; van der Merwe, A

    2012-07-16

    To investigate the possible reasons for repeated urethral dilatation or optical internal urethrotomy rather than urethroplasty in the treatment of male urethral strictures. Men referred to the stricture clinic of our institution during the period April 2007 - March 2008 were reviewed and the operative urological procedures performed in the same period were analysed. Statistical analysis was performed using Student's t-test and Fisher's exact test (purethrotomy in 26%, 15% and 28%, and urethroplasty in 4%, 9% and 0, respectively. The group with 5 - 6 compared with 1 - 2 previous treatments was significantly older (mean age 60.2 v. 46.6 years) and had a significantly greater proportion with underlying co-morbidities (80% v. 52%). The group that had undergone urethroplasty compared with 5 - 6 repeated dilatations or urethrotomies was significantly younger (mean age 48.2 v. 60.2 years) with a lower prevalence of co-morbidities (47% v. 80%). During the study period urethroplasty was performed in 16 (2%) of 821 inpatients, whereas 55 men were seen who had undergone ≥3 previous procedures, indicating that urethroplasty was performed in less than one-third of cases in which it would have been the optimal treatment. Owing to limited theatre time, procedures indicated for malignancy, urolithiasis, renal failure and congenital anomalies were performed more often than urethroplasty. Factors that possibly influenced the decision to perform repeated urethrotomy or dilatation instead of urethroplasty were limited theatre time, increased patient age and the presence of underlying co-morbidities.

  15. CAR T-Cell Therapies in Glioblastoma: A First Look.

    Science.gov (United States)

    Migliorini, Denis; Dietrich, Pierre-Yves; Stupp, Roger; Linette, Gerald P; Posey, Avery D; June, Carl H

    2018-02-01

    Glioblastoma is an aggressive malignancy with a poor prognosis. The current standard of care for newly diagnosed glioblastoma patients includes surgery to the extent, temozolomide combined with radiotherapy, and alternating electric fields therapy. After recurrence, there is no standard therapy and survival is less than 9 months. Recurrent glioblastoma offers a unique opportunity to investigate new treatment approaches in a malignancy known for remarkable genetic heterogeneity, an immunosuppressive microenvironment, and a partially permissive anatomic blood-brain barrier. Results from three first-in-man chimeric antigen receptor (CAR) T-cell trials targeting IL13Rα2, Her2/CMV, and EGFRvIII have recently been reported. Each one of these trials addresses important questions, such as T-cell trafficking to CNS, engraftment and persistence, tumor microenvironment remodeling, and monitoring of glioma response to CAR T cells. Objective radiologic responses have been reported. Here, we discuss and summarize the results of these trials and suggest opportunities for the field. Clin Cancer Res; 24(3); 535-40. ©2017 AACR . ©2017 American Association for Cancer Research.

  16. A study of concurrent radiochemotherapy with paclitaxel in glioblastoma multiforme

    International Nuclear Information System (INIS)

    Julka, P.K.; Awasthy, B.S.; Rath, G.K.; Agarwal, S.; Varna, T.; Mahapatra, A.K.; Singh, R.

    2000-01-01

    Despite advances in neurosurgery and radiotherapy, the prognosis of patients with glioblastoma multiforme remains poor. Reports in the literature about the radiosensitizing properties of paclitaxel stimulated the authors to conduct a study using paclitaxel concurrently with radiation in a group of 18 patients who had residual disease postoperatively. Paclitaxel was delivered weekly as an intravenous infusion in a dose of 60 mg/m 2 along with radiation to the primary lesion. A total of 108 cycles of paclitaxel was given. All the patients tolerated the treatment well. The main side effects were haematological, and neuropathy which was self-limiting. The overall 1-year survival rate was 70%, with 12 patients alive at 13 months. The median survival has not yet been reached although it is more than 13 months. Thus, paclitaxel can be safely delivered concomitantly with radiation in patients with glioblastoma multiforme. Larger, randomized trials are required to establish the comparative efficacy of paclitaxel as a radiosensitizer in glioblastoma multiforme. Copyright (1999) Blackwell Science Pty Ltd

  17. PI3K and Bcl-2 inhibition primes glioblastoma cells to apoptosis through downregulation of Mcl-1 and Phospho-BAD.

    Science.gov (United States)

    Pareja, Fresia; Macleod, David; Shu, Chang; Crary, John F; Canoll, Peter D; Ross, Alonzo H; Siegelin, Markus D

    2014-07-01

    Glioblastoma multiforme (GBM) is a highly malignant human brain neoplasm with limited therapeutic options. GBMs display a deregulated apoptotic pathway with high levels of the antiapoptotic Bcl-2 family of proteins and overt activity of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Therefore, combined interference of the PI3K pathway and the Bcl-2 family of proteins is a reasonable therapeutic strategy. ABT-263 (Navitoclax), an orally available small-molecule Bcl-2 inhibitor, and GDC-0941, a PI3K inhibitor, were used to treat established glioblastoma and glioblastoma neurosphere cells, alone or in combination. Although GDC-0941 alone had a modest effect on cell viability, treatment with ABT-263 displayed a marked reduction of cell viability and induction of apoptotic cell death. Moreover, combinatorial therapy using ABT-263 and GDC-0941 showed an enhanced effect, with a further decrease in cellular viability. Furthermore, combination treatment abrogated the ability of stem cell-like glioma cells to form neurospheres. ABT-263 and GDC-0941, in combination, resulted in a consistent and significant increase of Annexin V positive cells and loss of mitochondrial membrane potential compared with either monotherapy. The combination treatment led to enhanced cleavage of both initiator and effector caspases. Mechanistically, GDC-0941 depleted pAKT (Serine 473) levels and suppressed Mcl-1 protein levels, lowering the threshold for the cytotoxic actions of ABT-263. GDC-0941 decreased Mcl-1 in a posttranslational manner and significantly decreased the half-life of Mcl-1 protein. Ectopic expression of human Mcl-1 mitigated apoptotic cell death induced by the drug combination. Furthermore, GDC-0941 modulated the phosphorylation status of BAD, thereby further enhancing ABT-263-mediated cell death. Combination therapy with ABT-263 and GDC-0941 has novel therapeutic potential by specifically targeting aberrantly active, deregulated pathways in GBM, overcoming

  18. Three-dimensional Invasion of Human Glioblastoma Cells Remains Unchanged by X-ray and Carbon Ion Irradiation In Vitro

    Energy Technology Data Exchange (ETDEWEB)

    Eke, Iris; Storch, Katja; Kaestner, Ina; Vehlow, Anne [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Faethe, Christina; Mueller-Klieser, Wolfgang [Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz (Germany); Taucher-Scholz, Gisela [Department of Biophysics, GSI Helmholtz Center for Heavy Ion Research, Darmstadt (Germany); Temme, Achim; Schackert, Gabriele [Section of Experimental Neurosurgery/Tumor Immunology, Department of Neurosurgery, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Cordes, Nils, E-mail: Nils.Cordes@Oncoray.de [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany)

    2012-11-15

    Purpose: Cell invasion represents one of the major determinants that treatment has failed for patients suffering from glioblastoma. Contrary findings have been reported for cell migration upon exposure to ionizing radiation. Here, the migration and invasion capability of glioblastoma cells on and in collagen type I were evaluated upon irradiation with X-rays or carbon ions. Methods and Materials: Migration on and invasion in collagen type I were evaluated in four established human glioblastoma cell lines exposed to either X-rays or carbon ions. Furthermore, clonogenic radiation survival, proliferation (5-bromo-2-deoxyuridine positivity), DNA double-strand breaks ({gamma}H2AX/53BP1-positive foci), and expression of invasion-relevant proteins (eg, {beta}1 integrin, FAK, MMP2, and MMP9) were explored. Migration and invasion assays for primary glioblastoma cells also were carried out with X-ray irradiation. Results: Neither X-ray nor carbon ion irradiation affected glioblastoma cell migration and invasion, a finding similarly observed in primary glioblastoma cells. Intriguingly, irradiated cells migrated unhampered, despite DNA double-strand breaks and reduced proliferation. Clonogenic radiation survival was increased when cells had contact with extracellular matrix. Specific inhibition of the {beta}1 integrin or proliferation-associated signaling molecules revealed a critical function of JNK, PI3K, and p38 MAPK in glioblastoma cell invasion. Conclusions: These findings indicate that X-rays and carbon ion irradiation effectively reduce proliferation and clonogenic survival without modifying the migration and invasion ability of glioblastoma cells in a collagen type I environment. Addition of targeted agents against members of the MAPK and PI3K signaling axis to conventional chemoradiation therapy seems potentially useful to optimize glioblastoma therapy.

  19. Aplastic anemia as a cause of death in a patient with glioblastoma multiforme treated with temozolomide

    International Nuclear Information System (INIS)

    Kopecky, Jindrich; Priester, Peter; Slovacek, Ladislav; Petera, Jiri; Macingova, Zuzana; Kopecky, Otakar

    2010-01-01

    Background: Standard treatment of glioblastoma multiforme consists of postoperative radiochemotherapy with temozolomide, followed by a 6-month chemotherapy. Serious hematologic complications are rarely reported. Case Report and Results: The authors present the case of a 61-year-old female patient with glioblastoma multiforme treated with external-beam radiation therapy and concomitant temozolomide. After completion of treatment, the patient developed symptoms of serious aplastic anemia that eventually led to death due to prolonged neutro- and thrombocytopenia followed by infectious complications. Conclusion: Lethal complications following temozolomide are, per se, extremely rare, however, a total of four other cases of aplastic anemia have been reported in the literature so far. (orig.)

  20. Aplastic anemia as a cause of death in a patient with glioblastoma multiforme treated with temozolomide

    Energy Technology Data Exchange (ETDEWEB)

    Kopecky, Jindrich; Priester, Peter; Slovacek, Ladislav; Petera, Jiri; Macingova, Zuzana [Dept. of Clinical Oncology and Radiotherapy, Charles Univ. Hospital and Faculty of Medicine in Hradec Kralove (Czech Republic); Kopecky, Otakar [Clinical Oncology, Regional Hospital Nachod (Czech Republic)

    2010-08-15

    Background: Standard treatment of glioblastoma multiforme consists of postoperative radiochemotherapy with temozolomide, followed by a 6-month chemotherapy. Serious hematologic complications are rarely reported. Case Report and Results: The authors present the case of a 61-year-old female patient with glioblastoma multiforme treated with external-beam radiation therapy and concomitant temozolomide. After completion of treatment, the patient developed symptoms of serious aplastic anemia that eventually led to death due to prolonged neutro- and thrombocytopenia followed by infectious complications. Conclusion: Lethal complications following temozolomide are, per se, extremely rare, however, a total of four other cases of aplastic anemia have been reported in the literature so far. (orig.)

  1. The ER stress inducer DMC enhances TRAIL-induced apoptosis in glioblastoma

    NARCIS (Netherlands)

    van Roosmalen, Ingrid A. M.; Dos Reis, Carlos R; Setroikromo, Rita; Yuvaraj, Saravanan; Joseph, Justin V.; Tepper, Pieter G.; Kruyt, Frank A. E.; Quax, Wim J.

    2014-01-01

    Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumour in humans and is highly resistant to current treatment modalities. We have explored the combined treatment of the endoplasmic reticulum (ER) stress-inducing agent 2,5-dimethyl-celecoxib (DMC) and TNF-related

  2. Histology-Based Expression Profiling Yields Novel Prognostic Markers in Human Glioblastoma

    Science.gov (United States)

    Dong, Shumin; Nutt, Catherine L.; Betensky, Rebecca A.; Stemmer-Rachamimov, Anat O.; Denko, Nicholas C.; Ligon, Keith L.; Rowitch, David H.; Louis, David N.

    2006-01-01

    Although the prognosis for patients with glioblastoma is poor, survival is variable, with some patients surviving longer than others. For this reason, there has been longstanding interest in the identi-fication of prognostic markers for glioblastoma. We hypothesized that specific histologic features known to correlate with malignancy most likely express molecules that are directly related to the aggressive behavior of these tumors. We further hypothesized that such molecules could be used as biomarkers to predict behavior in a manner that might add prognostic power to sole histologic observation of the feature. We reasoned that perinecrotic tumor cell palisading, which denotes the most aggressive forms of malignant gliomas, would be a striking histologic feature on which to test this hypothesis. We therefore used laser capture microdissection and oligonucleotide arrays to detect molecules differentially expressed in perinecrotic palisades. A set of RNAs (including POFUT2, PTDSR, PLOD2, ATF5, and HK2) that were differentially expressed in 3 initially studied, micro-dissected glioblastomas also provided prognostic information in an independent set of 28 glioblastomas that did not all have perinecrotic palisades. On validation in a second, larger independent series, this approach could be applied to other human glioma types to derive tissue biomarkers that could offer ancillary prognostic and predictive information alongside standard histopathologic examination. PMID:16254489

  3. Alcohol use disorder severity and reported reasons not to seek treatment: a cross-sectional study in European primary care practices.

    Science.gov (United States)

    Probst, Charlotte; Manthey, Jakob; Martinez, Alicia; Rehm, Jürgen

    2015-08-12

    Alcohol use disorders are among the mental disorders with the lowest treatment rates. Increasing the treatment rates requires insight on the reasons why patients do not seek treatment. This study examined self-reported reasons for not seeking treatment and their association with alcohol use disorder severity among primary health care patients diagnosed with an alcohol use disorder. Alcohol use disorders, health service utilization, and reasons for not seeking treatment were assessed via interviews on regionally representative samples of primary care patients from 6 European countries (Italy, Germany, Hungary, Latvia, Poland and Spain, total N = 9,098). Additionally, general practitioners had to fill in a questionnaire assessing their patients' alcohol use and alcohol use disorders. A multinomial logistic regression was performed to investigate the association between reasons for not seeking treatment and alcohol use disorder severity. Of 1,008 patients diagnosed with an alcohol use disorder (via general practitioner or patient interview) in the past 12 months, the majority (N = 810) did not receive treatment and 251 of those gave a reason for not seeking treatment. The most frequent reason was 'lack of problem awareness' (55.3% of those who responded), the second most common response was 'stigma or shame' (28.6%), followed by 'encounter barriers' (22.8%) and 'cope alone' (20.9%). The results indicated lower probabilities of reporting 'denial' and higher probabilities to report 'encounter barriers' as alcohol use disorders severity increases. However, both trends were discontinued for patients with severe alcohol use disorders. Particularly at lower levels of alcohol use disorder severity, a lack of problem awareness prevents patients from seeking treatment. Routinely alcohol consumption monitoring in primary care practices could help primary and secondary prevention of alcohol use disorders and increase treatment coverage.

  4. Role of differentiation in glioblastoma invasion

    NARCIS (Netherlands)

    Vareecal Joseph, Justin

    2015-01-01

    Glioblastoma (GBM) is de meest agressieve hersentumor en diffuse infiltratie in het normale hersenweefsel is een van de hoofdoorzaken van een slechte prognose, aangezien volledige chirurgische verwijdering hierdoor vrijwel onmogelijk is. Het belangrijkste doel van het in dit proefschrift beschreven

  5. MicroRNA involvement in glioblastoma pathogenesis

    International Nuclear Information System (INIS)

    Novakova, Jana; Slaby, Ondrej; Vyzula, Rostislav; Michalek, Jaroslav

    2009-01-01

    MicroRNAs are endogenously expressed regulatory noncoding RNAs. Altered expression levels of several microRNAs have been observed in glioblastomas. Functions and direct mRNA targets for these microRNAs have been relatively well studied over the last years. According to these data, it is now evident, that impairment of microRNA regulatory network is one of the key mechanisms in glioblastoma pathogenesis. MicroRNA deregulation is involved in processes such as cell proliferation, apoptosis, cell cycle regulation, invasion, glioma stem cell behavior, and angiogenesis. In this review, we summarize the current knowledge of miRNA functions in glioblastoma with an emphasis on its significance in glioblastoma oncogenic signaling and its potential to serve as a disease biomarker and a novel therapeutic target in oncology.

  6. Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis.

    Science.gov (United States)

    Cui, Qi; Yang, Su; Ye, Peng; Tian, E; Sun, Guoqiang; Zhou, Jiehua; Sun, Guihua; Liu, Xiaoxuan; Chen, Chao; Murai, Kiyohito; Zhao, Chunnian; Azizian, Krist T; Yang, Lu; Warden, Charles; Wu, Xiwei; D'Apuzzo, Massimo; Brown, Christine; Badie, Behnam; Peng, Ling; Riggs, Arthur D; Rossi, John J; Shi, Yanhong

    2016-02-03

    Glioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is critical for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumour development and prolongs survival. Moreover, we identify TET3 as a potent tumour suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma.

  7. SU-F-J-93: Automated Segmentation of High-Resolution 3D WholeBrain Spectroscopic MRI for Glioblastoma Treatment Planning

    Energy Technology Data Exchange (ETDEWEB)

    Schreibmann, E; Shu, H [Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA (United States); Cordova, J; Gurbani, S; Holder, C; Cooper, L; Shim, H [Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA (United States)

    2016-06-15

    Purpose: We report on an automated segmentation algorithm for defining radiation therapy target volumes using spectroscopic MR images (sMRI) acquired at nominal voxel resolution of 100 microliters. Methods: Wholebrain sMRI combining 3D echo-planar spectroscopic imaging, generalized auto-calibrating partially-parallel acquisitions, and elliptical k-space encoding were conducted on 3T MRI scanner with 32-channel head coil array creating images. Metabolite maps generated include choline (Cho), creatine (Cr), and N-acetylaspartate (NAA), as well as Cho/NAA, Cho/Cr, and NAA/Cr ratio maps. Automated segmentation was achieved by concomitantly considering sMRI metabolite maps with standard contrast enhancing (CE) imaging in a pipeline that first uses the water signal for skull stripping. Subsequently, an initial blob of tumor region is identified by searching for regions of FLAIR abnormalities that also display reduced NAA activity using a mean ratio correlation and morphological filters. These regions are used as starting point for a geodesic level-set refinement that adapts the initial blob to the fine details specific to each metabolite. Results: Accuracy of the segmentation model was tested on a cohort of 12 patients that had sMRI datasets acquired pre, mid and post-treatment, providing a broad range of enhancement patterns. Compared to classical imaging, where heterogeneity in the tumor appearance and shape across posed a greater challenge to the algorithm, sMRI’s regions of abnormal activity were easily detected in the sMRI metabolite maps when combining the detail available in the standard imaging with the local enhancement produced by the metabolites. Results can be imported in the treatment planning, leading in general increase in the target volumes (GTV60) when using sMRI+CE MRI compared to the standard CE MRI alone. Conclusion: Integration of automated segmentation of sMRI metabolite maps into planning is feasible and will likely streamline acceptance of this

  8. TSPO Imaging in Glioblastoma Multiforme

    DEFF Research Database (Denmark)

    Jensen, Per; Feng, Ling; Law, Ian

    2015-01-01

    -CLINDE is superior to (18)F-FET in predicting progression of glioblastoma multiforme (GBM) at follow-up. METHODS: Three patients with World Health Organization grade IV GBM were scanned with (123)I-CLINDE SPECT, (18)F-FET PET, and gadolinium-enhanced MR imaging. Molecular imaging data were compared with follow......-CLINDE (15%-30%). In contrast, VOIs of increased contrast enhancement at follow-up compared with baseline overlapped to a greater extent with baseline (123)I-CLINDE VOIs than (18)F-FET VOIs (21% vs. 8% and 72% vs. 55%). CONCLUSION: Our preliminary results suggest that TSPO brain imaging in GBM may...... be a useful tool for predicting tumor progression at follow-up and may be less susceptible to changes in blood-brain barrier permeability than (18)F-FET. Larger studies are warranted to test the clinical potential of TSPO imaging in GBM, including presurgical planning and radiotherapy....

  9. A case showing effective radiotherapy for a radiation-induced glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Fukui, Kimiko; Inamura, Takanori; Nakamizo, Akira; Ikezaki, Kiyonobu; Inoha, Satoshi; Nakamura, Kazumasa; Matsuzaki, Akinobu; Fukui, Masashi [Kyushu Univ., Fukuoka (Japan). Graduate School of Medical Sciences

    2001-07-01

    Radiation-induced glioblastoma is usually resistant to all treatments. We report a case with radiation-induced glioblastoma, in which radiotherapy was remarkably effective. A 14-year-old female with a history of acute lymphoblastic leukemia, at the age of 7, underwent 15 Gy of radiotherapy to the whole brain. She was admitted to our department due to the development of headache and nausea. Magnetic resonance imaging showed an irregularly enhanced mass in the left frontal lobe. Partial removal of the mass was performed and histological examination showed it to be glioblastoma with a high MIB-1 index. The patient underwent 40 Gy of local radiotherapy and chemotherapy with ACNU and Interferon-{beta} for 2 years. The residual tumor disappeared after the radiotherapy, and her status is still ''complete remission'', 29 months after the onset. (author)

  10. Clinical results of boron neutron capture therapy (BNCT) for glioblastoma

    International Nuclear Information System (INIS)

    Kageji, T.; Mizobuchi, Y.; Nagahiro, S.; Nakagawa, Y.; Kumada, H.

    2011-01-01

    The purpose of this study was to evaluate the clinical outcome of BSH-based intra-operative BNCT (IO-BNCT) and BSH and BPA-based non-operative BNCT (NO-BNCT). We have treated 23 glioblastoma patients with BNCT without any additional chemotherapy since 1998. The median survival time (MST) of BNCT was 19.5 months, and 2-year, 3-year and 5-year survival rates were 26.1%, 17.4% and 5.8%, respectively. This clinical result of BNCT in patients with GBM is superior to that of single treatment of conventional radiotherapy compared with historical data of conventional treatment. - Highlights: ► In this study, we evaluate the clinical outcome of boron neutron capture therapy (BNCT) for malignant brain tumors. ► We have treated 23 glioblastoma (GBM) patients with BNCT without any additional chemotherapy. ► Clinical results of BNCT in patients with GBM are superior to that of single treatment of conventional radiotherapy compared with historical data of conventional treatment.

  11. Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme

    DEFF Research Database (Denmark)

    Muhic, Aida; Poulsen, Hans Skovgaard; Mau-Sørensen, Paul Morten

    2013-01-01

    glioblastoma multiforme (GBM) who had previously failed radiotherapy plus temozolomide as first-line therapy (STUPP), or the same regimen with subsequent bevacizumab-based therapy as second-line treatment (BEV). Patients with a performance status of 0-1, histologically proven GBM, and measurable disease (by...... GBM who had failed 1-2 prior lines of therapy....

  12. Third-line therapy in recurrent glioblastoma: is it another chance for bevacizumab?

    Science.gov (United States)

    Franceschi, Enrico; Lamberti, Giuseppe; Paccapelo, Alexandro; Di Battista, Monica; Genestreti, Giovenzio; Minichillo, Santino; Mura, Antonella; Bartolini, Stefania; Agati, Raffaele; Brandes, Alba A

    2018-04-18

    Standard glioblastoma therapy is long-lasting. Among second-line therapy, choices could be bevacizumab and nitrosoureas depending on National Agencies approval. There is no consensus on 3rd line therapy or clinical trials specifically designed for this setting. We reviewed our institutional database on all consecutive patients who received 3rd line therapy for glioblastoma. Data on 168 out of 1337 (12.6%) glioblastoma patients who underwent 3rd line therapy treatment were collected. Third line treatments were bevacizumab or chemotherapy (nitrosourea, temozolomide or carboplatin plus etoposide). Median progression free survival was 2.9 months and median survival time was 6.6 months from the start of 3rd line therapy. Bevacizumab significantly improved progression-free survival (4.7 vs. 2.6 months, p = .020) and survival from 3rd line start (8.0 vs. 6.0 months, p = .014) in respect to chemotherapy. Toxicity of grade ≥ 3 occurred in 13.7% of patients. In multivariate analysis, survival in 3rd line treatment depends on MGMT methylation (p = .006) and treatment with Bevacizumab (p = .011). Third line therapy in selected glioblastoma patients may be feasible and well tolerated. Bevacizumab improved outcome in 3rd line in respect to chemotherapy.

  13. β-Arrestin 1 has an essential role in neurokinin-1 receptor-mediated glioblastoma cell proliferation and G2/M phase transition.

    Science.gov (United States)

    Zhang, Yi-Xin; Li, Xiao-Fang; Yuan, Guo-Qiang; Hu, Hui; Song, Xiao-Yun; Li, Jing-Yi; Miao, Xiao-Kang; Zhou, Tian-Xiong; Yang, Wen-Le; Zhang, Xiao-Wei; Mou, Ling-Yun; Wang, Rui

    2017-05-26

    Glioblastoma is the most common malignant brain tumor and has a poor prognosis. Tachykinin receptor neurokinin-1 (NK1R) is a promising target in glioblastoma therapy because of its overexpression in human glioblastoma. NK1R agonists promote glioblastoma cell growth, whereas NK1R antagonists efficiently inhibit cell growth both in vitro and in vivo However, the molecular mechanisms involved in these effects are incompletely understood. β-Arrestins (ARRBs) serve as scaffold proteins and adapters to mediate intracellular signal transduction. Here we show that the ARRB1-mediated signaling pathway is essential for NK1-mediated glioblastoma cell proliferation. ARRB1 knockdown significantly inhibited NK1-mediated glioblastoma cell proliferation and induced G 2 /M phase cell cycle arrest. ARRB1 knockdown cells showed remarkable down-regulation of CDC25C/CDK1/cyclin B1 activity. We also demonstrated that ARRB1 mediated prolonged phosphorylation of ERK1/2 and Akt in glioblastoma cells induced by NK1R activation. ERK1/2 and Akt phosphorylation are involved in regulating CDC25C/CDK1/cyclin B1 activity. The lack of long-term ERK1/2 and Akt activation in ARRB1 knockdown cells was at least partly responsible for the delayed cell cycle progression and proliferation. Moreover, we found that ARRB1-mediated ERK1/2 and Akt phosphorylation regulated the transcriptional activity of both NF-κB and AP-1, which were involved in cyclin B1 expression. ARRB1 deficiency increased the sensitivity of glioblastoma cells to the treatment of NK1R antagonists. Taken together, our results suggest that ARRB1 plays an essential role in NK1R-mediated cell proliferation and G 2 /M transition in glioblastoma cells. Interference with ARRB1-mediated signaling via NK1R may have potential significance for therapeutic strategies targeting glioblastoma. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Second Generation Amphiphilic Poly-Lysine Dendrons Inhibit Glioblastoma Cell Proliferation without Toxicity for Neurons or Astrocytes.

    Directory of Open Access Journals (Sweden)

    Jolanta Janiszewska

    Full Text Available Glioblastomas are the most common malignant primary brain tumours in adults and one of the most aggressive and difficult-to-treat cancers. No effective treatment exits actually for this tumour and new therapeutic approaches are needed for this disease. One possible innovative approach involves the nanoparticle-mediated specific delivery of drugs and/or genetic material to glioblastoma cells where they can provide therapeutic benefits. In the present work, we have synthesised and characterised several second generation amphiphilic polylysine dendrons to be used as siRNA carriers. We have found that, in addition to their siRNA binding properties, these new compounds inhibit the proliferation of two glioblastoma cell lines while being nontoxic for non-tumoural central nervous system cells like neurons and glia, cell types that share the anatomical space with glioblastoma cells during the course of the disease. The selective toxicity of these nanoparticles to glioblastoma cells, as compared to neurons and glial cells, involves mitochondrial depolarisation and reactive oxygen species production. This selective toxicity, together with the ability to complex and release siRNA, suggests that these new polylysine dendrons might offer a scaffold in the development of future nanoparticles designed to restrict the proliferation of glioblastoma cells.

  15. Gaussian graphical modeling reveals specific lipid correlations in glioblastoma cells

    Science.gov (United States)

    Mueller, Nikola S.; Krumsiek, Jan; Theis, Fabian J.; Böhm, Christian; Meyer-Bäse, Anke

    2011-06-01

    Advances in high-throughput measurements of biological specimens necessitate the development of biologically driven computational techniques. To understand the molecular level of many human diseases, such as cancer, lipid quantifications have been shown to offer an excellent opportunity to reveal disease-specific regulations. The data analysis of the cell lipidome, however, remains a challenging task and cannot be accomplished solely based on intuitive reasoning. We have developed a method to identify a lipid correlation network which is entirely disease-specific. A powerful method to correlate experimentally measured lipid levels across the various samples is a Gaussian Graphical Model (GGM), which is based on partial correlation coefficients. In contrast to regular Pearson correlations, partial correlations aim to identify only direct correlations while eliminating indirect associations. Conventional GGM calculations on the entire dataset can, however, not provide information on whether a correlation is truly disease-specific with respect to the disease samples and not a correlation of control samples. Thus, we implemented a novel differential GGM approach unraveling only the disease-specific correlations, and applied it to the lipidome of immortal Glioblastoma tumor cells. A large set of lipid species were measured by mass spectrometry in order to evaluate lipid remodeling as a result to a combination of perturbation of cells inducing programmed cell death, while the other perturbations served solely as biological controls. With the differential GGM, we were able to reveal Glioblastoma-specific lipid correlations to advance biomedical research on novel gene therapies.

  16. MiR-18a regulates the proliferation, migration and invasion of human glioblastoma cell by targeting neogenin

    Energy Technology Data Exchange (ETDEWEB)

    Song, Yichen, E-mail: jeff200064017@163.com [Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004 (China); Wang, Ping, E-mail: pingwang8000@163.com [Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001 (China); Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001 (China); Zhao, Wei, E-mail: 15669746@qq.com [Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001 (China); Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001 (China); Yao, Yilong, E-mail: yaoyilong_322@163.com [Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004 (China); Liu, Xiaobai, E-mail: paganizonda1991@qq.com [The 96th Class, 7-year Program, China Medical University, Shenyang, Liaoning Province 110001 (China); Ma, Jun, E-mail: majun_724@163.com [Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001 (China); Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001 (China); Xue, Yixue, E-mail: xueyixue888@163.com [Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001 (China); Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001 (China); Liu, Yunhui, E-mail: liuyh@sj-hospital.org [Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004 (China)

    2014-05-15

    MiR-17-92 cluster has recently been reported as an oncogene in some tumors. However, the association of miR-18a, an important member of this cluster, with glioblastoma remains unknown. Therefore, this study aims to investigate the expression of miR-18a in glioblastoma and its role in biological behavior of U87 and U251 human glioblastoma cell lines. Quantitative RT-PCR results showed that miR-18a was highly expressed in glioblastoma tissues and U87 and U251 cell lines compared with that in human brain tissues and primary normal human astrocytes, and the expression levels were increased along with the rising pathological grades of glioblastoma. Neogenin was identified as the target gene of miR-18a by dual-luciferase reporter assays. RT-PCR and western blot results showed that its expression levels were decreased along with the rising pathological grades of glioblastoma. Inhibition of miR-18a expression was established by transfecting exogenous miR-18a inhibitor into U87 and U251 cells, and its effects on the biological behavior of glioblastoma cells were studied using CCK-8 assay, transwell assay and flow cytometry. Inhibition of miR-18a expression in U87 and U251 cells significantly up-regulated neogenin, and dramatically suppressed the abilities of cell proliferation, migration and invasion, induced cell cycle arrest and promoted cellular apoptosis. Collectively, these results suggest that miR-18a may regulate biological behavior of human glioblastoma cells by targeting neogenin, and miR-18a can serve as a potential target in the treatment of glioblastoma. - Highlights: • MiR-18a was highly expressed in glioblastoma tissues and U87 and U251 cell lines. • Neogenin was identified as the target gene of miR-18a. • Neogenin expressions were decreased along with the rising pathological grades of glioblastoma. • Inhibition of miR-18a suppressed biological behavior of glioma cells by up-regulating neogenin.

  17. MiR-18a regulates the proliferation, migration and invasion of human glioblastoma cell by targeting neogenin

    International Nuclear Information System (INIS)

    Song, Yichen; Wang, Ping; Zhao, Wei; Yao, Yilong; Liu, Xiaobai; Ma, Jun; Xue, Yixue; Liu, Yunhui

    2014-01-01

    MiR-17-92 cluster has recently been reported as an oncogene in some tumors. However, the association of miR-18a, an important member of this cluster, with glioblastoma remains unknown. Therefore, this study aims to investigate the expression of miR-18a in glioblastoma and its role in biological behavior of U87 and U251 human glioblastoma cell lines. Quantitative RT-PCR results showed that miR-18a was highly expressed in glioblastoma tissues and U87 and U251 cell lines compared with that in human brain tissues and primary normal human astrocytes, and the expression levels were increased along with the rising pathological grades of glioblastoma. Neogenin was identified as the target gene of miR-18a by dual-luciferase reporter assays. RT-PCR and western blot results showed that its expression levels were decreased along with the rising pathological grades of glioblastoma. Inhibition of miR-18a expression was established by transfecting exogenous miR-18a inhibitor into U87 and U251 cells, and its effects on the biological behavior of glioblastoma cells were studied using CCK-8 assay, transwell assay and flow cytometry. Inhibition of miR-18a expression in U87 and U251 cells significantly up-regulated neogenin, and dramatically suppressed the abilities of cell proliferation, migration and invasion, induced cell cycle arrest and promoted cellular apoptosis. Collectively, these results suggest that miR-18a may regulate biological behavior of human glioblastoma cells by targeting neogenin, and miR-18a can serve as a potential target in the treatment of glioblastoma. - Highlights: • MiR-18a was highly expressed in glioblastoma tissues and U87 and U251 cell lines. • Neogenin was identified as the target gene of miR-18a. • Neogenin expressions were decreased along with the rising pathological grades of glioblastoma. • Inhibition of miR-18a suppressed biological behavior of glioma cells by up-regulating neogenin

  18. Phase II, two-arm RTOG trial (94-11) of bischloroethyl-nitrosourea plus accelerated hyperfractionated radiotherapy (64.0 or 70.4 Gy) based on tumor volume (> 20 or ≤ 20 cm2, respectively) in the treatment of newly-diagnosed radiosurgery-ineligible glioblastoma multiforme patients

    International Nuclear Information System (INIS)

    Coughlin, C.; Scott, C.; Langer, C.; Coia, L.; Curran, W.; Rubin, P.

    2000-01-01

    Purpose: To compare survivorship, and acute and delayed toxicities following radiation therapy (RT) of radiosurgery-ineligible glioblastoma multiforme (GBM) patients treated with tumor volume-influenced, high-dose accelerated, hyperfractionated RT plus bischloroethyl-nitrosourea (BCNU), using prior RTOG malignant glioblastoma patients as historical controls. Methods and Materials: One hundred four of 108 patients accrued from June 1994 through May 1995 from 26 institutions were analyzable. Patients were histologically confirmed with GBM, and previously untreated. Treatment assignment (52 patients/arm) was based on tumor mass (TM), defined as the product of the maximum diameter and greatest perpendicular dimension of the titanium-gadolinium-enhanced postoperative MRI: Arm A, 64 Gy, TM > 20 cm 2 ; or Arm B, 70.4 Gy, TM ≤ 20 cm 2 . Both Arms A and B received BCNU (80 mg/m 2 , under hyperhydration) days 1-3, 56-58, then 4 cycles, each 8 weeks, for a total of 6 treatment series. Results: During the 24 months immediately post-treatment, the overall median survival was 9.1 months in Arm A (64 Gy) and 11.0 months in Arm B (70.4 Gy). Median survival in recursive partitioning analysis (RPA) Class III/IV was 10.4 months in Arm A and 12.2 months in Arm B, while RPA Class V/VI was 7.6 months in Arm A and 6.1 months in Arm B. There were no grade 4 neurological toxicities in Arm A; 2 grade 4 neurological toxicities were observed in Arm B (1 motor deficit, 1 necrosis at 157 days post-treatment). Conclusion: This strategy of high-dose, accelerated hyperfractionated radiotherapy shortens overall RT treatment times while allowing dose escalation, and it provides the potential for combination with currently available, as well as newer, chemotherapy agents. Survival is comparable with previously published RTOG data, and toxicities are within acceptable limits.

  19. Pertinent reasoning

    CSIR Research Space (South Africa)

    Britz, K

    2010-05-01

    Full Text Available In this paper the authors venture beyond one of the fundamental assumptions in the non-monotonic reasoning community, namely that non-monotonic entailment is supra-classical. They investigate reasoning which uses an infra-classical entailment...

  20. Development of bioactive materials for glioblastoma therapy

    Directory of Open Access Journals (Sweden)

    Jun Yang

    2016-09-01

    Full Text Available Glioblastoma is the most common and deadly human brain cancers. Unique barriers hinder the drug delivering pathway due to the individual position of glioblastoma, including blood-brain barrier and blood-brain tumor barrier. Numerous bioactive materials have been exploited and applied as the transvascular delivery carriers of therapeutic drugs. They promote site-specific accumulation and long term release of the encapsulated drugs at the tumor sites and reduce side effects with systemic delivery. And the delivery systems exhibit a certain extent of anti-glioblastoma effect and extend the median survival time. However, few of them step into the clinical trials. In this review, we will investigate the recent studies of bioactive materials for glioblastoma chemotherapy, including the inorganic materials, lipids and polymers. These bioactive materials construct diverse delivery vehicles to trigger tumor sites in brain intravenously. Herein, we exploit their functionality in drug delivery and discuss the deficiency for the featured tumors, to provide guidance for establishing optimized therapeutic drug formulation for anti-glioblastoma therapy and pave the way for clinical application.

  1. Modeling microenvironmental regulation of glioblastoma stem cells: a biomaterials perspective

    Science.gov (United States)

    Heffernan, John M.; Sirianni, Rachael W.

    2018-02-01

    Following diagnosis of a glioblastoma (GBM) brain tumor, surgical resection, chemotherapy and radiation together yield a median patient survival of only 15 months. Importantly, standard treatments fail to address the dynamic regulation of the brain tumor microenvironment that actively supports tumor progression and treatment resistance. It is becoming increasingly recognized that specialized niches within the tumor microenvironment maintain a population of highly malignant glioblastoma stem-like cells (GSCs). GSCs are resistant to traditional chemotherapy and radiation therapy, suggesting that they may be responsible for the near universal rates of tumor recurrence and associated morbidity in GBM. Thus, disrupting microenvironmental support for GSCs could be critical to developing more effective GBM therapies. Three-dimensional (3D) culture models of the tumor microenvironment are powerful tools for identifying key biochemical and biophysical inputs that impact malignant behaviors. Such systems have been used effectively to identify conditions that regulate GSC proliferation, invasion, stem-specific phenotypes, and treatment resistance. Considering the significant role that GSC microenvironments play in regulating this tumorigenic sub-population, these models may be essential for uncovering mechanisms that limit GSCs malignancy.

  2. Psychosocial and cultural reasons for delay in seeking help and nonadherence to treatment in Indonesian women with breast cancer: A qualitative study.

    NARCIS (Netherlands)

    Iskandarsyah, A.; Klerk, C.D.; Suardi, D.R.; Soemitro, M.P.; Sadarjoen, S.S.; Passchier, J.

    2014-01-01

    Objective: The aim of this study was to explore reasons for delay in seeking medical help and nonadherence to treatment in Indonesian women with breast cancer. Method: Semistructured interviews were conducted by purposive sampling, using a consecutive sample of 50 breast cancer patients who were

  3. Early presentation of primary glioblastoma.

    Science.gov (United States)

    Faguer, R; Tanguy, J-Y; Rousseau, A; Clavreul, A; Menei, P

    2014-08-01

    Clinical and neuroimaging findings of glioblastomas (GBM) at an early stage have rarely been described and those tumors are most probably under-diagnosed. Furthermore, their genetic alterations, to our knowledge, have never been previously reported. We report the clinical as well as neuroimaging findings of four early cases of patients with GBM. In our series, early stage GBM occurred at a mean age of 57 years. All patients had seizures as their first symptom. In all early stages, MRI showed a hyperintense signal on T2-weighted sequences and an enhancement on GdE-T1WI sequences. A hyperintense signal on diffusion sequences with a low ADC value was also found. These early observed occurrences of GBM developed rapidly and presented the MRI characteristics of classic GBM within a few weeks. The GBM size was multiplied by 32 in one month. Immunohistochemical analysis indicated the de novo nature of these tumors, i.e. absence of mutant IDH1 R132H protein expression, which is a diagnostic marker of low-grade diffuse glioma and secondary GBM. A better knowledge of early GBM presentation would allow a more suitable management of the patients and may improve their prognosis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  4. Adoptive Cell Therapies for Glioblastoma

    Directory of Open Access Journals (Sweden)

    Kevin James Bielamowicz

    2013-11-01

    Full Text Available Glioblastoma (GBM is the most common and most aggressive primary brain malignancy and, as it stands, is virtually incurable. With the current standard-of-care, maximum feasible surgical resection followed by radical radiotherapy and adjuvant temozolomide, survival rates are at a median of 14.6 months from diagnosis in molecularly unselected patients(1. Collectively, the current knowledge suggests that the continued tumor growth and survival is in part due to failure to mount an effective immune response. While this tolerance is subtended by the tumor being utterly self, it is to a great extent due to local and systemic immune compromise mediated by the tumor. Different cell modalities including lymphokine-activated killer (LAK cells, natural killer (NK cells, cytotoxic T lymphocytes (CTL, and transgenic chimeric antigen receptor (CAR- or αβ T cell receptor (TCR grafted T cells are being explored to recover and or redirect the specificity of the cellular arm of the immune system towards the tumor complex. Promising phase I/II trials of such modalities have shown early indications of potential efficacy while maintaining a favorable toxicity profile. Efficacy will need to be formally tested in phase II/III clinical trials. Given the high morbidity and mortality of GBM, it is imperative to further investigate and possibly integrate such novel cell-based therapies into the current standards-of-care and herein we collectively assess and critique the state-of-the-knowledge pertaining to these efforts.

  5. Adoptive Cell Therapies for Glioblastoma

    Science.gov (United States)

    Bielamowicz, Kevin; Khawja, Shumaila; Ahmed, Nabil

    2013-01-01

    Glioblastoma (GBM) is the most common and most aggressive primary brain malignancy and, as it stands, is virtually incurable. With the current standard of care, maximum feasible surgical resection followed by radical radiotherapy and adjuvant temozolomide, survival rates are at a median of 14.6 months from diagnosis in molecularly unselected patients (1). Collectively, the current knowledge suggests that the continued tumor growth and survival is in part due to failure to mount an effective immune response. While this tolerance is subtended by the tumor being utterly “self,” it is to a great extent due to local and systemic immune compromise mediated by the tumor. Different cell modalities including lymphokine-activated killer cells, natural killer cells, cytotoxic T lymphocytes, and transgenic chimeric antigen receptor or αβ T cell receptor grafted T cells are being explored to recover and or redirect the specificity of the cellular arm of the immune system toward the tumor complex. Promising phase I/II trials of such modalities have shown early indications of potential efficacy while maintaining a favorable toxicity profile. Efficacy will need to be formally tested in phase II/III clinical trials. Given the high morbidity and mortality of GBM, it is imperative to further investigate and possibly integrate such novel cell-based therapies into the current standards-of-care and herein we collectively assess and critique the state-of-the-knowledge pertaining to these efforts. PMID:24273748

  6. Toward a noncytotoxic glioblastoma therapy: blocking MCP-1 with the MTZ Regimen

    Directory of Open Access Journals (Sweden)

    Salacz ME

    2016-04-01

    Full Text Available Michael E Salacz,1,2 Richard E Kast,3 Najmaldin Saki,4 Ansgar Brüning,5 Georg Karpel-Massler,6 Marc-Eric Halatsch6 1Department of Internal Medicine, 2Department of Neurosurgery, University of Kansas, Kansas City, KS, USA; 3IIAIGC Study Center, Burlington, VT, USA; 4Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 5Molecular Biology Laboratory, University Hospital Munich, Munich, Germany; 6Department of Neurosurgery, University of Ulm, Ulm, Germany Abstract: To improve the prognosis of glioblastoma, we developed an adjuvant treatment directed to a neglected aspect of glioblastoma growth, the contribution of nonmalignant monocyte lineage cells (MLCs (monocyte, macrophage, microglia, dendritic cells that infiltrated a main tumor mass. These nonmalignant cells contribute to glioblastoma growth and tumor homeostasis. MLCs comprise of approximately 10%–30% of glioblastoma by volume. After integration into the tumor mass, these become polarized toward an M2 immunosuppressive, pro-angiogenic phenotype that promotes continued tumor growth. Glioblastoma cells initiate and promote this process by synthesizing 13 kDa MCP-1 that attracts circulating monocytes to the tumor. Infiltrating monocytes, after polarizing toward an M2 phenotype, synthesize more MCP-1, forming an amplification loop. Three noncytotoxic drugs, an antibiotic – minocycline, an antihypertensive drug – telmisartan, and a bisphosphonate – zoledronic acid, have ancillary attributes of MCP-1 synthesis inhibition and could be re-purposed, singly or in combination, to inhibit or reverse MLC-mediated immunosuppression, angiogenesis, and other growth-enhancing aspects. Minocycline, telmisartan, and zoledronic acid – the MTZ Regimen – have low-toxicity profiles and could be added to standard radiotherapy and temozolomide. Re-purposing older drugs has advantages of established safety and low

  7. Phase II trial of upfront bevacizumab and temozolomide for unresectable or multifocal glioblastoma

    International Nuclear Information System (INIS)

    Lou, Emil; Peters, Katherine B; Sumrall, Ashley L; Desjardins, Annick; Reardon, David A; Lipp, Eric S; Herndon, James E II; Coan, April; Bailey, Leighann; Turner, Scott; Friedman, Henry S; Vredenburgh, James J

    2013-01-01

    Patients with unresectable glioblastomas have a poor prognosis, with median survival of 6–10 months. We conducted a phase II trial of upfront 5-day temozolomide (TMZ) and bevacizumab (BV) in patients with newly diagnosed unresectable or multifocal glioblastoma. Patients received up to four cycles of TMZ at 200 mg/m 2 on days 1–5, and BV at 10 mg/kg on days 1 and 15 of a 28-day cycle. Brain magnetic resonance imaging (MRI) was performed monthly. Therapy was continued as long as there was no tumor progression, grade 4 nonhematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary end point was best tumor response as measured on MRI. Forty-one patients were accrued over 12 months; 39 had a full set of MRI scans available for evaluation. Assessment for best radiographic responses was as follows: partial responses in 24.4%, stable disease in 68.3%, and progressive disease in 2.4%. Treatment-related toxicities included seven grade 4 toxicities and one grade 5 toxicity (myocardial infarction). From this study, it was concluded that an upfront regimen of TMZ and BV for unresectable glioblastoma was well tolerated and provided a significant level of disease stabilization. Therapeutic toxicities were consistent with those seen in the adjuvant setting using these agents. The upfront approach to treatment of glioblastoma in the unresectable population warrants further investigation in randomized controlled phase III trials

  8. Coordination of glioblastoma cell motility by PKCι

    Directory of Open Access Journals (Sweden)

    Baldwin R Mitchell

    2010-09-01

    Full Text Available Abstract Background Glioblastoma is one of the deadliest forms of cancer, in part because of its highly invasive nature. The tumor suppressor PTEN is frequently mutated in glioblastoma and is known to contribute to the invasive phenotype. However the downstream events that promote invasion are not fully understood. PTEN loss leads to activation of the atypical protein kinase C, PKCι. We have previously shown that PKCι is required for glioblastoma cell invasion, primarily by enhancing cell motility. Here we have used time-lapse videomicroscopy to more precisely define the role of PKCι in glioblastoma. Results Glioblastoma cells in which PKCι was either depleted by shRNA or inhibited pharmacologically were unable to coordinate the formation of a single leading edge lamellipod. Instead, some cells generated multiple small, short-lived protrusions while others generated a diffuse leading edge that formed around the entire circumference of the cell. Confocal microscopy showed that this behavior was associated with altered behavior of the cytoskeletal protein Lgl, which is known to be inactivated by PKCι phosphorylation. Lgl in control cells localized to the lamellipod leading edge and did not associate with its binding partner non-muscle myosin II, consistent with it being in an inactive state. In PKCι-depleted cells, Lgl was concentrated at multiple sites at the periphery of the cell and remained in association with non-muscle myosin II. Videomicroscopy also identified a novel role for PKCι in the cell cycle. Cells in which PKCι was either depleted by shRNA or inhibited pharmacologically entered mitosis normally, but showed marked delays in completing mitosis. Conclusions PKCι promotes glioblastoma motility by coordinating the formation of a single leading edge lamellipod and has a role in remodeling the cytoskeleton at the lamellipod leading edge, promoting the dissociation of Lgl from non-muscle myosin II. In addition PKCι is required

  9. Glioblastoma extracellular vesicles: reservoirs of potential biomarkers

    Directory of Open Access Journals (Sweden)

    Redzic JS

    2014-02-01

    Full Text Available Jasmina S Redzic,1 Timothy H Ung,2 Michael W Graner2 1Skaggs School of Pharmacy and Pharmaceutical Sciences, 2Department of Neurosurgery, School of Medicine, University of Colorado Denver, Aurora, CO, USA Abstract: Glioblastoma multiforme (GBM is the most frequent and most devastating of the primary central nervous system tumors, with few patients living beyond 2 years postdiagnosis. The damage caused by the disease and our treatments for the patients often leave them physically and cognitively debilitated. Generally, GBMs appear after very short clinical histories and are discovered by imaging (using magnetic resonance imaging [MRI], and the diagnosis is validated by pathology, following surgical resection. The treatment response and diagnosis of tumor recurrence are also tracked by MRI, but there are numerous problems encountered with these monitoring modalities, such as ambiguous interpretation and forms of pseudoprogression. Diagnostic, prognostic, and predictive biomarkers would be an immense boon in following treatment schemes and in determining recurrence, which often requires an invasive intracranial biopsy to verify imaging data. Extracellular vesicles (EVs are stable, membrane-enclosed, virus-sized particles released from either the cell surface or from endosomal pathways that lead to the systemic release of EVs into accessible biofluids, such as serum/plasma, urine, cerebrospinal fluid, and saliva. EVs carry a wide variety of proteins, nucleic acids, lipids, and other metabolites, with many common features but with enough individuality to be able to identify the cell of origin of the vesicles. These components, if properly interrogated, could allow for the identification of tumor-derived EVs in biofluids, indicating tumor progression, relapse, or treatment failure. That knowledge would allow clinicians to continue with treatment regimens that were actually effective or to change course if the therapies were failing. Here, we review

  10. Toxicity after radiochemotherapy for glioblastoma using temozolomide - a retrospective evaluation

    International Nuclear Information System (INIS)

    Niewald, Marcus; Berdel, Christian; Fleckenstein, Jochen; Licht, Norbert; Ketter, Ralf; Rübe, Christian

    2011-01-01

    Retrospective evaluation of toxicity and results after radiochemotherapy for glioblastoma. 46 patients with histopathologically proven glioblastoma received simultaneous radiochemotherapy (RCT). The mean age at the beginning of therapy was 59 years, the mean Karnofsky performance index 80%. 44 patients had been operated on before radiotherapy, two had not. A total dose of 60 Gy was applied in daily single fractions of 2.0 Gy within six weeks, 75 mg/m 2 /day Temozolomide were given orally during the whole radiotherapy period. A local progression could be diagnosed in 34/46 patients (70%). The median survival time amounted to 13.6 months resulting in one-year and two-year survival probabilities of 48% and 8%, respectively. Radiotherapy could be applied completely in 89% of the patients. Chemotherapy could be completed according to schedule only in 56.5%, the main reason being blood toxicity (50% of the interruptions). Most of those patients suffered from leucopenia and/or thrombopenia grade III and IV CTC (Common toxicity criteria). Further reasons were an unfavourable general health status or a rise of liver enzymes. The mean duration of thrombopenia and leucopenia amounted to 64 and 20 days. In two patients, blood cell counts remained abnormal until death. In two patients we noticed a rise of liver enzymes. In one of these in the healing phase of hepatitis a rise of ASAT and ALAT CTC grade IV was diagnosed. These values normalized after termination of temozolomide medication. One patient died of pneumonia during therapy. Our survival data were well within the range taken from the literature. However, we noticed a considerable frequency and intensity of side effects to bone marrow and liver. These lead to the recommendations that regular examinations of blood cell count and liver enzymes should be performed during therapy and temozolomide should not be applied or application should be terminated according to the criteria given by the manufacturer

  11. Dropout in the treatment of erectile dysfunction with PDE5: a study on predictors and a qualitative analysis of reasons for discontinuation.

    Science.gov (United States)

    Carvalheira, Ana A; Pereira, Nuno Monteiro; Maroco, João; Forjaz, Vera

    2012-09-01

    Phosphodiesterase type 5 inhibitors (PDE5) are currently the first line treatment for erectile dysfunction (ED). However, previous research shows that PDE5 treatments have high discontinuation rates. Understanding the reasons for discontinuing PDE5 will be necessary to optimize the response to treatment. The main goals were: (i) to analyze discontinuation rate of PDE5; (ii) to identify the discontinuation predictors; and (iii) to study the reasons for discontinuation using a qualitative methodology. The PDE5 discontinuation rates, predictors, and reasons for discontinuation treatment. A total of 327 men with clinical diagnosis for ED who had been treated with PDE5 were successfully interviewed by telephone, after giving their informed consent by snail mail. Telephone interviews, concerning their ongoing treatment, were carried out using a standardized questionnaire form with quantitative and qualitative items. Participation rate was 71.8%. Of the total sample, 160 men (48.9%) had discontinued PDE5 treatment. The discontinuation rate was higher among men with diabetes (73%) and in iatrogenic group (65%), and lower in venogenic etiology (38.7%). We differentiated three groups of men who discontinued treatment (i) during the first 3 months (55.1%); (ii) between 4 and 12 months (26.9%); and (iii) after a period of 12 months (18%). Qualitative analyses revealed diverse reasons for discontinuation: non-effectiveness of PDE5 (36.8%), psychological factors (e.g., anxiety, negative emotions, fears, concerns, dysfunctional beliefs) (17.5%), erection recovery (14.4%), and concerns about the cardiovascular safety of PDE5 (8.7%) were the most common. Older men and men whose partners were involved in the treatment, were less likely to discontinue treatment. Half the subjects discontinued medication. Mostly, there was a combination of factors that led to discontinuation: non-effectiveness and psychosocial factors appear to be the main reasons. Addressing those factors will allow

  12. Low dopamine transporter occupancy by methylphenidate as a possible reason for reduced treatment effectiveness in ADHD patients with cocaine dependence

    NARCIS (Netherlands)

    Crunelle, Cleo L.; van den Brink, Wim; Veltman, Dick J.; van Emmerik-van Oortmerssen, Katelijne; Dom, Geert; Schoevers, Robert A.; Booij, Jan

    2013-01-01

    Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the

  13. Cerebellar giant cell glioblastoma multiforme in an adult

    Directory of Open Access Journals (Sweden)

    Sudhansu Sekhar Mishra

    2014-01-01

    Full Text Available Cerebellar glioblastoma multiforme (GBM is a rare tumor that accounts for only 1% of all cases of GBM and its giant cell variant is even much rarely encountered in adults. A case of cerebellar giant cell GBM managed at our institution reporting its clinical presentation, radiological and histological findings, and treatment instituted is described. In conjunction, a literature review, including particular issues, clinical data, advances in imaging studies, pathological characteristics, treatment options, and the behavior of such malignant tumor is presented. It is very important for the neurosurgeon to make the differential diagnosis between the cerebellar GBM, and other diseases such as metastasis, anaplastic astrocytomas, and cerebellar infarct because their treatment modalities, prognosis, and outcome are different.

  14. Glioblastoma multiforme of the pineal region: case report Glioblastoma multiforme de região pineal: relato de caso

    Directory of Open Access Journals (Sweden)

    Emerson Leandro Gasparetto

    2003-06-01

    Full Text Available PURPOSE: pineal region tumors are uncommon, and comprise more frequently three categories: germ cell, parenchymal cell and glial tumors. Most pineal gliomas are low-grade astrocytomas. Glioblastoma multiforme, the most aggressive and common brain tumor, is extremely rare at this location with only few cases reported. CASE DESCRIPTION: a 29-year-old woman with a two month history of headache, nuchal pain, fever, nausea and seizures and physical examination showing nuchal rigidity, generalized hypotony, hypotrophy and hyper-reflexia, Babinski sign and left VI cranial par palsy. CT scan examination revealed a ill-defined hypodense lesion at the pineal region with heterogeneous contrast enhancement. MRI showed a lesion at the pineal region infiltrating the right thalamic region. The patient underwent a right craniotomy with partial resection of the mass. The histological examination of paraffin-embedded material defined the diagnosis of glioblastoma multiforme. Post-operative radiotherapy was indicated but the patient refused the treatment and died two months afterwards. CONCLUSION: in spite of its rarity at this location, glioblastoma multiforme should be considered in the differential diagnosis of aggressive lesions at the pineal region.OBJETIVO: Os tumores da região pineal são incomuns e podem ser divididos em três categorias de acordo com a sua origem: células germinativas, células do parênquima e células gliais. Em sua maioria, os gliomas de pineal são astrocitomas de baixo grau, sendo que o seu correspondente maligno, glioblastoma multiforme, é o mais comum e agressivo tumor encefálico e é extremamente raro nesta localização, com apenas alguns casos relatados na literatura. CASO: Mulher com 29 anos apresentando há 2 meses cefaléia, nucalgia, febre, náuseas e crises convulsivas. O exame físico mostrou rigidez de nuca, hipotonia, hipotrofia e hiperreflexia generalizadas, sinal de Babinski e paralisia do VI nervo craniano. A

  15. Novel strategies in glioblastoma surgery aim at safe, super-maximum resection in conjunction with local therapies

    NARCIS (Netherlands)

    J.G. Wolbers (John)

    2014-01-01

    textabstractThe biggest challenge in neuro-oncology is the treatment of glioblastoma, which exhibits poor prognosis and is increasing in incidence in an increasing aging population. Diverse treatment strategies aim at maximum cytoreduction and ensuring good quality of life. We discuss multimodal

  16. Blocking epithelial-to-mesenchymal transition in glioblastoma with a sextet of repurposed drugs: the EIS regimen.

    Science.gov (United States)

    Kast, Richard E; Skuli, Nicolas; Karpel-Massler, Georg; Frosina, Guido; Ryken, Timothy; Halatsch, Marc-Eric

    2017-09-22

    This paper outlines a treatment protocol to run alongside of standard current treatment of glioblastoma- resection, temozolomide and radiation. The epithelial to mesenchymal transition (EMT) inhibiting sextet, EIS Regimen, uses the ancillary attributes of six older medicines to impede EMT during glioblastoma. EMT is an actively motile, therapy-resisting, low proliferation, transient state that is an integral feature of cancers' lethality generally and of glioblastoma specifically. It is believed to be during the EMT state that glioblastoma's centrifugal migration occurs. EMT is also a feature of untreated glioblastoma but is enhanced by chemotherapy, by radiation and by surgical trauma. EIS Regimen uses the antifungal drug itraconazole to block Hedgehog signaling, the antidiabetes drug metformin to block AMP kinase (AMPK), the analgesic drug naproxen to block Rac1, the anti-fibrosis drug pirfenidone to block transforming growth factor-beta (TGF-beta), the psychiatric drug quetiapine to block receptor activator NFkB ligand (RANKL) and the antibiotic rifampin to block Wnt- all by their previously established ancillary attributes. All these systems have been identified as triggers of EMT and worthy targets to inhibit. The EIS Regimen drugs have a good safety profile when used individually. They are not expected to have any new side effects when combined. Further studies of the EIS Regimen are needed.

  17. Radiation induced glioblastoma. A case report

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Naoki; Kayama, Takamasa; Sakurada, Kaori; Saino, Makoto; Kuroki, Akira [Yamagata Univ. (Japan). School of Medicine

    2000-05-01

    We report a surgical case of a 54-year-old woman with a radiation induced glioblastoma. At the age of 34, the patient was diagnosed to have a non-functioning pituitary adenoma. It was partially removed followed by 50 Gy focal irradiation with a 5 x 5 cm lateral opposed field. Twenty years later, she suffered from rapidly increasing symptoms such as aphasia and right hemiparesis. MRI showed a large mass lesion in the left temporal lobe as well as small mass lesions in the brain stem and the right medial temporal lobe. These lesions situated within the irradiated field. Magnetic resonance spectroscopy revealed relatively high lactate signal and decreased N-acetyl aspartate, choline, creatine and phosphocreatine signals. Increased lactate signal meant anaerobic metabolism that suggested the existence of a rapidly growing malignant tumor. Thus, we planned surgical removal of the left temporal lesion with the diagnosis of a radiation induced malignant glioma. The histological examination revealed a glioblastoma with radiation necrosis. MIB-1 staining index was 65%. Postoperatively, her symptoms improved, but she died from pneumonia 1 month after the surgery. A autopsy was obtained. The lesion of the left temporal lobe was found to have continuity to the lesion in the midbrain, the pons and the right temporal lobe as well. High MIB-1 staining index suggested that a radiation induced glioblastoma had high proliferative potential comparing with a de novo and secondary glioblastoma. (author)

  18. [Glioblastoma and nursing care in neurosurgery].

    Science.gov (United States)

    Lefort, Mathilde

    2017-02-01

    Nurses in neurosurgical departments play a critical role as they are involved in the first stages of the care pathway of patients with glioblastoma. Indeed, surgery enables a definitive histopathological diagnosis to be established and the size of the tumour to be significantly reduced, thereby improving the prognosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  19. Immunological targeting of cytomegalovirus for glioblastoma therapy

    OpenAIRE

    Nair, Smita K; Sampson, John H; Mitchell, Duane A

    2014-01-01

    Human cytomegalovirus (CMV) is purportedly present in glioblastoma (GBM) while absent from the normal brain, making CMV antigens potentially ideal immunological anti-GBM targets. We recently demonstrated that patient-derived CMV pp65-specific T cells are capable of recognizing and killing autologous GBM tumor cells. This data supports CMV antigen-directed immunotherapies against GBM.

  20. Immunotherapy for glioblastoma: playing chess, not checkers.

    Science.gov (United States)

    Jackson, Christopher M; Lim, Michael

    2018-04-24

    Patients with glioblastoma (GBM) exhibit a complex state of immune dysfunction involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for GBM. Copyright ©2018, American Association for Cancer Research.

  1. Glioblastoma after radiotherapy for craniopharyngioma: case report

    International Nuclear Information System (INIS)

    Ushio, Y.; Arita, N.; Yoshimine, T.; Nagatani, M.; Mogami, H.

    1987-01-01

    A 6-year-old girl developed a glioblastoma in the basal ganglia and brain stem 5 years after surgical excision and local irradiation (5460 cGy) for craniopharyngioma. Clinical and histological details are presented, and the literature on radiation-induced gliomas is reviewed

  2. Small cell glioblastoma or small cell carcinoma

    DEFF Research Database (Denmark)

    Hilbrandt, Christine; Sathyadas, Sathya; Dahlrot, Rikke H

    2013-01-01

    was admitted to the hospital with left-sided loss of motor function. A MRI revealed a 6 cm tumor in the right temporoparietal area. The histology was consistent with both glioblastoma multiforme (GBM) and small cell lung carcinoma (SCLC) but IHC was suggestive of a SCLC metastasis. PET-CT revealed...

  3. Visualizing molecular profiles of glioblastoma with GBM-BioDP.

    Directory of Open Access Journals (Sweden)

    Orieta Celiku

    Full Text Available Validation of clinical biomarkers and response to therapy is a challenging topic in cancer research. An important source of information for virtual validation is the datasets generated from multi-center cancer research projects such as The Cancer Genome Atlas project (TCGA. These data enable investigation of genetic and epigenetic changes responsible for cancer onset and progression, response to cancer therapies, and discovery of the molecular profiles of various cancers. However, these analyses often require bulk download of data and substantial bioinformatics expertise, which can be intimidating for investigators. Here, we report on the development of a new resource available to scientists: a data base called Glioblastoma Bio Discovery Portal (GBM-BioDP. GBM-BioDP is a free web-accessible resource that hosts a subset of the glioblastoma TCGA data and enables an intuitive query and interactive display of the resultant data. This resource provides visualization tools for the exploration of gene, miRNA, and protein expression, differential expression within the subtypes of GBM, and potential associations with clinical outcome, which are useful for virtual biological validation. The tool may also enable generation of hypotheses on how therapies impact GBM molecular profiles, which can help in personalization of treatment for optimal outcome. The resource can be accessed freely at http://gbm-biodp.nci.nih.gov (a tutorial is included.

  4. Proportional reasoning

    DEFF Research Database (Denmark)

    Dole, Shelley; Hilton, Annette; Hilton, Geoff

    2015-01-01

    Proportional reasoning is widely acknowledged as a key to success in school mathematics, yet students’ continual difficulties with proportion-related tasks are well documented. This paper draws on a large research study that aimed to support 4th to 9th grade teachers to design and implement tasks...

  5. Verbal Reasoning

    Science.gov (United States)

    1992-08-31

    Psicologia , 4(3), 183-198. 94 Guyote, M.J. and Sternberg, R.J. (1981). A transitive-chain theory of syllogistic reasoning. Cognitive Psychology, 13(4), 461...personal connections. Journal of Social Psychology, 20, 39-59. Newell, A. (1990). Unified Theories of Cognition. Cambridge, Massachusetts: Harvard

  6. Diagrammatic Reasoning

    DEFF Research Database (Denmark)

    Tylén, Kristian; Fusaroli, Riccardo; Stege Bjørndahl, Johanne

    2015-01-01

    of representational artifacts for purposes of thinking and communicating is discussed in relation to C.S. Peirce’s notion of diagrammatical reasoning. We propose to extend Peirce’s original ideas and sketch a conceptual framework that delineates different kinds of diagram manipulation: Sometimes diagrams...

  7. Downregulation of mitochondrial UQCRB inhibits cancer stem cell-like properties in glioblastoma.

    Science.gov (United States)

    Jung, Narae; Kwon, Ho Jeong; Jung, Hye Jin

    2018-01-01

    Glioblastoma stem cell targeted therapies have become a powerful strategy for the treatment of this deadliest brain tumor. We demonstrate for the first time that downregulation of mitochondrial ubiquinol-cytochrome c reductase binding protein (UQCRB) inhibits the cancer stem cell-like properties in human glioblastoma cells. The synthetic small molecules targeting UQCRB significantly suppressed not only the self-renewal capacity such as growth and neurosphere formation, but also the metastatic potential such as migration and invasion of glioblastoma stem‑like cells (GSCs) derived from U87MG and U373MG at subtoxic concentrations. Notably, the UQCRB inhibitors repressed c‑Met-mediated downstream signal transduction and hypoxia‑inducible factor‑1α (HIF‑1α) activation, thereby reducing the expression levels of GSC markers including CD133, Nanog, Oct4 and Sox2 in the GSCs. Furthermore, the UQCRB inhibitors decreased mitochondrial ROS generation and mitochondrial membrane potential in the GSCs, indicating that they regulate the mitochondrial function in GSCs. Indeed, the knockdown of UQCRB gene by UQCRB siRNA significantly inhibited the cancer stem cell-like phenotypes as well as the expression of stemness markers by blocking mitochondrial ROS/HIF‑1α/c‑Met pathway in U87MG GSCs. These findings suggest that UQCRB and its inhibitors could be a new therapeutic target and lead compounds for eliminating cancer stem cells in glioblastoma.

  8. Active CREB1 promotes a malignant TGFβ2 autocrine loop in glioblastoma.

    Science.gov (United States)

    Rodón, Laura; Gonzàlez-Juncà, Alba; Inda, María del Mar; Sala-Hojman, Ada; Martínez-Sáez, Elena; Seoane, Joan

    2014-10-01

    In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identified cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma. TGFβ is considered a promising therapeutic target, and several clinical trials using TGFβ inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFβ2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFβ therapies. ©2014 American Association for Cancer Research.

  9. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.

    Directory of Open Access Journals (Sweden)

    Jeffrey C Lee

    2006-12-01

    Full Text Available Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy.Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132 of glioblastomas and 12.5% (1/8 of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors.Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

  10. The prognostic value of FET PET at radiotherapy planning in newly diagnosed glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Hoejklint Poulsen, Sidsel [The Finsen Center, Rigshospitalet, Department of Radiation Biology, Copenhagen (Denmark); Center of Diagnostic Investigation, Rigshospitalet, Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen (Denmark); Urup, Thomas; Grunnet, Kirsten; Skovgaard Poulsen, Hans [The Finsen Center, Rigshospitalet, Department of Radiation Biology, Copenhagen (Denmark); The Finsen Center, Rigshospitalet, Department of Oncology, Copenhagen (Denmark); Jarle Christensen, Ib [University of Copenhagen, Hvidovre Hospital, Laboratory of Gastroenterology, Copenhagen (Denmark); Larsen, Vibeke Andree [Center of Diagnostic Investigation, Rigshospitalet, Department of Radiology, Copenhagen (Denmark); Lundemann Jensen, Michael; Munck af Rosenschoeld, Per [The Finsen Center, Rigshospitalet, Department of Oncology, Copenhagen (Denmark); The Finsen Center, Rigshospitalet, Section of Radiotherapy, Copenhagen (Denmark); Law, Ian [Center of Diagnostic Investigation, Rigshospitalet, Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen (Denmark)

    2017-03-15

    Glioblastoma patients show a great variability in progression free survival (PFS) and overall survival (OS). To gain additional pretherapeutic information, we explored the potential of O-(2-{sup 18}F-fluoroethyl)-L-tyrosine (FET) PET as an independent prognostic biomarker. We retrospectively analyzed 146 consecutively treated, newly diagnosed glioblastoma patients. All patients were treated with temozolomide and radiation therapy (RT). CT/MR and FET PET scans were obtained postoperatively for RT planning. We used Cox proportional hazards models with OS and PFS as endpoints, to test the prognostic value of FET PET biological tumor volume (BTV). Median follow-up time was 14 months, and median OS and PFS were 16.5 and 6.5 months, respectively. In the multivariate analysis, increasing BTV (HR = 1.17, P < 0.001), poor performance status (HR = 2.35, P < 0.001), O(6)-methylguanine-DNA methyltransferase protein status (HR = 1.61, P = 0.024) and higher age (HR = 1.32, P = 0.013) were independent prognostic factors of poor OS. For poor PFS, only increasing BTV (HR = 1.18; P = 0.002) was prognostic. A prognostic index for OS was created based on the identified prognostic factors. Large BTV on FET PET is an independent prognostic factor of poor OS and PFS in glioblastoma patients. With the introduction of FET PET, we obtain a prognostic index that can help in glioblastoma treatment planning. (orig.)

  11. Shift of microRNA profile upon orthotopic xenografting of glioblastoma spheroid cultures

    DEFF Research Database (Denmark)

    Halle, Bo; Thomassen, Mads; Venkatesan, Ranga

    2016-01-01

    Glioblastomas always recur despite surgery, radiotherapy and chemotherapy. A key player in the therapeutic resistance may be immature tumor cells with stem-like properties (TSCs) escaping conventional treatment. A group of promising molecular targets are microRNAs (miRs). miRs are small non-codin...... therapeutic targets for anti-miRs to identify novel treatment options for GBM patients....

  12. Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma.

    Science.gov (United States)

    Stark, Andreas M; Doukas, Alexander; Hugo, Heinz-Herrmann; Hedderich, Jürgen; Hattermann, Kirsten; Maximilian Mehdorn, H; Held-Feindt, Janka

    2015-02-01

    Methylated O6-methylguanin-DNA-methytransferase (MGMT) promoter methylation is associated with survival in patients with glioblastoma. Current evidence suggests that further mismatch repair genes play a pivotal role in the tumor response to treatment. Candidate genes are MLH1, MSH2, and MSH6. Formerly, we found evidence of prognostic impact of MLH1 and MSH6 immunohistochemical expression in a small series of patients with initial glioblastoma. Two hundred and eleven patients were included who underwent macroscopically total removal of primary glioblastoma and at least one re-craniotomy for recurrence. Immunohistochemical staining was performed on paraffin-embedded specimens of initial tumors with specific antibodies against MLH1, MSH2, and MSH6. RESULTS were compared to the Ki67 proliferation index and patient survival. Additionally, fresh frozen samples from 16 paired initial and recurrent specimens were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) with specific primers against MLH1, MSH2, and MSH6. RESULTS were compared to MGMT status and survival. (1) Immunohistochemical expression of MSH6 was significantly associated with the Ki67 proliferation index (PMLH1, MLH2, and MSH6 over treatment combined with lacking MGMT methylation. In another two patients, decreased MLH1, MSH2, and MSH6 expression was observed in combination with MGMT promoter methylation. Our data indicate that there may be glioblastoma patient subgroups characterized by MMR-expression changes beyond MGMT promoter methylation. The immunohistochemical expression of MLH1, MSH2, and MSH6 in initial glioblastoma is not associated with patient survival.

  13. Glioblastoma as differential diagnosis of autoimmune encephalitis.

    Science.gov (United States)

    Vogrig, Alberto; Joubert, Bastien; Ducray, Francois; Thomas, Laure; Izquierdo, Cristina; Decaestecker, Kévin; Martinaud, Olivier; Gerardin, Emmanuel; Grand, Sylvie; Honnorat, Jérome

    2018-03-01

    To identify the clinical and radiological features that should raise suspicion for the autoimmune encephalitis (AE)-like presentation of glioblastoma. This is an observational, retrospective case series of patients referred to the French National Reference Center on Paraneoplastic Neurological Diseases for suspected AE (possible, probable or definite, using the 2016 criteria) who later received a final diagnosis of glioblastoma according to 2016 WHO criteria. An extensive literature search was also conducted for similar existing cases. Between 2014 and 2016, 306 patients were referred to our center for suspected AE. Six of these patients (2%) later developed pathologically confirmed glioblastoma. Thirteen patients (9 male) were included for analysis (6 from the present series and 7 from the literature); median age was 63. Initially, a diagnosis of AE was clinically suspected based on: working memory deficits (77%), seizures (62%) (including status epilepticus in 23%), and psychiatric symptoms (46%). Initial brain MRI was not in favor of a typical glioblastoma pattern and showed bilateral (54%) or unilateral selective limbic involvement. Five patients exhibited initial slight contrast enhancement. A clear inflammatory CSF was present in five patients and three from the literature showed autoantibody positivity (NMDAR, VGKC, GluRepsilon2). Median delay between suspicions of AE to GBM diagnosis was 3 months (range 1.5-24) and one patient from the literature was diagnosed post-mortem. An alternative diagnosis of glioblastoma should be considered in patients presenting initially as AE, especially in patients who do not fulfill the criteria for definite AE and in those with a poor clinical evolution despite initial improvement.

  14. Clinical inertia in poorly controlled elderly hypertensive patients: a cross-sectional study in Spanish physicians to ascertain reasons for not intensifying treatment.

    Science.gov (United States)

    Gil-Guillén, Vicente; Orozco-Beltrán, Domingo; Carratalá-Munuera, Concepción; Márquez-Contreras, Emilio; Durazo-Arvizu, Ramón; Cooper, Richard; Pertusa-Martínez, Salvador; Pita-Fernandez, Salvador; González-Segura, Diego; Martin-de-Pablo, José Luis; Pallarés, Vicente; Fernández, Antonio; Redón, Josep

    2013-06-01

    Clinical inertia, the failure of physicians to initiate or intensify therapy when indicated, is a major problem in the management of hypertension and may be more prevalent in elderly patients. Overcoming clinical inertia requires understanding its causes and evaluating certain factors, particularly those related to physicians. The objective of our study was to determine the rate of clinical inertia and the physician-reported reasons for it. An observational, cross-sectional, multi-center study was carried out in a primary care setting. We included 512 physicians, with a consecutive sampling of 1,499 hypertensive patients with clinical inertia. Clinical inertia was defined when physicians did not modify treatment despite knowing that the therapeutic target had not been reached. Clinical inertia was considered to be justified (JCI) when physicians provided an explanation for not intensifying treatment and as not justified (nJCI) when no reasons were given. JCI was observed in 30.1 % (95 % CI 27.8-32.4) of patients (n = 451) and nJCI in 69.9 % (95 % CI 67.6-72.2) (n = 1,058). JCI was associated with higher blood pressure (BP) values (both systolic and diastolic) and diabetes (p = 0.012) than nJCI. nJCI was associated with patients having an isolated increase of systolic or diastolic or high borderline BP values or cardiovascular disease. Physicians provided reasons for not intensifying treatment in poorly controlled patients in only 30 % of instances. Main reasons for not intensifying treatment were borderline BP values, co-morbidity, suspected white coat effect, or perceived difficulty achieving target. nJCI was associated with high borderline BP values and cardiovascular disease.

  15. The strong anti-glioblastoma capacity of the plasma-stimulated lysine-rich medium

    International Nuclear Information System (INIS)

    Yan, Dayun; Keidar, Michael; Nourmohammadi, Niki; Talbot, Annie; Sherman, Jonathan H

    2016-01-01

    Plasma-stimulated medium (PSM) shows a remarkable anti-cancer capacity as strong as the direct cold atmospheric plasma (CAP) treatment of cancer cells. PSM is able to effectively resist the growth of several cancer cell lines. To date, the sole approach to strengthen the anti-cancer capacity of PSM is extending the plasma treatment time. In this study, we demonstrated that the anti-glioblastoma capacity of PSM could be significantly increased by adding 20 mM lysine in Dulbecco’s modified Eagle’s medium (DMEM). This study provides clear evidence that the anti-glioblastoma capacity of PSM could be noticeably enhanced by modifying the composition of medium without increasing the CAP treatment time. (paper)

  16. Fertility-preservation counselling and treatment for medical reasons: data from a multinational network of over 5000 women.

    Science.gov (United States)

    von Wolff, Michael; Dittrich, Ralf; Liebenthron, Jana; Nawroth, Frank; Schüring, Andreas N; Bruckner, Thomas; Germeyer, Ariane

    2015-11-01

    Fertility-preservation techniques for medical reasons are increasingly offered in national networks. Knowledge of the characteristics of counselled patients and techniques used are essential. The FertiPROTEKT network registry was analysed between 2007 and 2013, and included up to 85 university and non-university centres in Germany, Austria and Switzerland; 5159 women were counselled and 4060 women underwent fertility preservation. In 2013, fertility-preservation counselling for medical reasons increased significantly among nullipara and women aged between 21 and 35 years (n = 1043; P years predominantly opted for GnRH agonists and ovarian tissue cryopreservation; women aged between 20 and 40 years underwent a variety of techniques; and women over 40 years opted for GnRH agonists. The average number of aspirated oocytes per stimulation cycle decreased as age increased (years: 12.9; 31-35 years: 12.3; 36-46: 9.0; > 41 years: 5.7). For ovarian tissue cryopreservation, removal and cryopreservation of fewer than one ovary was preferred and carried out in 97% of cases in 2013. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  17. Molecular and cellular heterogeneity: the hallmark of glioblastoma.

    Science.gov (United States)

    Aum, Diane J; Kim, David H; Beaumont, Thomas L; Leuthardt, Eric C; Dunn, Gavin P; Kim, Albert H

    2014-12-01

    There has been increasing awareness that glioblastoma, which may seem histopathologically similar across many tumors, actually represents a group of molecularly distinct tumors. Emerging evidence suggests that cells even within the same tumor exhibit wide-ranging molecular diversity. Parallel to the discoveries of molecular heterogeneity among tumors and their individual cells, intense investigation of the cellular biology of glioblastoma has revealed that not all cancer cells within a given tumor behave the same. The identification of a subpopulation of brain tumor cells termed "glioblastoma cancer stem cells" or "tumor-initiating cells" has implications for the management of glioblastoma. This focused review will therefore summarize emerging concepts on the molecular and cellular heterogeneity of glioblastoma and emphasize that we should begin to consider each individual glioblastoma to be an ensemble of molecularly distinct subclones that reflect a spectrum of dynamic cell states.

  18. Reasons Underlying the Consent to Endovascular Treatment, Displayed by Patients Diagnosed with Asymptomatic Internal Carotid Artery Stenosis

    OpenAIRE

    Stanišić, Michał-Goran; Rzepa, Teresa

    2014-01-01

    Background Endovascular treatment of internal carotid artery stenosis (ICAS) has gained popularity in recent years. Offering CAS, which is a controversial treatment in asymptomatic disease, may provoke patient distrust of the diagnosis and intervention benefit. The aim of this study was to prove that asymptomatic ICAS patients tend to show an emotional attitude to their illness, and therefore their decisions regarding carotid artery stenting are externally motivated and assessed emotionally. ...

  19. Live attenuated measles virus vaccine therapy for locally established malignant glioblastoma tumor cells

    Directory of Open Access Journals (Sweden)

    Al-Shammari AM

    2014-05-01

    , and 120 hours of infection compared with control cells. This study concludes that live attenuated MV Schwarz vaccine induces the oncolytic effect in Iraqi tumor cell line ANGM5 and in the rhabdomyosarcoma cell line through syncytia in tumor cells, which is one of the causes of cell death. The MV vaccine strain has the ability to insert its hemagglutinin protein into the tumor cell surface, leading to modification of the antigenic surface of tumor cells that may induce an antitumor immune response, MV vaccine strain induced cell killing by direct cytolysis and apoptosis induction. These antitumor features may indicate the use of MV in the treatment of glioblastoma.Keywords: virotherapy, glioblastoma multiforme

  20. PCDH10 is required for the tumorigenicity of glioblastoma cells

    International Nuclear Information System (INIS)

    Echizen, Kanae; Nakada, Mitsutoshi; Hayashi, Tomoatsu; Sabit, Hemragul; Furuta, Takuya; Nakai, Miyuki; Koyama-Nasu, Ryo; Nishimura, Yukiko; Taniue, Kenzui; Morishita, Yasuyuki; Hirano, Shinji; Terai, Kenta; Todo, Tomoki; Ino, Yasushi; Mukasa, Akitake; Takayanagi, Shunsaku; Ohtani, Ryohei; Saito, Nobuhito; Akiyama, Tetsu

    2014-01-01

    Highlights: • PCDH10 is required for the proliferation, survival and self-renewal of glioblastoma cells. • PCDH10 is required for glioblastoma cell migration and invasion. • PCDH10 is required for the tumorigenicity of glioblastoma cells. • PCDH10 may be a promising target for the therapy of glioblastoma. - Abstract: Protocadherin10 (PCDH10)/OL-protocadherin is a cadherin-related transmembrane protein that has multiple roles in the brain, including facilitating specific cell–cell connections, cell migration and axon guidance. It has recently been reported that PCDH10 functions as a tumor suppressor and that its overexpression inhibits proliferation or invasion of multiple tumor cells. However, the function of PCDH10 in glioblastoma cells has not been elucidated. In contrast to previous reports on other tumors, we show here that suppression of the expression of PCDH10 by RNA interference (RNAi) induces the growth arrest and apoptosis of glioblastoma cells in vitro. Furthermore, we demonstrate that knockdown of PCDH10 inhibits the growth of glioblastoma cells xenografted into immunocompromised mice. These results suggest that PCDH10 is required for the proliferation and tumorigenicity of glioblastoma cells. We speculate that PCDH10 may be a promising target for the therapy of glioblastoma

  1. Inductive reasoning.

    Science.gov (United States)

    Hayes, Brett K; Heit, Evan; Swendsen, Haruka

    2010-03-01

    Inductive reasoning entails using existing knowledge or observations to make predictions about novel cases. We review recent findings in research on category-based induction as well as theoretical models of these results, including similarity-based models, connectionist networks, an account based on relevance theory, Bayesian models, and other mathematical models. A number of touchstone empirical phenomena that involve taxonomic similarity are described. We also examine phenomena involving more complex background knowledge about premises and conclusions of inductive arguments and the properties referenced. Earlier models are shown to give a good account of similarity-based phenomena but not knowledge-based phenomena. Recent models that aim to account for both similarity-based and knowledge-based phenomena are reviewed and evaluated. Among the most important new directions in induction research are a focus on induction with uncertain premise categories, the modeling of the relationship between inductive and deductive reasoning, and examination of the neural substrates of induction. A common theme in both the well-established and emerging lines of induction research is the need to develop well-articulated and empirically testable formal models of induction. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website. Copyright © 2010 John Wiley & Sons, Ltd.

  2. [Degree of compliance with health care quality criteria in the treatment of lower airway obstruction in Spanish pediatric emergency departments, reasons for noncompliance, and recommendations for improvement].

    Science.gov (United States)

    Claret Teruel, Gemma; Solé Ribalta, Anna; González Balenciaga, María; Paniagua Calzón, Natalia Marta; Korta Murua, Javier

    2016-06-01

    To determine the degree of compliance with health care quality criteria in the treatment of patients with lower airway obstruction in Spanish pediatric emergency departments (PEDs), to explore the reasons for noncompliance, and to make recommendations for improvement. We carried out a retrospective, cross-sectional study of a series of patients under the age of 14 years to determine the degree of compliance with 5 quality indicators. The patients were attended in 22 PEDs on days 1 and 15 of each month in 2013. We also distributed a questionnaire to chiefs of department to discover possible reasons for noncompliance. Finally, a group of experts followed a process to produce consensus-based recommendations to improve quality of care through compliance with the indicators. We included 2935 patients with a median (interquartile range) age of 2.8 (1.4-5.1) years. The overall rates of compliance were 39.8% for assessment of severity, 0.1% for measurement of peak flow, 64.4% for delay in attending a patient with severe shortness of breath, 59.1% for checking oxygen saturation and respiratory frequency, and 34.3% for treatment with inhalers and a spacer. The most common reasons for noncompliance were lack of time or material and the absence of the recommendation in protocols. The following improvement steps were recommended: reassess the usefulness of peak flow measurement in PEDs, reformulate the criteria for delay in attending patients with severe dyspnea, and adopt new indicators and templates that facilitate the recording of vital constants and scores on severity scales. An acceptable level of compliance was not achieved on any of the health care quality indicators for a variety of reasons. A series of steps should be taken to improve compliance.

  3. The reasons for the epilepsy treatment gap in Kilifi, Kenya: using formative research to identify interventions to improve adherence to antiepileptic drugs.

    Science.gov (United States)

    Carter, Julie A; Molyneux, Catherine S; Mbuba, Caroline K; Jenkins, Jo; Newton, Charles R J C; Hartley, Sally D

    2012-12-01

    Many people with epilepsy (PWE) in resource-poor countries do not receive appropriate treatment, a phenomenon referred to as the epilepsy treatment gap (ETG). We conducted a qualitative study to explore the reasons for this gap and to identify possible interventions in Kilifi, Kenya. Focus group discussions (FGDs) were carried out of PWE and their caregivers. Individual interviews were conducted of PWE, their caregivers, traditional healers, community health workers and leaders, nurses and doctors. In addition, a series of workshops was conducted, and four factors contributing to the ETG were identified: 1) lack of knowledge about the causes, treatment and prognosis of epilepsy; 2) inaccessibility to antiepileptic drugs; 3) misconceptions about epilepsy derived from superstitions about its origin; 4) and dissatisfaction with the communication skills of health providers. These data indicated possible interventions: 1) education and support for PWE and their caregivers; 2) communication skills training for health providers; 3) and improved drug provision. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Glioblastoma multiforme after radiotherapy for acromegaly

    Energy Technology Data Exchange (ETDEWEB)

    Piatt, J.H. Jr.; Blue, J.M.; Schold, S.C. Jr.; Burger, P.C.

    1983-07-01

    A case of glioblastoma multiforme that occurred 14 years after radiotherapy for acromegaly is presented. The striking correspondence between the anatomy of the tumor and the geometry of the radiation ports is suggestive of a causal relationship. Previously reported cases of radiation-associated glioma are reviewed, and a brief appraisal of the evidence for induction of these lesions by radiation is presented. The differentiation of radiation-associated neoplasms from radionecrosis is also discussed.

  5. Glioblastoma multiforme after radiotherapy for acromegaly

    International Nuclear Information System (INIS)

    Piatt, J.H. Jr.; Blue, J.M.; Schold, S.C. Jr.; Burger, P.C.

    1983-01-01

    A case of glioblastoma multiforme that occurred 14 years after radiotherapy for acromegaly is presented. The striking correspondence between the anatomy of the tumor and the geometry of the radiation ports is suggestive of a causal relationship. Previously reported cases of radiation-associated glioma are reviewed, and a brief appraisal of the evidence for induction of these lesions by radiation is presented. The differentiation of radiation-associated neoplasms from radionecrosis is also discussed

  6. Routine drug and food interactions during antihelminthic treatment of neurocysticercosis: a reason for the variable efficacy of albendazole and praziquantel?

    Science.gov (United States)

    Romo, Matthew L; Carpio, Arturo; Kelvin, Elizabeth A

    2014-04-01

    Neurocysticercosis (NC) or infection of the central nervous system with Taenia solium larvae is a leading cause of preventable seizures and epilepsy in endemic regions across the globe. Albendazole and praziquantel are commonly used antihelminthic agents to treat NC; however, viable cysts persist in the majority of patients, putting them at risk for future seizures and other neurological complications. Because of their pharmacokinetic profiles, albendazole and praziquantel have the potential to interact with many different drugs. During antihelminthic treatment, antiepileptic drugs and corticosteroids are commonly co-administered to manage seizures and cerebral edema; however, the most commonly used agents from these drug classes are known to significantly alter plasma concentrations of albendazole and praziquantel. The overarching issue with drug interactions during the treatment of NC is whether or not they have clinical relevance, as the plasma concentrations of albendazole and praziquantel have not been directly linked with eradication of viable cysts. Future studies should attempt to evaluate the validity of a causal relationship between antihelminthic plasma concentrations and outcomes so that drug interactions can be better understood and managed and so that treatment can be optimized. © 2014, The American College of Clinical Pharmacology.

  7. Heuristic reasoning

    CERN Document Server

    2015-01-01

    How can we advance knowledge? Which methods do we need in order to make new discoveries? How can we rationally evaluate, reconstruct and offer discoveries as a means of improving the ‘method’ of discovery itself? And how can we use findings about scientific discovery to boost funding policies, thus fostering a deeper impact of scientific discovery itself? The respective chapters in this book provide readers with answers to these questions. They focus on a set of issues that are essential to the development of types of reasoning for advancing knowledge, such as models for both revolutionary findings and paradigm shifts; ways of rationally addressing scientific disagreement, e.g. when a revolutionary discovery sparks considerable disagreement inside the scientific community; frameworks for both discovery and inference methods; and heuristics for economics and the social sciences.

  8. APNG as a prognostic marker in patients with glioblastoma

    DEFF Research Database (Denmark)

    Fosmark, Sigurd; Hellwege, Sofie; Dahlrot, Rikke H

    2017-01-01

    AIM: Expression of the base excision repair enzyme alkylpurine-DNA-N-glycosylase (APNG) has been correlated to temozolomide resistance. Our aim was to evaluate the prognostic value of APNG in a population-based cohort with 242 gliomas including 185 glioblastomas (GBMs). Cellular heterogeneity...... of GBMs was taken into account by excluding APNG expression in non-tumor cells from the analysis. METHODS: APNG expression was evaluated using automated image analysis and a novel quantitative immunohistochemical (IHC) assay (qIHC), where APNG protein expression was evaluated through countable dots. Non...... was an independent prognostic factor among patients with a methylated MGMT promoter. We expect that APNG qIHC can potentially identify GBM patients who will not benefit from treatment with temozolomide....

  9. Reciprocal Supportive Interplay between Glioblastoma and Tumor-Associated Macrophages

    International Nuclear Information System (INIS)

    Zhou, Wenchao; Bao, Shideng

    2014-01-01

    Glioblastoma multiforme (GBM) is the most lethal and aggressive type of primary brain malignancy. Failures of the traditional therapies in treating GBMs raise the urgent requirement to develop new approaches with more responsive targets. The phenomenon of the high infiltration of tumor-associated macrophages (TAMs) into GBMs has been observed for a long time. Regardless of the limited knowledge about TAMs, the high percentage of supportive TAM in GBM tumor mass makes it possible to be a good target for GBM treatment. In this review, we discussed the unique features of TAMs in GBMs, including their origin, the tumor-supportive properties, the secreted cytokines, and the relevant mechanisms. In addition, we tried to interpret the current understandings about the interplay between GBM cancer cells and TAMs. Finally, the translational studies of targeting TAMs were also described

  10. Reciprocal Supportive Interplay between Glioblastoma and Tumor-Associated Macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Wenchao; Bao, Shideng, E-mail: baos@ccf.org [Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195 (United States)

    2014-03-26

    Glioblastoma multiforme (GBM) is the most lethal and aggressive type of primary brain malignancy. Failures of the traditional therapies in treating GBMs raise the urgent requirement to develop new approaches with more responsive targets. The phenomenon of the high infiltration of tumor-associated macrophages (TAMs) into GBMs has been observed for a long time. Regardless of the limited knowledge about TAMs, the high percentage of supportive TAM in GBM tumor mass makes it possible to be a good target for GBM treatment. In this review, we discussed the unique features of TAMs in GBMs, including their origin, the tumor-supportive properties, the secreted cytokines, and the relevant mechanisms. In addition, we tried to interpret the current understandings about the interplay between GBM cancer cells and TAMs. Finally, the translational studies of targeting TAMs were also described.

  11. Comparison of vitamins K1, K2 and K3 effects on growth of rat glioma and human glioblastoma multiforme cells in vitro.

    Science.gov (United States)

    Oztopçu, Pinar; Kabadere, Selda; Mercangoz, Ayşe; Uyar, Ruhi

    2004-09-01

    Glioblastoma multiforme is characterized as highly invasive and rapidly growing astrocytomas, and scientists have sought for efficient treatment against malignant gliomas for a long time. Therefore, we compared the respond of rat glioma (C6) and glioblastoma multiforme cells derived from two patients to vitamins K1, K2 and K3. The cells were exposed to 100, 250, 500, 750 and 1000 microM of vitamins K1 and K2, and 1, 10, 25, 50, 75 and 100 microM of vitamin K3 for 24 hours in an incubator atmosphere of 5% CO2, 37 degrees C and 100% humidity. Cell viability was estimated by MTT assay. Vitamin K1 showed no growth effect on all the glioma cells examined. Vitamin K2 did not cause any change in number of C6, however induced growth inhibition in a dose-dependent manner on glioblastoma multiforme. The IC50 values of vitamin K2 were 960 microM and 970 microM for glioblastoma multiforme, respectively. Vitamin K3 had also growth inhibitory effect in a dose-dependent manner on both C6 and glioblastoma multiforme. The IC50 values were 41 microM, 24 microM and 23 microM for vitamin K3, respectively. We concluded that vitamin K3 is more effective than vitamin K2 for inhibition of cancer cell growth, and might have an alternative value as an anticancer drug against glioblastoma multiforme.

  12. Giant cell glioblastoma in childhood - clinical case from our practice and literature survey

    International Nuclear Information System (INIS)

    Marinova, L.; Hristozova, I.; Minkin, K.; Mihaylova, I.; Katzarov, D.

    2015-01-01

    We present a rare clinical case of brain tumor in childhood - giant cells glioblastoma- The disease was diagnosed in July 2014. Following an evidently total tumor excision, a course of chemotherapy with Vincristine, Vepesid and Cisplatine was applied followed by external beam radiotherapy of total dose 56 Gy. After 4 courses of chemotherapy (Vepesid, Cisplatine and Cyclophosphamide), on the regular MRI - performed in January 2015, local tumor recurrence was discovered requiring re-operation. A local progression of the disease was manifested after 6 courses chemotherapy (Temodal 100 mg 1 tablet daily for 5 days monthly) with increased intracranial pressure, followed by exitus letalis of the patient, 12 months after the diagnosis being made. A rarely met pathology subtype of giant cells glioblastoma in childhood was discussed, its typical MRI image, unfavorable prognosis and manifested radio- and chemo-resistance. Despite the complex treatment including total tumor excision, postoperative radiotherapy with radical irradiation dose and adjuvant chemotherapy the risk of local recurrences and tumor progression is high. With the help of this rarely diagnosed aggressive brain tumor in childhood, we present the need of optimization of the multidisciplinary treatment approach. (authors) Key words: Giant Cell Glioblastoma. Childhood. Surgery. Radiotherapy. Chemotherapy. Complex Treatment

  13. Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Bernhart, Eva; Damm, Sabine; Wintersperger, Andrea [Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz (Austria); DeVaney, Trevor [Institute of Biophysics, Medical University of Graz (Austria); Zimmer, Andreas [Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, Karl-Franzens University, Graz (Austria); Raynham, Tony; Ireson, Christopher [Cancer Research Technology Ltd, London (United Kingdom); Sattler, Wolfgang, E-mail: wolfgang.sattler@medunigraz.at [Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz (Austria)

    2013-08-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which, despite combined modality treatment, reoccurs and is invariably fatal for affected patients. Recently, a member of the serine/threonine protein kinase D (PRKD) family, PRKD2, was shown to be a potent mediator of glioblastoma growth. Here we studied the role of PRKD2 in U87MG glioblastoma cell migration and invasion in response to sphingosine-1-phosphate (S1P), an activator of PRKD2 and a GBM mitogen. Time-lapse microscopy demonstrated that random cell migration was significantly diminished in response to PRKD2 silencing. The pharmacological PRKD family inhibitor CRT0066101 decreased chemotactic migration and invasion across uncoated or matrigel-coated Transwell inserts. Silencing of PRKD2 attenuated migration and invasion of U87MG cells even more effectively. In terms of downstream signaling, CRT0066101 prevented PRKD2 autophosphorylation and inhibited p44/42 MAPK and to a smaller extent p54/46 JNK and p38 MAPK activation. PRKD2 silencing impaired activation of p44/42 MAPK and p54/46 JNK, downregulated nuclear c-Jun protein levels and decreased c-Jun{sup S73} phosphorylation without affecting the NFκB pathway. Finally, qPCR array analyses revealed that silencing of PRKD2 downregulates mRNA levels of integrin alpha-2 and -4 (ITGA2 and -4), plasminogen activator urokinase (PLAU), plasminogen activator urokinase receptor (PLAUR), and matrix metallopeptidase 1 (MMP1). Findings of the present study identify PRKD2 as a potential target to interfere with glioblastoma cell migration and invasion, two major determinants contributing to recurrence of glioblastoma after multimodality treatment. Highlights: • Sphingosine-1-phosphate induces glioma cell migration and invasion. • Part of the effects is mediated by protein kinase D2 (PRKD2) activation. • Inactivation of PRKD2 attenuates glioblastoma cell migration and invasion. • Both, RNAi and pharmacological inhibition of PRKD2 inhibits MAPK

  14. Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro

    International Nuclear Information System (INIS)

    Bernhart, Eva; Damm, Sabine; Wintersperger, Andrea; DeVaney, Trevor; Zimmer, Andreas; Raynham, Tony; Ireson, Christopher; Sattler, Wolfgang

    2013-01-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which, despite combined modality treatment, reoccurs and is invariably fatal for affected patients. Recently, a member of the serine/threonine protein kinase D (PRKD) family, PRKD2, was shown to be a potent mediator of glioblastoma growth. Here we studied the role of PRKD2 in U87MG glioblastoma cell migration and invasion in response to sphingosine-1-phosphate (S1P), an activator of PRKD2 and a GBM mitogen. Time-lapse microscopy demonstrated that random cell migration was significantly diminished in response to PRKD2 silencing. The pharmacological PRKD family inhibitor CRT0066101 decreased chemotactic migration and invasion across uncoated or matrigel-coated Transwell inserts. Silencing of PRKD2 attenuated migration and invasion of U87MG cells even more effectively. In terms of downstream signaling, CRT0066101 prevented PRKD2 autophosphorylation and inhibited p44/42 MAPK and to a smaller extent p54/46 JNK and p38 MAPK activation. PRKD2 silencing impaired activation of p44/42 MAPK and p54/46 JNK, downregulated nuclear c-Jun protein levels and decreased c-Jun S73 phosphorylation without affecting the NFκB pathway. Finally, qPCR array analyses revealed that silencing of PRKD2 downregulates mRNA levels of integrin alpha-2 and -4 (ITGA2 and -4), plasminogen activator urokinase (PLAU), plasminogen activator urokinase receptor (PLAUR), and matrix metallopeptidase 1 (MMP1). Findings of the present study identify PRKD2 as a potential target to interfere with glioblastoma cell migration and invasion, two major determinants contributing to recurrence of glioblastoma after multimodality treatment. Highlights: • Sphingosine-1-phosphate induces glioma cell migration and invasion. • Part of the effects is mediated by protein kinase D2 (PRKD2) activation. • Inactivation of PRKD2 attenuates glioblastoma cell migration and invasion. • Both, RNAi and pharmacological inhibition of PRKD2 inhibits MAPK

  15. Limited role for extended maintenance temozolomide for newly diagnosed glioblastoma.

    Science.gov (United States)

    Gramatzki, Dorothee; Kickingereder, Philipp; Hentschel, Bettina; Felsberg, Jörg; Herrlinger, Ulrich; Schackert, Gabriele; Tonn, Jörg-Christian; Westphal, Manfred; Sabel, Michael; Schlegel, Uwe; Wick, Wolfgang; Pietsch, Torsten; Reifenberger, Guido; Loeffler, Markus; Bendszus, Martin; Weller, Michael

    2017-04-11

    To explore an association with survival of modifying the current standard of care for patients with newly diagnosed glioblastoma of surgery followed by radiotherapy plus concurrent and 6 cycles of maintenance temozolomide chemotherapy (TMZ/RT → TMZ) by extending TMZ beyond 6 cycles. The German Glioma Network cohort was screened for patients with newly diagnosed glioblastoma who received TMZ/RT → TMZ and completed ≥6 cycles of maintenance chemotherapy without progression. Associations of clinical patient characteristics, molecular markers, and residual tumor determined by magnetic resonance imaging after 6 cycles of TMZ with progression-free survival (PFS) and overall survival (OS) were analyzed with the log-rank test. Multivariate analyses using the Cox proportional hazards model were performed to assess associations of prolonged TMZ use with outcome. Sixty-one of 142 identified patients received at least 7 maintenance TMZ cycles (median 11, range 7-20). Patients with extended maintenance TMZ treatment had better PFS (20.5 months, 95% confidence interval [CI] 17.7-23.3, vs 17.2 months, 95% CI 10.2-24.2, p = 0.035) but not OS (32.6 months, 95% CI 28.9-36.4, vs 33.2 months, 95% CI 25.3-41.0, p = 0.126). However, there was no significant association of prolonged TMZ chemotherapy with PFS (hazard ratio [HR] = 0.8, 95% CI 0.4-1.6, p = 0.559) or OS (HR = 1.6, 95% CI 0.8-3.3, p = 0.218) adjusted for age, extent of resection, Karnofsky performance score, presence of residual tumor, O 6 -methylguanine DNA methyltransferase (MGMT) promoter methylation status, or isocitrate dehydrogenase ( IDH ) mutation status. These data may not support the practice of prolonging maintenance TMZ chemotherapy beyond 6 cycles. This study provides Class III evidence that in patients with newly diagnosed glioblastoma, prolonged TMZ chemotherapy does not significantly increase PFS or OS. © 2017 American Academy of Neurology.

  16. Reasons underlying the consent to endovascular treatment, displayed by patients diagnosed with asymptomatic internal carotid artery stenosis.

    Science.gov (United States)

    Stanišić, Michał-Goran; Rzepa, Teresa

    2014-08-24

    Endovascular treatment of internal carotid artery stenosis (ICAS) has gained popularity in recent years. Offering CAS, which is a controversial treatment in asymptomatic disease, may provoke patient distrust of the diagnosis and intervention benefit. The aim of this study was to prove that asymptomatic ICAS patients tend to show an emotional attitude to their illness, and therefore their decisions regarding carotid artery stenting are externally motivated and assessed emotionally. This study was conducted by a questionnaire consisting of 18 half-open questions (obtained from 25 consecutive patients) in categories of self-image, attitude to illness, and decision-making regarding CAS. Descriptive analysis was performed. Reaction: "Nothing to worry about - every illness can be cured" evidenced the rational attitude to the disease. Attitude towards oneself after receiving the unexpected information about the disease did not change. Most patients pursued a second opinion before the intervention. Most patients showed internal motivation (78.7%). Rational assessment of the decision on CAS relied on consulting and insights into the disease and the intervention-related risk compared to risk of "doing nothing" In decision-making about CAS by asymptomatic patients, the emotional attitude to disease and negative expectations pertaining to postoperative health lead to an internally-motivated and rationally assessed decision. At least 2 conversations with the patient should be scheduled. The primary purpose of the second visit should be dissipating any doubts and repeating the arguments for the intervention. Patients should be provided with an appropriate amount of information to reduce their fear of neurological complications and mental disturbances. Conversation should be concentrated on life-quality improvement instead of controversies about the intervention.

  17. Phenylbutyrate Sensitizes Human Glioblastoma Cells Lacking Wild-Type P53 Function to Ionizing Radiation

    International Nuclear Information System (INIS)

    Lopez, Carlos A.; Feng, Felix Y.; Herman, Joseph M.; Nyati, Mukesh K.; Lawrence, Theodore S.; Ljungman, Mats

    2007-01-01

    Purpose: Histone deacetylase (HDAC) inhibitors induce growth arrest, differentiation, and apoptosis in cancer cells. Phenylbutyrate (PB) is a HDAC inhibitor used clinically for treatment of urea cycle disorders. Because of its low cytotoxicity, cerebrospinal fluid penetration, and high oral bioavailability, we investigated PB as a potential radiation sensitizer in human glioblastoma cell lines. Methods and Materials: Four glioblastoma cell lines were selected for this study. Phenylbutyrate was used at a concentration of 2 mM, which is achievable in humans. Western blots were used to assess levels of acetylated histone H3 in tumor cells after treatment with PB. Flow cytometry was used for cell cycle analysis. Clonogenic assays were performed to assess the effect of PB on radiation sensitivity. We used shRNA against p53 to study the role of p53 in radiosensitization. Results: Treatment with PB alone resulted in hyperacetylation of histones, confirmed by Western blot analysis. The PB alone resulted in cytostatic effects in three cell lines. There was no evidence of G 1 arrest, increase in sub-G 1 fraction or p21 protein induction. Clonogenic assays showed radiosensitization in two lines harboring p53 mutations, with enhancement ratios (± SE) of 1.5 (± 0.2) and 1.3 (± 0.1), respectively. There was no radiopotentiating effect in two cell lines with wild-type p53, but knockdown of wild-type p53 resulted in radiosensitization by PB. Conclusions: Phenylbutyrate can produce p21-independent cytostasis, and enhances radiation sensitivity in p53 mutant human glioblastoma cells in vitro. This suggests the potential application of combined PB and radiotherapy in glioblastoma harboring mutant p53

  18. Amnesia due to bilateral hippocampal glioblastoma. MRI finding

    Energy Technology Data Exchange (ETDEWEB)

    Shimauchi, M.; Wakisaka, S.; Kinoshita, K. (Miyazaki Medical Coll., Kiyotake (Japan). Dept. of Neurosurgery)

    1989-11-01

    The authors report a unique case of glioblastoma which caused permanent amnesia. Magnetic resonance imaging showed the lesion to be limited to the hippocampal formation bilaterally. Although glioblastoma extends frequently into fiber pathways and expands into the opposite cerebral hemisphere, making a 'butterfly' lesion, it is unusual for it to invade the limbic system selectively to this extent. (orig.).

  19. Recurrent glioblastoma: Current patterns of care in an Australian population.

    Science.gov (United States)

    Parakh, Sagun; Thursfield, Vicky; Cher, Lawrence; Dally, Michael; Drummond, Katharine; Murphy, Michael; Rosenthal, Mark A; Gan, Hui K

    2016-02-01

    This retrospective population-based survey examined current patterns of care for patients with recurrent glioblastoma (rGBM) who had previously undergone surgery and post-operative therapy at original diagnosis. The patients were identified from the Victorian Cancer Registry (VCR) from 2006 to 2008. Patient demographics, tumour characteristics and oncological management were extracted using a standardised survey by the treating clinicians/VCR staff and results analysed by the VCR. Kaplan-Meier estimates of overall survival (OS) at diagnosis and progression were calculated. A total of 95 patients (48%) received treatment for first recurrence; craniotomy and post-operative treatment (38), craniotomy only (34) and non-surgical treatment (23). Patients receiving treatment at first progression had a higher median OS than those who did not (7 versus 3 months, ppattern of care survey of treatment for rGBM in an era where post-operative "Stupp" chemo-radiation is standard. First and second line therapy for rGBM is common and associated with significant benefit. Treatment generally includes re-resection and/or systemic therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene.

    Directory of Open Access Journals (Sweden)

    Rebecca L Skalsky

    Full Text Available Glioblastoma is a highly aggressive malignant tumor involving glial cells in the human brain. We used high-throughput sequencing to comprehensively profile the small RNAs expressed in glioblastoma and non-tumor brain tissues. MicroRNAs (miRNAs made up the large majority of small RNAs, and we identified over 400 different cellular pre-miRNAs. No known viral miRNAs were detected in any of the samples analyzed. Cluster analysis revealed several miRNAs that were significantly down-regulated in glioblastomas, including miR-128, miR-124, miR-7, miR-139, miR-95, and miR-873. Post-transcriptional editing was observed for several miRNAs, including the miR-376 family, miR-411, miR-381, and miR-379. Using the deep sequencing information, we designed a lentiviral vector expressing a cell suicide gene, the herpes simplex virus thymidine kinase (HSV-TK gene, under the regulation of a miRNA, miR-128, that was found to be enriched in non-tumor brain tissue yet down-regulated in glioblastomas, Glioblastoma cells transduced with this vector were selectively killed when cultured in the presence of ganciclovir. Using an in vitro model to recapitulate expression of brain-enriched miRNAs, we demonstrated that neuronally differentiated SH-SY5Y cells transduced with the miRNA-regulated HSV-TK vector are protected from killing by expression of endogenous miR-128. Together, these results provide an in-depth analysis of miRNA dysregulation in glioblastoma and demonstrate the potential utility of these data in the design of miRNA-regulated therapies for the treatment of brain cancers.

  1. Prognosis value of the COX-2 expression on radiotherapy efficiency and on survival without progression of patients reached by an unoperative glioblastoma; Valeur pronostique de l'expression de COX-2 sur l'efficacite de la radiotherapie et sur la survie sans progression des patients atteints d'un glioblastome inoperable

    Energy Technology Data Exchange (ETDEWEB)

    Simon, J.M.; Mazeron, J.J. [Groupe Hospitalier de la Pitie-Salepetriere, APHP, Service de Radiotherapie Oncologique, 75 - Paris (France); Mokhtari, K. [Groupe Hospitalier de la Pitie-Salepetriere, APHP, Lab. de Neuropathologie, 75 - Paris (France); Genestie, C. [Groupe Hospitalier de la Pitie-Salepetriere, APHP, Lab. d' Anatomie Pathologique, 75 - Paris (France); Bissery, A. [Groupe Hospitalier de la Pitie-Salepetriere, APHP, Dept. de biostatistiques et d' Anformation Medicale, 75 - Paris (France); Jaillon, P. [Hopital Saint-Antoine, Service de Pharmacologie, 75 - Paris (France)

    2006-11-15

    The expression of COX-2 is a prediction factor of the lack of response to the radiotherapy of glioblastomas and a less good survival rate without tumor progression, aside other known prognosis factors. These results suggest a selective treatment by an anti-COX-2 could have a radiosensitizer contribution during the radiotherapy of glioblastomas. (N.C.)

  2. Glioblastoma multiforme of the cerebellum: description of three cases.

    Science.gov (United States)

    Luccarelli, G

    1980-01-01

    Only 43 cases of glioblastoma multiforme of the cerebellum have been reported in the literature. This report is based on the findings of 3 cerebellar glioblastomas in a review of 1,206 consecutive confirmed cases of glioblastoma operated on between 1947 and 1977 at the Istituto Neurologico of Milan, giving an incidence of 0.24%. Clinical features are similar to those of any other fast-growing subtentorial tumour. Neuroradiological studies, including CAT, are of little help in predicting the exact nature of these tumours before surgery. A correct diagnosis can be reached only by microscopic examination. Histological patterns appear in no way to differ from those of cerebral glioblastoma. The biological behaviour of these tumours is in all respects identical to that of glioblastoma of cerebral hemispheres.

  3. Diagnostic reasoning in action

    DEFF Research Database (Denmark)

    Rasmussen, Jens

    1993-01-01

    of system failures; and in medicine, diagnosis is the basis for any patient treatment. The paper presents a discussion of the basic nature of causal reasoning as applied for diagnosis and the mental strategies applied when diagnosis is viewed as an integrated part of ''natural decision making...

  4. Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients

    DEFF Research Database (Denmark)

    Urup, Thomas; Staunstrup, Line Maersk; Michaelsen, Signe Regner

    2017-01-01

    Background: Bevacizumab combined with chemotherapy produces clinical durable response in 25-30% of recurrent glioblastoma patients. This group of patients has shown improved survival and quality of life. The aim of this study was to investigate changes in gene expression associated with response...... and resistance to bevacizumab combination therapy.Methods: Recurrent glioblastoma patients who had biomarker-accessible tumor tissue surgically removed both before bevacizumab treatment and at time of progression were included. Patients were grouped into responders (n = 7) and non-responders (n = 14). Gene...... expression profiling of formalin-fixed paraffin-embedded tumor tissue was performed using RNA-sequencing.Results: By comparing pretreatment samples of responders with those of non-responders no significant difference was observed. In a paired comparison analysis of pre- and posttreatment samples of non...

  5. Synchronous glioblastoma and medulloblastoma in a child with mismatch repair mutation.

    Science.gov (United States)

    Amayiri, Nisreen; Al-Hussaini, Maysa; Swaidan, Maisa; Jaradat, Imad; Qandeel, Monther; Tabori, Uri; Hawkins, Cynthia; Musharbash, Awni; Alsaad, Khulood; Bouffet, Eric

    2016-03-01

    Synchronous primary malignant brain tumors are rare. We present a 5-year-old boy with synchronous glioblastoma and medulloblastoma. Both tumor samples had positive p53 stain and loss of PMS2 and MLH1 stains. The child had multiple café au lait spots and a significant family history of cancer. After subtotal resection of both tumors, he received craniospinal radiation with concomitant temozolomide followed by chemotherapy, alternating cycles of cisplatin/lomustine/vincristine with temozolomide. Then, he started maintenance treatment with cis-retinoic acid (100 mg/m(2)/day for 21 days). He remained asymptomatic for 34 months despite a follow-up brain MRI consistent with glioblastoma relapse 9 months before his death. Cis-retinoic acid may have contributed to prolong survival in this child with a probable biallelic mismatch repair syndrome.

  6. Domestic Violence against Children: Nature, Reason and Some Solutions for Its Treatment in the Light of Legal Attempts

    Directory of Open Access Journals (Sweden)

    Seyed Masoud Noori

    2007-11-01

    Full Text Available International and national documents consider family as the fundamental social institute and the natural base of growth and development of the personality of children. On the basis of this principle and according to the religious teachings and local traditions and customs, the positive laws consider family as a strong sanctuary. The governments are not much inclined to extend the field of their supervision to the inner perimeters of family. The judicial procedures too more or less follow the same pattern. On the other hand, the studies conducted in different parts of the world indicate that child abuse in the family occurs by the parents, legal custodians and the close relatives of the children and adolescents. Overemphasis on the sanctity of family and weak incentive of the families in interfering in the perimeters of family have landed the children and adolescents in an undesirable situation. The present paper is an attempt to define violence against children and introduce its various kinds. Then attempts have been made to discuss the reasons for child abuse in the family. The principles of the convention on the child’s rights (CRC for protection of the children against violence as well as Iranian laws have been taken into consideration in this study. Also the media, religion, and the social functions of the religious leaders and their role in campaign against domestic violence against children have been also discussed. اسناد بین المللی و ملی، خانواده را رکن اساسی اجتماع و جایگاه طبیعی رشد و شکوفایی شخصیت کودکان شمرده‌اند. بر این اساس و همسو با آموزه‌های دینی و آداب و رسوم محلی، قوانین موضوعه برای خانواده حریم مستحکمی قائل شده‌اند و دولت‌ها نیز کمتر مایلند نظارت و حوزه رفتار خود را به درون خانواده تسری

  7. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma.

    Science.gov (United States)

    Rieger, Johannes; Bähr, Oliver; Maurer, Gabriele D; Hattingen, Elke; Franz, Kea; Brucker, Daniel; Walenta, Stefan; Kämmerer, Ulrike; Coy, Johannes F; Weller, Michael; Steinbach, Joachim P

    2014-06-01

    Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20 patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients (15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6 weeks. Median PFS of all patients was 5 (range, 3-13) weeks, median survival from enrollment was 32 weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was 20.1 (range, 12-124) weeks, for a PFS at 6 months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (pketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma. Further clinical trials are necessary to clarify whether calorie restriction or the combination with other therapeutic modalities, such as radiotherapy or anti-angiogenic treatments, could enhance the efficacy of the ketogenic diet.

  8. ERGO: A pilot study of ketogenic diet in recurrent glioblastoma

    Science.gov (United States)

    RIEGER, JOHANNES; BÄHR, OLIVER; MAURER, GABRIELE D.; HATTINGEN, ELKE; FRANZ, KEA; BRUCKER, DANIEL; WALENTA, STEFAN; KÄMMERER, ULRIKE; COY, JOHANNES F.; WELLER, MICHAEL; STEINBACH, JOACHIM P.

    2014-01-01

    Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20 patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients (15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6 weeks. Median PFS of all patients was 5 (range, 3–13) weeks, median survival from enrollment was 32 weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was 20.1 (range, 12–124) weeks, for a PFS at 6 months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (pketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma. Further clinical trials are necessary to clarify whether calorie restriction or the combination with other therapeutic modalities, such as radiotherapy or anti-angiogenic treatments, could enhance the efficacy of the ketogenic diet. PMID:24728273

  9. Circulating endothelial cells and procoagulant microparticles in patients with glioblastoma: prognostic value.

    Directory of Open Access Journals (Sweden)

    Gaspar Reynés

    Full Text Available AIM: Circulating endothelial cells and microparticles are prognostic factors in cancer. However, their prognostic and predictive value in patients with glioblastoma is unclear. The objective of this study was to investigate the potential prognostic value of circulating endothelial cells and microparticles in patients with newly diagnosed glioblastoma treated with standard radiotherapy and concomitant temozolomide. In addition, we have analyzed the methylation status of the MGMT promoter. METHODS: Peripheral blood samples were obtained before and at the end of the concomitant treatment. Blood samples from healthy volunteers were also obtained as controls. Endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Microparticles were quantified by flow cytometry. Microparticle-mediated procoagulant activity was measured by endogen thrombin generation and by phospholipid-dependent clotting time. Methylation status of MGMT promoter was determined by multiplex ligation-dependent probe amplification. RESULTS: Pretreatment levels of circulating endothelial cells and microparticles were higher in patients than in controls (p<0.001. After treatment, levels of microparticles and thrombin generation decreased, and phospholipid-dependent clotting time increased significantly. A high pretreatment endothelial cell count, corresponding to the 99(th percentile in controls, was associated with poor overall survival. MGMT promoter methylation was present in 27% of tumor samples and was associated to a higher overall survival (66 weeks vs 30 weeks, p<0.004. CONCLUSION: Levels of circulating endothelial cells may have prognostic value in patients with glioblastoma.

  10. Clinical implications of in silico mathematical modeling for glioblastoma: a critical review.

    Science.gov (United States)

    Protopapa, Maria; Zygogianni, Anna; Stamatakos, Georgios S; Antypas, Christos; Armpilia, Christina; Uzunoglu, Nikolaos K; Kouloulias, Vassilis

    2018-01-01

    Glioblastoma remains a clinical challenge in spite of years of extensive research. Novel approaches are needed in order to integrate the existing knowledge. This is the potential role of mathematical oncology. This paper reviews mathematical models on glioblastoma from the clinical doctor's point of view, with focus on 3D modeling approaches of radiation response of in vivo glioblastomas based on contemporary imaging techniques. As these models aim to provide a clinically useful tool in the era of personalized medicine, the integration of the latest advances in molecular and imaging science and in clinical practice by the in silico models is crucial for their clinical relevance. Our aim is to indicate areas of GBM research that have not yet been addressed by in silico models and to point out evidence that has come up from in silico experiments, which may be worth considering in the clinic. This review examines how close these models have come in predicting the outcome of treatment protocols and in shaping the future of radiotherapy treatments.

  11. Radiotherapy and chemotherapy with or without carbogen and nicotinamide in inoperable biopsy-proven glioblastoma multiforme

    International Nuclear Information System (INIS)

    Simon, Jean-Marc; Noeel, Georges; Chiras, Jacques; Khe, H.-X.; Delattre, Jean-Yves; Baillet, Francois; Mazeron, Jean-Jacques

    2003-01-01

    Background: Nicotinamide and carbogen have been shown to enhance the radiation effect in tumour models. Purpose: Prospective evaluation of the toxicity and efficacy of carbogen and nicotinamide with external beam radiotherapy in the management of inoperable glioblastoma. Patients and methods: From April 1995 to December 1997, 33 patients with inoperable biopsy-proven glioblastoma multiforme (GBM) were enrolled in a phase II trial, to undergo radiotherapy (59.4 Gy in 1.8 Gy/fraction), intra-arterial cerebral chemotherapy (ACNU 100 mg/m 2 , three cycles), carbogen breathing (15 l/min), and nicotinamide (85 mg/kg). This experimental group was compared to a control group of 38 patients with inoperable GBM treated with radiotherapy and three cycles of nitrosourea-based chemotherapy from January 1990 to March 1995, in our institution. Results: In the experimental group, carbogen breathing was well tolerated, but only 51.5% of patients completed daily nicotinamide over the 6.5-week treatment period. Nausea and vomiting were the most frequent side effects of nicotinamide. No significant difference in overall survival was observed among the two treatment groups: median survival times were 36.7 and 35.3 weeks for patients treated with carbogen and nicotinamide, and for those treated in the control group, respectively. Conclusion: The association of carbogen and nicotinamide with radiotherapy is feasible, but tolerable only in 51.5% of patients with GBM. Carbogen and nicotinamide did not appear to modify the evolution of glioblastoma

  12. Quantitative Magnetization Transfer in Monitoring Glioblastoma (GBM) Response to Therapy.

    Science.gov (United States)

    Mehrabian, Hatef; Myrehaug, Sten; Soliman, Hany; Sahgal, Arjun; Stanisz, Greg J

    2018-02-06

    Quantitative magnetization transfer (qMT) was used as a biomarker to monitor glioblastoma (GBM) response to chemo-radiation and identify the earliest time-point qMT could differentiate progressors from non-progressors. Nineteen GBM patients were recruited and MRI-scanned before (Day 0 ), two weeks (Day 14 ), and four weeks (Day 28 ) into the treatment, and one month after the end of the treatment (Day 70 ). Comprehensive qMT data was acquired, and a two-pool MT model was fit to the data. Response was determined at 3-8 months following the end of chemo-radiation. The amount of magnetization transfer ([Formula: see text]) was significantly lower in GBM compared to normal appearing white matter (p GBM are more sensitive to treatment effects compared to clinically used metrics. qMT could assess tumor aggressiveness and identify early progressors even before the treatment. Changes in qMT parameters within the first 14 days of the treatment were capable of separating early progressors from non-progressors, making qMT a promising biomarker to guide adaptive radiotherapy for GBM.

  13. Photodynamic therapy platform for glioblastoma and intrabronchial tumors

    Science.gov (United States)

    Orsila, Lasse; Alanko, Jukka-Pekka; Kaivosoja, Visa; Uibu, Toomas

    2018-02-01

    Photodynamic therapy (PDT) is bringing new, effective, and less invasive, possibilities for cancer treatment. ML7710 (Modulight Inc.) medical laser system offers a platform for performing PDT for multiple indications and drugs. Latest avenue is glioblastoma treatment with 5-Aminolevulinic acid (ALA-5) and 635-nm light, where clinical trials are about to begin. Preliminary work suggests major advantages in treatment control, including active in-situ feedback. ML7710 platform has already proven itself for clinical work with intrabronchial obstructive tumors. Preliminary result with 10 patients show that intrabronchial tumors, that strongly affect both the survival and the performance of the patient, can be significantly reduced with ML7710 operated at 665 nm and sodium chlorine E6 photosensitizer. The aim in most of the patients has been a palliative recanalization of the bronchial lumen in order to alleviate the symptoms such as breathlessness and hemoptysis. The illumination dose for the target area was 50-75 J/cm2. All the patients have received multimodality cancer treatment using other intrabronchial interventions, radiotherapy and chemotherapy as needed. In most of the patients, satisfactory treatment results were achieved and it was possible to restart chemotherapy in several patients. In one patient with local cancer a complete remission was established. PDT has also the advantage that it is possible to give PDT after a maximum dose of radiation therapy has already been used and fewer side effects if used in locally advanced intraluminar lung cancer.

  14. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells

    Directory of Open Access Journals (Sweden)

    Costello Joseph F

    2008-06-01

    Full Text Available Abstract Background Glioblastoma multiforme (GBM is an invariably fatal central nervous system tumor despite treatment with surgery, radiation, and chemotherapy. Further insights into the molecular and cellular mechanisms that drive GBM formation are required to improve patient outcome. MicroRNAs are emerging as important regulators of cellular differentiation and proliferation, and have been implicated in the etiology of a variety of cancers, yet the role of microRNAs in GBM remains poorly understood. In this study, we investigated the role of microRNAs in regulating the differentiation and proliferation of neural stem cells and glioblastoma-multiforme tumor cells. Methods We used quantitative RT-PCR to assess microRNA expression in high-grade astrocytomas and adult mouse neural stem cells. To assess the function of candidate microRNAs in high-grade astrocytomas, we transfected miR mimics to cultured-mouse neural stem cells, -mouse oligodendroglioma-derived stem cells, -human glioblastoma multiforme-derived stem cells and -glioblastoma multiforme cell lines. Cellular differentiation was assessed by immunostaining, and cellular proliferation was determined using fluorescence-activated cell sorting. Results Our studies revealed that expression levels of microRNA-124 and microRNA-137 were significantly decreased in anaplastic astrocytomas (World Health Organization grade III and glioblastoma multiforme (World Health Organization grade IV relative to non-neoplastic brain tissue (P erbB tumors and cluster of differentiation 133+ human glioblastoma multiforme-derived stem cells (SF6969. Transfection of microRNA-124 or microRNA-137 also induced G1 cell cycle arrest in U251 and SF6969 glioblastoma multiforme cells, which was associated with decreased expression of cyclin-dependent kinase 6 and phosphorylated retinoblastoma (pSer 807/811 proteins. Conclusion microRNA-124 and microRNA-137 induce differentiation of adult mouse neural stem cells, mouse

  15. Radiotherapy plus concomitant adjuvant temozolomide for glioblastoma: Japanese mono-institutional results.

    Directory of Open Access Journals (Sweden)

    Takahiro Oike

    Full Text Available This study was conducted to investigate the feasibility and survival benefits of combined treatment with radiotherapy and temozolomide (TMZ, which has been covered by the national health insurance in Japanese patients with glioblastoma since September 2006. Between September 2006 and December 2011, 47 patients with newly diagnosed and histologically confirmed glioblastoma received radiotherapy for 60 Gy in 30 fractions. Among them, 45 patients (TMZ group received concomitant TMZ (75 mg/m(2/day, every day and adjuvant TMZ (200 mg/m(2/day, 5 days during each 28-days. All 36 of the glioblastoma patients receiving radiotherapy between January 1988 and August 2006 were analyzed as historical controls (control group. All patients were followed for at least 1 year or until they died. The median survival was 15.8 months in the TMZ group and 12.0 months in the control group after a median follow-up of 14.0 months. The hazard ratio for death in the TMZ group relative to the control group was 0.52 (P<0.01; the 2-year survival rate was 27.7% in the TMZ group and 14.6% in the control group. Hematologic toxicity of grade 3 and higher was observed in 20.4% in the TMZ group. Multivariate analysis showed that extent of surgery had the strongest impact on survival (P<0.01, while the use of TMZ had the second largest impact on survival (P = 0.035. The results indicate that combined treatment with radiotherapy and TMZ has a significant survival benefit for Japanese patients with newly diagnosed glioblastoma with slightly higher toxicities than previously reported.

  16. Efficient chemotherapy of rat glioblastoma using doxorubicin-loaded PLGA nanoparticles with different stabilizers.

    Directory of Open Access Journals (Sweden)

    Stefanie Wohlfart

    Full Text Available BACKGROUND: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid (PLGA nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods. METHODOLOGY: The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA or human serum albumin (PLGA/HSA as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3 × 2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density. CONCLUSION: The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations.

  17. Investigating Ceria Nanocrystals Uptake by Glioblastoma Multiforme Cells and its Related Effects: An Electron Microscopy Study

    KAUST Repository

    Aloufi, Bader

    2017-01-22

    Cerium oxide nanoparticles have been utilized widely nowadays in cancer research. It has been suggested by many studies that these nanoparticles are capable of having dual antioxidant behavior in healthy and cancer microenvironment; where in physiological condition, they act as antioxidant and do not affect the healthy cells, while in tumor-like condition; they act as an oxidase, and result in a selective killing for the cancer cells. In this experiment, the interaction of nanoceria with glioblastoma and healthy astrocyte cells was examined, and further correlated with the in vitro cytotoxic effects of various nanoceria concentrations (100 and 300 µg/ml) and exposure times (12, 24, and 48 hours). Electron microscopes were used to investigate the cellular-NPs interactions, and to examine the related cytotoxic effects in combination with trypan blue and propidium iodide viability assays. Our data suggest the following results. First, the two cell lines demonstrated capability of taken up the ceria through endocytosis pathway, where the NPs were recognized engulfed by double membrane vesicles at various regions over the cellular cytoplasm. Secondly, cerium oxide nanoparticles were found to affect the glioblastoma cells, but not so severely the corresponding healthy astrocytes at the various concentrations and incubation times, as revealed by the viability assays and the electron microscopy analysis. Thirdly, the viability of the glioblastoma cells after the treatment displayed a declined trend when increasing the ceria concentrations, but did not show such dependency with regard to the different time points. In all cases, the healthy astrocyte cells showed slight alterations in mitochondrial shape which did not influence their viability. Among the various nanoceria concentrations and exposure times, the most efficient dose of treatment was found to be with a concentration of 300 µg/ml at a time point of 24-hour, where higher reduction on the viability of

  18. Impact of CD133 positive stem cell proportion on survival in patients with glioblastoma multiforme

    International Nuclear Information System (INIS)

    Kase, Marju; Minajeva, Ave; Niinepuu, Kristi; Kase, Sandra; Vardja, Markus; Asser, Toomas; Jaal, Jana

    2013-01-01

    The aim of the study was to assess the impact of CD133-positive (CD133+) cancer stem cell proportions on treatment results of glioblastoma multiforme (GBM) patients. Patients with GBM (n = 42) received postoperative radiotherapy (± chemotherapy). Surgically excised GBM tissue sections were immunohistochemically examined for CD133 expression. The proportions of CD133+ GBM cells were determined (%). The proportion of CD133+ GBM stem cells was established by 2 independent researchers whose results were in good accordance (R = 0.8, p < 0.01). Additionally, CD133 expression levels were correlated with patients overall survival. The proportion of CD133+ cells varied between patients, being from 0.5% to 82%. Mean and median proportions of CD133+ cells of the entire study group were 33% ± 24% (mean ± SD) and 28%, respectively. Clinical data do not support the association between higher proportion of stem cells and the aggressiveness of GBM. Median survival time of the study group was 10.0 months (95% CI 9.0–11.0). The survival time clearly depended on the proportion of CD133+ cells (log rank test, p = 0.02). Median survival times for patients with low (< median) and high (≥ median) proportion of CD133+ cells were 9.0 months (95% CI 7.6–10.5) and 12.0 months (95% CI 9.3–14.7), respectively. In multivariate analysis, the proportion of CD133+ cells emerged as a significant independent predictor for longer overall survival (HR 2.0, 95% CI 1.0–3.8, p = 0.04). In patients with higher stem cell proportion, significantly longer survival times after postoperative radiotherapy were achieved. Underlying reasons and possible higher sensitivity of GBM stem cells to fractionated radio-therapy should be clarified in further studies

  19. MRI and the diagnosis of glioblastomas

    International Nuclear Information System (INIS)

    Bowe, S.

    2002-01-01

    This paper is based on an oral presentation given at the Sydney conference in February 2000. Two cases will be presented to demonstrate the use of this imaging modality in the diagnosis of glioblastomas, MRI has superior soft tissue imaging abilities making it ideal for imaging the brain. Conventional MRI is good for evaluating oedema and haemorrhage and offers high resolution without associated bone artefacts. However, as with all imaging modalities there are some disadvantages. Patients with pacemakers, certain types of metallic clips, or claustrophobia may not be suitable for an MRI scan. Copyright (2002) Australian Institute of Radiography

  20. Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma.

    Science.gov (United States)

    Annovazzi, Laura; Mellai, Marta; Schiffer, Davide

    2017-05-26

    Despite improvements in therapeutic strategies, glioblastoma (GB) remains one of the most lethal cancers. The presence of the blood-brain barrier, the infiltrative nature of the tumor and several resistance mechanisms account for the failure of current treatments. Distinct DNA repair pathways can neutralize the cytotoxicity of chemo- and radio-therapeutic agents, driving resistance and tumor relapse. It seems that a subpopulation of stem-like cells, indicated as glioma stem cells (GSCs), is responsible for tumor initiation, maintenance and recurrence and they appear to be more resistant owing to their enhanced DNA repair capacity. Recently, attention has been focused on the pivotal role of the DNA damage response (DDR) in tumorigenesis and in the modulation of therapeutic treatment effects. In this review, we try to summarize the knowledge concerning the main molecular mechanisms involved in the removal of genotoxic lesions caused by alkylating agents, emphasizing the role of GSCs. Beside their increased DNA repair capacity in comparison with non-stem tumor cells, GSCs show a constitutive checkpoint expression that enables them to survive to treatments in a quiescent, non-proliferative state. The targeted inhibition of checkpoint/repair factors of DDR can contribute to eradicate the GSC population and can have a great potential therapeutic impact aiming at sensitizing malignant gliomas to treatments, improving the overall survival of patients.

  1. Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

    International Nuclear Information System (INIS)

    Jhanwar-Uniyal, Meena; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj

    2015-01-01

    Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM

  2. Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

    Energy Technology Data Exchange (ETDEWEB)

    Jhanwar-Uniyal, Meena, E-mail: meena_jhanwar@nymc.edu; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj [Department of Neurosurgery, New York Medical College, Valhalla, NY 10595 (United States)

    2015-03-25

    Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM.

  3. Reticence in disclosure of HIV infection and reasons for bereavement: impact on perinatally infected adolescents' mental health and understanding of HIV treatment and prevention in Johannesburg, South Africa.

    Science.gov (United States)

    Woollett, Nataly; Black, Vivian; Cluver, Lucie; Brahmbhatt, Heena

    2017-07-01

    Survival rates of perinatally infected HIV-positive adolescents (PIA) are increasing in sub-Saharan Africa. There is a gap in understanding how disclosure and bereavement have an impact on PIA beliefs and understanding of their HIV infection and its management. In-depth interviews were conducted with 25 purposively selected adolescents aged 13-19 years from 5 public health clinics in Johannesburg, South Africa. Data were analysed using NVivo 10 using a thematic approach. PIA experience incomplete disclosure both of their HIV status and reasons for their bereavements, which limits their understanding of how they became infected, vertical transmission and prevention options like prevention of mother-to-child transmission (PMTCT). Most participants were orphaned and were experiencing complicated grieving (i.e., engaged in unresolved tasks of grieving) which had a negative impact on their mental health, and ability to accept their HIV status and adhere to treatment. PIA need improved communication regarding vertical transmission and how they became HIV-positive, as well as reasons for death of their loved ones to properly understand their HIV status and engage effectively in management. Honest communication about how relatives died and truthful engagement in the process of disclosure of HIV status is necessary to reduce stigma and complicated grieving, and improve mental health in this population.

  4. Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature

    Directory of Open Access Journals (Sweden)

    Maria-del-Mar Inda

    2014-01-01

    Full Text Available Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM, the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

  5. Glioblastoma multiforme: a look inside its heterogeneous nature.

    Science.gov (United States)

    Inda, Maria-Del-Mar; Bonavia, Rudy; Seoane, Joan

    2014-01-27

    Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

  6. Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature

    International Nuclear Information System (INIS)

    Inda, Maria-del-Mar; Bonavia, Rudy; Seoane, Joan

    2014-01-01

    Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape

  7. Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature

    Energy Technology Data Exchange (ETDEWEB)

    Inda, Maria-del-Mar, E-mail: mminda@vhio.net; Bonavia, Rudy [Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, 119-129 Passeig Vall d’Hebron, Barcelona 08035 (Spain); Seoane, Joan [Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, 119-129 Passeig Vall d’Hebron, Barcelona 08035 (Spain); Catalan Institution of Research and Advanced Studies (ICREA), Barcelona 08035 (Spain)

    2014-01-27

    Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.

  8. Reasons behind Greek problem drug users’ decisions to quit using drugs and engage in treatment of their own volition: sense of self and the Greek filotimo.

    Science.gov (United States)

    Fotopoulou, Maria

    2014-04-01

    The aim of this study was to explore Greek problem drug users’ perceptions of the reasons that led them to quit using drugs and engage in treatment of their own volition. Qualitative semi-structured in-depth interviews. Two state drug agencies in Thessaloniki, Greece. A total of 40 adult problem drug-using men and women participated in the study. Participants were asked to reflect on their decisions to wean themselves from drugs and enter treatment. Findings Participants reported that their decisions centred on the re-conceptualization of the drug-using community and their membership in it, the desire to restore aspects of identities thatwere deemed to be spoiled, and finally memories of their drug-free selves. The importance of the distinctively Greek notion of filotimo in this discussion is highlighted. Primarily in relation to filotimo (a concept that represents a complex array of virtues that regulates behaviour towards one’s family), the desire to restore one’s spoiled identity plays a pivotal role in Greek problem drug users’ decisions to cease drug use and engage in treatment.

  9. Synemin promotes AKT-dependent glioblastoma cell proliferation by antagonizing PP2A.

    Science.gov (United States)

    Pitre, Aaron; Davis, Nathan; Paul, Madhumita; Orr, A Wayne; Skalli, Omar

    2012-04-01

    The intermediate filament protein synemin is present in astrocyte progenitors and glioblastoma cells but not in mature astrocytes. Here we demonstrate a role for synemin in enhancing glioblastoma cell proliferation and clonogenic survival, as synemin RNA interference decreased both behaviors by inducing G1 arrest along with Rb hypophosphorylation and increased protein levels of the G1/S inhibitors p21(Cip1) and p27(Kip1). Akt involvement was demonstrated by decreased phosphorylation of its substrate, p21(Cip1), and reduced Akt catalytic activity and phosphorylation at essential activation sites. Synemin silencing, however, did not affect the activities of PDPK1 and mTOR complex 2, which directly phosphorylate Akt activation sites, but instead enhanced the activity of the major regulator of Akt dephosphorylation, protein phosphatase type 2A (PP2A). This was accompanied by changes in PP2A subcellular distribution resulting in increased physical interactions between PP2A and Akt, as shown by proximity ligation assays (PLAs). PLAs and immunoprecipitation experiments further revealed that synemin and PP2A form a protein complex. In addition, treatment of synemin-silenced cells with the PP2A inhibitor cantharidic acid resulted in proliferation and pAkt and pRb levels similar to those of controls. Collectively these results indicate that synemin positively regulates glioblastoma cell proliferation by helping sequester PP2A away from Akt, thereby favoring Akt activation.

  10. Anticancer activity of 7-epiclusianone, a benzophenone from Garcinia brasiliensis, in glioblastoma.

    Science.gov (United States)

    Sales, Leilane; Pezuk, Julia Alejandra; Borges, Kleiton Silva; Brassesco, María Sol; Scrideli, Carlos Alberto; Tone, Luiz Gonzaga; dos Santos, Marcelo Henrique; Ionta, Marisa; de Oliveira, Jaqueline Carvalho

    2015-10-30

    Glioblastoma is the most common tumor of the central nervous system and one of the hardest tumors to treat. Consequently, the search for novel therapeutic options is imperative. 7-epiclusianone, a tetraprenylated benzophenone isolated from the epicarp of the native plant Garcinia brasiliensis, exhibits a range of biological activities but its prospect anticancer activity is underexplored. Thus, the aim of the present study was to evaluate the influence of 7-epiclusianone on proliferation, clonogenic capacity, cell cycle progression and induction of apoptosis in two glioblastoma cell lines (U251MG and U138MG). Cell viability was measured by the MTS assay; for the clonogenic assay, colonies were stained with Giemsa and counted by direct visual inspection; For cell cycle analysis, cells were stained with propidium iodide and analyzed by cytometry; Cyclin A expression was determined by immunoblotting; Apoptotic cell death was determined by annexin V fluorescein isothiocyanate labeling and Caspase-3 activity in living cells. Viability of both cell lines was drastically inhibited; moreover, the colony formation capacity was significantly reduced, demonstrating long-term effects even after removal of the drug. 7-epiclusianone treatment at low concentrations also altered cell cycle progression, decreased the S and G2/M populations and at higher concentrations increased the number of cells at sub-G1, in concordance with the increase of apoptotic cells. The present study demonstrates for the first time the anticancer potential of 7-epiclusianone against glioblastoma cells, thus meriting its further investigation as a potential therapeutic agent.

  11. Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells

    Directory of Open Access Journals (Sweden)

    Araceli Gutiérrez-Rodríguez

    2017-01-01

    Full Text Available Progesterone-induced blocking factor (PIBF is a progesterone (P4 regulated protein expressed in different types of high proliferative cells including astrocytomas, the most frequent and aggressive brain tumors. It has been shown that PIBF increases the number of human astrocytoma cells. In this work, we evaluated PIBF regulation by P4 and the effects of PIBF on proliferation, migration, and invasion of U87 and U251 cells, both derived from human glioblastomas. PIBF mRNA expression was upregulated by P4 (10 nM from 12 to 24 h. Glioblastoma cells expressed two PIBF isoforms, 90 and 57 kDa. The content of the shorter isoform was increased by P4 at 24 h, while progesterone receptor antagonist RU486 (10 μM blocked this effect. PIBF (100 ng/mL increased the number of U87 cells on days 4 and 5 of treatment and induced cell proliferation on day 4. Wound-healing assays showed that PIBF increased the migration of U87 (12–48 h and U251 (24 and 48 h cells. Transwell invasion assays showed that PIBF augmented the number of invasive cells in both cell lines at 24 h. These data suggest that PIBF promotes proliferation, migration, and invasion of human glioblastoma cells.

  12. A quasi-randomized feasibility pilot study of specific treatments to improve emotion recognition and mental-state reasoning impairments in schizophrenia.

    Science.gov (United States)

    Marsh, Pamela Jane; Polito, Vince; Singh, Subba; Coltheart, Max; Langdon, Robyn; Harris, Anthony W

    2016-10-24

    Impaired ability to make inferences about what another person might think or feel (i.e., social cognition impairment) is recognised as a core feature of schizophrenia and a key determinant of the poor social functioning that characterizes this illness. The development of treatments to target social cognitive impairments as a causal factor of impaired functioning in schizophrenia is of high priority. In this study, we investigated the acceptability, feasibility, and limited efficacy of 2 programs targeted at specific domains of social cognition in schizophrenia: "SoCog" Mental-State Reasoning Training (SoCog-MSRT) and "SoCog" Emotion Recognition Training (SoCog-ERT). Thirty-one participants with schizophrenia or schizoaffective disorder were allocated to either SoCog-MSRT (n = 19) or SoCog-ERT (n = 12). Treatment comprised 12 twice-weekly sessions for 6 weeks. Participants underwent assessments of social cognition, neurocognition and symptoms at baseline, post-training and 3-months after completing training. Attendance at training sessions was high with an average of 89.29 % attendance in the SoCog-MSRT groups and 85.42 % in the SoCog-ERT groups. Participants also reported the 2 programs as enjoyable and beneficial. Both SoCog-MSRT and SoCog-ERT groups showed increased scores on a false belief reasoning task and the Reading the Mind in the Eyes test. The SoCog-MSRT group also showed reduced personalising attributional biases in a small number of participants, while the SoCog-ERT group showed improved emotion recognition. The results are promising and support the feasibility and acceptability of the 2 SoCog programs as well as limited efficacy to improve social cognitive abilities in schizophrenia. There is also some evidence that skills for the recognition of basic facial expressions need specific training. Australian New Zealand Clinical Trials Registry ACTRN12613000978763 . Retrospectively registered 3/09/2013.

  13. HAX-1 Protects Glioblastoma Cells from Apoptosis through the Akt1 Pathway

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    Xin Deng

    2017-12-01

    Full Text Available Glioblastoma is the most common malignant tumor in central nervous system (CNS, and it is still insurmountable and has a poor prognosis. The proliferation and survival mechanism of glioma cells needs to be explored further for the development of glioma treatment. Hematopoietic-substrate-1 associated protein X-1 (HAX-1 has been reported as an anti-apoptosis protein that plays an important role in several malignant tumors. However, the effect and mechanism of HAX-1 in glioblastomas remains unknown. This study aimed to investigate the effect of HAX-1 in glioblastoma cells and explore the mechanism. The results of clone formation and Edu proliferation assay showed slower multiplication in HAX-1 knock-out cells. Flow cytometry showed cell cycle arrest mainly in G0/G1 phase. Apoptosis due to oxidative stress was increased after HAX-1 was knocked out. Western-blot assay exhibited that the levels of p21, Bax, and p53 proteins were significantly raised, and that the activation of the caspase cascade was enhanced in the absence of HAX-1. The degradation rate and ubiquitination of p53 declined because of the decrease in phosphorylation of proteins MDM2 and Akt1. Co-immunoprecipitation (Co-IP and immunefluorescent co-localization assays were performed to test the influence of HAX-1 on the interaction between Akt1 and Hsp90, which is crucial for the activity of Akt1. In conclusion, this novel study suggested that HAX-1 could affect the Akt1 pathway through Hsp90. The knock-out of HAX-1 leads to the inactivity of the Ak1t/MDM2 axis, which leads to increased levels of p53, and finally generates cell cycle arrest and results in the apoptosis of glioblastoma cells.

  14. Repopulation capacity during fractionated irradiation of squamous cell carcinomas and glioblastomas in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Budach, Wilfried; Gioioso, Danielle; Taghian, Alphonse; Stuschke, Martin; Suit, Herman D

    1997-10-01

    Purpose: Determination of clonogenic cell proliferation of three highly malignant squamous cell carcinomas (SCC) and two glioblastoma cell lines during a 20-day course of fractionated irradiation under in vitro conditions. Methods and Materials: Tumor cells in exponential growth phase were plated in 24-well plastic flasks and irradiated 24 h after plating with 250 kV x-rays at room temperature. Six fractions with single doses between 0.6 and 9 Gy were administered in 1.67, 5, 10, 15, and 20 days. Colony growth was monitored for at least 60 days after completion of irradiation. Wells with confluent colonies were considered as 'recurrences' and wells without colonies as 'controlled'. The dose required to control 50% of irradiated wells (WCD{sub 50}) was estimated by a logistic regression for the different overall treatment times. The effective doubling time of clonogenic cells (T{sub eff}) was determined by a direct fit using the maximum likelihood method. Results: The increase of WCD{sub 50} within 18.3 days was highly significant for all tumor cell lines accounting for 7.9 and 12.0 Gy in the two glioblastoma cell lines and for 12.7, 14.0, and 21.7 Gy in the three SCC cell lines. The corresponding T{sub eff}s were 4.4 and 2.0 days for glioblastoma cell lines and 2.4, 4.2, and 1.8 days for SCC cell lines. Population doubling times (PDT) of untreated tumor cells ranged from 1.0 to 1.9 days, showing no correlation with T{sub eff}s. T{sub eff} was significantly longer than PDT in three of five tumor cell lines. No significant differences were observed comparing glioblastomas and SCC. Increase of WCD{sub 50} with time did not correlate with T{sub eff} but with T{sub eff}* InSF2 (surviving fraction at 2 Gy). Conclusion: The intrinsic ability of SCC and glioblastoma cells to repopulate during fractionated irradiation could be demonstrated. Repopulation induced dose loss per day depends on T{sub eff} and intrinsic radiation sensitivity. Proliferation during treatment was

  15. Radiotherapy Results of Brain Astrocytoma and Glioblastoma Multiforme

    International Nuclear Information System (INIS)

    Choi, Doo Ho; Kim, Il Han; Ha, Sung Whan; Chi, Je Geun

    1988-01-01

    A retrospective analysis was performed on 49 patients with astrocytoma of glioblastoma multiforme of brain who received postoperative radiotherapy in the period between February 1979 and December 1985. Fourteen patients had grade I astrocytoma, 11 patients grade II, 14 patients grade III, and 10 patients glioblastoma multiforme. Three year actuarial survival rates were 85.7%, 44.6% and 23.1% for grade I, II, and III astrocytomas, respectively. One and 2 year actuarial survival rates for patients with glioblastoma multiforme were 54.5% and 27.3%, respectively. Histologic grade, age, extent of operation and tumor location were revealed to be prognosticators

  16. Clinical implications of microRNAs in human glioblastoma

    Directory of Open Access Journals (Sweden)

    Masahiro eMizoguchi

    2013-02-01

    Full Text Available Glioblastoma (GBM is one of the most common and dismal brain tumors in adults. Further elucidation of the molecular pathogenesis of GBM is mandatory to improve the overall survival of patients. A novel small non-coding RNA molecule, microRNA (miRNA, appears to represent one of the most attractive target molecules contributing to the pathogenesis of various types of tumors. Recent global analyses have revealed that several miRNAs are clinically implicated in GBM, with some reports indicating the association of miRNA dysregulation with acquired temozolomide (TMZ resistance. More recent studies have revealed that miRNAs could play a role in cancer stem cell (CSC properties, contributing to treatment resistance. In addition, greater impact might be expected from miRNA-targeted therapies based on tumor-derived exosomes that contain numerous functional miRNAs, which could be transferred between tumor cells and surrounding structures. Tumor-derived miRNAs are now considered to be a novel molecular mechanism promoting the progression of GBM. Establishment of miRNA-targeted therapies based on miRNA dysregulation of CSCs could provide effective therapeutic strategies for TMZ-resistant GBM. Recent progress has revealed that miRNAs are not only putative biological markers for diagnosis, but also one of the most promising targets for GBM treatment. Herein, we summarize the translational aspects of miRNAs in the diagnosis and treatment of GBM.

  17. Hypofractionated stereotactic radiation therapy for recurrent glioblastoma: single institutional experience

    International Nuclear Information System (INIS)

    Ciammella, Patrizia; Podgornii, Ala; Galeandro, Maria; D’Abbiero, Nunziata; Pisanello, Anna; Botti, Andrea; Cagni, Elisabetta; Iori, Mauro; Iotti, Cinzia

    2013-01-01

    Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Tumor control and survival have improved with the use of radiotherapy (RT) plus concomitant and adjuvant chemotherapy, but the prognosis remain poor. In most cases the recurrence occurs within 7–9 months after primary treatment. Currently, many approaches are available for the salvage treatment of patients with recurrent GBM, including resection, re-irradiation or systemic agents, but no standard of care exists. We analysed a cohort of patients with recurrent GBM treated with frame-less hypofractionated stereotactic radiation therapy with a total dose of 25 Gy in 5 fractions. Of 91 consecutive patients with newly diagnosed GBM treated between 2007 and 2012 with conventional adjuvant chemo-radiation therapy, 15 underwent salvage RT at recurrence. The median time interval between primary RT and salvage RT was 10.8 months (range, 6–54 months). Overall, patients undergoing salvage RT showed a longer survival, with a median survival of 33 vs. 9.9 months (p= 0.00149). Median overall survival (OS) from salvage RT was 9.5 months. No patients demonstrated clinically significant acute morbidity, and all patients were able to complete the prescribed radiation therapy without interruption. Our results suggest that hypofractionated stereotactic radiation therapy is effective and safe in recurrent GBM. However, until prospective randomized trials will confirm these results, the decision for salvage treatment should remain individual and based on a multidisciplinary evaluation of each patient

  18. Variegated colors of pediatric glioblastoma multiforme: what to expect?

    Directory of Open Access Journals (Sweden)

    Vivek Immanuel

    2017-08-01

    Full Text Available Malignant gliomas account for 35-45% of primary brain tumors; among these glioblastoma multiforme (GBM is the most common adult brain tumor constituting approximately 85%. Its incidence is quite less in the pediatric population and treatment of these patients is particularly challenging. Exposure to ionizing radiation is the only environmental factor found to have any significant association with GBM. Several genetic alterations associated with GBM in adults have been well documented such as epidermal growth factor receptor amplification, overexpression of mouse double minute 2 homolog also known as E3 ubiquitin-protein ligase, Phosphatase and tensin homolog gene mutation, loss of heterozygosity of chromosome 10p and isocitrate dehydrogenase-1 mutation. However, data on genetic mutations in pediatric GBM is still lacking. Exophytic brain stem gliomas are rare tumors and are usually associated with a poor prognosis. The most effective treatment in achieving long-term survival in such patients, is surgical excision of the tumor and then chemoradiotherapy followed by adjuvant chemotherapy by temozolomide. This schedule is the standard treatment for GBM patients. In view of the rarity of pediatric GBM, we report here a case of pontine GBM in a 5-year-old girl.

  19. Long non-coding RNA taurine upregulated 1 enhances tumor-induced angiogenesis through inhibiting microRNA-299 in human glioblastoma.

    Science.gov (United States)

    Cai, H; Liu, X; Zheng, J; Xue, Y; Ma, J; Li, Z; Xi, Z; Li, Z; Bao, M; Liu, Y

    2017-01-19

    Angiogenesis is one of the critical biological elements affecting the development and progression of cancer. Long non-coding RNAs (lncRNAs) are important regulators and aberrantly expressed in various types of human cancer. Our previous studies indicated that lncRNA taurine upregulated 1 (TUG1) implicated in the regulation of blood-tumor barrier permeability; however, its role in glioblastoma angiogenesis still unclear. Here we demonstrated that TUG1 was up-expressed in human glioblastoma tissues and glioblastoma cell lines. Knockdown of TUG1 remarkably suppressed tumor-induced endothelial cell proliferation, migration and tube formation as well as reducing spheroid-based angiogenesis ability in vitro, which are the critical steps for tumor angiogenesis. Besides, knockdown of TUG1 significantly increased the expression of mircroRNA-299 (miR-299), which was down-expressed in glioblastoma tissues and glioblastoma cell lines. Bioinformatics analysis and luciferase reporter assay revealed that TUG1 influenced tumor angiogenesis via directly binding to the miR-299 and there was a reciprocal repression between TUG1 and miR-299 in the same RNA-induced silencing complex. Moreover, knockdown of TUG1 reduced the expression of vascular endothelial growth factor A (VEGFA), which was defined as a functional downstream target of miR-299. In addition, knockdown of TUG1, shown in the in vivo studies, has effects on suppressing tumor growth, reducing tumor microvessel density and decreasing the VEGFA expression by upregulating miR-299 in xenograft glioblastoma model. Overall, the results demonstrated that TUG1 enhances tumor-induced angiogenesis and VEGF expression through inhibiting miR-299. Also, the inhibition of TUG1 could provide a novel therapeutic target for glioblastoma treatment.

  20. Modeled microgravity suppressed invasion and migration of human glioblastoma U87 cells through downregulating store-operated calcium entry

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Zi-xuan [Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Rao, Wei [Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Wang, Huan [Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Wang, Nan-ding [Department of Cardiology, Xi' an Traditional Chinese Medicine Hospital, Xi' an, 710032 (China); Si, Jing-Wen; Zhao, Jiao; Li, Jun-chang [Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Wang, Zong-ren, E-mail: zongren@fmmu.edu.cn [Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China)

    2015-02-13

    Glioblastoma is the most common brain tumor and is characterized with robust invasion and migration potential resulting in poor prognosis. Previous investigations have demonstrated that modeled microgravity (MMG) could decline the cell proliferation and attenuate the metastasis potential in several cell lines. In this study, we studied the effects of MMG on the invasion and migration potentials of glioblastoma in human glioblastoma U87 cells. We found that MMG stimulation significantly attenuated the invasion and migration potentials, decreased thapsigargin (TG) induced store-operated calcium entry (SOCE) and downregulated the expression of Orai1 in U87 cells. Inhibition of SOCE by 2-APB or stromal interaction molecule 1 (STIM1) downregulation both mimicked the effects of MMG on the invasion and migration potentials in U87 cells. Furthermore, upregulation of Orai1 significantly weakened the effects of MMG on the invasion and migration potentials in U87 cells. Therefore, these findings indicated that MMG stimulation inhibited the invasion and migration potentials of U87 cells by downregulating the expression of Orai1 and sequentially decreasing the SOCE, suggesting that MMG might be a new potential therapeutic strategy in glioblastoma treatment in the future. - Highlights: • Modeled microgravity (MMG) suppressed migration and invasion in U87 cells. • MMG downregulated the SOCE and the expression of Orai1. • SOCE inhibition mimicked the effects of MMG on migration and invasion potentials. • Restoration of SOCE diminished the effects of MMG on migration and invasion.

  1. Modeled microgravity suppressed invasion and migration of human glioblastoma U87 cells through downregulating store-operated calcium entry

    International Nuclear Information System (INIS)

    Shi, Zi-xuan; Rao, Wei; Wang, Huan; Wang, Nan-ding; Si, Jing-Wen; Zhao, Jiao; Li, Jun-chang; Wang, Zong-ren

    2015-01-01

    Glioblastoma is the most common brain tumor and is characterized with robust invasion and migration potential resulting in poor prognosis. Previous investigations have demonstrated that modeled microgravity (MMG) could decline the cell proliferation and attenuate the metastasis potential in several cell lines. In this study, we studied the effects of MMG on the invasion and migration potentials of glioblastoma in human glioblastoma U87 cells. We found that MMG stimulation significantly attenuated the invasion and migration potentials, decreased thapsigargin (TG) induced store-operated calcium entry (SOCE) and downregulated the expression of Orai1 in U87 cells. Inhibition of SOCE by 2-APB or stromal interaction molecule 1 (STIM1) downregulation both mimicked the effects of MMG on the invasion and migration potentials in U87 cells. Furthermore, upregulation of Orai1 significantly weakened the effects of MMG on the invasion and migration potentials in U87 cells. Therefore, these findings indicated that MMG stimulation inhibited the invasion and migration potentials of U87 cells by downregulating the expression of Orai1 and sequentially decreasing the SOCE, suggesting that MMG might be a new potential therapeutic strategy in glioblastoma treatment in the future. - Highlights: • Modeled microgravity (MMG) suppressed migration and invasion in U87 cells. • MMG downregulated the SOCE and the expression of Orai1. • SOCE inhibition mimicked the effects of MMG on migration and invasion potentials. • Restoration of SOCE diminished the effects of MMG on migration and invasion

  2. Anticancer potential and mechanism of action of mango ginger (Curcuma amada Roxb.) supercritical CO₂ extract in human glioblastoma cells.

    Science.gov (United States)

    Ramachandran, Cheppail; Lollett, Ivonne V; Escalon, Enrique; Quirin, Karl-Werner; Melnick, Steven J

    2015-04-01

    Mango ginger (Curcuma amada Roxb.) is among the less-investigated species of Curcuma for anticancer properties. We have investigated the anticancer potential and the mechanism of action of a supercritical CO2 extract of mango ginger (CA) in the U-87MG human glioblastoma cell line. CA demonstrated higher cytotoxicity than temozolomide, etoposide, curcumin, and turmeric force with IC50, IC75, and IC90 values of 4.92 μg/mL, 12.87 μg/mL, and 21.30 μg/mL, respectively. Inhibitory concentration values of CA for normal embryonic mouse hypothalamus cell line (mHypoE-N1) is significantly higher than glioblastoma cell line, indicating the specificity of CA against brain tumor cells. CompuSyn analysis indicates that CA acts synergistically with temozolomide and etoposide for the cytotoxicity with combination index values of <1. CA treatment also induces apoptosis in glioblastoma cells in a dose-dependent manner and downregulates genes associated with apoptosis, cell proliferation, telomerase activity, oncogenesis, and drug resistance in glioblastoma cells. © The Author(s) 2014.

  3. Healthy lifestyle factors and risk of cardiovascular events and mortality in treatment-resistant hypertension: the Reasons for Geographic and Racial Differences in Stroke study.

    Science.gov (United States)

    Diaz, Keith M; Booth, John N; Calhoun, David A; Irvin, Marguerite R; Howard, George; Safford, Monika M; Muntner, Paul; Shimbo, Daichi

    2014-09-01

    Few data exist on whether healthy lifestyle factors are associated with better prognosis among individuals with apparent treatment-resistant hypertension, a high-risk phenotype of hypertension. The purpose of this study was to assess the association of healthy lifestyle factors with cardiovascular events, all-cause mortality, and cardiovascular mortality among individuals with apparent treatment-resistant hypertension. We studied participants (n=2043) from the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with apparent treatment-resistant hypertension (blood pressure ≥140/90 mm Hg despite the use of 3 antihypertensive medication classes or the use of ≥4 classes of antihypertensive medication regardless of blood pressure control). Six healthy lifestyle factors adapted from guidelines for the management of hypertension (normal waist circumference, physical activity ≥4 times/week, nonsmoking, moderate alcohol consumption, high Dietary Approaches to Stop Hypertension diet score, and low sodium-to-potassium intake ratio) were examined. A greater number of healthy lifestyle factors were associated with lower risk for cardiovascular events (n=360) during a mean follow-up of 4.5 years. Multivariable-adjusted hazard ratios [HR (95% confidence interval)] for cardiovascular events comparing individuals with 2, 3, and 4 to 6 versus 0 to 1 healthy lifestyle factors were 0.91 (0.68-1.21), 0.80 (0.57-1.14), and 0.63 (0.41-0.95), respectively (P-trend=0.020). Physical activity and nonsmoking were individual healthy lifestyle factors significantly associated with lower risk for cardiovascular events. Similar associations were observed between healthy lifestyle factors and risk for all-cause and cardiovascular mortality. In conclusion, healthy lifestyle factors, particularly physical activity and nonsmoking, are associated with a lower risk for cardiovascular events and mortality among individuals with apparent treatment

  4. Development and validation of a prognostic model for recurrent glioblastoma patients treated with bevacizumab and irinotecan

    DEFF Research Database (Denmark)

    Urup, Thomas; Dahlrot, Rikke Hedegaard; Grunnet, Kirsten

    2016-01-01

    Background Predictive markers and prognostic models are required in order to individualize treatment of recurrent glioblastoma (GBM) patients. Here, we sought to identify clinical factors able to predict response and survival in recurrent GBM patients treated with bevacizumab (BEV) and irinotecan....... Material and methods A total of 219 recurrent GBM patients treated with BEV plus irinotecan according to a previously published treatment protocol were included in the initial population. Prognostic models were generated by means of multivariate logistic and Cox regression analysis. Results In multivariate...

  5. The reasonable timing of the adjuvant radiotherapy in the treatment of uterine carcinosarcoma according to the surgical intent: suggestion based on progression patterns

    International Nuclear Information System (INIS)

    Yu, Jeong Il; Choi, Doo Ho; Huh, Seung Jae; Park, Won; Oh, Dong Ryul; Bae, Duk Soo

    2013-01-01

    We designed this study to identify and suggest the reasonable timing of adjuvant radiotherapy in the treatment of uterine carcinosarcoma according to the surgical intent and patterns of progression. We retrospectively analyzed a total of 50 carcinosarcoma patients diagnosed between 1995 and 2010. Among these 50 patients, 32 underwent curative surgery and 13 underwent maximal tumor debulking surgery. The remaining five patients underwent biopsy only. Twenty-six patients received chemotherapy, and 15 patients received adjuvant radiotherapy. The median follow-up period was 17.3 months. Curative resection (p < 0.001) and stage (p < 0.001) were statistically significant factors affecting survival. During follow-up, 30 patients showed progression. Among these, eight patients (16.0%) had loco-regional progression only. The patients who had received adjuvant radiotherapy did not show loco-regional progression, and radiotherapy was a significant negative risk factor for loco-regional progression (p = 0.01). The time to loco-regional progression was much earlier for non-curative than curative resection (range, 0.7 to 7.6 months vs. 7.5 to 39.0 months). Adjuvant radiotherapy in the treatment of carcinosarcoma might be related to a low loco-regional progression rate. Radiotherapy should be considered in non-curatively resected patients as soon as possible.

  6. Is Glioblastoma an Epigenetic Malignancy?

    International Nuclear Information System (INIS)

    Maleszewska, Marta; Kaminska, Bozena

    2013-01-01

    Epigenetic modifications control gene expression by regulating the access of nuclear proteins to their target DNA and have been implicated in both normal cell differentiation and oncogenic transformation. Epigenetic abnormalities can occur both as a cause and as a consequence of cancer. Oncogenic transformation can deeply alter the epigenetic information enclosed in the pattern of DNA methylation or histone modifications. In addition, in some cancers epigenetic dysfunctions can drive oncogenic transformation. Growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer, i.e., mutations in the metabolic enzymes SDH, FH, and IDH may contribute to cancer development. Epigenetic-based mechanisms are reversible and the possibility of “resetting” the abnormal cancer epigenome by applying pharmacological or genetic strategies is an attractive, novel approach. Gliomas are incurable with all current therapeutic approaches and new strategies are urgently needed. Increasing evidence suggests the role of epigenetic events in development and/or progression of gliomas. In this review, we summarize current data on the occurrence and significance of mutations in the epigenetic and metabolic enzymes in pathobiology of gliomas. We discuss emerging therapies targeting specific epigenetic modifications or chromatin modifying enzymes either alone or in combination with other treatment regimens

  7. TCGA Workshop: Genomics and Biology of Glioblastoma Multiforme (GBM) - TCGA

    Science.gov (United States)

    The National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI) held a workshop entitled, “Genomics and Biology of Glioblastoma Multiforme (GBM),” to review the initial GBM data from the TCGA pilot project.

  8. Target-specific delivery of doxorubicin to human glioblastoma cell ...

    Indian Academy of Sciences (India)

    Abdullah Tahir Bayraç

    2018-01-29

    Jan 29, 2018 ... was previously selected for specific recognition of glioblastoma and represented many advantageous ... antigens, receptors or any 3-D structure on the target cells ..... both PSMA (?) and PSMA (-) prostate cancers.

  9. Unsupervised deep learning reveals prognostically relevant subtypes of glioblastoma.

    Science.gov (United States)

    Young, Jonathan D; Cai, Chunhui; Lu, Xinghua

    2017-10-03

    One approach to improving the personalized treatment of cancer is to understand the cellular signaling transduction pathways that cause cancer at the level of the individual patient. In this study, we used unsupervised deep learning to learn the hierarchical structure within cancer gene expression data. Deep learning is a group of machine learning algorithms that use multiple layers of hidden units to capture hierarchically related, alternative representations of the input data. We hypothesize that this hierarchical structure learned by deep learning will be related to the cellular signaling system. Robust deep learning model selection identified a network architecture that is biologically plausible. Our model selection results indicated that the 1st hidden layer of our deep learning model should contain about 1300 hidden units to most effectively capture the covariance structure of the input data. This agrees with the estimated number of human transcription factors, which is approximately 1400. This result lends support to our hypothesis that the 1st hidden layer of a deep learning model trained on gene expression data may represent signals related to transcription factor activation. Using the 3rd hidden layer representation of each tumor as learned by our unsupervised deep learning model, we performed consensus clustering on all tumor samples-leading to the discovery of clusters of glioblastoma multiforme with differential survival. One of these clusters contained all of the glioblastoma samples with G-CIMP, a known methylation phenotype driven by the IDH1 mutation and associated with favorable prognosis, suggesting that the hidden units in the 3rd hidden layer representations captured a methylation signal without explicitly using methylation data as input. We also found differentially expressed genes and well-known mutations (NF1, IDH1, EGFR) that were uniquely correlated with each of these clusters. Exploring these unique genes and mutations will allow us to

  10. Volumetric and MGMT parameters in glioblastoma patients: Survival analysis

    International Nuclear Information System (INIS)

    Iliadis, Georgios; Kotoula, Vassiliki; Chatzisotiriou, Athanasios; Televantou, Despina; Eleftheraki, Anastasia G; Lambaki, Sofia; Misailidou, Despina; Selviaridis, Panagiotis; Fountzilas, George

    2012-01-01

    In this study several tumor-related volumes were assessed by means of a computer-based application and a survival analysis was conducted to evaluate the prognostic significance of pre- and postoperative volumetric data in patients harboring glioblastomas. In addition, MGMT (O 6 -methylguanine methyltransferase) related parameters were compared with those of volumetry in order to observe possible relevance of this molecule in tumor development. We prospectively analyzed 65 patients suffering from glioblastoma (GBM) who underwent radiotherapy with concomitant adjuvant temozolomide. For the purpose of volumetry T1 and T2-weighted magnetic resonance (MR) sequences were used, acquired both pre- and postoperatively (pre-radiochemotherapy). The volumes measured on preoperative MR images were necrosis, enhancing tumor and edema (including the tumor) and on postoperative ones, net-enhancing tumor. Age, sex, performance status (PS) and type of operation were also included in the multivariate analysis. MGMT was assessed for promoter methylation with Multiplex Ligation-dependent Probe Amplification (MLPA), for RNA expression with real time PCR, and for protein expression with immunohistochemistry in a total of 44 cases with available histologic material. In the multivariate analysis a negative impact was shown for pre-radiochemotherapy net-enhancing tumor on the overall survival (OS) (p = 0.023) and for preoperative necrosis on progression-free survival (PFS) (p = 0.030). Furthermore, the multivariate analysis confirmed the importance of PS in PFS and OS of patients. MGMT promoter methylation was observed in 13/23 (43.5%) evaluable tumors; complete methylation was observed in 3/13 methylated tumors only. High rate of MGMT protein positivity (> 20% positive neoplastic nuclei) was inversely associated with pre-operative tumor necrosis (p = 0.021). Our findings implicate that volumetric parameters may have a significant role in the prognosis of GBM patients. Furthermore

  11. Protein Kinase CK2 Content in GL261 Mouse Glioblastoma.

    Science.gov (United States)

    Ferrer-Font, Laura; Alcaraz, Estefania; Plana, Maria; Candiota, Ana Paula; Itarte, Emilio; Arús, Carles

    2016-07-01

    Glioblastoma (GBM) is the most prevalent and aggressive human glial tumour with a median survival of 14-15 months. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment. Unfortunately, chemoresistence always ensues with concomitant tumour regrowth. Protein kinase CK2 (CK2) contributes to tumour development, proliferation, and suppression of apoptosis in cancer and it is overexpressed in human GBM. Targeting CK2 in GBM treatment may benefit patients. With this translational perspective in mind, we have studied the CK2 expression level by Western blot analysis in a preclinical model of GBM: GL261 cells growing orthotopically in C57BL/6 mice. The expression level of the CK2 catalytic subunit (CK2α) was higher in tumour (about 4-fold) and in contralateral brain parenchyma (more than 2-fold) than in normal brain parenchyma (p < 0.05). In contrast, no significant changes were found in CK2 regulatory subunit (CK2β) expression, suggesting an increased unbalance of CK2α/CK2β in GL261 tumours with respect to normal brain parenchyma, in agreement with a differential role of these two subunits in tumours.

  12. Glioblastoma and acute myeloid leukemia: malignancies with striking similarities.

    Science.gov (United States)

    Goethe, Eric; Carter, Bing Z; Rao, Ganesh; Pemmaraju, Naveen

    2018-01-01

    Acute myeloid leukemia (AML) and glioblastoma (GB) are two malignancies associated with high incidence of treatment refractoriness and generally, uniformly poor survival outcomes. While the former is a hematologic (i.e. a "liquid") malignancy and the latter a solid tumor, the two diseases share both clinical and biochemical characteristics. Both diseases exist predominantly in primary (de novo) forms, with only a small subset of each progressing from precursor disease states like the myelodysplastic syndromes or diffuse glioma. More importantly, the primary and secondary forms of each disease are characterized by common sets of mutations and gene expression abnormalities. The primary versions of AML and GB are characterized by aberrant RAS pathway, matrix metalloproteinase 9, and Bcl-2 expression, and their secondary counterparts share abnormalities in TP53, isocitrate dehydrogenase, ATRX, inhibitor of apoptosis proteins, and survivin that both influence the course of the diseases themselves and their progression from precursor disease. An understanding of these shared features is important, as it can be used to guide both the research about and treatment of each.

  13. Logic, reasoning, and verbal behavior

    OpenAIRE

    Terrell, Dudley J.; Johnston, J. M.

    1989-01-01

    This paper analyzes the traditional concepts of logic and reasoning from the perspective of radical behaviorism and in the terms of Skinner's treatment of verbal behavior. The topics covered in this analysis include the proposition, premises and conclusions, logicality and rules, and deductive and inductive reasoning.

  14. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

    Science.gov (United States)

    Karpel-Massler, Georg; Pareja, Fresia; Aimé, Pascaline; Shu, Chang; Chau, Lily; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Crary, John F.; Canoll, Peter; Siegelin, Markus D.

    2014-01-01

    Background Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. Methods The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. Results The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. Conclusions PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. PMID:25531448

  15. Clonal Evolution of Glioblastoma under Therapy

    Science.gov (United States)

    Wang, Jiguang; Cazzato, Emanuela; Ladewig, Erik; Frattini, Veronique; Rosenbloom, Daniel I. S.; Zairis, Sakellarios; Abate, Francesco; Liu, Zhaoqi; Elliott, Oliver; Shin, Yong-Jae; Lee, Jin-Ku; Lee, In-Hee; Park, Woong-Yang; Eoli, Marica; Blumberg, Andrew J.; Lasorella, Anna; Nam, Do-Hyun; Finocchiaro, Gaetano; Iavarone, Antonio; Rabadan, Raul

    2017-01-01

    Glioblastoma (GBM) constitutes the most common and aggressive primary brain tumor. To better understand how GBM evolves we analyzed longitudinal genomic and transcriptomic data of 114 patients. The analysis reveals a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern together with estimates of evolutionary rates suggest that the relapse associated clone typically preexisted years before diagnosis. 15% of tumors present hypermutations at relapse in highly expressed genes with a clear mutational signature. We find that 11% of recurrent tumors harbor mutations in LTBP4, a protein binding to TGF-β. Silencing LTBP4 in GBM cells leads to TGF-β activity suppression and decreased proliferation. In IDH1-wild-type recurrent GBM, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-β pathway as a potential therapeutic target in GBM. PMID:27270107

  16. Statin use and survival following glioblastoma multiforme

    DEFF Research Database (Denmark)

    Gaist, David; Hallas, Jesper; Friis, Søren

    2014-01-01

    with glioblastoma multiforme (GBM). METHODS: We identified 1562 patients diagnosed with GBM during 2000-2009 from the Danish Cancer Registry and linked this cohort to Danish nationwide demographic and health registries. Within the GBM cohort, each patient recorded as using statins prior to diagnosis (defined as ≥2......-cause death associated with prediagnostic statin use. RESULTS: A total of 339 GBM patients were included in the analyses. Of these, 325 died during median follow-up of 6.9 months (interquartile range: 3.8-13.4 months). Prediagnostic statin use was associated with a reduced HR of death (0.79; 95% CI: 0......: 0.63-1.01). CONCLUSION: Long-term prediagnostic statin use may improve survival following GBM....

  17. Biomimetic strategies for the glioblastoma microenvironment

    Science.gov (United States)

    Cha, Junghwa; Kim, Pilnam

    2017-12-01

    Glioblastoma multiforme (GBM) is a devastating type of tumor with high mortality, caused by extensive infiltration into adjacent tissue and rapid recurrence. Most therapies for GBM have focused on the cytotoxicity, and have not targeted GBM spread. However, there have been numerous attempts to improve therapy by addressing GBM invasion, through understanding and mimicking its behavior using three-dimensional (3D) experimental models. Compared with two-dimensional models and in vivo animal models, 3D GBM models can capture the invasive motility of glioma cells within a 3D environment comprising many cellular and non-cellular components. Based on tissue engineering techniques, GBM invasion has been investigated within a biologically relevant environment, from biophysical and biochemical perspectives, to clarify the pro-invasive factors of GBM. This review discusses the recent progress in techniques for modeling the microenvironments of GBM tissue and suggests future directions with respect to recreating the GBM microenvironment and preclinical applications.

  18. Glioblastoma Multiforme and Lipid Nanocapsules: A Review.

    Science.gov (United States)

    Aparicio-Blanco, Juan; Torres-Suárez, Ana-Isabel

    2015-08-01

    Epidemiological data on central nervous system disorders call for a focus on the major hindrance to brain drug delivery, blood-central nervous system barriers. Otherwise, there is little chance of improving the short-term survival of patients with diseases such as glioblastoma multiforme, which is one of the brain disorders associated with many years of life lost. Targetable nanocarriers for treating malignant gliomas are a unique way to overcome low chemotherapeutic levels at target sites devoid of systemic toxicity. This review describes the currently available targetable nanocarriers, focusing particularly on one of the newest nanocarriers, lipid nanocapsules. All of the strategies that are likely to be exploited by lipid nanocapsules to bypass blood-central nervous system barriers, including the most recent targeting approaches (mesenchymal cells), and novel administration routes (convection enhanced delivery) are discussed, together with their most remarkable achievements in glioma-implanted animal models. Although these systems are promising, much research remains to be done in this field.

  19. Glioblastoma Multiforme Presenting as Spontaneous Intracerebral Hemorrhage

    Directory of Open Access Journals (Sweden)

    Cagatay Ozdol

    2014-06-01

    Full Text Available Brain tumors with concomitant intracerebral hemorrhage are rarely encountered. Hemorrhage as the initial presentation of a brain tumour may pose some diagnostic problems, especially if the tumour is small or the hemorrhage is abundant. We present a 47-year-old man who admitted to the emergency department with sudden onset headache, right blurred vision and gait disturbance. A non-contrast cranial computerized tomography scan performed immediately after his admission revealed a well circumscribed right occipitoparietal haematoma with intense peripheral edema causing compression of the ipsilateral ventricles. On 6th hour of his admission the patient%u2019s neurological status deteriorated and he subsequently underwent emergent craniotomy and microsurgical evacuation of the haematoma. The histopathological examination of the mass was consistent with a glioblastoma multiforme. Neoplasms may be hidden behind each case of spontaneous intracerebral hemorrhage. Histological sampling and investigation is mandatory in the presence of preoperative radiological features suggesting a neoplasm.

  20. Current status of intratumoral therapy for glioblastoma.

    Science.gov (United States)

    Mehta, Ankit I; Linninger, Andreas; Lesniak, Maciej S; Engelhard, Herbert H

    2015-10-01

    With emerging drug delivery technologies becoming accessible, more options are expected to become available to patients with glioblastoma (GBM) in the near future. It is important for clinicians to be familiar with the underlying mechanisms and limitations of intratumoral drug delivery, and direction of recent research efforts. Tumor-adjacent brain is an extremely complex living matrix that creates challenges with normal tissue intertwining with tumor cells. For convection-enhanced delivery (CED), the role of tissue anisotropy for better predicting the biodistribution of the infusate has recently been studied. Computational predictive methods are now available to better plan CED therapy. Catheter design and placement—in addition to the agent being used—are critical components of any protocol. This paper overviews intratumoral therapies for GBM, highlighting key anatomic and physiologic perspectives, selected agents (especially immunotoxins), and some new developments such as the description of the glymphatic system.

  1. An Update in the Use of Antibodies to Treat Glioblastoma Multiforme

    Directory of Open Access Journals (Sweden)

    Norma Y. Hernández-Pedro

    2013-01-01

    Full Text Available Glioblastoma is a deadly brain disease and modest improvement in survival has been made. At initial diagnosis, treatment consists of maximum safe surgical resection, followed by temozolomide and chemoirradiation or adjuvant temozolomide alone. However, these treatments do not improve the prognosis and survival of patients. New treatment strategies are being sought according to the biology of tumors. The epidermal growth factor receptor has been considered as the hallmark in glioma tumors; thereby, some antibodies have been designed to bind to this receptor and block the downstream signaling pathways. Also, it is known that vascularization plays an important role in supplying new vessels to the tumor; therefore, new therapy has been guided to inhibit angiogenic growth factors in order to limit tumor growth. An innovative strategy in the treatment of glial tumors is the use of toxins produced by bacteria, which may be coupled to specific carrier-ligands and used for tumoral targeting. These carrier-ligands provide tumor-selective properties by the recognition of a cell-surface receptor on the tumor cells and promote their binding of the toxin-carrier complex prior to entry into the cell. Here, we reviewed some strategies to improve the management and treatment of glioblastoma and focused on the use of antibodies.

  2. Effectiveness of maximal safe resection for glioblastoma including elderly and low karnofsky performance status patients. Retrospective review at a single institute

    International Nuclear Information System (INIS)

    Uzuka, Takeo; Takahashi, Hideaki; Aoki, Hiroshi; Natsumeda, Manabu; Fujii, Yukihiko

    2012-01-01

    Elderly and low Karnofsky performance status (KPS) patients have been excluded from most prospective trials. This retrospective study investigated glioblastoma treatment outcomes, including those of elderly and low KPS patients, and analyzed the prognostic factors using the medical records of 107 consecutive patients, 59 men and 48 women aged from 21 to 85 years (median 65 years), with newly diagnosed glioblastoma treated at our institute. There were 71 high-risk patients with age >70 years and/or KPS 6 -methylguanine-deoxyribonucleic acid methyltransferase-negative (p=0.027), and more than subtotal removal (p=0.003) were significant prognostic factors. The median postoperative KPS score tended to be better than the preoperative score, even in the high-risk group. We recommend maximal safe resection for glioblastoma patients, even those with advanced age and/or with low KPS scores. (author)

  3. Factors influencing oral hygiene behaviour and gingival outcomes 3 and 12 months after initial periodontal treatment: an exploratory test of an extended Theory of Reasoned Action.

    Science.gov (United States)

    Jönsson, Birgitta; Baker, Sarah R; Lindberg, Per; Oscarson, Nils; Ohrn, Kerstin

    2012-02-01

    The aim was to empirically test the extended Theory of Reasoned Action (TRA) and the prospective direct and indirect role of attitudes, beliefs, subjective norms, self-efficacy, and a cognitive behavioural intervention in adult's oral hygiene behaviour and gingival outcomes at 3- and 12-month follow-up. Data were derived from an RCT evaluating the effectiveness of oral hygiene educational programs integrated in non-surgical periodontal treatment (n = 113). Before baseline examination, participants completed a self-report questionnaire. Structural equation modelling using maximum likelihood estimation with bootstrapping was used to test the direct and indirect (mediated) pathways within the extended TRA model. The extended TRA model explained a large amount of variance in gingival outcome scores at 12 months (56%). A higher level of self-efficacy at baseline was associated with higher frequencies of oral hygiene behaviour at 3 months. Being female was linked to more normative beliefs that, in turn, related to greater behavioural beliefs and self-efficacy. Gender was also related to behavioural beliefs, attitudes and subjective norms. Both frequency of oral hygiene behaviour at 3 months and the cognitive behavioural intervention predicted gingival outcome at 12 months. The model demonstrated that self-efficacy, gender and a cognitive behavioural intervention were important predictors of oral hygiene behavioural change. © 2011 John Wiley & Sons A/S.

  4. Temozolomide during radiotherapy of glioblastoma multiforme. Daily administration improves survival

    Energy Technology Data Exchange (ETDEWEB)

    Nachbichler, Silke Birgit; Schupp, Gabi; Ballhausen, Hendrik; Niyazi, Maximilian; Belka, Claus [LMU Munich, Department of Radiation Oncology, Munich (Germany)

    2017-11-15

    Temozolomide-(TMZ)-based chemoradiotherapy defines the current gold standard for the treatment of newly diagnosed glioblastoma. Data regarding the influence of TMZ dose density during chemoradiotherapy are currently not available. We retrospectively compared outcomes in patients receiving no TMZ, TMZ during radiotherapy on radiotherapy days only, and TMZ constantly 7 days a week. From 2002-2012, a total of 432 patients with newly diagnosed glioblastoma received radiotherapy in our department: 118 patients had radiotherapy alone, 210 had chemoradiotherapy with TMZ (75 mg/m{sup 2}) daily (7/7), and 104 with TMZ only on radiotherapy days (5/7). Radiotherapy was applied to a total dose of 60 Gy. Median survival after radiotherapy alone was 9.1 months, compared to 12.6 months with 5/7-TMZ and to 15.7 months with 7/7-TMZ. The 1-year survival rates were 33, 52, and 64%, respectively. Kaplan-Meier analysis showed a significant improvement of TMZ-7/7 vs. 5/7 (p = 0.01 by the log-rank test), while 5/7-TMZ was still superior to no TMZ at all (p = 0.02). Multivariate Cox regression showed a significant influence of TMZ regimen (p = 0.009) on hazard rate (+58% between groups) even in the presence of confounding factors age, sex, resection status, and radiotherapy dose concept. Our results confirm the findings of the EORTC/NCIC trial. It seems that also a reduced TMZ scheme can at first prolong the survival of glioblastoma patients, but not as much as the daily administration. (orig.) [German] Eine Temozolomid-(TMZ-)basierte Radiochemotherapie ist der gegenwaertige Goldstandard in der Behandlung von neu diagnostizierten Glioblastomen. Daten bezueglich des Einflusses der TMZ-Dosisdichte waehrend der Radiochemotherapie sind derzeit nicht vorhanden. Wir haben retrospektiv die Ergebnisse von Patienten verglichen, die entweder kein TMZ, TMZ zur Strahlentherapie nur an Bestrahlungstagen oder TMZ konstant 7 Tage/Woche erhalten hatten. Von 2002-2012 bekamen insgesamt 432 Patienten mit

  5. Relations between Inductive Reasoning and Deductive Reasoning

    Science.gov (United States)

    Heit, Evan; Rotello, Caren M.

    2010-01-01

    One of the most important open questions in reasoning research is how inductive reasoning and deductive reasoning are related. In an effort to address this question, we applied methods and concepts from memory research. We used 2 experiments to examine the effects of logical validity and premise-conclusion similarity on evaluation of arguments.…

  6. Methionine Uptake and Required Radiation Dose to Control Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Iuchi, Toshihiko, E-mail: tiuchi@chiba-cc.jp [Division of Neurological Surgery, Chiba Cancer Center, Chiba (Japan); Hatano, Kazuo [Division of Radiation Oncology, Tokyo Bay Advanced Imaging and Radiation Oncology Clinic, Makuhari, Chiba (Japan); Uchino, Yoshio [Division of Nuclear Medicine, Chiba Ryogo Center, Chiba (Japan); Itami, Makiko [Division of Surgical Pathology, Chiba Cancer Center, Chiba (Japan); Hasegawa, Yuzo; Kawasaki, Koichiro; Sakaida, Tsukasa [Division of Neurological Surgery, Chiba Cancer Center, Chiba (Japan); Hara, Ryusuke [Division of Radiation Oncology, Chiba Cancer Center, Chiba (Japan)

    2015-09-01

    Purpose: The purpose of this study was to retrospectively assess the feasibility of radiation therapy planning for glioblastoma multiforme (GBM) based on the use of methionine (MET) positron emission tomography (PET), and the correlation among MET uptake, radiation dose, and tumor control. Methods and Materials: Twenty-two patients with GBM who underwent MET-PET prior to radiation therapy were enrolled. MET uptake in 30 regions of interest (ROIs) from 22 GBMs, biologically effective doses (BEDs) for the ROIs and their ratios (MET uptake:BED) were compared in terms of whether the ROIs were controlled for >12 months. Results: MET uptake was significantly correlated with tumor control (odds ratio [OR], 10.0; P=.005); however, there was a higher level of correlation between MET uptake:BED ratio and tumor control (OR, 40.0; P<.0001). These data indicated that the required BEDs for controlling the ROIs could be predicted in terms of MET uptake; BED could be calculated as [34.0 × MET uptake] Gy from the optimal threshold of the MET uptake:BED ratio for tumor control. Conclusions: Target delineation based on MET-PET was demonstrated to be feasible for radiation therapy treatment planning. MET-PET could not only provide precise visualization of infiltrating tumor cells but also predict the required radiation doses to control target regions.

  7. Arsenic trioxide sensitizes glioblastoma to a myc inhibitor.

    Directory of Open Access Journals (Sweden)

    Yayoi Yoshimura

    Full Text Available Glioblastoma multiforme (GBM is associated with high mortality due to infiltrative growth and recurrence. Median survival of the patients is less than 15 months, increasing requirements for new therapies. We found that both arsenic trioxide and 10058F4, an inhibitor of Myc, induced differentiation of cancer stem-like cells (CSC of GBM and that arsenic trioxide drastically enhanced the anti-proliferative effect of 10058F4 but not apoptotic effects. EGFR-driven genetically engineered GBM mouse model showed that this cooperative effect is higher in EGFRvIII-expressing INK4a/Arf-/- neural stem cells (NSCs than in control wild type NSCs. In addition, treatment of GBM CSC xenografts with arsenic trioxide and 10058F4 resulted in significant decrease in tumor growth and increased differentiation with concomitant decrease of proneural and mesenchymal GBM CSCs in vivo. Our study was the first to evaluate arsenic trioxide and 10058F4 interaction in GBM CSC differentiation and to assess new opportunities for arsenic trioxide and 10058F4 combination as a promising approach for future differentiation therapy of GBM.

  8. Molecular Characteristics in MRI-classified Group 1 Glioblastoma Multiforme

    Directory of Open Access Journals (Sweden)

    William E Haskins

    2013-07-01

    Full Text Available Glioblastoma multiforme (GBM is a clinically and pathologically heterogeneous brain tumor. Previous study of MRI-classified GBM has revealed a spatial relationship between Group 1 GBM (GBM1 and the subventricular zone (SVZ. The SVZ is an adult neural stem cell niche and is also suspected to be the origin of a subtype of brain tumor. The intimate contact between GBM1 and the SVZ raises the possibility that tumor cells in GBM1 may be most related to SVZ cells. In support of this notion, we found that neural stem cell and neuroblast markers are highly expressed in GBM1. Additionally, we identified molecular characteristics in this type of GBM that include up-regulation of metabolic enzymes, ribosomal proteins, heat shock proteins, and c-Myc oncoprotein. As GBM1 often recurs at great distances from the initial lesion, the rewiring of metabolism and ribosomal biogenesis may facilitate cancer cells’ growth and survival during tumor migration. Taken together, combined our findings and MRI-based classification of GBM1 would offer better prediction and treatment for this multifocal GBM.

  9. Tumor and Endothelial Cell Hybrids Participate in Glioblastoma Vasculature

    Directory of Open Access Journals (Sweden)

    Soufiane El Hallani

    2014-01-01

    Full Text Available Background. Recently antiangiogenic therapy with bevacizumab has shown a high but transient efficacy in glioblastoma (GBM. Indeed, GBM is one of the most angiogenic human tumors and endothelial proliferation is a hallmark of the disease. We therefore hypothesized that tumor cells may participate in endothelial proliferation of GBM. Materials and Methods. We used EGFR FISH Probe to detect EGFR amplification and anti-CD31, CD105, VE-cadherin, and vWF to identify endothelial cells. Endothelial and GBM cells were grown separately, labeled with GFP and DsRed lentiviruses, and then cocultured with or without contact. Results. In a subset of GBM tissues, we found that several tumor endothelial cells carry EGFR amplification, characteristic of GBM tumor cells. This observation was reproduced in vitro: when tumor stem cells derived from GBM were grown in the presence of human endothelial cells, a fraction of them acquired endothelial markers (CD31, CD105, VE-cadherin, and vWF. By transduction with GFP and DsRed expressing lentiviral vectors, we demonstrate that this phenomenon is due to cell fusion and not transdifferentiation. Conclusion. A fraction of GBM stem cells thus has the capacity to fuse with endothelial cells and the resulting hybrids may participate in tumor microvascular proliferation and in treatment resistance.

  10. The antiproliferative and apoptotic effects of apigenin on glioblastoma cells.

    Science.gov (United States)

    Stump, Trevor A; Santee, Brittany N; Williams, Lauren P; Kunze, Rachel A; Heinze, Chelsae E; Huseman, Eric D; Gryka, Rebecca J; Simpson, Denise S; Amos, Samson

    2017-07-01

    Glioblastoma (GBM) is highly proliferative, infiltrative, malignant and the most deadly form of brain tumour. The epidermal growth factor receptor (EGFR) is overexpressed, amplified and mutated in GBM and has been shown to play key and important roles in the proliferation, growth and survival of this tumour. The goal of our study was to investigate the antiproliferative, apoptotic and molecular effects of apigenin in GBM. Proliferation and viability tests were carried out using the trypan blue exclusion, MTT and lactate dehydrogenase (LDH) assays. Flow cytometry was used to examine the effects of apigenin on the cell cycle check-points. In addition, we determined the effects of apigenin on EGFR-mediated signalling pathways by Western blot analyses. Our results showed that apigenin reduced cell viability and proliferation in a dose- and time-dependent manner while increasing cytotoxicity in GBM cells. Treatment with apigenin-induced is poly ADP-ribose polymerase (PARP) cleavage and caused cell cycle arrest at the G2M checkpoint. Furthermore, our data revealed that apigenin inhibited EGFR-mediated phosphorylation of mitogen-activated protein kinase (MAPK), AKT and mammalian target of rapamycin (mTOR) signalling pathways and attenuated the expression of Bcl-xL. Our results demonstrated that apigenin has potent inhibitory effects on pathways involved in GBM proliferation and survival and could potentially be used as a therapeutic agent for GBM. © 2017 Royal Pharmaceutical Society.

  11. Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response.

    Science.gov (United States)

    Hombach-Klonisch, Sabine; Mehrpour, Maryam; Shojaei, Shahla; Harlos, Craig; Pitz, Marshall; Hamai, Ahmed; Siemianowicz, Krzysztof; Likus, Wirginia; Wiechec, Emilia; Toyota, Brian D; Hoshyar, Reyhane; Seyfoori, Amir; Sepehri, Zahra; Ande, Sudharsana R; Khadem, Forough; Akbari, Mohsen; Gorman, Adrienne M; Samali, Afshin; Klonisch, Thomas; Ghavami, Saeid

    2018-04-01

    Despite advances in neurosurgical techniques and radio-/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Analysis of Electronic Densities and Integrated Doses in Multiform Glioblastomas Stereotactic Radiotherapy

    International Nuclear Information System (INIS)

    Baron-Aznar, C.; Moreno-Jimenez, S.; Celis, M. A.; Ballesteros-Zebadua, P.; Larraga-Gutierrez, J. M.

    2008-01-01

    Integrated dose is the total energy delivered in a radiotherapy target. This physical parameter could be a predictor for complications such as brain edema and radionecrosis after stereotactic radiotherapy treatments for brain tumors. Integrated Dose depends on the tissue density and volume. Using CT patients images from the National Institute of Neurology and Neurosurgery and BrainScan(c) software, this work presents the mean density of 21 multiform glioblastomas, comparative results for normal tissue and estimated integrated dose for each case. The relationship between integrated dose and the probability of complications is discussed

  13. Spinal Cord Glioblastoma Induced by Radiation Therapy of Nasopharyngeal Rhabdomyosarcoma with MRI Findings: Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Se Jin; Kim, In One [Dept. of Radiology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2012-09-15

    Radiation-induced spinal cord gliomas are extremely rare. Since the first case was reported in 1980, only six additional cases have been reported.; The radiation-induced gliomas were related to the treatment of Hodgkin's lymphoma, thyroid cancer, and medullomyoblastoma, and to multiple chest fluoroscopic examinations in pulmonary tuberculosis patient. We report a case of radiation-induced spinal cord glioblastoma developed in a 17-year-old girl after a 13-year latency period following radiotherapy for nasopharyngeal rhabdomyosarcoma. MRI findings of our case are described.

  14. Use of ERC-1671 Vaccine in a Patient with Recurrent Glioblastoma Multiforme after Progression during Bevacizumab Therapy: First Published Report.

    Science.gov (United States)

    Bota, Daniela A; Alexandru-Abrams, Daniela; Pretto, Chrystel; Hofman, Florence M; Chen, Thomas C; Fu, Beverly; Carrillo, Jose A; Schijns, Virgil Ejc; Stathopoulos, Apostolos

    2015-01-01

    Glioblastoma multiforme is a highy aggressive tumor that recurs despite resection, focal beam radiation, and temozolamide chemotherapy. ERC-1671 is an experimental treatment strategy that uses the patient's own immune system to attack the tumor cells. The authors report preliminary data on the first human administration of ERC-1671 vaccination under a single-patient, compassionate-use protocol. The patient survived for ten months after the vaccine administration without any other adjuvant therapy and died of complications related to his previous chemotherapies.

  15. Synthetic miR-145 Mimic Enhances the Cytotoxic Effect of the Antiangiogenic Drug Sunitinib in Glioblastoma.

    Science.gov (United States)

    Liu, Hongwei; Liu, Zhixiong; Jiang, Bing; Huo, Lei; Liu, Jinfang; Lu, Jingchen

    2015-06-01

    Although aggressive therapeutic regimen has been applied in the treatment of Glioblastoma (GBM), the prognosis of patients with GBM remains poor. Preclinical studies have demonstrated the efficacy of Suntinib in GBM both in vitro and in vivo. In this study, we showed that the cytotoxicity was enhanced by transfection with miR-145 mimic. In addition, we suggested that the enhanced cytotoxicity of Sunitinib by miR-145 mimic was mediated by inhibition of both P-gp and Bcrp.

  16. Long-Term Survival after Gamma Knife Radiosurgery in a Case of Recurrent Glioblastoma Multiforme: A Case Report and Review of the Literature

    Science.gov (United States)

    Thumma, Sudheer R.; Elaimy, Ameer L.; Daines, Nathan; Mackay, Alexander R.; Lamoreaux, Wayne T.; Fairbanks, Robert K.; Demakas, John J.; Cooke, Barton S.; Lee, Christopher M.

    2012-01-01

    The management of recurrent glioblastoma is highly challenging, and treatment outcomes remain uniformly poor. Glioblastoma is a highly infiltrative tumor, and complete surgical resection of all microscopic extensions cannot be achieved at the time of initial diagnosis, and hence local recurrence is observed in most patients. Gamma Knife radiosurgery has been used to treat these tumor recurrences for select cases and has been successful in prolonging the median survival by 8–12 months on average for select cases. We present the unique case of a 63-year-old male with multiple sequential recurrences of glioblastoma after initial standard treatment with surgery followed by concomitant external beam radiation therapy and chemotherapy (temozolomide). The patient was followed clinically as well as with surveillance MRI scans at every 2-3-month intervals. The patient underwent Gamma Knife radiosurgery three times for 3 separate tumor recurrences, and the patient survived for seven years following the initial diagnosis with this aggressive treatment. The median survival in patients with recurrent glioblastoma is usually 8–12 months after recurrence, and this unique case illustrates that aggressive local therapy can lead to long-term survivors in select situations. We advocate that each patient treatment at the time of recurrence should be tailored to each clinical situation and desire for quality of life and improved longevity. PMID:22548078

  17. The effects of antiepileptic drugs on the growth of glioblastoma cell lines

    OpenAIRE

    Lee, Ching-Yi; Lai, Hung-Yi; Chiu, Angela; Chan, She-Hung; Hsiao, Ling-Ping; Lee, Shih-Tseng

    2016-01-01

    To determine the effects of antiepileptic drug compounds on glioblastoma cellular growth, we exposed glioblastoma cell lines to select antiepileptic drugs. The effects of selected antiepileptic drugs on glioblastoma cells were measured by MTT assay. For compounds showing significant inhibition, cell cycle analysis was performed. Statistical analysis was performed using SPSS. The antiepileptic compounds selected for screening included carbamazepine, ethosuximide, gabapentin, lamotrigine, levet...

  18. Clinical Neuropathology practice news 1-2014: Pyrosequencing meets clinical and analytical performance criteria for routine testing of MGMT promoter methylation status in glioblastoma

    Science.gov (United States)

    Preusser, Matthias; Berghoff, Anna S.; Manzl, Claudia; Filipits, Martin; Weinhäusel, Andreas; Pulverer, Walter; Dieckmann, Karin; Widhalm, Georg; Wöhrer, Adelheid; Knosp, Engelbert; Marosi, Christine; Hainfellner, Johannes A.

    2014-01-01

    Testing of the MGMT promoter methylation status in glioblastoma is relevant for clinical decision making and research applications. Two recent and independent phase III therapy trials confirmed a prognostic and predictive value of the MGMT promoter methylation status in elderly glioblastoma patients. Several methods for MGMT promoter methylation testing have been proposed, but seem to be of limited test reliability. Therefore, and also due to feasibility reasons, translation of MGMT methylation testing into routine use has been protracted so far. Pyrosequencing after prior DNA bisulfite modification has emerged as a reliable, accurate, fast and easy-to-use method for MGMT promoter methylation testing in tumor tissues (including formalin-fixed and paraffin-embedded samples). We performed an intra- and inter-laboratory ring trial which demonstrates a high analytical performance of this technique. Thus, pyrosequencing-based assessment of MGMT promoter methylation status in glioblastoma meets the criteria of high analytical test performance and can be recommended for clinical application, provided that strict quality control is performed. Our article summarizes clinical indications, practical instructions and open issues for MGMT promoter methylation testing in glioblastoma using pyrosequencing. PMID:24359605

  19. Intravoxel Incoherent Motion Metrics as Potential Biomarkers for Survival in Glioblastoma.

    Directory of Open Access Journals (Sweden)

    Josep Puig

    Full Text Available Intravoxel incoherent motion (IVIM is an MRI technique with potential applications in measuring brain tumor perfusion, but its clinical impact remains to be determined. We assessed the usefulness of IVIM-metrics in predicting survival in newly diagnosed glioblastoma.Fifteen patients with glioblastoma underwent MRI including spin-echo echo-planar DWI using 13 b-values ranging from 0 to 1000 s/mm2. Parametric maps for diffusion coefficient (D, pseudodiffusion coefficient (D*, and perfusion fraction (f were generated for contrast-enhancing regions (CER and non-enhancing regions (NCER. Regions of interest were manually drawn in regions of maximum f and on the corresponding dynamic susceptibility contrast images. Prognostic factors were evaluated by Kaplan-Meier survival and Cox proportional hazards analyses.We found that fCER and D*CER correlated with rCBFCER. The best cutoffs for 6-month survival were fCER>9.86% and D*CER>21.712 x10-3mm2/s (100% sensitivity, 71.4% specificity, 100% and 80% positive predictive values, and 80% and 100% negative predictive values; AUC:0.893 and 0.857, respectively. Treatment yielded the highest hazard ratio (5.484; 95% CI: 1.162-25.88; AUC: 0.723; P = 0.031; fCER combined with treatment predicted survival with 100% accuracy.The IVIM-metrics fCER and D*CER are promising biomarkers of 6-month survival in newly diagnosed glioblastoma.

  20. Leptomeningeal enhancement on preoperative brain MRI in patients with glioblastoma and its clinical impact.

    Science.gov (United States)

    Kim, Hakyoung; Lim, Do Hoon; Kim, Tae Gyu; Lee, Jung-Il; Nam, Do-Hyun; Seol, Ho Jun; Kong, Doo-Sik; Choi, Jung Won; Suh, Yeon-Lim; Kim, Sung Tae

    2018-02-23

    Leptomeningeal enhancement (LME) on preoperative brain magnetic resonance imaging (MRI) does not always indicate leptomeningeal seeding (LMS). With Stupp's regimen, authors have treated glioblastoma patients with LME on preoperative brain MRI but here we tried to find the clinical impact of LME. From 2005 to 2015, 290 patients with glioblastoma have been treated with Stupp's regimen at Samsung Medical Center. Among these, 33 patients showed LME on preoperative brain MRI. We compared the clinical outcomes between the patients with or without LME on preoperative brain MRI and analyzed the clinical results according to changes of LME at following MRI. The median survival was 23 months, and 2-year overall survival (OS) and disease-free survival (DFS) rate was 46.3% and 19.6%, respectively. Prognostic factors for OS and DFS were Karnofsky performance status, extent of resection and adjuvant chemotherapy. MGMT promoter methylation status was a significant prognostic factor for DFS. However, LME was not a significant prognostic factor for OS (P = 0.156) or DFS (P = 0.193). Among the 33 patients with LME on preoperative MRI, 21 (63.6%) showed persistent LME at the next MRI. A statistically significant difference in 2-year survival was evident between patients with and without persistent LME (OS, 17.3% and 70.1%, respectively, P = 0.044; DFS, 5.3% and 54.0%, respectively, P = 0.006). The most common pattern of failure was local recurrence. However, patients with persistent LME displayed a higher incidence of LMS than patients without LME. LME on preoperative brain MRI did not affect the clinical results in glioblastoma patients treated with the Stupp's regimen. However, persistence of LME was associated with poor survival and high possibility of LMS. For these patients, the postoperative adjuvant treatment should focus on palliative aim or more aggressive treatment scheme should be followed to overcome the disastrous results. © 2018 John Wiley & Sons Australia, Ltd.

  1. Glioblastoma with Oligodendroglioma Component (GBMO in an adolescent: a case report

    Directory of Open Access Journals (Sweden)

    Amanda Lopes Maia Rodrigues

    2018-06-01

    Full Text Available Background:Glioblastoma with oligodendroglioma component (GBMO is a recently classified subtype of glioblastoma, which carries different clinical and prognostic outcomes, being frequently misdiagnosed. Both glioblastoma and GBMO are mainly seen in older ages, such as the 5th and 6th decades of life, being an extremely rare occurrence in children or adolescents and more frequent in male patients.  Case report: A 15-year-old girl, presented with history of daily headache, not relieved by painkillers, vomiting, blurred vision and strabismus. Magnetic resonance imaging of the brain revealed expansive tumour on left temporo-occipital lobe. Patient was submitted to intracranial exeresis, along with histopathological examination: glial neoplasm with areas of pleomorphism, hyperchromatism, anaplasia, foci of oligodendroglial component, perinuclear halo and ramified capillaries, resembling oligodendroglioma, necrosis and intense mitotic activity. The immunohistochemical analysis revealed positive Glial Fibrillary Acidic Protein (GFAP, synaptophysin, Ki-67 (MindBomb E3 ubiquitin protein ligase 1 – MIB-1and hyperexpression of Epidermal Growth Factor Receptor (EGFR, indicating GBMO. Subsequently, Fluorescence in situ Hybridization (FISH showed 1p/19q codeletion and Isocitrate Dehydrogenase 1 (IDH 1 mutation, suggesting an oligodendroglioma component. Tumour resection was total and symptoms disappeared. Afterwards, she started adjuvant oral chemotherapy with temozolomide. Treatment was completed nine months after the diagnosis, with no greater symptoms or complications and complete remission.  Conclusion: GBMO must be considered as a possible diagnosis when confronted with a malignant glioma with oligodendroglial tumour component, independent of age or genre. Necrosis upon histopathological examination has a strong relation to shorter median overall survival. IDH mutation and 1p/19q codeletion should be analyzed by immunohistochemistry

  2. Hippocampal sparing radiotherapy for glioblastoma patients: a planning study using volumetric modulated arc therapy

    International Nuclear Information System (INIS)

    Hofmaier, Jan; Kantz, Steffi; Söhn, Matthias; Dohm, Oliver S.; Bächle, Stefan; Alber, Markus; Parodi, Katia; Belka, Claus; Niyazi, Maximilian

    2016-01-01

    The purpose of this study is to investigate the potential to reduce exposure of the contralateral hippocampus in radiotherapy for glioblastoma using volumetric modulated arc therapy (VMAT). Datasets of 27 patients who had received 3D conformal radiotherapy (3D-CRT) for glioblastoma with a prescribed dose of 60Gy in fractions of 2Gy were included in this planning study. VMAT plans were optimized with the aim to reduce the dose to the contralateral hippocampus as much as possible without compromising other parameters. Hippocampal dose and treatment parameters were compared to the 3D-CRT plans using the Wilcoxon signed-rank test. The influence of tumour location and PTV size on the hippocampal dose was investigated with the Mann–Whitney-U-test and Spearman’s rank correlation coefficient. The median reduction of the contralateral hippocampus generalized equivalent uniform dose (gEUD) with VMAT was 36 % compared to the original 3D-CRT plans (p < 0.05). Other dose parameters were maintained or improved. The median V30Gy brain could be reduced by 17.9 % (p < 0.05). For VMAT, a parietal and a non-temporal tumour localisation as well as a larger PTV size were predictors for a higher hippocampal dose (p < 0.05). Using VMAT, a substantial reduction of the radiotherapy dose to the contralateral hippocampus for patients with glioblastoma is feasible without compromising other treatment parameters. For larger PTV sizes, less sparing can be achieved. Whether this approach is able to preserve the neurocognitive status without compromising the oncological outcome needs to be investigated in the setting of prospective clinical trials

  3. Location of subventricular zone recurrence and its radiation dose predicts survival in patients with glioblastoma.

    Science.gov (United States)

    Weinberg, Brent D; Boreta, Lauren; Braunstein, Steve; Cha, Soonmee

    2018-07-01

    Glioblastomas are aggressive brain tumors that frequently recur in the subventricular zone (SVZ) despite maximal treatment. The purpose of this study was to evaluate imaging patterns of subventricular progression and impact of recurrent subventricular tumor involvement and radiation dose to patient outcome. Retrospective review of 50 patients diagnosed with glioblastoma and treated with surgery, radiation, and concurrent temozolomide from January 2012 to June 2013 was performed. Tumors were classified based on location, size, and cortical and subventricular zone involvement. Survival was compared based on recurrence type, distance from the initial enhancing tumor (local ≤ 2 cm, distant > 2 cm), and the radiation dose at the recurrence site. Progression of enhancing subventricular tumor was common at both local (58%) and distant (42%) sites. Median survival was better after local SVZ recurrence than distant SVZ recurrence (8.7 vs. 4.3 months, p = 0.04). Radiation doses at local SVZ recurrence sites recurrence averaged 57.0 ± 4.0 Gy compared to 44.7 ± 6.7 Gy at distant SVZ recurrence sites (p = 0.008). Distant subventricular progression at a site receiving ≤ 45 Gy predicted worse subsequent survival (p = 0.05). Glioblastomas frequently recurred in the subventricular zone, and patient survival was worse when enhancing tumor occurred at sites that received lower radiation doses. This recurrent disease may represent disease undertreated at the time of diagnosis, and further study is needed to determine if improved treatment strategies, such as including the subventricular zone in radiation fields, could improve clinical outcomes.

  4. Hemolytic anemia in two patients with glioblastoma multiforme: A possible interaction between vorinostat and dapsone.

    Science.gov (United States)

    Lewis, Jennifer A; Petty, William J; Harmon, Michele; Peacock, James E; Valente, Kari; Owen, John; Pirmohamed, Munir; Lesser, Glenn J

    2015-06-01

    Patients undergoing treatment for glioblastoma multiforme are routinely placed on prophylactic treatment for Pneumocystis jirovecii pneumonia because of significant therapy-induced lymphopenia. In patients with sulfa allergies, dapsone prophylaxis is often used due to its efficacy, long half-life, cost effectiveness, and general safety at low doses. However, dapsone may uncommonly induce a hemolytic anemia, particularly in patients deficient of glucose-6-phosphate dehydrogenase. This hemolysis is thought to be a result of oxidative stress on red blood cells induced by dapsone metabolites which produce reactive oxygen species that disrupt the red blood cell membrane and promote splenic sequestration. A single case report of dapsone-induced hemolytic anemia in a patient with glioblastoma multiforme has been reported. We present two patients with glioblastoma multiforme who developed severe hemolytic anemia shortly after initiating therapy with vorinostat, a pan-active histone deacetylase inhibitor, while on prophylactic dapsone. There are several potential mechanisms by which histone deacetylase inhibition may alter dapsone metabolism including changes in hepatic acetylation or N-glucuronidation leading to an increase in the bioavailability of dapsone's hematotoxic metabolites. In addition, vorinostat may lead to increased hemolysis through inhibition of heat shock protein-90, a chaperone protein that maintains the integrity of the red blood cell membrane cytoskeleton. The potential interaction between dapsone and vorinostat may have important clinical implications as more than 10 clinical trials evaluating drug combinations with vorinostat in patients with malignant glioma are either ongoing or planned in North America. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  5. Defeasibility in Legal Reasoning

    OpenAIRE

    SARTOR, Giovanni

    2009-01-01

    I shall first introduce the idea of reasoning, and of defeasible reasoning in particular. I shall then argue that cognitive agents need to engage in defeasible reasoning for coping with a complex and changing environment. Consequently, defeasibility is needed in practical reasoning, and in particular in legal reasoning

  6. Clinical outcomes following salvage Gamma Knife radiosurgery for recurrent glioblastoma

    Science.gov (United States)

    Larson, Erik W; Peterson, Halloran E; Lamoreaux, Wayne T; MacKay, Alexander R; Fairbanks, Robert K; Call, Jason A; Carlson, Jonathan D; Ling, Benjamin C; Demakas, John J; Cooke, Barton S; Lee, Christopher M

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with a survival prognosis of 14-16 mo for the highest functioning patients. Despite aggressive, multimodal upfront therapies, the majority of GBMs will recur in approximately six months. Salvage therapy options for recurrent GBM (rGBM) are an area of intense research. This study compares recent survival and quality of life outcomes following Gamma Knife radiosurgery (GKRS) salvage therapy. Following a PubMed search for studies using GKRS as salvage therapy for malignant gliomas, nine articles from 2005 to July 2013 were identified which evaluated rGBM treatment. In this review, we compare Overall survival following diagnosis, Overall survival following salvage treatment, Progression-free survival, Time to recurrence, Local tumor control, and adverse radiation effects. This report discusses results for rGBM patient populations alone, not for mixed populations with other tumor histology grades. All nine studies reported median overall survival rates (from diagnosis, range: 16.7-33.2 mo; from salvage, range: 9-17.9 mo). Three studies identified median progression-free survival (range: 4.6-14.9 mo). Two showed median time to recurrence of GBM. Two discussed local tumor control. Six studies reported adverse radiation effects (range: 0%-46% of patients). The greatest survival advantages were seen in patients who received GKRS salvage along with other treatments, like resection or bevacizumab, suggesting that appropriately tailored multimodal therapy should be considered with each rGBM patient. However, there needs to be a randomized clinical trial to test GKRS for rGBM before the possibility of selection bias can be dismissed. PMID:24829861

  7. Differentiating Tumor Progression from Pseudoprogression in Patients with Glioblastomas Using Diffusion Tensor Imaging and Dynamic Susceptibility Contrast MRI.

    Science.gov (United States)

    Wang, S; Martinez-Lage, M; Sakai, Y; Chawla, S; Kim, S G; Alonso-Basanta, M; Lustig, R A; Brem, S; Mohan, S; Wolf, R L; Desai, A; Poptani, H

    2016-01-01

    Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression. Forty-one patients with glioblastomas exhibiting enhancing lesions within 6 months after completion of chemoradiation therapy were retrospectively studied. All patients underwent surgery after MR imaging and were histologically classified as having true progression (>75% tumor), mixed response (25%-75% tumor), or pseudoprogression (<25% tumor). Mean diffusivity, fractional anisotropy, linear anisotropy coefficient, planar anisotropy coefficient, spheric anisotropy coefficient, and maximum relative cerebral blood volume values were measured from the enhancing tissue. A multivariate logistic regression analysis was used to determine the best model for classification of true progression from mixed response or pseudoprogression. Significantly elevated maximum relative cerebral blood volume, fractional anisotropy, linear anisotropy coefficient, and planar anisotropy coefficient and decreased spheric anisotropy coefficient were observed in true progression compared with pseudoprogression (P < .05). There were also significant differences in maximum relative cerebral blood volume, fractional anisotropy, planar anisotropy coefficient, and spheric anisotropy coefficient measurements between mixed response and true progression groups. The best model to distinguish true progression from non-true progression (pseudoprogression and mixed) consisted of fractional anisotropy, linear anisotropy coefficient, and maximum relative cerebral blood volume, resulting in an area under the curve of 0.905. This model also differentiated true progression from mixed response with an area under the curve of 0.901. A combination of fractional anisotropy and maximum relative cerebral blood volume differentiated pseudoprogression from

  8. The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells.

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    Sarah Ball

    Full Text Available Tumors of the central nervous system represent a major source of cancer-related deaths, with medulloblastoma and glioblastoma being the most common malignant brain tumors in children and adults respectively. While significant advances in treatment have been made, with the 5-year survival rate for medulloblastoma at 70-80%, treating patients under 3 years of age still poses a problem due to the deleterious effects of radiation on the developing brain, and the median survival for patients with glioblastoma is only 15 months. The transcription factor, STAT3, has been found constitutively activated in a wide variety of cancers and in recent years it has become an attractive therapeutic target. We designed a non-peptide small molecule STAT3 inhibitor, LLL12, using structure-based design. LLL12 was able to inhibit STAT3 phosphorylation, decrease cell viability and induce apoptosis in medulloblastoma and glioblastoma cell lines with elevated levels of p-STAT3 (Y705. IC(50 values for LLL12 were found to be between 1.07 µM and 5.98 µM in the five cell lines expressing phosphorylated STAT3. STAT3 target genes were found to be downregulated and a decrease in STAT3 DNA binding was observed following LLL12 treatment, indicating that LLL12 is an effective STAT3 inhibitor. LLL12 was also able to inhibit colony formation, wound healing and decreased IL-6 and LIF secretion. Our results suggest that LLL12 is a potent STAT3 inhibitor and that it may be a potential therapeutic treatment for medulloblastoma and glioblastoma.

  9. Age groups related glioblastoma study based on radiomics approach.

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    Li, Zeju; Wang, Yuanyuan; Yu, Jinhua; Guo, Yi; Zhang, Qi

    2017-12-01

    Glioblastoma is the most aggressive malignant brain tumor with poor prognosis. Radiomics is a newly emerging and promising technique to reveal the complex relationships between high-throughput medical image features and deep information of disease including pathology, biomarkers and genomics. An approach was developed to investigate the internal relationship between magnetic resonance imaging (MRI) features and the age-related origins of glioblastomas based on a quantitative radiomics method. A fully automatic image segmentation method was applied to segment the tumor regions from three dimensional MRI images. 555 features were then extracted from the image data. By analyzing large numbers of quantitative image features, some predictive and prognostic information could be obtained by the radiomics approach. 96 patients diagnosed with glioblastoma pathologically have been divided into two age groups (age groups (T test, p age difference (T test, p= .006). In conclusion, glioblastoma in different age groups present different radiomics-feature patterns with statistical significance, which indicates that glioblastoma in different age groups should have different pathologic, protein, or genic origins.

  10. Nuclear receptor TLX inhibits TGF-β signaling in glioblastoma.

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    Johansson, Erik; Zhai, Qiwei; Zeng, Zhao-Jun; Yoshida, Takeshi; Funa, Keiko

    2016-05-01

    TLX (also called NR2E1) is an orphan nuclear receptor that maintains stemness of neuronal stem cells. TLX is highly expressed in the most malignant form of glioma, glioblastoma multiforme (GBM), and is important for the proliferation and maintenance of the stem/progenitor cells of the tumor. Transforming Growth Factor-β (TGF-β) is a cytokine regulating many different cellular processes such as differentiation, migration, adhesion, cell death and proliferation. TGF-β has an important function in cancer where it can work as either a tumor suppressor or oncogene, depending on the cancer type and stage of tumor development. Since glioblastoma often have dysfunctional TGF-β signaling we wanted to find out if there is any interaction between TLX and TGF-β in glioblastoma cells. We demonstrate that knockdown of TLX enhances the canonical TGF-β signaling response in glioblastoma cell lines. TLX physically interacts with and stabilizes Smurf1, which can ubiquitinate and target TGF-β receptor II for degradation, whereas knockdown of TLX leads to stabilization of TGF-β receptor II, increased nuclear translocation of Smad2/3 and enhanced expression of TGF-β target genes. The interaction between TLX and TGF-β may play an important role in the regulation of proliferation and tumor-initiating properties of glioblastoma cells. Copyright © 2016. Published by Elsevier Inc.

  11. High-resolution blood-pool-contrast-enhanced MR angiography in glioblastoma: tumor-associated neovascularization as a biomarker for patient survival. A preliminary study

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    Puig, Josep; Blasco, Gerard; Remollo, Sebastian; Hernandez, David; Pedraza, Salvador [Hospital Universitari Dr Josep Trueta, Research Unit of Diagnostic Imaging Institute (IDI), Department of Radiology [Girona Biomedical Research Institute] IDIBGI, Girona (Spain); Daunis-i-Estadella, Josep; Mateu, Gloria [University of Girona, Department of Computer Science, Applied Mathematics and Statistics, Girona (Spain); Alberich-Bayarri, Angel [La Fe Polytechnics and University Hospital, Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, Valencia (Spain); Essig, Marco [University of Manitoba, Department of Radiology, Winnipeg (Canada); Jain, Rajan [NYU School of Medicine, Division of Neuroradiology, Department of Radiology, New York, NY (United States); Puigdemont, Montserrat [Hospital Universitari Dr Josep Trueta, Catalan Institute of Oncology (ICO), Hospital Cancer Registry, Girona (Spain); Sanchez-Gonzalez, Javier [Philips Healthcare Iberica, Madrid (Spain); Wintermark, Max [Stanford University, Department of Radiology, Neuroradiology Division, Palo Alto, CA (United States)

    2016-01-15

    The objective of the study was to determine whether tumor-associated neovascularization on high-resolution gadofosveset-enhanced magnetic resonance angiography (MRA) is a useful biomarker for predicting survival in patients with newly diagnosed glioblastomas. Before treatment, 35 patients (25 men; mean age, 64 ± 14 years) with glioblastoma underwent MRI including first-pass dynamic susceptibility contrast (DSC) perfusion and post-contrast T1WI sequences with gadobutrol (0.1 mmol/kg) and, 48 h later, high-resolution MRA with gadofosveset (0.03 mmol/kg). Volumes of interest for contrast-enhancing lesion (CEL), non-CEL, and contralateral normal-appearing white matter were obtained, and DSC perfusion and DWI parameters were evaluated. Prognostic factors were assessed by Kaplan-Meier survival and Cox proportional hazards model. Eighteen (51.42 %) glioblastomas were hypervascular on high-resolution MRA. Hypervascular glioblastomas were associated with higher CEL volume and lower Karnofsky score. Median survival rates for patients with hypovascular and hypervascular glioblastomas treated with surgery, radiotherapy, and chemotherapy were 15 and 9.75 months, respectively (P < 0.001). Tumor-associated neovascularization was the best predictor of survival at 5.25 months (AUC = 0.794, 81.2 % sensitivity, 77.8 % specificity, 76.5 % positive predictive value, 82.4 % negative predictive value) and yielded the highest hazard ratio (P < 0.001). Tumor-associated neovascularization detected on high-resolution blood-pool-contrast-enhanced MRA of newly diagnosed glioblastoma seems to be a useful biomarker that correlates with worse survival. (orig.)

  12. Impact of oligodendroglial component in glioblastoma (GBM-O): Is the outcome favourable than glioblastoma?

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    Goda, Jayant S; Lewis, Shirley; Agarwal, Aditi; Epari, Sridhar; Churi, Shraddha; Padmavati, A; Gupta, Tejpal; Shetty, Prakash; Moiyadi, Aliasgar; Jalali, Rakesh

    2015-08-01

    Prognosis of patients with glioblastoma with oligodendroglial component (GBM-O) is not well defined. We report our experience of patients of GBM-O treated at our center. Between January 2007 and August 2013, out of 817 consecutive patients with glioblastoma (GBM), 74 patients with GBM-O were identified in our prospectively maintained database. An experienced neuropathologist revaluated the histopathology of all these 74 patients and the diagnosis of GBM-O was eventually confirmed in 57 patients. Patients were uniformly treated with maximal safe resection followed by focal radiotherapy with concurrent and adjuvant temozolamide (TMZ). At a median follow up of 16 months, median overall survival (OS) and progression free survival (PFS) of the entire cohort was 23 months and 13 months respectively. Near total excision was performed in 30/57 (52.6%). On univariate analysis, age GBM-O patients with a similarly treated cohort of 105 GBM patients during the same period revealed significantly better median OS in favour of GBM-O (p = 0.01). Our experience suggests patients with GBM-O have a more favourable clinical outcome as compared to GBM. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Targeting and Therapy of Glioblastoma in a Mouse Model Using Exosomes Derived From Natural Killer Cells

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    Liya Zhu

    2018-04-01

    expression of effluc in U87/MG/F cells, with the bioluminescence activity of U87/MG/F cells increasing with an increase in cell number. NTA and DLS results indicated that the size of NK-Exo was ~100 nm, and the western blot results confirmed that NK-Exo expressed exosome markers CD63 and Alix. We confirmed the in vitro cytotoxic effects of NK-Exo on U87/MG/F cells by performing BLI, and the killing effect on U87/MG and U87MG/F cells was measured by CCK-8 and MTT assays (p < 0.001. ELISA results indicated that NK-Exo contained tumor necrosis factor-α and granzyme B. In vivo NK-Exo treatment inhibited tumor growth compared to in control mice (p < 0.001, and pretreatment of xenograft mice with dextran sulfate 2 h before NK-Exo treatment increased the antitumor effect of NK-Exo (p < 0.01 compared to in control and NK-Exo-alone-treated mice.ConclusionNK-Exo targeted and exerted antitumor effects on glioblastoma cells both in vitro and in vivo, suggesting their utility in treating incurable glioblastoma.

  14. Heterogeneity maintenance in glioblastoma: a social network.

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    Bonavia, Rudy; Inda, Maria-del-Mar; Cavenee, Webster K; Furnari, Frank B

    2011-06-15

    Glioblastoma multiforme (GBM), the most common intracranial tumor in adults, is characterized by extensive heterogeneity at the cellular and molecular levels. This insidious feature arises inevitably in almost all cancers and has great significance for the general outcome of the malignancy, because it confounds our understanding of the disease and also intrinsically contributes to the tumor's aggressiveness and poses an obstacle to the design of effective therapies. The classic view that heterogeneity arises as the result of a tumor's "genetic chaos" and the more contemporary cancer stem cell (CSC) hypothesis tend to identify a single cell population as the therapeutic target: the prevailing clone over time in the first case and the CSC in the latter. However, there is growing evidence that the different tumor cell populations may not be simple bystanders. Rather, they can establish a complex network of interactions between each other and with the tumor microenvironment that eventually strengthens tumor growth and increases chances to escape therapy. These differing but complementary ideas about the origin and maintenance of tumor heterogeneity and its importance in GBM are reviewed here.

  15. CANINE BUTTERFLY GLIOBLASTOMAS: A NEURORADIOLOGICAL REVIEW

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    John Henry Rossmeisl

    2016-05-01

    Full Text Available In humans, high-grade gliomas may infiltrate across the corpus callosum resulting in bihemispheric lesions that may have symmetrical, winged-like appearances. This particular tumor manifestation has been coined a ‘butterfly’ glioma (BG. While canine and human gliomas share many neuroradiological and pathological features, the BG morphology has not been previously reported in dogs. Here we describe the magnetic resonance imaging (MRI characteristics of BG in three dogs, and review the potential differential diagnoses based on neuroimaging findings. All dogs presented with generalized seizures and interictal neurological deficits referable to multifocal or diffuse forebrain disease. MRI examinations revealed asymmetrical (2/3 or symmetrical (1/3, bihemispheric intra-axial mass lesions that predominantly affected the frontoparietal lobes and associated with extensive perilesional edema, and involvement of the corpus callosum. The masses displayed heterogeneous T1, T2, and FLAIR signal intensities, variable contrast enhancement (2/3, and mass effect. All tumors demonstrated classical histopathological features of glioblastoma (GBM including glial cell pseudopalisading, serpentine necrosis, microvascular proliferation, as well as invasion of the corpus callosum by neoplastic astrocytes. Although rare, GBM should be considered a differential diagnosis in dogs with MRI evidence of asymmetric or symmetric bilateral, intra-axial cerebral mass lesions with signal characteristics compatible with glioma.

  16. Strategies in Gene Therapy for Glioblastoma

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    Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S.

    2013-01-01

    Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy

  17. Strategies in Gene Therapy for Glioblastoma

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    Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S., E-mail: mviapiano@partners.org [Department of Neurosurgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 (United States)

    2013-10-22

    Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy.

  18. Extracts of Artocarpus communis Induce Mitochondria-Associated Apoptosis via Pro-oxidative Activity in Human Glioblastoma Cells

    Directory of Open Access Journals (Sweden)

    Chiang-Wen Lee

    2018-05-01

    Full Text Available Glioblastoma multiforme (GBM is an extremely aggressive and devastating malignant tumor in the central nervous system. Its incidence is increasing and the prognosis is poor. Artocarpin is a natural prenylated flavonoid with various anti-inflammatory and anti-tumor properties. Studies have shown that artocarpin is associated with cell death of primary glioblastoma cells. However, the in vivo effects and the cellular and molecular mechanisms modulating the anticancer activities of artocarpin remain unknown. In this study, we demonstrated that treating the glioblastoma cell lines U87 and U118 cells with artocarpin induced apoptosis. Artocarpin-induced apoptosis is associated with caspase activation and poly (ADP-ribose polymerase (PARP cleavage and is mediated by the mitochondrial pathway. This is associated with mitochondrial depolarization, mitochondrial-derived reactive oxidative species (ROS production, cytochrome c release, Bad and Bax upregulations, and Bcl-2 downregulation. Artocarpin induced NADPH oxidase/ROS generation plays an important role in the mitochondrial pathway activation. Furthermore, we found artocarpin-induced ROS production in mitochondria is associated with Akt- and ERK1/2 activation. After treatment with artocarpin, ROS causes PI3K/Akt/ERK1/2-induced cell death of these tumor cells. These observations were further verified by the results from the implantation of both U87 and U118 cells into in vivo mouse. In conclusion, our findings suggest that artocarpin induces mitochondria-associated apoptosis of glioma cells, suggesting that artocarpine can be a potential chemotherapeutic agent for future GBM treatment.

  19. The response of human glioblastoma in culture to radiation

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    Masuda, Koji; Aramaki, Ryoji; Takagi, Tosuke

    1980-01-01

    Cells from two human glioblastoma multiforme and one mouse glioma were grown in tissue cultures and their X-ray survival curve parameters were determined under oxygenated and hypoxic conditions. These were compared with the survival parameters for mouse fibroblasts (L5) and established cell lines from human carcinoma coli (HeLa S3) irradiated under identical conditions. There was no significant difference in response among the cell lines used. Repair of potentially lethal damage for human glioblastoma and HeLa S3 was assessed by the increase in survival which occurred as the cells were held in density inhibited stationary phase. The magnitude of repair of potentially lethal damage (slope modifying factors) for the glioblastoma and HeLa were 1.9 and 1.1, respectively. (author)

  20. Study of interaction of GNR with glioblastoma cells

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    Hole, Arti; Cardoso-Avila, P. E.; Sridharan, Sangita; Sahu, Aditi; Nair, Jyothi; Dongre, Harsh; Goda, Jayant S.; Sawant, Sharada; Dutt, Shilpee; Pichardo-Molina, J. L.; Murali Krishna, C.

    2018-01-01

    Radiation resistance is one of the major causes of recurrence and failure of radiotherapy. Different methods have been used to increase the efficacy of radiation therapy and at the same time restrict the radiation resistivity. From last few years nanoparticles have played a key role in the enhancement of radiosensitization. The densely packed nanoparticles can selectively scatter or absorb the high radiations, which allow better targeting of cellular components within the tumor hence resulting in increased radiation damage to the cancer cells. Glioblastoma multiforme (GBM) is one of the highly radioresistant brain cancer. Current treatment methods are surgical resection followed by concurrent chemo and radiation therapy. In this study we have used in-house engineered gold nano rodes (GNR) and analyzed their effect on U-87MG cell lines. MTT assay was employed to determine the cytotoxic concentration of the nanoparticles. Raman spectroscopy was used to analyze the effect of gold nanoparticles on glioma cells, which was followed by transmission electron microscopic examinations to visualize their cellular penetration. Our data shows that GNR were able to penetrate the cells and induce cytotoxicity at the concentration of 198 μM as determined by MTT assay at 24 post GNP treatment. Additionally, we show that Raman spectroscopy, could classify spectra between untreated and cells treated with nanoparticles. Taken together, this study shows GNR penetration and cytotoxicity in glioma cells thereby providing a rationale to use them in cancer therapeutics. Future studies will be carried out to study the biological activity of the formulation as a radiosensitizer in GBM.

  1. A simplified approach for the molecular classification of glioblastomas.

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    Marie Le Mercier

    Full Text Available Glioblastoma (GBM is the most common malignant primary brain tumors in adults and exhibit striking aggressiveness. Although GBM constitute a single histological entity, they exhibit considerable variability in biological behavior, resulting in significant differences in terms of prognosis and response to treatment. In an attempt to better understand the biology of GBM, many groups have performed high-scale profiling studies based on gene or protein expression. These studies have revealed the existence of several GBM subtypes. Although there remains to be a clear consensus, two to four major subtypes have been identified. Interestingly, these different subtypes are associated with both differential prognoses and responses to therapy. In the present study, we investigated an alternative immunohistochemistry (IHC-based approach to achieve a molecular classification for GBM. For this purpose, a cohort of 100 surgical GBM samples was retrospectively evaluated by immunohistochemical analysis of EGFR, PDGFRA and p53. The quantitative analysis of these immunostainings allowed us to identify the following two GBM subtypes: the "Classical-like" (CL subtype, characterized by EGFR-positive and p53- and PDGFRA-negative staining and the "Proneural-like" (PNL subtype, characterized by p53- and/or PDGFRA-positive staining. This classification represents an independent prognostic factor in terms of overall survival compared to age, extent of resection and adjuvant treatment, with a significantly longer survival associated with the PNL subtype. Moreover, these two GBM subtypes exhibited different responses to chemotherapy. The addition of temozolomide to conventional radiotherapy significantly improved the survival of patients belonging to the CL subtype, but it did not affect the survival of patients belonging to the PNL subtype. We have thus shown that it is possible to differentiate between different clinically relevant subtypes of GBM by using IHC

  2. A novel prognostic six-CpG signature in glioblastomas.

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    Yin, An-An; Lu, Nan; Etcheverry, Amandine; Aubry, Marc; Barnholtz-Sloan, Jill; Zhang, Lu-Hua; Mosser, Jean; Zhang, Wei; Zhang, Xiang; Liu, Yu-He; He, Ya-Long

    2018-03-01

    We aimed to identify a clinically useful biomarker using DNA methylation-based information to optimize individual treatment of patients with glioblastoma (GBM). A six-CpG panel was identified by incorporating genome-wide DNA methylation data and clinical information of three distinct discovery sets and was combined using a risk-score model. Different validation sets of GBMs and lower-grade gliomas and different statistical methods were implemented for prognostic evaluation. An integrative analysis of multidimensional TCGA data was performed to molecularly characterize different risk tumors. The six-CpG risk-score signature robustly predicted overall survival (OS) in all discovery and validation cohorts and in a treatment-independent manner. It also predicted progression-free survival (PFS) in available patients. The multimarker epigenetic signature was demonstrated as an independent prognosticator and had better performance than known molecular indicators such as glioma-CpG island methylator phenotype (G-CIMP) and proneural subtype. The defined risk subgroups were molecularly distinct; high-risk tumors were biologically more aggressive with concordant activation of proangiogenic signaling at multimolecular levels. Accordingly, we observed better OS benefits of bevacizumab-contained therapy to high-risk patients in independent sets, supporting its implication in guiding usage of antiangiogenic therapy. Finally, the six-CpG signature refined the risk classification based on G-CIMP and MGMT methylation status. The novel six-CpG signature is a robust and independent prognostic indicator for GBMs and is of promising value to improve personalized management. © 2018 John Wiley & Sons Ltd.

  3. Inhibition of AKT signaling by supercritical CO2 extract of mango ginger (Curcuma amada Roxb.) in human glioblastoma cells.

    Science.gov (United States)

    Ramachandran, Cheppail; Portalatin, Gilda; Quirin, Karl-W; Escalon, Enrique; Khatib, Ziad; Melnick, Steven J

    2015-12-01

    Mango ginger (Curcuma amada Roxb.) is a less-investigated herb for anticancer properties than other related Curcuma species. AKT (a serine/threonine protein kinase B, originally identified as an oncogene in the transforming retrovirus AKT8) plays a central role in the development and promotion of cancer. In this investigation, we have analyzed the effect of supercritical CO2 extract of mango ginger (CA) on the genetic pathways associated with AKT signaling in human glioblastoma cells. The inhibitory effect of supercritical CO2 extract of mango ginger (Curcuma amada) on AKT signaling was investigated in U-87MG glioblastoma cells. CA was highly cytotoxic to glioblastoma cell line (IC50=4.92±0.81 µg/mL) compared to mHypoE-N1 normal mouse hypothalamus cell line (IC50=40.57±0.06 µg/mL). CA inhibits AKT (protein Kinase B) and adenosine monophophate -activated protein kinase α (AMPKα) phosphorylation significantly in a dose-dependent manner. The cell migration which is necessary for invasion and metastasis was also inhibited by CA treatment, with about 43% reduction at 20 µg/mL concentration. Analysis of mRNA and protein expression of genes associated with apoptosis, cell proliferation and angiogenesis showed that CA modulates expression of genes associated with apoptosis (Bax, Bcl-2, Bcl-X, BNIP3, caspase-3, mutant p53 and p21), cell proliferation (Ki67) and angiogenesis vascular endothelial growth factor (VEGF). Additionally, heat shock protein 90 (HSP90) and AMPKα genes interacting with the AKT signaling pathway were also downregulated by CA treatment. These results indicate the molecular targets and mechanisms underlying the anticancer effect of CA in human glioblastoma cells.

  4. Activation of p53 by nutlin-3a induces apoptosis and cellular senescence in human glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Ruth Villalonga-Planells

    2011-04-01

    Full Text Available Glioblastoma multiforme (GBM is the most common and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies and develop novel clinical approaches, patient survival remains poor. As such, increasing attention has focused on developing new therapeutic strategies that specifically target the apoptotic pathway in order to improve treatment responses. Recently, nutlins, small-molecule antagonists of MDM2, have been developed to inhibit p53-MDM2 interaction and activate p53 signaling in cancer cells. Glioma cell lines and primary cultured glioblastoma cells were treated with nutlin-3a. Nutlin-3a induced p53-dependent G1- and G2-M cell cycle arrest and apoptosis in glioma cell lines with normal TP53 status. In addition, nutlin-arrested glioma cells show morphological features of senescence and persistent induction of p21 protein. Furthermore, senescence induced by nutlin-3a might be depending on mTOR pathway activity. In wild-type TP53 primary cultured cells, exposure to nutlin-3a resulted in variable degrees of apoptosis as well as cellular features of senescence. Nutlin-3a-induced apoptosis and senescence were firmly dependent on the presence of functional p53, as revealed by the fact that glioblastoma cells with knockdown p53 with specific siRNA, or cells with mutated or functionally impaired p53 pathway, were completely insensitive to the drug. Finally, we also found that nutlin-3a increased response of glioma cells to radiation therapy. The results provide a basis for the rational use of MDM2 antagonists as a novel treatment option for glioblastoma patients.

  5. Pattern of Failure After Limited Margin Radiotherapy and Temozolomide for Glioblastoma

    International Nuclear Information System (INIS)

    McDonald, Mark W.; Shu, Hui-Kuo G.; Curran, Walter J.; Crocker, Ian R.

    2011-01-01

    Purpose: To evaluate the pattern of failure after limited margin radiotherapy for glioblastoma. Methods and Materials: We analyzed 62 consecutive patients with newly diagnosed glioblastoma treated between 2006 and 2008 with standard fractionation to a total dose of 60Gy with concurrent temozolomide (97%) or arsenic trioxide (3%). The initial clinical target volume included postoperative T2 abnormality with a median margin of 0.7cm. The boost clinical target volume included residual T1-enhancing tumor and resection cavity with a median margin of 0.5cm. Planning target volumes added a 0.3- or 0.5-cm margin to clinical target volumes. The total boost planning target volume (PTV boost ) margin was 1cm or less in 92% of patients. The volume of recurrent tumor (new T1 enhancement) was categorized by the percent within the 60-Gy isodose line as central (>95%), infield (81-95%), marginal (20-80%), or distant ( boost with a 2.5-cm margin were created for each patient. Results: With a median follow-up of 12 months, radiographic tumor progression developed in 43 of 62 patients. Imaging was available for analysis in 41: 38 (93%) had central or infield failure, 2 (5%) had marginal failure, and 1 (2%) had distant failure relative to the 60-Gy isodose line. The treated PTV boost (median, 140cm 3 ) was, on average, 70% less than the PTV boost with a 2.5-cm margin (median, 477cm 3 ) (p boost margin of 1cm or less did not appear to increase the risk of marginal and/or distant tumor failures compared with other published series. With careful radiation planning and delivery, it appears that treatment margins for glioblastoma can be reduced.

  6. Induction of cell death in a glioblastoma line by hyperthermic therapy based on gold nanorods

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    Fernandez Cabada T

    2012-03-01

    Full Text Available Tamara Fernandez Cabada1,2,*, Cristina Sanchez Lopez de Pablo1,3,*, Alberto Martinez Serrano2, Francisco del Pozo Guerrero1,3, Jose Javier Serrano Olmedo1,3,*, Milagros Ramos Gomez1–3,* 1Centre for Biomedical Technology, Universidad Politecnica de Madrid, Madrid, Spain; 2Centre for Molecular Biology, "Severo Ochoa" Universidad Autonoma de Madrid, Madrid, Spain; 3Biomedical Research Networking Center in Bioengineering Biomaterials and Nanomedicine (CIBER-bbn, Zaragoza, Spain.*These authors contributed equally to this workBackground: Metallic nanorods are promising agents for a wide range of biomedical applications. In this study, we developed an optical hyperthermia method capable of inducing in vitro death of glioblastoma cells.Methods: The procedure used was based on irradiation of gold nanorods with a continuous wave laser. This kind of nanoparticle converts absorbed light into localized heat within a short period of time due to the surface plasmon resonance effect. The effectiveness of the method was determined by measuring changes in cell viability after laser irradiation of glioblastoma cells in the presence of gold nanorods.Results: Laser irradiation in the presence of gold nanorods induced a significant decrease in cell viability, while no decrease in cell viability was observed with laser irradiation or incubation with gold nanorods alone. The mechanism of cell death mediated by gold nanorods during photothermal ablation was analyzed, indicating that treatment compromised the integrity of the cell membrane instead of initiating the process of programmed cell death.Conclusion: The use of gold nanorods in hyperthermal therapies is very effective in eliminating glioblastoma cells, and therefore represents an important area of research for therapeutic development.Keywords: laser irradiation, photothermal therapy, surface plasmon resonance, cancer

  7. P53-dependent antiproliferative and pro-apoptotic effects of trichostatin A (TSA) in glioblastoma cells.

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    Bajbouj, K; Mawrin, C; Hartig, R; Schulze-Luehrmann, J; Wilisch-Neumann, A; Roessner, A; Schneider-Stock, R

    2012-05-01

    Glioblastomas are known to be highly chemoresistant, but HDAC inhibitors (HDACi) have been shown to be of therapeutic relevance for this aggressive tumor type. We treated U87 glioblastoma cells with trichostatin A (TSA) to define potential epigenetic targets for HDACi-mediated antitumor effects. Using a cDNA array analysis covering 96 cell cycle genes, cyclin-dependent kinase inhibitor p21(WAF1) was identified as the major player in TSA-induced cell cycle arrest. TSA slightly inhibited proliferation and viability of U87 cells, cumulating in a G1/S cell cycle arrest. This effect was accompanied by a significant up-regulation of p53 and its transcriptional target p21(WAF1) and by down-regulation of key G1/S regulators, such as cdk4, cdk6, and cyclin D1. Nevertheless, TSA did not induce apoptosis in U87 cells. As expected, TSA promoted the accumulation of total acetylated histones H3 and H4 and a decrease in endogenous HDAC activity. Characterizing the chromatin modulation around the p21(WAF1) promoter after TSA treatment using chromatin immunoprecipitation, we found (1) a release of HDAC1, (2) an increase of acetylated H4 binding, and (3) enhanced recruitment of p53. p53-depleted U87 cells showed an abrogation of the G1/S arrest and re-entered the cell cycle. Immunofluorescence staining revealed that TSA induced the nuclear translocation of p21(WAF1) verifying a cell cycle arrest. On the other hand, a significant portion of p21(WAF1) was present in the cytoplasmic compartment causing apoptosis resistance. Furthermore, TSA-treated p53-mutant cell line U138 failed to show an induction in p21(WAF1), showed a deficient G2/M checkpoint, and underwent mitotic catastrophe. We suggest that HDAC inhibition in combination with other clinically used drugs may be considered an effective strategy to overcome chemoresistance in glioblastoma cells.

  8. Odds of death after glioblastoma diagnosis in the United States by chemotherapeutic era

    International Nuclear Information System (INIS)

    Wachtel, Mitchell S; Yang, Shengping

    2014-01-01

    Bevacizumab (BZM) and temozolomide (TMZ) have been shown to be beneficial in the treatment of patients with glioblastoma. We sought evidence for the benefit of BZM in the general patient population at large. The Surveillance, Epidemiology, and End Results SEER database was queried for patients diagnosed with glioblastoma between 2000 and 2009, divided into a pre-TMZ era (January 2000–June 2003), a transitional era (July 2003–March 2005), a TMZ era (April 2005–October 2007), and a BZM-TMZ era (November 2007–December 2009). Binomial logit regression analyzed odds of death, taking into account age at diagnosis, tumor size, gender, race, marital status, radiotherapy, and extensive surgery. Compared with the pre-TMZ era, odds of death were decreased in the TMZ era by 12% (97.5% CI [confidence interval] 3–20%) 6 months after diagnosis and 36% (30–42%) a year after diagnosis; corresponding values for BZM-TMZ were 31% (24–37%) and 50% (45–55%). For era comparisons, decreases in odds of death were larger at 12 than 6 months; the opposite was true for extensive surgery and radiotherapy (P < 0.025, Wald χ 2 test, for each analysis). For both 6 and 12 month comparisons, odds of death in the BZM-TMZ era were lower than in the TMZ era (P < 0.025, Wald χ 2 test, for each analysis). The results provide evidence that TMZ positively impacted survival of glioblastoma patients and that the addition of BZM further improved survival, this lends support to the addition of BZM to the chemotherapeutic armamentarium. Evaluation of odds of death is an attractive alternative to Cox regression when proportional hazards assumptions are violated and follow-up is good

  9. Enhanced tumor control of human Glioblastoma Multiforme xenografts with the concomitant use of radiotherapy and an attenuated herpes simplex-1 virus (ASTRO research fellowship)

    International Nuclear Information System (INIS)

    Song, Paul Y.; Sibley, Gregory S.; Advani, Sunil; Hallahan, Dennis; Hyland, John; Kufe, Donald W.; Chou, Joany; Roizman, Bernard; Weichselbaum, Ralph R.

    1996-01-01

    Purpose: Glioblastoma Multiforme remains one of the most incurable of human tumors. The current treatment outcomes are dismal. There are several recent reports which suggest that some human glioblastoma xenografts implanted in the brains of athymic mice may be potentially cured with the use of an attenuated herpes simplex-1 virus alone. We have chosen a replication competent, non-neurovirulent HSV-1 mutant, designated R3616 to determine whether there is an interactive cell killing and enhanced tumor control with radiotherapy in the treatment of a human glioblastoma xenograft. Materials and Methods: In vivo, 1 mm 3 pieces of U-87 human glioblastoma cell line xenografts were implanted into the right hind limb of athymic mice and grown to > 200 mm 3 . A total of 112 mice were then equally distributed within four treatment arms (see chart below) based upon tumor volume. Xenografts selected to receive virus as part of the therapy were inoculated with three injections of 2 x 10 7 plaque forming units (PFU) of R3616 virus given on day 1, 2, and 3 for a total dose of 6 x 10 7 PFU. R3616 is a non-neurovirulent HSV-1 mutant created by the deletion of the γ 34.5 gene. Local field irradiation was delivered on day 2 (20 Gy) and day 3 (25 Gy). The mice were then followed for 60 days during which time the xenografts were measured twice weekly. A clinically non-palpable tumor (< 10% original volume) was scored as a cure. In addition percent-fractional tumor volume (FTV) and mean tumor volume (MTV) were calculated for each group. Results: Conclusion: While our tumor control with R3616 alone is similar to that reported in the literature, we have seen significantly enhanced tumor control and cell killing with the addition of RT suggesting a synergistic interaction between an oncolytic virus and radiation in the treatment of human glioblastoma multiforme xenografts

  10. Nuclear receptor TLX inhibits TGF-β signaling in glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Johansson, Erik; Zhai, Qiwei [Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, SE 405 30 Gothenburg (Sweden); Zeng, Zhao-jun [Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, SE 405 30 Gothenburg (Sweden); Molecular Biology Research Center, School of Life Sciences, Central South University, 110, Xiangya Road, Changsha, Hunan 410078 (China); Yoshida, Takeshi [Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, SE 405 30 Gothenburg (Sweden); Funa, Keiko, E-mail: keiko.funa@gu.se [Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, SE 405 30 Gothenburg (Sweden)

    2016-05-01

    TLX (also called NR2E1) is an orphan nuclear receptor that maintains stemness of neuronal stem cells. TLX is highly expressed in the most malignant form of glioma, glioblastoma multiforme (GBM), and is important for the proliferation and maintenance of the stem/progenitor cells of the tumor. Transforming Growth Factor-β (TGF-β) is a cytokine regulating many different cellular processes such as differentiation, migration, adhesion, cell death and proliferation. TGF-β has an important function in cancer where it can work as either a tumor suppressor or oncogene, depending on the cancer type and stage of tumor development. Since glioblastoma often have dysfunctional TGF-β signaling we wanted to find out if there is any interaction between TLX and TGF-β in glioblastoma cells. We demonstrate that knockdown of TLX enhances the canonical TGF-β signaling response in glioblastoma cell lines. TLX physically interacts with and stabilizes Smurf1, which can ubiquitinate and target TGF-β receptor II for degradation, whereas knockdown of TLX leads to stabilization of TGF-β receptor II, increased nuclear translocation of Smad2/3 and enhanced expression of TGF-β target genes. The interaction between TLX and TGF-β may play an important role in the regulation of proliferation and tumor-initiating properties of glioblastoma cells. - Highlights: • TLX knockdown enhances TGF-β dependent Smad signaling in glioblastoma cells • TLX knockdown increases the protein level of TGF-β receptor II. • TLX stabilizes and retains Smurf1 in the cytoplasm. • TLX enhances Smurf1-dependent ubiquitination and degradation of TGF-β receptor II.

  11. Nuclear receptor TLX inhibits TGF-β signaling in glioblastoma

    International Nuclear Information System (INIS)

    Johansson, Erik; Zhai, Qiwei; Zeng, Zhao-jun; Yoshida, Takeshi; Funa, Keiko

    2016-01-01

    TLX (also called NR2E1) is an orphan nuclear receptor that maintains stemness of neuronal stem cells. TLX is highly expressed in the most malignant form of glioma, glioblastoma multiforme (GBM), and is important for the proliferation and maintenance of the stem/progenitor cells of the tumor. Transforming Growth Factor-β (TGF-β) is a cytokine regulating many different cellular processes such as differentiation, migration, adhesion, cell death and proliferation. TGF-β has an important function in cancer where it can work as either a tumor suppressor or oncogene, depending on the cancer type and stage of tumor development. Since glioblastoma often have dysfunctional TGF-β signaling we wanted to find out if there is any interaction between TLX and TGF-β in glioblastoma cells. We demonstrate that knockdown of TLX enhances the canonical TGF-β signaling response in glioblastoma cell lines. TLX physically interacts with and stabilizes Smurf1, which can ubiquitinate and target TGF-β receptor II for degradation, whereas knockdown of TLX leads to stabilization of TGF-β receptor II, increased nuclear translocation of Smad2/3 and enhanced expression of TGF-β target genes. The interaction between TLX and TGF-β may play an important role in the regulation of proliferation and tumor-initiating properties of glioblastoma cells. - Highlights: • TLX knockdown enhances TGF-β dependent Smad signaling in glioblastoma cells • TLX knockdown increases the protein level of TGF-β receptor II. • TLX stabilizes and retains Smurf1 in the cytoplasm. • TLX enhances Smurf1-dependent ubiquitination and degradation of TGF-β receptor II.

  12. Relations between inductive reasoning and deductive reasoning.

    Science.gov (United States)

    Heit, Evan; Rotello, Caren M

    2010-05-01

    One of the most important open questions in reasoning research is how inductive reasoning and deductive reasoning are related. In an effort to address this question, we applied methods and concepts from memory research. We used 2 experiments to examine the effects of logical validity and premise-conclusion similarity on evaluation of arguments. Experiment 1 showed 2 dissociations: For a common set of arguments, deduction judgments were more affected by validity, and induction judgments were more affected by similarity. Moreover, Experiment 2 showed that fast deduction judgments were like induction judgments-in terms of being more influenced by similarity and less influenced by validity, compared with slow deduction judgments. These novel results pose challenges for a 1-process account of reasoning and are interpreted in terms of a 2-process account of reasoning, which was implemented as a multidimensional signal detection model and applied to receiver operating characteristic data. PsycINFO Database Record (c) 2010 APA, all rights reserved.

  13. Combined stereotactic biopsy and stepping-source interstitial irradiation of glioblastoma multiforme.

    Science.gov (United States)

    Brehmer, Stefanie; Guthier, Christian V; Clausen, Sven; Schneider, Frank; Schulte, Dirk-Michael; Benker, Matthias; Bludau, Frederic; Glatting, Gerhard; Marx, Alexander; Schmiedek, Peter; Hesser, Jürgen; Wenz, Frederik; Giordano, Frank A

    2018-04-01

    Patients diagnosed with glioblastoma multiforme receiving stereotactic biopsy only either due to tumor localization or impaired clinical status face a devastating prognosis with very short survival times. One strategy to provide an initial cytoreductive and palliative therapy at the time of the stereotactic biopsy is interstitial irradiation through the pre-defined trajectory of the biopsy channel. We designed a novel treatment planning system and evaluated the treatment potential of a fixed-source and a stepping-source algorithm for interstitial radiosurgery on non-spherical glioblastoma in direct adjacency to risk structures. Using both setups, we show that radiation doses delivered to 100% of the gross tumor volume shifts from sub-therapeutic (10-12 Gy) to sterilizing single doses (25-30 Gy) when using the stepping source algorithm due to improved sparing of organs-at-risk. Specifically, the maximum doses at the brain stem were 100% of the PTV dose when a fixed central source and 38% when a stepping-source algorithm was used. We also demonstrated precision of intracranial target points and stability of superficial and deep trajectories using both a phantom and a body donor study. Our setup now for the first time provides a basis for a clinical proof-of-concept trial and may widen palliation options for patients with limited life expectancy that should not undergo time-consuming therapies.

  14. Probing the Oncolytic and Chemosensitizing Effects of Dihydrotanshinone in an In Vitro Glioblastoma Model.

    Science.gov (United States)

    Kumar, Varun; Radin, Daniel; Leonardi, Donna

    2017-11-01

    Temozolomide is the primary chemotherapeutic agent used to treat glioblastoma. However, many tumors are initially resistant to or develop resistance to temozolomide, mainly due to high levels of O 6 -methylguanine DNA transferase (MGMT) which repairs DNA damage traditionally caused by temozolomide. Dihydrotanshinone (DHT) is extracted from Salvia miltiorrhiza, a Chinese medicinal plant, and has also been shown to have antiproliferative effects on various cancer cell lines. DHT has been to shown to induce apoptosis via induction endoplasmic reticulum stress, that can reportedly sensitize cells to temozolomide. MTS cellular proliferation assays or trypan blue viability assays were used to determine the effects of DHT/temozolomide combinatorial treatment. Enzyme-linked immunosorbent assay (ELISA) was used to determine effects on MGMT and P-glycoprotein levels after singular and combinatorial treatment. DHT had a synergistic oncolytic effect in a MGMT-deficient cell line and a sensitizing effect in a MGMT-expressing cell line. Cytotoxicity due to DHT was shown to be reactive oxygen species-dependent, while the combinatorial effect of DHT and temozolomide synergistically reduced MGMT and P-glycoprotein levels. DHT was shown to augment temozolomide efficacy, indicating that, since DHT can penetrate the blood-brain barrier, temozolomide in combination with DHT may represent a promising therapeutic option for glioblastoma. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  15. Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma.

    Directory of Open Access Journals (Sweden)

    Maria Kärrlander

    Full Text Available Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the modest efficacy of these drugs and emerging problems with anti-VEGF treatment resistance welcome the development of alternative antiangiogenic therapies. One potential candidate is histidine-rich glycoprotein (HRG, a plasma protein with antiangiogenic properties that can inhibit endothelial cell adhesion and migration. We have used the RCAS/TV-A mouse model for gliomas to investigate the effect of HRG on brain tumor development. Tumors were induced with platelet-derived growth factor-B (PDGF-B, in the presence or absence of HRG. We found that HRG had little effect on tumor incidence but could significantly inhibit the development of malignant glioma and completely prevent the occurrence of grade IV tumors (glioblastoma.

  16. A miR-21 inhibitor enhances apoptosis and reduces G2-M accumulation induced by ionizing radiation in human glioblastoma U251 cells

    International Nuclear Information System (INIS)

    Li, Yi; Li, Qiang; Asai, Akio; Kawamoto, Keiji; Zhao Shiguang; Zhen Yunbo; Teng Lei

    2011-01-01

    MicroRNAs (miRNAs) are small noncoding RNAs that take part in diverse biological processes by suppressing target gene expression. Elevated expression of miR-21 has been reported in many types of human cancers. Radiotherapy is a standard adjuvant treatment for patients with glioblastoma. However, the resistance of glioblastoma cells to radiation limits the success of this treatment. In this study, we found that miR-21 expression was upregulated in response to ionizing radiation (IR) in U251 cells, which suggested that miR-21 could be involved in the response of U251 cells to radiation. We showed that a miR-21 inhibitor enhanced IR-induced glioblastoma cell growth arrest and increased the level of apoptosis, which was probably caused by abrogation of the G 2 -M arrest induced by IR. Further research demonstrated that the miR-21 inhibitor induced the upregulation of Cdc25A. Taken together, these findings suggest that miR-21 inhibitor can increase IR-induced growth arrest and apoptosis in U251 glioblastoma cells, at least in part by abrogating G 2 -M arrest, and that Cdc25A is a potential target of miR-21. (author)

  17. P16.30 4th ventricle glioblastoma

    Science.gov (United States)

    Unal, E.; Isik, S.; Gurbuz, M.; Kilic, K.

    2017-01-01

    Abstract Introduction: We present the 2nd case ever known in English literature describing a glioblastoma of the fourth ventricle originating from cerebellar peduncle. CASE DESCIPTION: A 66 years old woman was admitted to hospital with dizziness and nausea for four months. An MRI scan showed fourth ventricle mass. First impression was an ependymoma due to MRI scan characteristics. Results: A surgery was performed and histopathology revealed Grade IV glial tumor. Radiotherapy was done. CONCLUSION: This report suggests that GBM can mimic every tumor in the CNS. Surgery is the best option for these tumors not only for aggressive behaviour of glioblastoma but also to prevent hydrocephalus and associated symptoms.

  18. Combined Modality Approaches in the Management of Adult Glioblastoma

    International Nuclear Information System (INIS)

    Shirazi, Haider A.; Grimm, Sean; Raizer, Jeffrey; Mehta, Minesh P.

    2011-01-01

    Over the past two decades, management of newly diagnosed glioblastoma has undergone significant evolution. While surgery has long been a mainstay of management for this disease, and while radiotherapy has a proven survival role, initial efforts at radiotherapy dose escalation, use of radiosurgery, brachytherapy, and altered fractionation did not improve patient survival. Recently, multiple modality therapy integrating maximal safe resection, postoperative radiation, and new systemic therapies have resulted in improved patient outcomes compared with older regimens utilizing surgery and postoperative radiation alone. Numerous trials are currently underway investigating the combination of surgery, radiation, and systemic therapy with targeted agents to find ways to further improve outcomes for adults with glioblastoma.

  19. Micro RNAs as molecular markers of glioblastoma multiform

    Energy Technology Data Exchange (ETDEWEB)

    Farace, M G [Department Experimental Medicine and Biochemical Sciences, University of Tor Vergata, Rome (Italy); Finocchiaro, G [Istituto Neurologico Besta, Milan (Italy); Ricci Vitiani, L [Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome (Italy)

    2009-07-01

    The aim of this project was to unravel the role that miR-221 and miR-222, of which we had already demonstrated the specific differential expression in glioblastoma multiforme compared to normal brain, play in the control of cell proliferation, with the ultimate goal to provide new insights in the molecular basis of cancer. The results of our research allowed to identify an important molecular target for miRNA-221 and miR-222, highly expressed in glioblastoma multiforme tissues and cell lines, and to precisely recognize the mRNA regions responsible for this regulation.

  20. Micro RNAs as molecular markers of glioblastoma multiform

    International Nuclear Information System (INIS)

    Farace, M.G.; Finocchiaro, G.; Ricci Vitiani, L.

    2009-01-01

    The aim of this project was to unravel the role that miR-221 and miR-222, of which we had already demonstrated the specific differential expression in glioblastoma multiforme compared to normal brain, play in the control of cell proliferation, with the ultimate goal to provide new insights in the molecular basis of cancer. The results of our research allowed to identify an important molecular target for miRNA-221 and miR-222, highly expressed in glioblastoma multiforme tissues and cell lines, and to precisely recognize the mRNA regions responsible for this regulation

  1. Combined Modality Approaches in the Management of Adult Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Shirazi, Haider A. [Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL (United States); Grimm, Sean; Raizer, Jeffrey [Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL (United States); Mehta, Minesh P., E-mail: mmehta@nmff.org [Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL (United States)

    2011-10-28

    Over the past two decades, management of newly diagnosed glioblastoma has undergone significant evolution. While surgery has long been a mainstay of management for this disease, and while radiotherapy has a proven survival role, initial efforts at radiotherapy dose escalation, use of radiosurgery, brachytherapy, and altered fractionation did not improve patient survival. Recently, multiple modality therapy integrating maximal safe resection, postoperative radiation, and new systemic therapies have resulted in improved patient outcomes compared with older regimens utilizing surgery and postoperative radiation alone. Numerous trials are currently underway investigating the combination of surgery, radiation, and systemic therapy with targeted agents to find ways to further improve outcomes for adults with glioblastoma.

  2. Inhibition of NF-κB Pathway and Modulation of MAPK Signaling Pathways in Glioblastoma and Implications for Lovastatin and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL Combination Therapy.

    Directory of Open Access Journals (Sweden)

    Pi Chu Liu

    Full Text Available Glioblastoma is a common malignant brain tumor and it is refractory to therapy because it usually contains a mixture of cell types. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL has been shown to induce apoptosis in a range of tumor cell types. Previously, we found that two human glioblastoma cell lines are resistant to TRAIL, while lovastatin sensitizes these glioblastoma cells to TRAIL-induced cell death. In this study, we investigated the mechanisms underlying the TRAIL-induced apoptosis in human glioblastoma cell lines by lovastatin. Furthermore, we have confirmed the anti-tumor effect of combination therapy with lovastatin and TRAIL in the subcutaneous brain tumor model. We showed that lovastatin significantly up-regulated the expression of death receptor 5 (DR5 in glioblastoma cell lines as well as in tumor-bearing mice with peri-tumoral administration of lovastatin. Further study in glioblastoma cell lines suggested that lovastatin treatment could inhibit NF-κB and Erk/MAPK pathways but activates JNK pathway. These results suggest that lovastatin sensitizes TRAIL-induced apoptosis by up-regulation of DR5 level via NF-κB inactivation, but also directly induces apoptosis by dysregulation of MAPK pathway. Our in vivo study showed that local peri-tumoral co-injection of lovastatin and TRAIL substantially reduced tumor growth compared with single injection of lovastatin or TRAIL in subcutaneous nude mice model. This study suggests that combined treatment of lovastatin and TRAIL is a promising therapeutic strategy to TRAIL-resistant glioblastoma.

  3. Stereotypical Reasoning: Logical Properties

    OpenAIRE

    Lehmann, Daniel

    2002-01-01

    Stereotypical reasoning assumes that the situation at hand is one of a kind and that it enjoys the properties generally associated with that kind of situation. It is one of the most basic forms of nonmonotonic reasoning. A formal model for stereotypical reasoning is proposed and the logical properties of this form of reasoning are studied. Stereotypical reasoning is shown to be cumulative under weak assumptions.

  4. Bioactive form of resveratrol in glioblastoma cells and its safety for normal brain cells

    Directory of Open Access Journals (Sweden)

    Xiao-Hong Shu

    2013-05-01

    Full Text Available ABSTRACTBackground: Resveratrol, a plant polyphenol existing in grapes and many other natural foods, possesses a wide range of biological activities including cancer prevention. It has been recognized that resveratrol is intracellularly biotransformed to different metabolites, but no direct evidence has been available to ascertain its bioactive form because of the difficulty to maintain resveratrol unmetabolized in vivo or in vitro. It would be therefore worthwhile to elucidate the potential therapeutic implications of resveratrol metabolism using a reliable resveratrol-sensitive cancer cells.Objective: To identify the real biological form of trans-resveratrol and to evaluate the safety of the effective anticancer dose of resveratrol for the normal brain cells.Methods: The samples were prepared from the condition media and cell lysates of human glioblastoma U251 cells, and were purified by solid phase extraction (SPE. The samples were subjected to high performance liquid chromatography (HPLC and liquid chromatography/tandem mass spectrometry (LC/MS analysis. According to the metabolite(s, trans-resveratrol was biotransformed in vitro by the method described elsewhere, and the resulting solution was used to treat U251 cells. Meanwhile, the responses of U251 and primarily cultured rat normal brain cells (glial cells and neurons to 100μM trans-resveratrol were evaluated by multiple experimental methods.Results: The results revealed that resveratrol monosulfate was the major metabolite in U251 cells. About half fraction of resveratrol monosulfate was prepared in vitro and this trans-resveratrol and resveratrol monosulfate mixture showed little inhibitory effect on U251 cells. It is also found that rat primary brain cells (PBCs not only resist 100μM but also tolerate as high as 200μM resveratrol treatment.Conclusions: Our study thus demonstrated that trans-resveratrol was the bioactive form in glioblastoma cells and, therefore, the biotransforming

  5. Toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients

    DEFF Research Database (Denmark)

    Jakobsen, J N; Urup, T; Grunnet, K

    2018-01-01

    The combination of lomustine and bevacizumab is a commonly used salvage treatment for recurrent glioblastoma (GBM). We investigated the toxicity and efficacy of lomustine plus bevacizumab (lom-bev) in a community-based patient cohort and made a comparison to another frequently used combination...... therapy consisting of irinotecan plus bevacizumab (iri-bev). Seventy patients with recurrent GBM were treated with lomustine 90 mg/m2 every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Toxicity was registered and compared to the toxicity observed in 219 recurrent GBM patients who had previously been......-bev is a well-tolerated treatment for recurrent GBM, although hematological toxicity may be a dose limiting factor. No significant differences between lom-bev and iri-bev were observed with regard to PFS or OS. The differences in toxicity profiles between lom-bev and iri-bev could guide treatment decision...

  6. Abscess within a glioblastoma: mimicking a matryoshka doll.

    Science.gov (United States)

    Kishore, Kislay; Beniwal, Manish; Rao, Shilpa; Rao, K V L N; Vazhayil, Vikas; Srinivas, Dwarkanath; Somanna, Sampath

    2018-02-14

    Abscess co-existing within a brain tumor is a rare entity. Case reports in literature primarily consist of sellar pathology and parenchymal lesions including meningioma, glioma, and metastases. We report a case of glioblastoma with an intra-tumoral abscess in a middle-aged lady with no prior invasive procedure or systemic focus of infection. A 45-year old lady presented with new onset generalized seizures and rapidly progressive left hemiparesis. Imaging showed right frontal necrotic lesion with peripherally enhancing wall with solid component posteriorly. There was no diffusion restriction within the lesion. She was non-toxic and there was no systemic focus of infection. With the provisional diagnosis of malignant glioma, she underwent surgical resection of the lesion. A differential of abscess, however, was considered pre-operatively because of the rapid increase in the size of the lesion. At surgery, there was a pus-filled cavity with few areas of greyish, soft, flimsy wall and thrombosed veins. This raised a strong suspicion of a co-existing abscess within a malignant glioma and was confirmed by histopathological and microbiological examination. It is important for neurosurgeons to be aware of this rare entity. The treatment protocol remains controversial and is primarily guided by expert opinion. It is important to aggressively treat the patient with antibiotics followed by adjuvant therapy for malignancy. The timing and administration of adjuvant therapy are unclear. We suggest a delay of chemotherapy until at least 4 weeks of therapy with sensitive antibiotics. Copyright © 2018. Published by Elsevier Inc.

  7. Evaluation of early imaging response criteria in glioblastoma multiforme

    International Nuclear Information System (INIS)

    Gladwish, Adam; Koh, Eng-Siew; Hoisak, Jeremy; Lockwood, Gina; Millar, Barbara-Ann; Mason, Warren; Yu, Eugene; Laperriere, Normand J; Ménard, Cynthia

    2011-01-01

    Early and accurate prediction of response to cancer treatment through imaging criteria is particularly important in rapidly progressive malignancies such as Glioblastoma Multiforme (GBM). We sought to assess the predictive value of structural imaging response criteria one month after concurrent chemotherapy and radiotherapy (RT) in patients with GBM. Thirty patients were enrolled from 2005 to 2007 (median follow-up 22 months). Tumor volumes were delineated at the boundary of abnormal contrast enhancement on T1-weighted images prior to and 1 month after RT. Clinical Progression [CP] occurred when clinical and/or radiological events led to a change in chemotherapy management. Early Radiologic Progression [ERP] was defined as the qualitative interpretation of radiological progression one month post-RT. Patients with ERP were determined pseudoprogressors if clinically stable for ≥6 months. Receiver-operator characteristics were calculated for RECIST and MacDonald criteria, along with alternative thresholds against 1 year CP-free survival and 2 year overall survival (OS). 13 patients (52%) were found to have ERP, of whom 5 (38.5%) were pseudoprogressors. Patients with ERP had a lower median OS (11.2 mo) than those without (not reached) (p < 0.001). True progressors fared worse than pseudoprogressors (median survival 7.2 mo vs. 19.0 mo, p < 0.001). Volume thresholds performed slightly better compared to area and diameter thresholds in ROC analysis. Responses of > 25% in volume or > 15% in area were most predictive of OS. We show that while a subjective interpretation of early radiological progression from baseline is generally associated with poor outcome, true progressors cannot be distinguished from pseudoprogressors. In contrast, the magnitude of early imaging volumetric response may be a predictive and quantitative metric of favorable outcome

  8. Cytoplasmic TRADD Confers a Worse Prognosis in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Sharmistha Chakraborty

    2013-08-01

    Full Text Available Tumor necrosis factor receptor 1 (TNFR1-associated death domain protein (TRADD is an important adaptor in TNFR1 signaling and has an essential role in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB activation and survival signaling. Increased expression of TRADD is sufficient to activate NF-κB. Recent studies have highlighted the importance of NF-κB activation as a key pathogenic mechanism in glioblastoma multiforme (GBM, the most common primary malignant brain tumor in adults.We examined the expression of TRADD by immunohistochemistry (IHC and find that TRADD is commonly expressed at high levels in GBM and is detected in both cytoplasmic and nuclear distribution. Cytoplasmic IHC TRADD scoring is significantly associated with worse progression-free survival (PFS both in univariate and multivariate analysis but is not associated with overall survival (n = 43 GBMs. PFS is a marker for responsiveness to treatment. We propose that TRADD-mediated NF-κB activation confers chemoresistance and thus a worse PFS in GBM. Consistent with the effect on PFS, silencing TRADD in glioma cells results in decreased NF-κB activity, decreased proliferation of cells, and increased sensitivity to temozolomide. TRADD expression is common in glioma-initiating cells. Importantly, silencing TRADD in GBM-initiating stem cell cultures results in decreased viability of stem cells, suggesting that TRADD may be required for maintenance of GBM stem cell populations. Thus, our study suggests that increased expression of cytoplasmic TRADD is both an important biomarker and a key driver of NF-κB activation in GBM and supports an oncogenic role for TRADD in GBM.

  9. Identification of repaglinide as a therapeutic drug for glioblastoma multiforme

    International Nuclear Information System (INIS)

    Xiao, Zui Xuan; Chen, Ruo Qiao; Hu, Dian Xing; Xie, Xiao Qiang; Yu, Shang Bin; Chen, Xiao Qian

    2017-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients. - Highlights: • Gene expression signarue in long-term survived GBM patients are identified from Gene Expression Omnibus database. • Repaglinide is identified as a survival-related drug for GBM via drug repositioning in CMap. • Repaglinide effectively kills GBM cells, inhibits GBM cell migration and increases survival of mice bearing orthotopic glioma. • Repaglinide reduces Bcl-2, Beclin-1 and PD-L1 in GBM tissues.

  10. Transcranial sonography: integration into target volume definition for glioblastoma multiforme

    International Nuclear Information System (INIS)

    Vordermark, Dirk; Becker, Georg; Flentje, Michael; Richter, Susanne; Goerttler-Krauspe, Irene; Koelbl, Oliver

    2000-01-01

    Purpose: Recent studies indicate that transcranial sonography (TCS) reliably displays the extension of malignant brain tumors. The effect of integrating TCS into radiotherapy planning for glioblastoma multiforme (GBM) was investigated herein. Methods and Materials: Thirteen patients subtotally resected for GBM underwent TCS during radiotherapy planning and were conventionally treated (54 to 60 Gy). Gross tumor volumes (GTVs) and stereotactic boost planning target volumes (PTVs, 3-mm margin) were created, based on contrast enhancement on computed tomography (CT) only (PTV CT ) or the combined CT and TCS information (PTV CT+TCS ). Noncoplonar conformal treatment plans for both PTVs were compared. Tumor progression patterns and preoperative magnetic resonance imaging (MRI) were related to both PTVs. Results: A sufficient temporal bone window for TCS was present in 11 of 13 patients. GTVs as defined by TCS were considerably larger than the respective CT volumes: Of the composite GTV CT+TCS (median volume 42 ml), 23%, 13%, and 66% (medians) were covered by the overlap of both methods, CT only and TCS only, respectively. Median sizes of PTV CT and PTV CT+TCS were 34 and 74 ml, respectively. Addition of TCS to CT information led to a median increase of the volume irradiated within the 80% isodose by 32 ml (median factor 1.51). PTV CT+TCS volume was at median 24% of a 'conventional' MRI(T2)-based PTV. Of eight progressions analyzed, three and six occurred inside the 80% isodose of the plans for PTV CT and for PTV CT+TCS , respectively. Conclusion: Addition of TCS tumor volume to the contrast-enhancing CT volume in postoperative radiotherapy planning for GBM increases the treated volume by a median factor of 1.5. Since a high frequency of marginal recurrences is reported from dose-escalation trials of this disease, TCS may complement established methods in PTV definition

  11. Daily Tracking of Glioblastoma Resection Cavity, Cerebral Edema, and Tumor Volume with MRI-Guided Radiation Therapy.

    Science.gov (United States)

    Mehta, Shahil; Gajjar, Shefali R; Padgett, Kyle R; Asher, David; Stoyanova, Radka; Ford, John C; Mellon, Eric A

    2018-03-19

    Radiation therapy (RT) plays a critical role in the treatment of glioblastoma. Studies of brain imaging during RT for glioblastoma have demonstrated changes in the brain during RT. However, frequent or daily utilization of standalone magnetic resonance imaging (MRI) scans during RT have limited feasibility. The recent release of the tri-cobalt-60 MRI-guided RT (MR-IGRT) device (ViewRay MRIdian, Cleveland, OH) allows for daily brain MRI for the RT setup. Daily MRI of three postoperative patients undergoing RT and temozolomide for glioblastoma over a six-week course allowed for the identification of changes to the cavity, edema, and visible tumor on a daily basis. The volumes and dimensions of the resection cavities, edema, and T2-hyperintense tumor were measured. A general trend of daily decreases in cavity measurements was observed in all patients. For the one patient with edema, a trend of daily increases followed by a trend of daily decreases were observed. These results suggest that daily MRI could be used for onboard resimulation and adaptive RT for future fluctuations in the sizes of brain tumors, cavities, or cystic components. This could improve tumor targeting and reduce RT of healthy brain tissue.

  12. Long-term Survival of Six Patients with Glioblastoma Multiforme: Case Series and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Shapour Omidvari

    2012-04-01

    Full Text Available The median overall survival in glioblastoma multiforme is usually less than one year. Long-term survival is rare and is seen in only 3%-6% of GBM patients. The present study reports the characteristics and treatment outcomes of six cases of glioblastoma multiforme with long-term survival. A literature review is also presented.Between 1990 and 2008, 217 glioblastoma multiforme patients have been treated at our center of which six cases (four males survived for three years or longer. The mean age of the six cases was 25.7 years. All patients received postoperative radiotherapy with a mean dose of 55 gray and four patients received nitrosourea-based chemotherapy.Patients' mean survival was 5.2 years. The results of this study and review of the literature have indicated that long-term (more than three years survival is exceptional and mainly observed in younger patients with good performance status and following complete surgical tumor resection.

  13. Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity

    International Nuclear Information System (INIS)

    Liu, Baohui; Lin, Xi; Yang, Xiangsheng; Dong, Huimin; Yue, Xiaojing; Andrade, Kelsey C; Guo, Zhentao; Yang, Jian; Wu, Liquan; Zhu, Xiaonan; Zhang, Shenqi; Tian, Daofeng; Wang, Junmin; Cai, Qiang; Chen, Qizuan; Mao, Shanping; Chen, Qianxue; Chang, Jiang

    2015-01-01

    Activation of Notch signaling contributes to glioblastoma multiform (GBM) tumorigenesis. However, the molecular mechanism that promotes the Notch signaling augmentation during GBM genesis remains largely unknown. Identification of new factors that regulate Notch signaling is critical for tumor treatment. The expression levels of RND3 and its clinical implication were analyzed in GBM patients. Identification of RND3 as a novel factor in GBM genesis was demonstrated in vitro by cell experiments and in vivo by a GBM xenograft model. We found that RND3 expression was significantly decreased in human glioblastoma. The levels of RND3 expression were inversely correlated with Notch activity, tumor size, and tumor cell proliferation, and positively correlated with patient survival time. We demonstrated that RND3 functioned as an endogenous repressor of the Notch transcriptional complex. RND3 physically interacted with NICD, CSL, and MAML1, the Notch transcriptional complex factors, promoted NICD ubiquitination, and facilitated the degradation of these cofactor proteins. We further revealed that RND3 facilitated the binding of NICD to FBW7, a ubiquitin ligase, and consequently enhanced NICD protein degradation. Therefore, Notch transcriptional activity was inhibited. Forced expression of RND3 repressed Notch signaling, which led to the inhibition of glioblastoma cell proliferation in vitro and tumor growth in the xenograft mice in vivo. Downregulation of RND3, however, enhanced Notch signaling activity, and subsequently promoted glioma cell proliferation. Inhibition of Notch activity abolished RND3 deficiency-mediated GBM cell proliferation. We conclude that downregulation of RND3 is responsible for the enhancement of Notch activity that promotes glioblastoma genesis

  14. Combined EGFR- and notch inhibition display additive inhibitory effect on glioblastoma cell viability and glioblastoma-induced endothelial cell sprouting in vitro

    DEFF Research Database (Denmark)

    Staberg, Mikkel; Michaelsen, Signe Regner; Olsen, Louise Stobbe

    2016-01-01

    BACKGROUND: For Glioblastoma (GBM) patients, a number of anti-neoplastic strategies using specifically targeting drugs have been tested; however, the effects on survival have been limited. One explanation could be treatment resistance due to redundant signaling pathways, which substantiates...... the need for combination therapies. In GBM, both the epidermal growth factor receptor (EGFR) and the notch signaling pathways are often deregulated and linked to cellular growth, invasion and angiogenesis. Several studies have confirmed cross-talk and co-dependence of these pathways. Therefore, this study....... In order to determine angiogenic processes, we used an endothelial spheroid sprouting assay. For assessment of secreted VEGF from GBM cells we performed a VEGF-quantikine ELISA. RESULTS: GBM cells were confirmed to express EGFR and Notch and to have the capacity to induce endothelial cell sprouting...

  15. Microenvironment involved in FPR1 expression by human glioblastomas

    NARCIS (Netherlands)

    Boer, J. C.; van Marion, D. M S; Joseph, J. V.; Kliphuis, N. M.; Timmer-Bosscha, H.; van Strijp, J. A G; de Vries, E. G E; den Dunnen, W. F A; Kruyt, F. A E; Walenkamp, A. M E

    2015-01-01

    Formyl peptide receptor 1 (FPR1) activity in U87 glioblastoma (GBM) cells contributes to tumor cell motility. The present study aimed to evaluate the FPR1 expression in human GBM, the possibility to elicit agonist induced FPR1 activation of GBM cells and inhibit this activation with chemotaxis

  16. Microenvironment involved in FPR1 expression by human glioblastomas

    NARCIS (Netherlands)

    Boer, J. C.; van Marion, D. M. S.; Vareecal Joseph, J.; Kliphuis, N. M.; Timmer-Bosscha, H.; van Strijp, J. A. G.; de Vries, E. G. E.; den Dunnen, W. F. A.; Kruyt, F. A. E.; Walenkamp, A. M. E.

    Formyl peptide receptor 1 (FPR1) activity in U87 glioblastoma (GBM) cells contributes to tumor cell motility. The present study aimed to evaluate the FPR1 expression in human GBM, the possibility to elicit agonist induced FPR1 activation of GBM cells and inhibit this activation with chemotaxis

  17. Investigation of platinum nanoparticle properties against U87 glioblastoma multiforme

    DEFF Research Database (Denmark)

    Kutwin, Marta; Sawosz, Ewa; Jaworski, Slawomir

    2017-01-01

    a harmful influence on viability of U87 glioblastoma multiforme (GBM) cells, but also showed genotoxic properties as well as a pro-apoptotic effect on cancer cells. It was found that NP-Pt decreased the weight and volume of U87 GBM tumor tissue and caused pathomorphological changes in the ultrastructure...

  18. Glioblastomas, astrocytomas and oligodendrogliomas linked to Lynch syndrome

    DEFF Research Database (Denmark)

    Therkildsen, C; Ladelund, S; Rambech, E

    2015-01-01

    .5%) in MSH2 gene mutation carriers compared to patients with mutations in MLH1 or MSH6. Glioblastomas predominated (56%), followed by astrocytomas (22%) and oligodendrogliomas (9%). MMR status was assessed in 10 tumors, eight of which showed MMR defects. None of these tumors showed immunohistochemical...

  19. Glioblastoma stem-like cells give rise to tumour endothelium

    NARCIS (Netherlands)

    Wang, Rong; Chadalavada, Kalyani; Wilshire, Jennifer; Kowalik, Urszula; Hovinga, Koos E.; Geber, Adam; Fligelman, Boris; Leversha, Margaret; Brennan, Cameron; Tabar, Viviane

    2010-01-01

    Glioblastoma (GBM) is among the most aggressive of human cancers. A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia. Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poorly

  20. Nestin expression in the cell lines derived from glioblastoma multiforme

    International Nuclear Information System (INIS)

    Veselska, Renata; Kuglik, Petr; Cejpek, Pavel; Svachova, Hana; Neradil, Jakub; Loja, Tomas; Relichova, Jirina

    2006-01-01

    Nestin is a protein belonging to class VI of intermediate filaments that is produced in stem/progenitor cells in the mammalian CNS during development and is consecutively replaced by other intermediate filament proteins (neurofilaments, GFAP). Down-regulated nestin may be re-expressed in the adult organism under certain pathological conditions (brain injury, ischemia, inflammation, neoplastic transformation). Our work focused on a detailed study of the nestin cytoskeleton in cell lines derived from glioblastoma multiforme, because re-expression of nestin together with down-regulation of GFAP has been previously reported in this type of brain tumor. Two cell lines were derived from the tumor tissue of patients treated for glioblastoma multiforme. Nestin and other cytoskeletal proteins were visualized using imunocytochemical methods: indirect immunofluorescence and immunogold-labelling. Using epifluorescence and confocal microscopy, we described the morphology of nestin-positive intermediate filaments in glioblastoma cells of both primary cultures and the derived cell lines, as well as the reorganization of nestin during mitosis. Our most important result came through transmission electron microscopy and provided clear evidence that nestin is present in the cell nucleus. Detailed information concerning the pattern of the nestin cytoskeleton in glioblastoma cell lines and especially the demonstration of nestin in the nucleus represent an important background for further studies of nestin re-expression in relationship to tumor malignancy and invasive potential

  1. Nanoparticles of carbon allotropes inhibit glioblastoma multiforme angiogenesis in ovo

    DEFF Research Database (Denmark)

    Grodzik, Marta; Sawosz, Ewa; Wierzbicki, Mateusz

    2011-01-01

    The objective of the study was to determine the effect of carbon nanoparticles produced by different methods on the growth of brain tumor and the development of blood vessels. Glioblastoma multiforme cells were cultured on the chrioallantoic membrane of chicken embryo and after 7 days of incubati...

  2. Short-term irradiation of the glioblastoma with high-dosed fractions

    International Nuclear Information System (INIS)

    Hinkelbein, W.; Bruggmoser, G.; Schmidt, M.; Wannenmacher, M.

    1984-01-01

    Compared to surgery alone, postoperative radiotherapy leads with glioblastomas (grade IV gliomas) to a significant improvement of the therapeutic results. The prolongation of survival time, however, is to a large extent compensated by the therapy itself (it normally implicates hospitalisation). Therefore, we tested the efficiency of rapid course irradiation with high fractions. 70 patients were treated daily with individual fractions of 3.5 Gy, 4 to 6 fractions per week. The entire dose amounted to 31.5 to 38.5 Gy. The average survival time was 33.5 weeks corresponding to the survival time known from the combined surgical and radiotherapeutical treatment of glioblastomas. An effective increase in therapy-free survival time seems possible, especially when the entire focal dose does not exceed 35 Gy. It is remarkable that the patients with the maximum exposure did not have the longest survival times and rates. Living conditions for the patients were similar to those with conventional fractioning, or even better. Rapid course irradiation with high fractions and a limited total dose (35 Gy) presently is - apart from the accelerated superfractioning - a successful measure to prolong the therapyfree survival time for patients with grade IV gliomas. (orig.) [de

  3. Subcutaneous tissue metastasis from glioblastoma multiforme: A case report and review of the literature.

    Science.gov (United States)

    Frade Porto, Natalia; Delgado Fernández, Juan; García Pallero, María de Los Ángeles; Penanes Cuesta, Juan Ramón; Pulido Rivas, Paloma; Gil Simoes, Ricardo

    2018-05-16

    Glioblastoma multiforme is the most common primary brain tumor, despite an aggressive clinical course, less than 2% of patients develop extraneural metastasis. We present a 72-year-old male diagnosed with a right temporal glioblastoma due to headache. He underwent total gross resection surgery and after that the patient was treated with adyuvant therapy. Five months after the patient returned with trigeminal neuralgia, and MRI showed an infratemporal cranial mass which infiltrates masticator space, the surrounding bone, the temporal muscle and superior cervical and parotid lymph nodes. The patient underwent a new surgery reaching partial resection of the temporal lesion. After that the patient continued suffering from disabling trigeminal neuralgia, that's why because of the bad clinical situation and the treatment failure we decided to restrict therapeutic efforts. The patient died 3 weeks after the diagnosis of extracranial metastasis. Copyright © 2018 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. Segmentation of corpus callosum using diffusion tensor imaging: validation in patients with glioblastoma

    International Nuclear Information System (INIS)

    Nazem-Zadeh, Mohammad-Reza; Saksena, Sona; Babajani-Fermi, Abbas; Jiang, Quan; Soltanian-Zadeh, Hamid; Rosenblum, Mark; Mikkelsen, Tom; Jain, Rajan

    2012-01-01

    This paper presents a three-dimensional (3D) method for segmenting corpus callosum in normal subjects and brain cancer patients with glioblastoma. Nineteen patients with histologically confirmed treatment naïve glioblastoma and eleven normal control subjects underwent DTI on a 3T scanner. Based on the information inherent in diffusion tensors, a similarity measure was proposed and used in the proposed algorithm. In this algorithm, diffusion pattern of corpus callosum was used as prior information. Subsequently, corpus callosum was automatically divided into Witelson subdivisions. We simulated the potential rotation of corpus callosum under tumor pressure and studied the reproducibility of the proposed segmentation method in such cases. Dice coefficients, estimated to compare automatic and manual segmentation results for Witelson subdivisions, ranged from 94% to 98% for control subjects and from 81% to 95% for tumor patients, illustrating closeness of automatic and manual segmentations. Studying the effect of corpus callosum rotation by different Euler angles showed that although segmentation results were more sensitive to azimuth and elevation than skew, rotations caused by brain tumors do not have major effects on the segmentation results. The proposed method and similarity measure segment corpus callosum by propagating a hyper-surface inside the structure (resulting in high sensitivity), without penetrating into neighboring fiber bundles (resulting in high specificity)

  5. Prognostic factors in glioblastoma multiforme. 10 years experience of a single institution

    International Nuclear Information System (INIS)

    Hulshof, M.C.C.M.; Schimmel, E.C.; Gonzalez, D.G.; Koot, R.W.; Bosch, D.A.; Dekker, F.

    2001-01-01

    Background: To analyze prognostic factors in patients with a glioblastoma multiforme treated in an academic institute over the last 10 years. Patients and method: From 1988 to 1998, 198 patients with pathologically confirmed glioblastoma multiforme were analyzed. Five radiation schedules were used mainly based on pretreatment selection criteria: 1. 60 Gy in 30 fractions followed by an interstitial iridium-192 (Ir-192) boost for selected patients with a good performance and a small circumscribed tumor, 2. 66 Gy in 33 fractions for good performance patients, 3. 40 Gy in eight fractions or 4. 28 Gy in four fractions for poor prognostic patients and 5. no irradiation. Results: Median survival was 16 months, 7 months, 5.6 months, 6.6 months and 1.8 months for the groups treated with Ir-192, 66 Gy, 40 Gy, 28 Gy and the group without treatment, respectively. No significant improvement in survival was encountered over the last 10 years. At multivariate analysis patients treated with a hypofractionated scheme showed a similar survival probability and duration of palliative effect compared to the conventionally fractionated group. The poor prognostic groups receiving radiotherapy had a highly significant better survival compared to the no-treatment group. Patients treated with an Ir-192 boost had a better median survival compared to a historical group matched on selection criteria but without boost treatment (16 vs 9.7 months, n.s.). However, survival at 2 years was similar. Analysis on pretreatment characteristics at multivariate analysis revealed age, neurological performance, addition of radiotherapy, total resection, tumor size post surgery and deterioration before start of radiotherapy (borderline) as significant prognostic factors for survival. Conclusion: Despite technical developments in surgery and radiotherapy over the last 10 years, survival of patients with a glioblastoma multiforme has not improved in our institution. The analysis of prognostic factors

  6. Overexpression of CD97 confers an invasive phenotype in glioblastoma cells and is associated with decreased survival of glioblastoma patients.

    Directory of Open Access Journals (Sweden)

    Michael Safaee

    Full Text Available Mechanisms of invasion in glioblastoma (GBM relate to differential expression of proteins conferring increased motility and penetration of the extracellular matrix. CD97 is a member of the epidermal growth factor seven-span transmembrane family of adhesion G-protein coupled receptors. These proteins facilitate mobility of leukocytes into tissue. In this study we show that CD97 is expressed in glioma, has functional effects on invasion, and is associated with poor overall survival. Glioma cell lines and low passage primary cultures were analyzed. Functional significance was assessed by transient knockdown using siRNA targeting CD97 or a non-target control sequence. Invasion was assessed 48 hours after siRNA-mediated knockdown using a Matrigel-coated invasion chamber. Migration was quantified using a scratch assay over 12 hours. Proliferation was measured 24 and 48 hours after confirmed protein knockdown. GBM cell lines and primary cultures were found to express CD97. Knockdown of CD97 decreased invasion and migration in GBM cell lines, with no difference in proliferation. Gene-expression based Kaplan-Meier analysis was performed using The Cancer Genome Atlas, demonstrating an inverse relationship between CD97 expression and survival. GBMs expressing high levels of CD97 were associated with decreased survival compared to those with low CD97 (p = 0.007. CD97 promotes invasion and migration in GBM, but has no effect on tumor proliferation. This phenotype may explain the discrepancy in survival between high and low CD97-expressing tumors. This data provides impetus for further studies to determine its viability as a therapeutic target in the treatment of GBM.

  7. Advanced MRI increases the diagnostic accuracy of recurrent glioblastoma: Single institution thresholds and validation of MR spectroscopy and diffusion weighted MR imaging

    Directory of Open Access Journals (Sweden)

    Tomas Kazda

    2016-01-01

    Full Text Available The accurate identification of glioblastoma progression remains an unmet clinical need. The aim of this prospective single-institutional study is to determine and validate thresholds for the main metabolite concentrations obtained by MR spectroscopy (MRS and the values of the apparent diffusion coefficient (ADC to enable distinguishing tumor recurrence from pseudoprogression. Thirty-nine patients after the standard treatment of a glioblastoma underwent advanced imaging by MRS and ADC at the time of suspected recurrence — median time to progression was 6.7 months. The highest significant sensitivity and specificity to call the glioblastoma recurrence was observed for the total choline (tCho to total N-acetylaspartate (tNAA concentration ratio with the threshold ≥1.3 (sensitivity 100.0% and specificity 94.7%. The ADCmean value higher than 1313 × 10−6 mm2/s was associated with the pseudoprogression (sensitivity 98.3%, specificity 100.0%. The combination of MRS focused on the tCho/tNAA concentration ratio and the ADCmean value represents imaging methods applicable to early non-invasive differentiation between a glioblastoma recurrence and a pseudoprogression. However, the institutional definition and validation of thresholds for differential diagnostics is needed for the elimination of setup errors before implementation of these multimodal imaging techniques into clinical practice, as well as into clinical trials.

  8. Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Carrasco-Garcia, Estefania; Saceda, Miguel [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad de Investigacion, Hospital General Universitario de Elche, 03203 Elche (Alicante) (Spain); Grasso, Silvina; Rocamora-Reverte, Lourdes; Conde, Mariano; Gomez-Martinez, Angeles [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Garcia-Morales, Pilar [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad de Investigacion, Hospital General Universitario de Elche, 03203 Elche (Alicante) (Spain); Ferragut, Jose A. [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Martinez-Lacaci, Isabel, E-mail: imlacaci@umh.es [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad AECC de Investigacion Traslacional en Cancer, Hospital Universitario Virgen de la Arrixaca, 30120 Murcia (Spain)

    2011-06-10

    Signaling through the epidermal growth factor receptor (EGFR) is relevant in glioblastoma. We have determined the effects of the EGFR inhibitor AG1478 in glioblastoma cell lines and found that U87 and LN-229 cells were very sensitive to this drug, since their proliferation diminished and underwent a marked G{sub 1} arrest. T98 cells were a little more refractory to growth inhibition and A172 cells did not undergo a G{sub 1} arrest. This G{sub 1} arrest was associated with up-regulation of p27{sup kip1}, whose protein turnover was stabilized. EGFR autophosphorylation was blocked with AG1478 to the same extent in all the cell lines. Other small-molecule EGFR tyrosine kinase inhibitors employed in the clinic, such as gefitinib, erlotinib and lapatinib, were able to abrogate proliferation of glioblastoma cell lines, which underwent a G{sub 1} arrest. However, the EGFR monoclonal antibody, cetuximab had no effect on cell proliferation and consistently, had no effect on cell cycle either. Similarly, cetuximab did not inhibit proliferation of U87 {Delta}EGFR cells or primary glioblastoma cell cultures, whereas small-molecule EGFR inhibitors did. Activity of downstream signaling molecules of EGFR such as Akt and especially ERK1/2 was interrupted with EGFR tyrosine kinase inhibitors, whereas cetuximab treatment could not sustain this blockade over time. Small-molecule EGFR inhibitors were able to prevent phosphorylation of erbB3 and erbB4, whereas cetuximab only hindered EGFR phosphorylation, suggesting that EGFR tyrosine kinase inhibitors may mediate their anti-proliferative effects through other erbB family members. We can conclude that small-molecule EGFR inhibitors may be a therapeutic approach for the treatment of glioblastoma patients.

  9. Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models

    Science.gov (United States)

    Piao, Yuji; Park, Soon Young; Henry, Verlene; Smith, Bryan D.; Tiao, Ningyi; Flynn, Daniel L.

    2016-01-01

    Background Glioblastoma highly expresses the proto-oncogene MET in the setting of resistance to bevacizumab. MET engagement by hepatocyte growth factor (HGF) results in receptor dimerization and autophosphorylation mediating tumor growth, invasion, and metastasis. Evasive revascularization and the recruitment of TIE2-expressing macrophages (TEMs) are also triggered by anti-VEGF therapy. Methods We investigated the activity of altiratinib (a novel balanced inhibitor of MET/TIE2/VEGFR2) against human glioblastoma stem cell lines in vitro and in vivo using xenograft mouse models. The biological activity of altiratinib was assessed in vitro by testing the expression of HGF-stimulated MET phosphorylation as well as cell viability after altiratinib treatment. Tumor volume, stem cell and mesenchymal marker levels, microvessel density, and TIE2-expressing monocyte infiltration were evaluated in vivo following treatment with a control, bevacizumab alone, bevacizumab combined with altiratinib, or altiratinib alone. Results In vitro, HGF-stimulated MET phosphorylation was completely suppressed by altiratinib in GSC17 and GSC267, and altiratinib markedly inhibited cell viability in several glioblastoma stem cell lines. More importantly, in multiple xenograft mouse models, altiratinib combined with bevacizumab dramatically reduced tumor volume, invasiveness, mesenchymal marker expression, microvessel density, and TIE2-expressing monocyte infiltration compared with bevacizumab alone. Furthermore, in the GSC17 xenograft model, altiratinib combined with bevacizumab significantly prolonged survival compared with bevacizumab alone. Conclusions Together, these data suggest that altiratinib may suppress tumor growth, invasiveness, angiogenesis, and myeloid cell infiltration in glioblastoma. Thus, altiratinib administered alone or in combination with bevacizumab may overcome resistance to bevacizumab and prolong survival in patients with glioblastoma. PMID:26965451

  10. Epigenetic suppression of EGFR signaling in G-CIMP+ glioblastomas.

    Science.gov (United States)

    Li, Jie; Taich, Zachary J; Goyal, Amit; Gonda, David; Akers, Johnny; Adhikari, Bandita; Patel, Kunal; Vandenberg, Scott; Yan, Wei; Bao, Zhaoshi; Carter, Bob S; Wang, Renzhi; Mao, Ying; Jiang, Tao; Chen, Clark C

    2014-09-15

    The intrinsic signaling cascades and cell states associated with the Glioma CpG Island Methylator Phenotype (G-CIMP) remain poorly understood. Using published mRNA signatures associated with EGFR activation, we demonstrate that G-CIMP+ tumors harbor decreased EGFR signaling using three independent datasets, including the Chinese Glioma Genome Atlas(CGGA; n=155), the REMBRANDT dataset (n=288), and The Cancer Genome Atlas (TCGA; n=406). Additionally, an independent collection of 25 fresh-frozen glioblastomas confirmed lowered pERK levels in G-CIMP+ specimens (pCIMP+ glioblastomas harbored lowered mRNA levels for EGFR and H-Ras. Induction of G-CIMP+ state by exogenous expression of a mutated isocitrate dehydrogenase 1, IDH1-R132H, suppressed EGFR and H-Ras protein expression as well as pERK accumulation in independent glioblastoma models. These suppressions were associated with increased deposition of the repressive histone markers, H3K9me3 and H3K27me3, in the EGFR and H-Ras promoter regions. The IDH1-R132H expression-induced pERK suppression can be reversed by exogenous expression of H-RasG12V. Finally, the G-CIMP+ Ink4a-Arf-/- EGFRvIII glioblastoma line was more resistant to the EGFR inhibitor, Gefitinib, relative to its isogenic G-CIMP- counterpart. These results suggest that G-CIMP epigenetically regulates EGFR signaling and serves as a predictive biomarker for EGFR inhibitors in glioblastoma patients.

  11. Irradiation combined with SU5416: Microvascular changes and growth delay in a human xenograft glioblastoma tumor line

    International Nuclear Information System (INIS)

    Schuuring, Janneke; Bussink, Johan; Bernsen, Hans; Peeters, Wenny; Kogel, Albert J. van der

    2005-01-01

    Purpose: The combination of irradiation and the antiangiogenic compound SU5416 was tested and compared with irradiation alone in a human glioblastoma tumor line xenografted in nude mice. The aim of this study was to monitor microenvironmental changes and growth delay. Methods and materials: A human glioblastoma xenograft tumor line was implanted in nude mice. Irradiations consisted of 10 Gy or 20 Gy with and without SU5416. Several microenvironmental parameters (tumor cell hypoxia, tumor blood perfusion, vascular volume, and microvascular density) were analyzed after imunohistochemical staining. Tumor growth delay was monitored for up to 200 days after treatment. Results: SU5416, when combined with irradiation, has an additive effect over treatment with irradiation alone. Analysis of the tumor microenvironment showed a decreased vascular density during treatment with SU5416. In tumors regrowing after reaching only a partial remission, vascular characteristics normalized shortly after cessation of SU5416. However, in tumors regrowing after reaching a complete remission, permanent microenvironmental changes and an increase of tumor necrosis with a subsequent slower tumor regrowth was found. Conclusions: Permanent vascular changes were seen after combined treatment resulting in complete remission. Antiangiogenic treatment with SU5416 when combined with irradiation has an additive effect over treatment with irradiation or antiangiogenic treatment alone

  12. Teaching for Ethical Reasoning

    Science.gov (United States)

    Sternberg, Robert J.

    2012-01-01

    This article argues for the importance of teaching for ethical reasoning. Much of our teaching is in vain if it is not applied to life in an ethical manner. The article reviews lapses in ethical reasoning and the great costs they have had for society. It proposes that ethical reasoning can be taught across the curriculum. It presents an eight-step…

  13. Inductive Reasoning and Writing

    Science.gov (United States)

    Rooks, Clay; Boyd, Robert

    2003-01-01

    Induction, properly understood, is not merely a game, nor is it a gimmick, nor is it an artificial way of explaining an element of reasoning. Proper understanding of inductive reasoning--and the various types of reasoning that the authors term inductive--enables the student to evaluate critically other people's writing and enhances the composition…

  14. A population-based study of glioblastoma multiforme

    International Nuclear Information System (INIS)

    Paszat, Lawrence; Laperriere, Normand; Groome, Patti; Schulze, Karleen; Mackillop, William; Holowaty, Eric

    2001-01-01

    Purpose: To describe (1) the use of surgery and radiotherapy (RT) in the treatment of patients with glioblastoma (GBM) in Ontario, (2) survival, and (3) proportion of survival time spent in the hospital after diagnosis. Methods and Materials: We performed a population-based cohort study of all Ontario Cancer Registry (OCR) cases of GBM diagnosed between 1982 and 1994. We linked OCR records, hospital files containing surgical procedure codes from the Canadian Institute for Health Information, and province-wide RT records. We studied the odds of treatment using multivariate logistic regression. We expressed the time spent in the hospital as the mean number of days per case, and as a proportion of the interval between diagnosis and death, or 24 months following diagnosis, whichever came first. We used the life-table method and Cox proportional hazards regression to describe survival. Results: The proportion of patients with GBM undergoing any surgery directed at the tumor varied with age (p<0.0001) and region of residence (p<0.0001). The proportion undergoing RT varied with age (p<0.0001), region of residence (p<0.0001), and year of diagnosis (p=0.01). RT dose ≥53.5 Gy varied with age (p<0.0001), region of residence (p<0.0001), and year of diagnosis (p=0.0002). Median survival was 11 months among patients receiving RT and 3 months among those not receiving RT. The percentage of survival time spent in the hospital was similar among those who received from 49.5 to <53.5 Gy, compared to ≥53.5 Gy. Overall survival and the adjusted relative risk of death varied with age and region of residence. Conclusion: We observed practice variation in the treatment of patients with GBM according to age, region of residence, and year of diagnosis. Survival did not increase during the study period. The variation in RT dose between those receiving from 49.5 to <53.5 Gy compared to ≥53.5 Gy was not paralleled by variation in survival between regions where one or the other of the

  15. Management of glioblastoma at safety-net hospitals.

    Science.gov (United States)

    Brandel, Michael G; Rennert, Robert C; Lopez Ramos, Christian; Santiago-Dieppa, David R; Steinberg, Jeffrey A; Sarkar, Reith R; Wali, Arvin R; Pannell, J Scott; Murphy, James D; Khalessi, Alexander A

    2018-04-24

    Safety-net hospitals (SNHs) provide disproportionate care for underserved patients. Prior studies have identified poor outcomes, increased costs, and reduced access to certain complex, elective surgeries at SNHs. However, it is unknown whether similar patterns exist for the management of glioblastoma (GBM). We sought to determine if patients treated at HBHs receive equitable care for GBM, and if safety-net burden status impacts post-treatment survival. The National Cancer Database was queried for GBM patients diagnosed between 2010 and 2015. Safety-net burden was defined as the proportion of Medicaid and uninsured patients treated at each hospital, and stratified as low (LBH), medium (MBH), and high-burden (HBH) hospitals. The impact of safety-net burden on the receipt of any treatment, trimodality therapy, gross total resection (GTR), radiation, or chemotherapy was investigated. Secondary outcomes included post-treatment 30-day mortality, 90-day mortality, and overall survival. Univariate and multivariate analyses were utilized. Overall, 40,082 GBM patients at 1202 hospitals (352 LBHs, 553 MBHs, and 297 HBHs) were identified. Patients treated at HBHs were significantly less likely to receive trimodality therapy (OR = 0.75, p < 0.001), GTR (OR = 0.84, p < 0.001), radiation (OR = 0.73, p < 0.001), and chemotherapy (OR = 0.78, p < 0.001) than those treated at LBHs. Patients treated at HBHs had significantly increased 30-day (OR = 1.25, p = 0.031) and 90-day mortality (OR = 1.24, p = 0.001), and reduced overall survival (HR = 1.05, p = 0.039). GBM patients treated at SNHs are less likely to receive standard-of-care therapies and have increased short- and long-term mortality. Additional research is needed to evaluate barriers to providing equitable care for GBM patients at SNHs.

  16. Raman spectroscopy for diagnosis of glioblastoma multiforme

    Science.gov (United States)

    Clary, Candace Elise

    Glioblastoma multiforme (GBM), the most common and most fatal malignant brain tumor, is highly infiltrative and incurable. Although improved prognosis has been demonstrated by surgically resecting the bulk tumor, a lack of clear borders at the tumor margins complicates the selection decision during surgery. This dissertation investigates the potential of Raman spectroscopy for distinguishing between normal and malignant brain tissue and sets the groundwork for a surgical diagnostic guide for resection of gross malignant gliomas. These studies revealed that Raman spectroscopy was capable of discriminating between normal scid mouse brain tissue and human xenograft tumors induced in those mice. The spectra of normal and malignant tissue were normalized by dividing by the respective magnitudes of the peaks near 1440 cm -1. Spectral differences include the shape of the broad peaks near 1440 cm-1 and 1660 cm-1 and the relative magnitudes of the peaks at 1264 cm-1, 1287 cm-1, 1297 cm-1, 1556 cm -1, 1586 cm-1, 1614 cm-1, and 1683 cm-1. From these studies emerged questions regarding how to objectively normalize and compare spectra for future automation. Some differences in the Raman spectra were shown to be inherent in the disease states of the cells themselves via differences in the Raman spectra of normal human astrocytes in culture and cultured cells derived from GBM tumors. The spectra of astrocytes and glioma cells were normalized by dividing by the respective magnitudes of the peaks near 1450 cm-1. The differences between the Raman spectra of normal and transformed cells include the ratio of the 1450 cm-1/1650 cm-1 peaks and the relative magnitudes of the peaks at 1181 cm-1, 1191 cm-1, 1225 cm-1, 1263 cm -1, 1300 cm-1, 1336 cm-1, 1477 cm-1, 1494 cm-1, and 1695 cm -1. Previous Raman spectroscopic studies of biological cells have shown that the magnitude of the Raman signal decreases over time, indicating sample damage. Cells exposed to laser excitation at similar power

  17. Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review.

    Science.gov (United States)

    Anjum, Komal; Shagufta, Bibi Ibtesam; Abbas, Syed Qamar; Patel, Seema; Khan, Ishrat; Shah, Sayed Asmat Ali; Akhter, Najeeb; Hassan, Syed Shams Ul

    2017-08-01

    Glioblastoma multiforme (GBM) is the deadliest form of heterogeneous brain cancer. It affects an enormous number of patients every year and the survival is approximately 8 to 15 months. GBM has driven by complex signaling pathways and considered as a most challenging to treat. Standard treatment of GBM includes surgery, radiation therapy, chemotherapy and also the combined treatment. This review article described inter and intra- tumor heterogeneity of GMB. In addition, recent chemotherapeutic agents, with their mechanism of action have been defined. FDA-approved drugs also been focused over here and most importantly highlighting some natural and synthetic and novel anti- glioma agents, that are the main focus of researchers nowadays. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Prognostic significance of IDH 1 mutation in patients with glioblastoma multiforme.

    Science.gov (United States)

    Khan, Inamullah; Waqas, Muhammad; Shamim, Muhammad Shahzad

    2017-05-01

    Focus of brain tumour research is shifting towards tumour genesis and genetics, and possible development of individualized treatment plans. Genetic analysis shows recurrent mutation in isocitrate dehydrogenase (IDH1) gene in most Glioblastoma multiforme (GBM) cells. In this review we evaluated the prognostic significance of IDH 1 mutation on the basis of published evidence. Multiple retrospective clinical analyses correlate the presence of IDH1 mutation in GBM with good prognostic outcomes compared to wild-type IDH1. A systematic review reported similar results. Based on the review of current literature IDH1 mutation is an independent factor for longer overall survival (OS) and progression free survival (PFS) in GBM patients when compared to wild-type IDH1. The prognostic significance opens up new avenues for treatment.

  19. SlowMo, a digital therapy targeting reasoning in paranoia, versus treatment as usual in the treatment of people who fear harm from others: study protocol for a randomised controlled trial.

    Science.gov (United States)

    Garety, Philippa A; Ward, Thomas; Freeman, Daniel; Fowler, David; Emsley, Richard; Dunn, Graham; Kuipers, Elizabeth; Bebbington, Paul; Waller, Helen; Greenwood, Kathryn; Rus-Calafell, Mar; McGourty, Alison; Hardy, Amy

    2017-11-02

    Paranoia is one of the most common symptoms of schizophrenia-spectrum disorders, and is associated with significant distress and disruption to the person's life. Developing more effective and accessible psychological interventions for paranoia is a clinical priority. Our research team has approached this challenge in two main ways: firstly, by adopting an interventionist causal approach to increase effectiveness and secondly, by incorporating user-centred inclusive design methods to enhance accessibility and usability. Our resultant new digital intervention, SlowMo, intensively targets a reasoning style associated with paranoia, fast thinking, characterised by jumping to conclusions and belief inflexibility. It consists of an easy-to-use, enjoyable and memorable digital interface. An interactive web-based app facilitates delivery of face-to-face meetings which is then synchronised with an innovative mobile app for use in daily life. We aim to test the clinical efficacy of SlowMo over 24 weeks to determine the mechanisms through which it reduces paranoia, and to identify participant characteristics that moderate its effectiveness. In a parallel-group randomised controlled trial, with 1:1 allocation, 360 participants with distressing persecutory beliefs will be independently randomised to receive either the SlowMo intervention added to treatment as usual (TAU) or TAU, using randomly varying permuted blocks, stratified by paranoia severity and site. Research workers will be blind to therapy allocation. The primary outcome is paranoia severity over 24 weeks; our hypothesised mechanism of change is reasoning; moderators include negative symptoms and working memory; and secondary outcomes include wellbeing, quality of life, and service use. The accessibility, usability and acceptability of the digital platform will be assessed. SlowMo has been developed as the first blended digital therapy to target fears of harm from others through an inclusive design approach. In

  20. Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report

    Directory of Open Access Journals (Sweden)

    Servadei Franco

    2010-04-01

    Full Text Available Abstract Background Management of glioblastoma multiforme (GBM has been difficult using standard therapy (radiation with temozolomide chemotherapy. The ketogenic diet is used commonly to treat refractory epilepsy in children and, when administered in restricted amounts, can also target energy metabolism in brain tumors. We report the case of a 65-year-old woman who presented with progressive memory loss, chronic headaches, nausea, and a right hemisphere multi-centric tumor seen with magnetic resonance imaging (MRI. Following incomplete surgical resection, the patient was diagnosed with glioblastoma multiforme expressing hypermethylation of the MGMT gene promoter. Methods Prior to initiation of the standard therapy, the patient conducted water-only therapeutic fasting and a restricted 4:1 (fat: carbohydrate + protein ketogenic diet that delivered about 600 kcal/day. The patient also received the restricted ketogenic diet concomitantly during the standard treatment period. The diet was supplemented with vitamins and minerals. Steroid medication (dexamethasone was removed during the course of the treatment. The patient was followed using MRI and positron emission tomography with fluoro-deoxy-glucose (FDG-PET. Results After two months treatment, the patient's body weight was reduced by about 20% and no discernable brain tumor tissue was detected using either FDG-PET or MRI imaging. Biomarker changes showed reduced levels of blood glucose and elevated levels of urinary ketones. MRI evidence of tumor recurrence was found 10 weeks after suspension of strict diet therapy. Conclusion This is the first report of confirmed GBM treated with standard therapy together with a restricted ketogenic diet. As rapid regression of GBM is rare in older patients following incomplete surgical resection and standard therapy alone, the response observed in this case could result in part from the action of the calorie restricted ketogenic diet. Further studies are needed

  1. Understanding cytoskeleton regulators in glioblastoma multiforme for therapy design

    Directory of Open Access Journals (Sweden)

    Masoumi S

    2016-09-01

    Full Text Available Samaneh Masoumi,1,*, Aditya Harisankar,2,* Aileen Gracias,3 Fabian Bachinger,1 Temesgen Fufa,1,4 Gayathri Chandrasekar,5 Frank Gaunitz,4 Julian Walfridsson,2 Satish S Kitambi1 1Department of Microbiology Tumor and Cell Biology, 2Center for Hematology and Regenerative Medicine, Department of Medicine, 3Department of Neuroscience, Karolinska Institutet, Solna, Sweden; 4Department of Neurosurgery, University Hospital, Leipzig, Germany; 5Department of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden *These authors contributed equally to this work Abstract: The cellular cytoskeleton forms the primary basis through which a cell governs the changes in size, shape, migration, proliferation, and forms the primary means through which the cells respond to their environment. Indeed, cell and tissue morphologies are used routinely not only to grade tumors but also in various high-content screening methods with an aim to identify new small molecules with therapeutic potential. This study examines the expression of various cytoskeleton regulators in glioblastoma multiforme (GBM. GBM is a very aggressive disease with a low life expectancy even after chemo- and radiotherapy. Cancer cells of GBM are notorious for their invasiveness, ability to develop resistance to chemo- and radiotherapy, and to form secondary site tumors. This study aims to gain insight into cytoskeleton regulators in GBM cells and to understand the effect of various oncology drugs, including temozolomide, on cytoskeleton regulators. We compare the expression of various cytoskeleton regulators in GBM-derived tumor and normal tissue, CD133-postive and -negative cells from GBM and neural cells, and GBM stem-like and differentiated cells. In addition, the correlation between the expression of cytoskeleton regulators with the clinical outcome was examined to identify genes associated with longer patient survival. This was followed by a small molecule screening with US Food and Drug

  2. Glioblastomas with Oligodendroglial Component ? Common Origin of the Different Histological Parts and Genetic Subclassification